Environmental exposure of primary care personnel to ribavirin aerosol when supervising treatment of infants with respiratory syncytial virus infections.

PubMed Central

Rodriguez, W J; Bui, R H; Connor, J D; Kim, H W; Brandt, C D; Parrott, R H; Burch, B; Mace, J

1987-01-01

The potential exposure to ribavirin aerosol in the environment was assessed in nurses caring for infants and children with severe lower respiratory tract infections due to respiratory syncytial virus. Ribavirin aerosol was administered via a ventilator, oxygen tent, or oxygen hood. Participants worked directly with infants receiving ribavirin for 20.0 to 35.0 h over a 3-day period. No toxic or adverse effects of ribavirin aerosol were observed in any of the 19 nurses studied, and ribavirin was not detected in erythrocytes, plasma, or urine collected after the potential exposure period. PMID:3662474

Ribavirin has a Demonstrable Effect on Crimean-Congo Hemorrhagic Fever Viral Populations and Viral Load during Patient Treatment.

PubMed

Espy, Nicole; Pérez-Sautu, Unai; Ramírez de Arellano, Eva; Negredo, Anabel; Wiley, Michael R; Bavari, Sina; Díaz Menendez, Marta; Paz Sánchez-Seco, María; Palacios, Gustavo

2018-03-23

The use of ribavirin to treat infections of Crimean-Congo Hemorrhagic Fever virus (CCHFV) has been controversial based on uncertainties on its antiviral efficacy in clinical case studies. We studied the effect of ribavirin treatment on viral populations in a recent case by deep sequencing plasma samples taken from a CCHFV-infected patient before, during, and after a five-day regimen of ribavirin. CCHFV viral load dropped during ribavirin treatment and subclonal diversity (transitions) and indels increased in viral genomes during treatment. Although the results are based on a single case, these data demonstrate the mutagenic effect of ribavirin on CCHFV in vivo. (Word Count: 100).

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

PubMed

Fuchs, Edward J; Kiser, Jennifer J; Hendrix, Craig W; Sulkowski, Mark; Radebaugh, Christine; Bushman, Lane; Ray, Michelle L; Andrade, Adriana

2016-06-01

The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ± SD plasma ribavirin trough concentrations (μg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ± 0.60, 1.93 ± 0.54, 2.14 ± 0.73 and 2.54 ± 1.05) compared with ribavirin alone (1.48 ± 0.32, 2.08 ± 0.41, 2.32 ± 0.47 and 2.60 ± 0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ± 9.86 and 15.87 ± 12.52) and non-users (15.91 ± 15.58 and 15.93 ± 12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Ribavirin and boceprevir are able to reduce Canine distemper virus growth in vitro.

PubMed

Lanave, Gianvito; Cavalli, Alessandra; Martella, Vito; Fontana, Tommaso; Losappio, Ruggero; Tempesta, Maria; Decaro, Nicola; Buonavoglia, Domenico; Camero, Michele

2017-10-01

Canine distemper virus (CDV) is a major infectious disease of dogs. Although vaccines were successful to control CDV spread in canine population, the disease is still common and may pose a threat to unvaccinated dogs. In the attempt to develop specific anti-viral therapeutic tools, the efficacy of several molecules against CDV has been investigated in vitro. In this study the antiviral efficacy in vitro against CDV of ribavirin and boceprevir alone or in combination was evaluated. CDV growth in VERO cells was inhibited by ribavirin, by boceprevir and by a combination of the two molecules at non-cytotoxic concentrations, as evaluated by end-point viral titration in cell monolayers and by quantification of viral RNA using quantitative RT-PCR. By end-point titration, a statistically significant reduction in CDV replication was observed only using ribavirin and boceprevir in combination. By quantitative RT-PCR, a significant reduction of viral growth was observed either in cells treated with ribavirin or boceprevir or with both the two molecules. The association of ribavirin or boceprevir was able to decrease CDV growth by up to 3.4458 logs with respect to untreated infected cells, chiefly at the highest virus dilutions. The results obtained in this study may constitute an important basis for the development of CDV therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus.

PubMed

Ogg, Monica; Jonsson, Colleen B; Camp, Jeremy V; Hooper, Jay W

2013-11-08

Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.

Ribavirin Treatment of Toga-, Arena- and Bunyavirus Infections in Subhuman Primates and Other Laboratory Animal Species

DTIC Science & Technology

1979-09-01

trernd reversed. After 1 hour, only 15 -percent of the la - beled ribavirin was retained by BW-JII cells and only I1 percent at 24 hours. Glial and...days after the cessation of treatment. E. Studies in Subhuman Primates (Intramuscular Administracion of Ribavirin) Rhesus monkeys inoculated with FVF...guinea pigs) ~4AC + + (guinea pigs)+ LAS + + (guinea pigs) + Bunva- RVF +’ + + (mice) + SFS + No model No model MIyxo- Influenza + (mice) + Ribavirin

Efficacy of oral ribavirin in hematologic disease patients with paramyxovirus infection: analytic strategy using propensity scores.

PubMed

Park, So-Youn; Baek, Seunghee; Lee, Sang-Oh; Choi, Sang-Ho; Kim, Yang Soo; Woo, Jun Hee; Sung, Heungsup; Kim, Mi-Na; Kim, Dae-Young; Lee, Jung-Hee; Lee, Je-Hwan; Lee, Kyoo-Hyung; Kim, Sung-Han

2013-02-01

Few antiviral agents are available for treating paramyxovirus infections, such as those involving respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV). We evaluated the effect of oral ribavirin on clinical outcomes of paramyxovirus infections in patients with hematological diseases. All adult patients with paramyxovirus were retrospectively reviewed over a 2-year period. Patients who received oral ribavirin were compared to those who received supportive care without ribavirin therapy. A propensity-matched case-control study and a logistic regression model with inverse probability of treatment weighting (IPTW) were performed to reduce the effect of selection bias in assignment for oral ribavirin therapy. A total of 145 patients, including 64 (44%) with PIV, 60 (41%) with RSV, and 21 (15%) with hMPV, were analyzed. Of these 145 patients, 114 (78%) received oral ribavirin and the remaining 31 (21%) constituted the nonribavirin group. Thirty-day mortality and underlying respiratory death rates were 31% (35/114) and 12% (14/114), respectively, for the oral ribavirin group versus 19% (6/31) and 16% (5/31), respectively, for the nonribavirin group (P = 0.21 and P = 0.56). In the case-control study, the 30-day mortality rate in the ribavirin group was 24% (5/21) versus 19% (4/21) in the nonribavirin group (P = 0.71). In addition, the logistic regression model with IPTW revealed no significant difference in 30-day mortality (adjusted hazard ratio of 1.3; 95% confidence interval [95% CI] of 0.3 to 5.8) between the two groups. Steroid use (adjusted odds ratio, 5.67; P = 0.01) and upper respiratory tract infection (adjusted odds ratio, 0.07; P = 0.001) was independently associated with mortality. Our data suggest that oral ribavirin therapy may not improve clinical outcomes in hematologic disease patients infected with paramyxovirus.

Oral ribavirin for respiratory syncytial virus infection after lung transplantation: Efficacy and cost-efficiency.

PubMed

Burrows, Fay S; Carlos, Lilibeth M; Benzimra, Mark; Marriott, Deborah J E; Havryk, Adrian P; Plit, Marshall L; Malouf, Monique A; Glanville, Allan R

2015-07-01

Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx. Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days). Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001). To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Ribavirin, Interferon, and Antibody Approaches to Prophylaxis and Therapy for Viral Hemorrhagic Fevers

DTIC Science & Technology

1990-01-01

competitively inhibits intracellular pools of tive in preventing nosocomial infections (MMWR 1988, guanosine triphosphate required for viral nucleic...separation of cytotoxic and viral inhibitory activ- serious viral infections , they assume another dimension ities (Smith and Kirkpatrick, eds., Ribavirin, A...individuals or those exposed to clinical trials conducted since 1977, ribavirin has been self-limited viral infections must also take into account administered

Effect of oral ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.

PubMed

Bodur, Hürrem; Erbay, Ayşe; Akıncı, Esragül; Öngürü, Pınar; Bayazıt, Nurhayat; Eren, Selim Sırrı; Kubar, Ayhan

2011-01-01

Crimean-Congo hemorrhagic fever (CCHF) is a lethal hemorrhagic disease. There is currently no specific antiviral therapy for CCHF approved for use in humans. In this study we aimed to investigate the effect of oral ribavirin treatment on the viral load and disease progression in CCHF. The study population was composed of patients who had a definitive diagnosis of CCHF by means of clinical presentation plus detection of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR). Ten patients who received oral ribavirin for 10 days and 40 control patients who received supportive treatment only were included in the study. Ribavirin treatment consisted of oral ribavirin 4 g/day for 4 days and then 2.4 g/day for 6 days. Viral load and hematological and biochemical laboratory parameters, which were measured daily, were analyzed. Mean age (37.4 vs. 45.5, p=0.285), gender (male 50% vs. 62.5%, p=0.470), days from the appearance of symptoms to admission (4.3 vs.4.4 days, p=0.922), and initial complaints were similar between the ribavirin group and the control group. Upon hospital admission, mean viral load was 8.2×10⁸ copies/ml in the ribavirin group and 8.3×10⁸ copies/ml in the control group (p=0.994). During follow-up, no statistically significant differences were found between the groups with regard to the decrease in viral load, the reduction in alanine aminotransferase and aspartate aminotransferase levels, and the increase in platelet count. The case-fatality rate was 20% (2/10 patients) in the ribavirin group and 15% (6/40 patients) in the control group (p=0.509). In this study, oral ribavirin treatment in CCHF patients did not affect viral load or disease progression. Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

[Results of treatment with peginterferon plus ribavirin in patients with chronic hepatitis C].

PubMed

Pizarro, Carolina; Venegas, Mauricio; Hola, Karen; Smok, Gladys; Brahm, Javier

2011-06-01

The current treatment recommendation for chronic hepatitis C virus infection is the combination of peginterferon and ribavirin for 24 or 48 weeks, depending on the viral genotype. The aim of the therapy is to obtain a sustained virological response. To report our experience in the treatment of chronic hepatitis C. Analysis of 52 patients treated between September 2000 and June 2009. Patients with genotype 1 or 5 were treated with peginterferon alpha 2a (180 ug/week) and ribavirin (1000 mg/day for those weighing less than 75 kg and 1200 mg/day for those weighing more than 75 kg) during 48 weeks. Patients with genotypes 2 and 3 were treated for 24 weeks with the same dose of peginterferon and ribavirin 800 mg/day. Viral genotypes 1, 2, 3 and 5 were present in 81, 4, 11 and 4% of patients, respectively. Twenty four patients (46 %), 18 with genotype 1, achieved a sustained viral response. Age was the only variable that influenced the response to treatment. Approximately half of the patients with chronic hepatitis C, achieve a sustained viral response with peginterferon and ribavirin.

Poliovirus Polymerase Leu420 Facilitates RNA Recombination and Ribavirin Resistance

PubMed Central

Kempf, Brian J.; Peersen, Olve B.

2016-01-01

ABSTRACT RNA recombination is important in the formation of picornavirus species groups and the ongoing evolution of viruses within species groups. In this study, we examined the structure and function of poliovirus polymerase, 3Dpol, as it relates to RNA recombination. Recombination occurs when nascent RNA products exchange one viral RNA template for another during RNA replication. Because recombination is a natural aspect of picornavirus replication, we hypothesized that some features of 3Dpol may exist, in part, to facilitate RNA recombination. Furthermore, we reasoned that alanine substitution mutations that disrupt 3Dpol-RNA interactions within the polymerase elongation complex might increase and/or decrease the magnitudes of recombination. We found that an L420A mutation in 3Dpol decreased the frequency of RNA recombination, whereas alanine substitutions at other sites in 3Dpol increased the frequency of recombination. The 3Dpol Leu420 side chain interacts with a ribose in the nascent RNA product 3 nucleotides from the active site of the polymerase. Notably, the L420A mutation that reduced recombination also rendered the virus more susceptible to inhibition by ribavirin, coincident with the accumulation of ribavirin-induced G→A and C→U mutations in viral RNA. We conclude that 3Dpol Leu420 is critically important for RNA recombination and that RNA recombination contributes to ribavirin resistance. IMPORTANCE Recombination contributes to the formation of picornavirus species groups and the emergence of circulating vaccine-derived polioviruses (cVDPVs). The recombinant viruses that arise in nature are occasionally more fit than either parental strain, especially when the two partners in recombination are closely related, i.e., members of characteristic species groups, such as enterovirus species groups A to H or rhinovirus species groups A to C. Our study shows that RNA recombination requires conserved features of the viral polymerase. Furthermore, a

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anaemia in chronic hepatitis C Egyptian patients.

PubMed

El Desoky, Ehab S; Abdelhafez, Alaa T; Cusato, Jessica; Kamel, Sherif I; Hussein, Abeer Mr; De Nicolo, Amedeo; Di Perri, Giovanni; D'Avolio, Antonio

2017-09-01

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration. © 2017 John Wiley & Sons Australia, Ltd.

Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America.

PubMed

Mertz, Gregory J; Miedzinski, Lil; Goade, Diane; Pavia, Andrew T; Hjelle, Brian; Hansbarger, Christine O; Levy, Howard; Koster, Frederick T; Baum, Kenneth; Lindemulder, Adeline; Wang, Wenquan; Riser, Laura; Fernandez, Humberto; Whitley, Richard J

2004-11-01

BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive. Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were eligible for randomization to receive either intravenous ribavirin (33 mg/kg [ribavirin and the 13 subjects with HCPS who received placebo. The proportion of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups. The rate of accrual of subjects in the present study was inadequate to clearly assess the safety or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.

Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin.

PubMed

Barnard, Dale L; Day, Craig W; Bailey, Kevin; Heiner, Matthew; Montgomery, Robert; Lauridsen, Larry; Winslow, Scott; Hoopes, Justin; Li, Joseph K-K; Lee, Jongdae; Carson, Dennis A; Cottam, Howard B; Sidwell, Robert W

2006-08-01

Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1alpha, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response

Ribavirin Contributes to Hepatitis C Virus Suppression by Augmenting pDC Activation and Type 1 IFN Production.

PubMed

Wang, Yang; McGivern, David R; Cheng, Liang; Li, Guangming; Lemon, Stanley M; Niu, Junqi; Su, Lishan; Reszka-Blanco, Natalia J

2015-01-01

Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production.

Ribavirin Contributes to Hepatitis C Virus Suppression by Augmenting pDC Activation and Type 1 IFN Production

PubMed Central

Wang, Yang; McGivern, David R; Cheng, Liang; Li, Guangming; Lemon, Stanley M; Niu, Junqi; Su, Lishan; Reszka-Blanco, Natalia J

2015-01-01

Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production. PMID:26274905

Peginterferon Lambda-1a/Ribavirin with Daclatasvir or Peginterferon Alfa-2a/Ribavirin with Telaprevir for Chronic Hepatitis C Genotype 1b.

PubMed

Flisiak, Robert; Kawazoe, Seiji; Znoyko, Olga; Assy, Nimer; Gadano, Adrian; Kao, Jia-Horng; Lee, Kwan-Sik; Zwirtes, Ricardo; Portsmouth, Simon; Dong, Yuping; Xu, Dong; Kumada, Hiromitsu; Srinivasan, Subasree

2016-11-01

The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P < 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

Changes in serum hepatitis C virus RNA in interferon nonresponders retreated with interferon plus ribavirin: a preliminary report.

PubMed

Nyberg, L; Albrecht, J; Glue, P; Gianelli, G; Zambas, D; Elliot, M; Conrad, A; McHutchison, J

1999-06-01

Ribavirin, a nucleoside analogue, inhibits replication of RNA and DNA viruses and may control hepatitis C virus (HCV) infection through modulation of anti-inflammatory and antiviral actions. Ribavirin monotherapy has no effect on serum HCV RNA levels. In combination with interferon, this agent appears to enhance the efficacy of interferon. The aim of this study was to monitor serum HCV RNA levels early during therapy with interferon and ribavirin compared with that previously seen in the same patients during interferon monotherapy. Five patients who previously showed no response to therapy with interferon alfa 3 MU three times weekly for 6 months were retreated with the identical dose of interferon alfa 2b in combination with oral ribavirin 1,000 mg/day. Serum HCV RNA levels were monitored at baseline, week 4, week 8, and week 12 of therapy by a quantitative multicycle polymerase chain reaction assay. In the first 8 to 12 weeks, serum HCV RNA levels showed a greater decrease in all patients when retreated with combination therapy compared with interferon alone. Mean (+/- SEM) serum HCV RNA levels for interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/- 1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12, respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2, 0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the interferon and ribavirin group (p < 0.07 at week 8). Two of five patients had undetectable serum HCV RNA during combination therapy. Combination therapy with interferon and ribavirin in prior interferon nonresponders reduces serum HCV RNA levels compared with interferon alone. This may suggest some additional antiviral effect of ribavirin when given with interferon.

Application of inorganic oxidants to the spectrophotometric determination of ribavirin in bulk and capsules.

PubMed

Darwish, Ibrahim A; Khedr, Alaa S; Askal, Hassan F; Mohamed, Ramadan M

2006-01-01

Eight spectrophotometric methods for determination of ribavirin have been developed and validated. These methods were based on the oxidation of the drug by different inorganic oxidants: ceric ammonium sulfate, potassium permanganate, ammonium molybdate, ammonium metavanidate, chromium trioxide, potassium dichromate, potassium iodate, and potassium periodate. The oxidation reactions were performed in perchloric acid medium for ceric ammonium sulfate and in sulfuric acid medium for the other reagents. With ceric ammonium sulfate and potassium permanganate, the concentration of ribavirin in its samples was determined by measuring the decrease in the absorption intensity of the colored reagents at 315 and 525 nm, respectively. With the other reagents, the concentration of ribavirin was determined by measuring the intensity of the developed colored reaction products at the wavelengths of maximum absorbance: 675, 780, 595, 595, 475, and 475 nm for reactions with ammonium molybdate, ammonium metavanidate, chromium trioxide, potassium dichromate, potassium iodate, and potassium periodate, respectively. Different variables affecting the reaction conditions were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9984-0.9998) were found between the absorbance readings and the concentrations of ribavirin in the range of 4-1400 microg/mL. The molar absorptivities were correlated with the oxidation potential of the oxidants used. The precision of the methods were satisfactory; the values of relative standard deviation did not exceed 1.64%. The proposed methods were successfully applied to the analysis of ribavirin in pure drug material and capsules with good accuracy and precision; the recovery values were 99.2-101.2 +/- 0.48-1.30%. The results obtained using the proposed spectrophotometric methods were comparable with those obtained with the official method stated in the United States Pharmacopeia.

Rapid CO breath test screening of drugs for protective effects on ribavirin-induced hemolysis in a rabbit model: a pilot study.

PubMed

Ma, Yong-Jian; Zhang, Hou-De; Wu, Chuang-Hong; Zhu, Guo-Liang; Ji, Yong-Qiang; Huang, Jia-Liang; Du, Li-Tao; Cao, Ping; Zang, De-Yue; Ji, Kun-Mei

2016-08-10

Hemolytic anemia is a major side effect of ribavirin antiviral treatment for chronic hepatitis C. Ribavirin dose reduction may compromise the antiviral response and erythropoietin can take several weeks to alleviate anemia. The purpose of the present study was to screen potentially protective drugs against ribavirin-induced hemolytic anemia in a rabbit model, using our modified CO breath test for measuring erythrocyte (RBC) lifespan, the gold standard diagnostic index of hemolysis. Fifteen rabbits were divided randomly into five groups (N  =  3/group): one vehicle control group, one ribavirin (only)-treated (RBV) group, and three groups initially treated with ribavirin only, followed by a combination of ribavirin with prednisone (RBV  +  Pred), polyene phosphatidyl choline (RBV  +  PPC), or reduced glutathione (RBV  +  GSH). RBC lifespan was calculated from accumulated CO measured in a closed rebreath apparatus, blood volume measured by the Evan's blue dye (EBD) dilution test, and hemoglobin concentration data. The RBC lifespan was normal in the vehicle control group (44-60 d), but reduced significantly in all of the ribavirin-treated groups before the addition of screened drugs (17-35 d). RBC lifespan rebounded significantly with the addition of glutathione, but not with the addition of prednisone or polyene phosphatidyl choline. A similar overall drug effect pattern was seen in the hemoglobin concentration and reticulocyte count data. In conclusion, the results of this pilot study indicate that reduced glutathione can attenuate ribavirin-induced hemolytic anemia, and that the RBC lifespan measured with our modified rapid CO breath test is feasible and reliable for use in animal studies.

In Vitro and In Vivo Phlebovirus Inhibition by Ribavirin

DTIC Science & Technology

1988-03-01

as x%%eliais oin the encephalutic disease in viaj rechnassociates. Inc. I Rockx ille. Md. i in dry- poxvder mice Indtuced by a neurotropic strain oft...1980. Ribavirin treatment of its capping of messenger RNA. Biochem. Biophys. Res. Com- toga. arena - and bunvavirus infections in subhuman prittiates

How hepatitis C patients manage the treatment process of pegylated interferon and ribavirin therapy: a qualitative study.

PubMed

Tsai, Shu-Mei; Kao, Jung-Ta; Tsai, Yun-Fang

2016-07-11

Hepatitis C virus (HCV) infection is a global public health issue. Adequate treatment for hepatitis C patients is important, but anticipated side effects make patients fearful of receiving treatment. Little is known about the experiences of hepatitis C patients who have completed treatment with pegylated interferon and ribavirin. The purpose of this study was to explore the experiences of hepatitis C patients who had undergone therapy with pegylated interferon and ribavirin and gain an understanding of what factors contributed to completion of treatment. This was a qualitative study with 21 adult hepatitis C patients purposively sampled from outpatient liver clinics of a medical university hospital in Taichung City, Taiwan. Participants had completed 6-12 months of therapy with pegylated interferon and ribavirin. Data were collected through individual, face-to-face, in-depth interviews conducted in the participants' homes from June-October 2013. Data were analysed using conventional content analysis. Data analysis revealed three themes that described the strategies employed to alleviate and ease symptoms and manage the processes involved: restructuring their lifestyle, adopting a positive attitude, and seeking support. Hepatitis C patients face many challenges during treatment with pegylated interferon and ribavirin. These findings provide knowledge that can be used in designing effective programs to help other Hepatitis C patients manage the side effects of pegylated interferon and ribavirin therapy, complete treatment and improve quality of life.

Utility of high-resolution accurate MS to eliminate interferences in the bioanalysis of ribavirin and its phosphate metabolites.

PubMed

Wei, Cong; Grace, James E; Zvyaga, Tatyana A; Drexler, Dieter M

2012-08-01

The polar nucleoside drug ribavirin (RBV) combined with IFN-α is a front-line treatment for chronic hepatitis C virus infection. RBV acts as a prodrug and exerts its broad antiviral activity primarily through its active phosphorylated metabolite ribavirin 5´-triphosphate (RTP), and also possibly through ribavirin 5´-monophosphate (RMP). To study RBV transport, diffusion, metabolic clearance and its impact on drug-metabolizing enzymes, a LC-MS method is needed to simultaneously quantify RBV and its phosphorylated metabolites (RTP, ribavirin 5´-diphosphate and RMP). In a recombinant human UGT1A1 assay, the assay buffer components uridine and its phosphorylated derivatives are isobaric with RBV and its phosphorylated metabolites, leading to significant interference when analyzed by LC-MS with the nominal mass resolution mode. Presented here is a LC-MS method employing LC coupled with full-scan high-resolution accurate MS analysis for the simultaneous quantitative determination of RBV, RMP, ribavirin 5´-diphosphate and RTP by differentiating RBV and its phosphorylated metabolites from uridine and its phosphorylated derivatives by accurate mass, thus avoiding interference. The developed LC-high-resolution accurate MS method allows for quantitation of RBV and its phosphorylated metabolites, eliminating the interferences from uridine and its phosphorylated derivatives in recombinant human UGT1A1 assays.

Clinical Outcomes of Paramyxovirus Infections in Lung Transplant Recipients Treated With Oral Ribavirin: A Two-Center Case Series.

PubMed

Garcia, Bryan; Sharma, Nirmal; Johnson, Kevin; Salgado, Juan; Wille, Keith

2017-10-31

Paramyxoviruses contribute to morbidity and mortality after lung transplant and are associated with bronchiolitis obliterans syndrome. Oral ribavirin has been used off-label for treatment of paramyxoviruses in immunosuppressed patients; however, data supporting its use for this purpose are lacking. We conducted a retrospective review to evaluate clinical outcomes of lung transplant recipients infected with paramyxoviruses and received treatment with oral ribavirin at 2 tertiary referral centers. Patients who were diagnosed with paramyxovirus infection by polymerase chain reaction testing between January 2011 and December 2014 and who received oral ribavirin were included. Clinical outcomes included pulmonary function testing, infection severity, and adverse events related to treatment. Twenty-six patients were diagnosed with a paramyxovirus and received oral ribavirin. The changes in mean forced expiratory volume 1 second from preinfection to infection onset and from infection onset to postinfection were significant (1.79 ± 0.13 to 1.61 ± 0.12 L and 1.61 ± 0.12L to 1.74 ± 0.12 L; P = .0001). Similar results were seen in subgroup analysis when respiratory syncytial virus and parainfluenza infections were evaluated independently. Use of oral ribavirin for treatment of paramyxovirus infections in lung transplant recipients was safe and associated with recovery of lung function.

Broad spectrum antiviral agent ribavirin inhibits capping of mRNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goswami, B.B.; Borek, E.; Sharma, O.K.

1979-08-13

Ribavirin (1-..beta..-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad spectrum antiviral substance active against a wide range of both DNA and RNA viruses. It is, however, virtually inactive against polio virus. Its pharmacological mechanism of action was obscure. A possible common target for a chemotherapeutic agent in both DNA and RNA viruses is the capping reaction of mRNAs which inter alia involves the formation of a guanine pyrophosphate structure at the 5' terminus by mRNA guanylyl transferase. We have observed that Ribavirin triphosphate is a potent competitive inhibitor of the capping guanylation of viral mRNA. This finding could account for the antiviral potency ofmore » the drug against both DNA and RNA viruses and its ineffectiveness against a virus in which the mRNAs derived from them are not capped.« less

Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Dehua; Chen, Hujie; Tang, Jing

Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independentmore » OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment. - Highlights: • Ribavirin effectively targets OTSCC in vitro and in vivo. • Ribavirin acts synergistically with paclitaxel in OTSCC cells. • Ribavirin inhibits Akt/mTOR/eIF4E signaling in OTSCC. • eIF4E inhibition sensitizes OTSCC cell response to paclitaxel.« less

The antiviral effects of RSV fusion inhibitor, MDT-637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin.

PubMed

Kim, Young-In; Pareek, Rajat; Murphy, Ryan; Harrison, Lisa; Farrell, Eric; Cook, Robert; DeVincenzo, John

2017-11-01

Respiratory syncytial virus (RSV) viral load and disease severity associate, and the timing of viral load and disease run in parallel. An antiviral must be broadly effective against the natural spectrum of RSV genotypes and must attain concentrations capable of inhibiting viral replication within the human respiratory tract. We evaluated a novel RSV fusion inhibitor, MDT-637, and compared it with ribavirin for therapeutic effect in vitro to identify relative therapeutic doses achievable in humans. MDT-637 and ribavirin were co-incubated with RSV in HEp-2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations (IC 50 ) were compared to achievable human MDT-637 and ribavirin peak and trough concentrations. The IC 50 for MDT-637 and ribavirin (against RSV-A Long) was 1.42 and 16 973 ng/mL, respectively. The ratio of achievable peak respiratory secretion concentration to IC 50 was 6041-fold for MDT-637 and 25-fold for aerosolized ribavirin. The ratio of trough concentration to IC 50 was 1481-fold for MDT-637 and 3.29-fold for aerosolized ribavirin. Maximal peak and trough levels of oral or intravenous ribavirin were significantly lower than their IC 50 s. We also measured MDT-637 IC 50 s in 3 lab strains and 4 clinical strains. The IC 50 s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC 50 s by factors from hundreds to thousands of times greater than does ribavirin. Furthermore, MDT-637 has broad in vitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, these data imply that MDT-637 may produce a superior clinical effect compared to ribavirin on natural RSV infections. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever.

PubMed

Bausch, Daniel G; Hadi, Christiane M; Khan, Sheik Humarr; Lertora, Juan J L

2010-12-15

Lassa fever is an acute viral hemorrhagic illness; the virus is endemic in West Africa and also of concern with regard to bioterrorism. Transmission of Lassa virus between humans may occur through direct contact with infected blood or bodily secretions. Oral administration of the antiviral drug ribavirin is often considered for postexposure prophylaxis, but no systematically collected data or uniform guidelines exist for this indication. Furthermore, the relatively low secondary attack rates for Lassa fever, the restriction of the area of endemicity to West Africa, and the infrequency of high-risk exposures make it unlikely that controlled prospective efficacy trials will ever be possible. Recommendations for postexposure use of ribavirin can therefore be made only on the basis of a thorough understanding and logical extrapolation of existing data. Here, we review the pertinent issues and propose guidelines based on extensive review of the literature, as well as our experience in this field. We recommend oral ribavirin postexposure prophylaxis for Lassa fever exclusively for definitive high-risk exposures. These guidelines may also serve for exposure to other hemorrhagic fever viruses susceptible to ribavirin.

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients.

PubMed

Helal, Gouda Kamel; Gad, Magdy Abdelmawgoud; Abd-Ellah, Mohamed Fahmy; Eid, Mahmoud Saied

2016-12-01

The therapeutic effect of pegylated interferon (peg-IFN) alfa-2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa-2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa-2a (160 μg) subcutaneous once weekly and oral weight-based ribavirin (1000-1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170-2178, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Pegylated interferon alpha-2a and ribavirin combination therapy in HCV liver transplant recipients. Experience of 7 cases.

PubMed

Iacob, Speranta; Gheorghe, Liana; Hrehoret, Doina; Becheanu, Gabriel; Herlea, Vlad; Popescu, Irinel

2008-06-01

Hepatitis C virus (HCV) related cirrhosis represents the leading indication for liver transplantation (LT) worldwide and HCV reinfection is the rule among transplant recipients. Combination therapy with interferon and ribavirin is the treatment of choice for established recurrent hepatitis C. To evaluate the efficacy and safety of the combination of pegylated interferon alpha-2a and ribavirin in LT recipients with histological recurrence of hepatitis C. Seven LT recipients with chronic hepatitis C recurrence were treated with peginterferon alpha-2a with an initial intended dose of 180 microg/week and an intended dose of ribavirin 800-1000 mg/day for at least 12 months and followed-up for at least 24 weeks. Early virological response rate was 57.1%. Three patients (42.8%) had end of treatment virological response and all had also sustained viral response (SVR). Five patients had end of treatment biological response, out of which 4 had also sustained biochemical response. Three patients had both SVR and sustained biochemical response. Four patients had end of treatment histological response, out of which 3 patients had also SVR. Cytopenia was the most common adverse event: anemia (57.1%), leucopenia/neutropenia (71.4%), thrombocytopenia (42.8%). Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

PubMed

Hézode, Christophe; Hirschfield, Gideon M; Ghesquiere, Wayne; Sievert, William; Rodriguez-Torres, Maribel; Shafran, Stephen D; Thuluvath, Paul J; Tatum, Harvey A; Waked, Imam; Esmat, Gamal; Lawitz, Eric J; Rustgi, Vinod K; Pol, Stanislas; Weis, Nina; Pockros, Paul J; Bourlière, Marc; Serfaty, Lawrence; Vierling, John M; Fried, Michael W; Weiland, Ola; Brunetto, Maurizia R; Everson, Gregory T; Zeuzem, Stefan; Kwo, Paul Y; Sulkowski, Mark; Bräu, Norbert; Hernandez, Dennis; McPhee, Fiona; Wind-Rotolo, Megan; Liu, Zhaohui; Noviello, Stephanie; Hughes, Eric A; Yin, Philip D; Schnittman, Steven

2015-06-01

To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNAribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. NCT01125189

Stability of Ribavirin for Inhalation Packaged in Syringes or Glass Vials when Stored Frozen, Refrigerated, and at Room Temperature.

PubMed

Larson, Bayli; Bushman, Lane R; Casciano, Matthew L; Oldland, Alan R; Kiser, Jennifer J; Kiser, Tyree H

2016-01-01

The primary aim of this study was to investigate ribavirin solution for inhalation stability under three different conditions (frozen, refrigerated, room temperature) over a 45-day period. A ribavirin 6000-mg vial was reconstituted with 90 mL of Sterile Water for Injection per the package insert to yield a concentration of approximately 67 mg/mL. The solution was then placed in either syringes or empty glass vials and stored in the freezer (-20°C), in the refrigerator (~0°C to 4°C), or at room temperature (~20°C to 25°C). Original concentrations were measured on day 0 and subsequent concentrations were measured on day 2, 14, and 45 utilizing a validated liquid chromatography with tandem mass spectrometry assay. All analyses were performed in triplicate for each storage condition. Additionally, at each time point the physical stability was evaluated and the pH of solution was measured. The solution was considered stable if =90% of the original concentration was retained over the study period. A validated liquid chromatography with tandem mass spectrometry analysis demonstrated that >95% of the original ribavirin concentration was preserved over the 45-day period for all study conditions. The ribavirin concentration remained within the United States Pharmacopeia (USP)-required range of 95% to 105% of the original labeled product amount throughout the entire study period for all study conditions. Precipitation of ribavirin was noted during the thawing cycle for frozen samples, but the drug went back into solution once the thawing process was completed. No changes in color or turbidity were observed in any of the prepared solutions. Values for pH remained stable over the study period and ranged from 4.1 to 5.3. Ribavirin for inhalation solution is physically and chemically stable for at least 45 days when frozen, refrigerated, or kept at room temperature after reconstitution to a concentration of approximately 67 mg/mL and placed in syringes or glass vials

Peginterferon alfa‐2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy

PubMed Central

Sherman, M; Yoshida, E M; Deschenes, M; Krajden, M; Bain, V G; Peltekian, K; Anderson, F; Kaita, K; Simonyi, S; Balshaw, R; Lee, S S

2006-01-01

Background The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. Aims We evaluated the efficacy and safety of peginterferon alfa‐2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. Patients Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. Methods Patients were retreated with peginterferon alfa‐2a (40KD) 180 µg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators' discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. Results A total of 312 patients (212 non‐responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non‐responders and relapsers were similar although more non‐responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non‐responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. Conclusions These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non‐responders and relapsers by retreating with peginterferon alfa‐2a (40KD) plus ribavirin. PMID:16709661

Peginterferon Alfa-2a plus Ribavirin in Japanese Patients Infected with Hepatitis C Virus Genotype 2 Who Failed Previous Interferon Therapy

PubMed Central

Kanda, Tatsuo; Nakamoto, Shingo; Nishino, Takayoshi; Takada, Nobuo; Tsubota, Akihito; Kato, Keizo; Miyamura, Tatsuo; Maruoka, Daisuke; Wu, Shuang; Tanaka, Takeshi; Arai, Makoto; Mikami, Shigeru; Fujiwara, Keiichi; Imazeki, Fumio; Yokosuka, Osamu

2013-01-01

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients. PMID:23289004

Pharmacokinetics, efficacy prediction indexes, and residue depletion of ribavirin in Atlantic salmon's (Salmo salar) muscle after oral administration in feed.

PubMed

San Martín, B; Muñoz, R; Cornejo, J; Martínez, M A; Araya-Jordán, C; Maddaleno, A; Anadón, A

2016-08-01

Ribavirin is an antiviral used in human medicine, but it has not been authorized for use in veterinary medicine although it is effective against infectious salmon anemia (ISA) virus, between others. In this study, we present a pharmacokinetic profile of ribavirin in Atlantic salmon (Salmo salar), efficacy prediction indexes, and the measure of its withdrawal time. To determine the pharmacokinetic profile, fishes were orally administered with a single ribavirin dose of 1.6 mg/kg bw, and then, plasma concentrations were measured at different times. From the time-vs.-concentration curve, Cmax = 413.57 ng/mL, Tmax  = 6.96 h, AUC = 21394.01 μg·h/mL, t1/2  = 81.61 h, and K10  = 0.0421/h were obtained. Ribavirin reached adequate concentrations during the pharmacokinetic study, with prediction indexes of Cmax /IC50  = 20.7, AUC/IC50  = 1069.7, and T>IC50  = 71 h, where IC is the inhibitory concentration 50%. For ribavirin depletion study, fishes were orally administered with a dairy dose of 1.6 mg/kg bw during 10 days. Concentrations were measured on edible tissue on different days post-treatment. A linear regression of the time vs. concentration was conducted, obtaining a withdrawal time of 1966 °C days. Results obtained reveal that the dose of 1.6 mg/kg bw orally administered is effective for ISA virus, originating a reasonable withdrawal period within the productive schedules of Atlantic salmon. © 2016 John Wiley & Sons Ltd.

Treatment-emergent depression and anxiety between peginterferon alpha-2a versus alpha-2b plus ribavirin for chronic hepatitis C.

PubMed

Wang, Liang-Jen; Chen, Shuo-Wei; Chen, Chih-Ken; Yen, Cho-Li; Chang, Jia-Jang; Lee, Tsung-Shih; Liu, Ching-Jung; Chen, Li-Wei; Chien, Rong-Nan

2016-11-25

This study investigates differences in depression and anxiety between patients with chronic hepatitis C who are treated with peginterferon alpha-2a (PegIFN-α-2a) plus ribavirin and those who are treated with peginterferon alpha-2b (PegIFN-α-2b) plus ribavirin. In this 24 week, non-randomized, observational, prospective study, 55 patients with chronic hepatitis C were treated with PegIFN-α-2a plus ribavirin (Group 1), and 26 patients were treated with PegIFN-α-2b plus ribavirin (Group 2). All patients underwent assessment using the Hospital Anxiety and Depression Scale (HADS) at the baseline and at weeks 4, 12 and 24. Patients with depression scores (HADS-D) ≥ 8 and anxiety scores (HADS-A) ≥ 8 were defined as having depression and anxiety, respectively. The factors that were associated with depression and anxiety during the 24 week antiviral treatment were determined. During the 24 week antiviral treatment, the proportion of patients with depression significantly increased over time in both groups (Group 1: p = 0.048; Group 2: p = 0.044). The proportion of patients with anxiety did not significantly change during the follow-up period in either group. Incidences of depression or anxiety did not differ significantly between Group 1 and Group 2. A history of alcohol use disorder was an independent predictor of depression at week 12 (p < 0.001) and week 24 (p < 0.001), and a poor virological response to treatment was associated with depression at week 24 (p = 0.029). Patients who had more physical comorbidities were more likely to suffer from anxiety at week 12 (p = 0.038). This study did not identify significant differences in depression or anxiety between in patients with chronic hepatitis C who underwent a 24 week antiviral treatment regimen with PegIFN-α-2a plus ribavirin and those who underwent a regiment with PegIFN-α-2b plus ribavirin. Future research with larger samples and a randomized, controlled design are

Daclatasvir and Sofosbuvir With or Without Ribavirin in Liver Transplant Recipients: A Single-Center Real-World Study.

PubMed

Mucenic, M; Bandeira de Mello Brandao, A; Marroni, C A; Medeiros Fleck, A; Zanotelli, M L; Kiss, G; Meine, M H; Leipnitz, I; Soares Schlindwein, E; Martini, J; Costabeber, A M; Sacco, F K F; Cracco Cantisani, G P

2018-04-01

Treatment with direct-acting antiviral drugs in interferon-free regimens is currently recommended for viral hepatitis C recurrence after liver transplantation. There are limited data regarding its results in this population, and no optimal treatment scheme has yet been singled out. We report our real-world results in liver transplant (LT) recipients. All patients were hepatitis C virus (HCV) monoinfected and completed a 12-week treatment course, followed 12 weeks later by HCV polymerase chain reaction testing with 12 IU/mL sensibility. Liver fibrosis was graded with the use of biopsies taken <12 months before treatment and stratified as early (0-1) or moderate to advanced (2-4) according to the Metavir score. Median postoperative time was 5.2 years. Genotype 3 was found in 66.7% of the sample. The following regimens were prescribed: daclatasvir-sofosbuvir with (n = 11) or without (n = 28) ribavirin. Genotypes 1 and 3 were evenly distributed between the regimens. Sustained virologic response (SVR) was obtained in 24 out of 28 patients (85.7%) who received daclatasvir-sofosbuvir and in all patients (100%) who received daclatasvir-sofosbuvir-ribavirin (global SVR 89.7%). All patients that failed treatment had genotype 3 HCV. Fibrosis was evaluated in 79.5% of the sample: 48.4% had early and 51.6% had moderate to advanced fibrosis, for which ribavirin was more commonly prescribed (P = .001). The SVR rate in our LT recipients was similar to that previously reported in the literature. The addition of ribavirin to DAA treatment appears to be justified in this population. Copyright © 2018 Elsevier Inc. All rights reserved.

Hepatitis C treatment outcomes using interferon- and ribavirin-based therapy in Kigali, Rwanda.

PubMed

Riedel, David J; Taylor, Simone; Simango, Raulina; Kiromera, Athanase; Sebeza, Jackson; Baribwira, Cyprien; Musabeyezu, Emmanuel

2016-08-01

Hepatitis C virus (HCV) treatment data in sub-Saharan Africa are limited. This study was to determine HCV sustained virologic response(SVR) at 24 weeks in patients undergoing HCV therapy in Kigali, Rwanda. The paper presents data for all patients treated for HCV with ribavirin/interferon at King Faisal Hospital in Kigali, Rwanda, from 1 January 2007 to 31 December 2014. There were 69 evaluable patients. HCV genotype 4(61%, 42/69) predominated. 24-week SVR was 70%(26/37) by per-protocol and 32%(26/69) by intention-to-treat analysis. HCV treatment in Rwanda is feasible. SVR with interferon/ribavirin was acceptable in the per-protocol analysis. Transition to newer direct acting antivirals is urgently needed in Rwanda and sub-Saharan Africa more generally to improve treatment outcomes. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Case report: Ribavirin and vitamin A in a severe case of measles.

PubMed

Bichon, Amandine; Aubry, Camille; Benarous, Lucas; Drouet, Hortense; Zandotti, Christine; Parola, Philippe; Lagier, Jean-Christophe

2017-12-01

Despite a vaccine being widely available, measles continues to occur frequently, with sometimes lethal consequences. The mortality rate reaches 35% and measles represents 44% of the 1.4 million deaths which are due to preventable diseases. Severe forms of measles are reported, mainly in young, unvaccinated adults, and in specific populations. The risk factors for severe measles include no or incomplete vaccination and vitamin A deficiency. Apart from secondary measles-related infections, severe measles is mainly represented by neurological, respiratory, and digestive symptoms. Strengthening the hypothesis that there is a link between vitamin A deficiency and severe measles in this paper we report the case of a 25-year-old unvaccinated man hospitalized for severe and complicated measles. The evolution was good after administration of intramuscular vitamin A as well as intravenous ribavirin. Measles remains a fatal and serious disease. The early use of ribavirin and vitamin A shows significant improvements regarding morbimortality and should be systematic in severe cases. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Successful treatment of HCV/HBV/HDV-coinfection with pegylated interferon and ribavirin

PubMed Central

Hartl, Janine; Ott, Claudia; Kirchner, Gabriele; Salzberger, Bernd; Wiest, Reiner

2012-01-01

Dual and triple infections with hepatitis virus C (HCV), B (HBV) and D (HDV) frequently lead to severe liver damage. Hereby we describe a 38-year-old Caucasian male coinfected with HCV (genotype 3a), HBV [positive hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core antigen; negative hepatitis B e antigen (HbeAg) and antibody to hepatitis B e antigen (anti-HBe)] and HDV. Laboratory diagnostics revealed increased liver enzymes and histological examination of the liver showed signs of fibrosis with moderate inflammation. On therapy with pegIFN-α2b and ribavirin HCV-RNA was undetectable at week 8. After week 24 the antiviral therapy was stopped because of a HBs-seroconversion, the loss of HbeAg and the detection of anti-HBe. Furthermore the HCV-RNA was negative. Six months after successful treatment of the triple-infection, HCV- and HDV-RNA and HbsAg remained negative and the liver enzymes had been completely normalized. In conclusion, pegylated-interferon plus ribavirin may be an effective therapy for HCV, HBV and HDV-coinfected patients. PMID:24765463

Case report: Ribavirin and vitamin A in a severe case of measles

PubMed Central

Bichon, Amandine; Aubry, Camille; Benarous, Lucas; Drouet, Hortense; Zandotti, Christine; Parola, Philippe; Lagier, Jean-Christophe

2017-01-01

Abstract Rationale: Despite a vaccine being widely available, measles continues to occur frequently, with sometimes lethal consequences. Patients concerns: The mortality rate reaches 35% and measles represents 44% of the 1.4 million deaths which are due to preventable diseases. Severe forms of measles are reported, mainly in young, unvaccinated adults, and in specific populations. The risk factors for severe measles include no or incomplete vaccination and vitamin A deficiency. Apart from secondary measles-related infections, severe measles is mainly represented by neurological, respiratory, and digestive symptoms. Diagnoses: Strengthening the hypothesis that there is a link between vitamin A deficiency and severe measles in this paper we report the case of a 25-year-old unvaccinated man hospitalized for severe and complicated measles. Outcomes: The evolution was good after administration of intramuscular vitamin A as well as intravenous ribavirin. Lessons: Measles remains a fatal and serious disease. The early use of ribavirin and vitamin A shows significant improvements regarding morbimortality and should be systematic in severe cases. PMID:29390321

Conformational changes induced in the eukaryotic translation initiation factor eIF4E by a clinically relevant inhibitor, ribavirin triphosphate

PubMed Central

Volpon, Laurent; Osborne, Michael J.; Zahreddine, Hiba; Romeo, Andrea A.; Borden, Katherine L.B.

2013-01-01

The eukaryotic translation initiation factor eIF4E is highly elevated in human cancers including acute myeloid leukemia (AML). A potential anticancer agent, ribavirin, targets eIF4E activity in AML patients corresponding to clinical responses. To date, ribavirin is the only direct inhibitor of eIF4E to reach clinical trials. We showed that ribavirin acts as a competitive inhibitor of the methyl 7-guanosine (m7G) cap, the natural ligand of eIF4E. Here we examine the conformational changes occurring in human eIF4E upon binding the active metabolite of ribavirin, ribavirin triphosphate (RTP). Our NMR data revealed an unexpected concentration dependence on RTP affinity for eIF4E. We observed NMR spectra characteristic of tight binding at low micromolar concentrations (2-5μM eIF4E) but much weaker affinity at more typical NMR concentrations (50-200μM). Comparison of chemical shift perturbation and line broadening suggest that the two eIF4E-RTP complexes differ in the precise positioning of RTP within the cap binding pocket, with the high affinity complex showing more extensive changes to the central β-sheet and dorsal surface of eIF4E, similar to m7G cap. The differences between high and low affinity complexes arise due to concentration dependent aggregation of eIF4E and RTP. Given the intracellular concentrations of eIF4E and RTP and the differential binding toward the W56A eIF4E mutant the high affinity complex is the most physiologically relevant. In summary, these findings demonstrate that RTP binds in the cap-binding site but also suggests new features of this pocket that should be considered in both drug design efforts and reveal new insights into ligand eIF4E recognition. PMID:23583375

Onset of Type 1 Diabetes Mellitus During Pegylated-interferon Alfa and Ribavirin Therapy for Chronic Hepatitis C Virus Infection

PubMed Central

Ranganathan, Raghini; Janarthanan, Krishnaveni; Rajasekaran, Senthilkumar

2012-01-01

A 16-year-old female was treated with pegylated-interferon (PEG-IFN) alfa (a)-2b and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection. She attained rapid virological response. She presented with diabetic ketoacidosis after 41 weeks of therapy. Anti-glutamic acid decarboxylase antibodies and islet cell antibodies were negative. Her fasting serum C-peptide level was <0.1 ng/mL, and the treatment course was completed. This case underlines the importance of periodic plasma glucose monitoring in patients during and after PEG-IFN and ribavirin therapy. PMID:25755410

Production of Brugmansia plants free of Colombian datura virus by in vitro ribavirin chemotherapy

USDA-ARS?s Scientific Manuscript database

Brugmansia x candida Pers ‘Creamsickle’ plants produced by in vitro treatment with ribavirin, and no thermal therapy, remained polymerase chain reaction (PCR-) negative for Columbian datura virus (CDV) after one year. The plants were produced by establishing B. x candida ‘Creamsickle’ shoot cultures...

Nonarteritic anterior ischemic optic neuropathy associated with interferon and ribavirin in a patient with hepatitis C.

PubMed

Sharif, Walid; Sheikh, Khayam; De Silva, Ian; Elsherbiny, Samer

2017-04-01

To report a case of a temporal artery biopsy negative anterior ischemic optic neuropathy associated with a recently completed course of pegylated interferon 2 α with ribavirin for chronic hepatitis C. Despite the early presentation with symptoms and prompt treatment with systemic intravenous steroids the patient experienced deterioration of their optic neuropathy over the following few days. Although nonarteritic anterior ischemic optic neuropathy is a common disorder with known risk factors, the timing of onset of symptoms in our patient was suggestive of a possible etiology related to treatment with ribavirin and interferon 2 α, as found in the previously reported cases. There have been a few reported cases of the association between the use of interferon/ribavirin for treatment of chronic hepatitis with nonarteritic anterior ischemic optic neuropathy. In these cases stopping the drug caused some improvement of symptoms or halting the progression of optic neuropathy. Having reviewed the literature on previous cases, we postulate that there may be a dose related reaction to explain the delay and deterioration of vision in some cases despite stopping the drugs. We also advise that any person who is started on this treatment for chronic hepatitis are appropriately counselled as to the potential optic nerve side effect of the drug, based on the evidence reported in the literature.

[Autoimmunity in children with chronic hepatitis C treated with interferon alpha and ribavirin].

PubMed

Gora-Gebka, Magdalena; Liberek, Anna; Bako, Wanda; Raczkowska-Kozak, Janina; Sikorska-Wisniewska, Grazyna; Korzon, Maria

2004-01-01

The role of interferon alpha or the virus itself in the pathogenesis and the risk of autoimmunological disorders in patients infected with HCV, still remain unknown, especially in children. The aim of the study was to evaluate the incidence of autoantibodies and the risk of autoimmunological disorders in children with chronic hepatitis C, treated with interferon alpha and ribavirin in the Department of Paediatrics, Paediatric Gastroenterology and Oncology in Gdansk. In the studied group of 12 patients, in 4 cases autoantibodies were present in low titers prior to the treatment and they had no prognostic value for the response to the therapy or the risk of autoimmunological disorders. Positive response for the treatment was achieved in 4 cases; in 3 cases indications for discontinuation of the therapy were established. During the therapy with interferon alpha and ribavirin, in 2 children elevation of serum titers of antibodies to liver-kidney microsome type 1 (anti-LKM1) (> 1:640) with normal gammaglobulin levels was noted. In none of the children autoimmunological disorders were observed.

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever.

PubMed

Raabe, Vanessa N; Kann, Gerrit; Ribner, Bruce S; Morales, Andres; Varkey, Jay B; Mehta, Aneesh K; Lyon, G Marshall; Vanairsdale, Sharon; Faber, Kelly; Becker, Stephan; Eickmann, Markus; Strecker, Thomas; Brown, Shelley; Patel, Ketan; De Leuw, Philipp; Schuettfort, Gundolf; Stephan, Christoph; Rabenau, Holger; Klena, John D; Rollin, Pierre E; McElroy, Anita; Ströher, Ute; Nichol, Stuart; Kraft, Colleen S; Wolf, Timo

2017-09-01

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection.

PubMed

Foster, Graham R; Pianko, Stephen; Brown, Ashley; Forton, Daniel; Nahass, Ronald G; George, Jacob; Barnes, Eleanor; Brainard, Diana M; Massetto, Benedetta; Lin, Ming; Han, Bin; McHutchison, John G; Subramanian, G Mani; Cooper, Curtis; Agarwal, Kosh

2015-11-01

We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection. The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n = 196); sofosbuvir and ribavirin for 24 weeks (n = 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n = 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients-48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naïve and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January 2015. Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12 weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events. Among patients with genotype 3 HCV infection, including a large proportion of treatment

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.

PubMed

Hézode, Christophe; Asselah, Tarik; Reddy, K Rajender; Hassanein, Tarek; Berenguer, Marina; Fleischer-Stepniewska, Katarzyna; Marcellin, Patrick; Hall, Coleen; Schnell, Gretja; Pilot-Matias, Tami; Mobashery, Niloufar; Redman, Rebecca; Vilchez, Regis A; Pol, Stanislas

2015-06-20

Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and

Inhibition of Hazara nairovirus replication by small interfering RNAs and their combination with ribavirin.

PubMed

Flusin, Olivier; Vigne, Solenne; Peyrefitte, Christophe N; Bouloy, Michèle; Crance, Jean-Marc; Iseni, Frédéric

2011-05-21

The genus Nairovirus in the family Bunyaviridae contains 34 tick-borne viruses classified into seven serogroups. Hazara virus (HAZV) belongs to the Crimean-Congo hemorrhagic fever (CCHF) serogroup that also includes CCHF virus (CCHFV) a major pathogen for humans. HAZV is an interesting model to study CCHFV due to a close serological and phylogenetical relationship and a classification which allows handling in a BSL2 laboratory. Nairoviruses are characterized by a tripartite negative-sense single stranded RNA genome (named L, M and S segments) that encode the RNA polymerase, the Gn-Gc glycoproteins and the nucleoprotein (NP), respectively. Currently, there are neither vaccines nor effective therapies for the treatment of any bunyavirus infection in humans. In this study we report, for the first time, the use of RNA interference (RNAi) as an approach to inhibit nairovirus replication. Chemically synthesized siRNAs were designed to target the mRNA produced by the three genomic segments. We first demonstrated that the siRNAs targeting the NP mRNA displayed a stronger antiviral effect than those complementary to the L and M transcripts in A549 cells. We further characterized the two most efficient siRNAs showing, that the induced inhibition is specific and associated with a decrease in NP synthesis during HAZV infection. Furthermore, both siRNAs depicted an antiviral activity when used before and after HAZV infection. We next showed that HAZV was sensitive to ribavirin which is also known to inhibit CCHFV. Finally, we demonstrated the additive or synergistic antiviral effect of siRNAs used in combination with ribavirin. Our study highlights the interest of using RNAi (alone or in combination with ribavirin) to treat nairovirus infection. This approach has to be considered for the development of future antiviral compounds targeting CCHFV, the most pathogenic nairovirus.

In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus.

PubMed

Carvalho, Otávio V; Saraiva, Giuliana L; Ferreira, Caroline G T; Felix, Daniele M; Fietto, Juliana L R; Bressan, Gustavo C; Almeida, Márcia R; Silva Júnior, Abelardo

2014-10-01

Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection.

Pharmacogenetics of ribavirin-induced anemia in hepatitis C.

PubMed

Ampuero, Javier; Romero-Gómez, Manuel

2016-09-01

Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever.

PubMed

Oestereich, Lisa; Rieger, Toni; Lüdtke, Anja; Ruibal, Paula; Wurr, Stephanie; Pallasch, Elisa; Bockholt, Sabrina; Krasemann, Susanne; Muñoz-Fontela, César; Günther, Stephan

2016-03-15

We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

[Effect of interferon and ribavirin combination therapy in sixty-two patients with chronic hepatitis C originating from a single blood donor].

PubMed

Liu, San-du; Cheng, Ming-liang; Ren, Hong; Yang, Qing-kun; Shu, De-yun

2012-08-01

To investigate the efficacy of interferon alpha 2 b plus ribavirin combination therapy in sixty-two patients with chronic hepatitis c (CHC) infection originating from a single blood donor. The 62 patients who developed CHC following blood transfusion from a known single infected donor were treated with interferon and ribavirin combination therapy for 48 weeks and followed-up for 96 weeks. The therapy regimen consisted of subcutaneous administration of 3-500 MIU interferon alpha 2 b every other day and daily oral administration of 0.6-1.0 g of ribavirin. Patients were monitored during treatment and in follow-up for sustained virological response (SVR), early virology response (EVR), treatment end virology response (ETVR), biochemical response of withdrawals, and side effects. The SVR rate was 83.9% (52/62). The EVR rate was 95.2% (59/62). The ETVR rate was 87.1% (54/62). The biochemical response rate after withdrawal of treatment was 100.0%. Eight patients developed mildly abnormal thyroid function as a result of the interferon therapy, but all were able to complete the antiviral treatment regimen under the care of endocrinologists. Younger age, relatively short course of disease, low viral load, and better compliance, but not sex, were correlated to curative effect of the combination therapy. Interferon alpha 2 b plus ribavirin combination therapy had a significant curative effect on a group of 62 CHC patients originating from a single case, with 52 of the patients showing SVR out to 96 weeks after therapy. Antiviral treatment is recommended for hepatitis C virus-positive patients to eradicate the virus and prevent disease progression.

Predicting early and sustained virological responses in prior nonresponders to pegylated interferon alpha-2b plus ribavirin retreated with peginterferon alpha-2a plus ribavirin and the benefit-risk ratio of retreatment.

PubMed

Marcellin, Patrick; Craxi, Antonio; Brandao-Mello, Carlos E; Di Bisceglie, Adrian M; Andreone, Pietro; Freilich, Bradley; Rajender Reddy, K; Olveira Martín, Antonio; Teuber, Gerlinde; Messinger, Diethelm; Hooper, Greg; Wat, Cynthia; Tatsch, Fernando; Jensen, Donald M

2013-10-01

To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa). In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR. We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population. In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR). cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured.

In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus

PubMed Central

Carvalho, Otávio V.; Saraiva, Giuliana L.; Ferreira, Caroline G.T.; Felix, Daniele M.; Fietto, Juliana L.R.; Bressan, Gustavo C.; Almeida, Márcia R.; Silva Júnior, Abelardo

2014-01-01

Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection. PMID:25355997

Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team.

PubMed

Aweeka, F T; Kang, M; Yu, J-Y; Lizak, P; Alston, B; Chung, R T

2007-07-01

Ribavirin (RBV) is used for the treatment of hepatitis C virus (HCV) infection in subjects with HIV-1 infection who may require antiretroviral treatment (ART) with nucleoside reverse transcriptase inhibitors including zidovudine (ZDV). We sought to investigate the potential antagonism between RBV and ZDV by evaluating the impact of RBV on the formation of intracellular ZDV triphosphate (TP) in HIV-infected patients receiving ZDV who were treated for HCV infection. Serial plasma and intracellular ZDV TP pharmacokinetics (PK) were determined in 14 subjects at entry (within 2 weeks prior to RBV administration) and at 8 weeks following initiation of RBV. Intracellular ZDV TP in peripheral blood mononuclear cells (PBMC) was quantified by a validated cartridge/liquid chromatography/tandem mass spectrometry method. PK exposure was estimated from the steady-state area under the concentration vs time curve (AUC(0-12 h)) in plasma and PBMC. Ribavirin did not have a statistically significant impact on ZDV TP AUC(0-12 h), plasma ZDV AUC(0-12 h) or the ratio of ZDV TP AUC(0-12 h) to plasma ZDV AUC(0-12 h), although there was a trend towards an increase post-RBV ratio compared with pre-RBV. There was extensive variability in the ZDV TP AUC(0-12 h). Ribavirin did not inhibit formation of ZDV TP in PBMC in 14 patients receiving ZDV as part of ART and RBV-based HCV therapy for 8 weeks. These results are consistent with those of a previously published limited study in seven subjects. These PK findings should be weighed carefully against emerging clinical reports of significant anaemia associated with combination ZDV and high-dose RBV therapy.

Treatment Response and Long-Term Outcome of Peginterferon α and Ribavirin Therapy in Korean Patients with Chronic Hepatitis C.

PubMed

Jung, Chang Ho; Um, Soon Ho; Kim, Tae Hyung; Yim, Sun Young; Suh, Sang Jun; Yim, Hyung Joon; Seo, Yeon Seok; Choi, Hyuk Soon; Chun, Hoon Jai

2016-09-15

Peginterferon plus ribavirin remains a standard therapy for patients with chronic hepatitis C (CHC) in Korea. We investigated the efficacy and long-term outcome of peginterferon and ribavirin therapy in Korean patients with CHC, particularly in relation to the stage of liver fibrosis. The incidence of sustained virological response (SVR), hepatic decompensation, hepatocellular carcinoma, and liver-related death was analyzed in 304 patients with CHC; the patients were followed up for a median of 54 months. Among patients with HCV genotype 1, the SVR rate was 36.7% (18/49) and 67% (69/103) for patients with and without cirrhosis, respectively (p<0.001). For patients with non-1 HCV genotypes, the SVR rates were 86.0% (37/43) in cirrhotic patients and 86.2% (94/109) in noncirrhotic patients. SVR significantly reduced the risk of liverrelated death, hepatic decompensation, and hepatocellular carcinoma, which had hazard ratios of 0.27, 0.16, and 0.22, respectively (all p<0.05). However, despite the SVR rate, patients with advanced fibrosis were still at risk of developing liver-related complications. A relatively high SVR rate was achieved by peginterferon plus ribavirin therapy in Korean patients with CHC, which improved their long-term outcomes. However, all CHC patients with advanced hepatic fibrosis should receive close follow-up observations, even after successful antiviral treatment.

Factors associated with early virological response to peginterferon-α-2a/ribavirin in chronic hepatitis C

PubMed Central

García-Samaniego, Javier; Romero, Miriam; Granados, Rafael; Alemán, Remedios; Jorge Juan, Miguel; Suárez, Dolores; Pérez, Ramón; Castellano, Gregorio; González-Portela, Carlos

2013-01-01

AIM: To evaluate the impact of sociodemographic/clinical factors on early virological response (EVR) to peginterferon/ribavirin for chronic hepatitis C (CHC) in clinical practice. METHODS: We conducted a multicenter, cross-sectional, observational study in Hepatology Units of 91 Spanish hospitals. CHC patients treated with peginterferon α-2a plus ribavirin were included. EVR was defined as undetectable hepatitis C virus (HCV)-ribonucleic acid (RNA) or ≥ 2 log HCV-RNA decrease after 12 wk of treatment. A bivariate analysis of sociodemographic and clinical variables associated with EVR was carried out. Independent factors associated with an EVR were analyzed using a multiple regression analysis that included the following baseline demographic and clinical variables: age (≤ 40 years vs > 40 years), gender, race, educational level, marital status and family status, weight, alcohol and tobacco consumption, source of HCV infection, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and gamma glutamyl transpeptidase (GGT) (≤ 85 IU/mL vs > 85 IU/mL), serum ferritin, serum HCV-RNA concentration (< 400 000 vs ≥ 400 000), genotype (1/4 vs 3/4), cirrhotic status and ribavirin dose (800/1000/1200 mg/d). RESULTS: A total of 1014 patients were included in the study. Mean age of the patients was 44.3 ± 9.8 years, 70% were male, and 97% were Caucasian. The main sources of HCV infection were intravenous drug abuse (25%) and blood transfusion (23%). Seventy-eight percent were infected with HCV genotype 1/4 (68% had genotype 1) and 22% with genotypes 2/3. The HCV-RNA level was > 400 000 IU/mL in 74% of patients. The mean ALT and AST levels were 88.4 ± 69.7 IU/mL and 73.9 ± 64.4 IU/mL, respectively, and mean GGT level was 82 ± 91.6 IU/mL. The mean ferritin level was 266 ± 284.8 μg/L. Only 6.2% of patients presented with cirrhosis. All patients received 180 mg of peginterferon α-2a. The most frequently used ribavirin doses were 1000 mg/d (41

Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.

PubMed

Lawitz, Eric; Sulkowski, Mark S; Ghalib, Reem; Rodriguez-Torres, Maribel; Younossi, Zobair M; Corregidor, Ana; DeJesus, Edwin; Pearlman, Brian; Rabinovitz, Mordechai; Gitlin, Norman; Lim, Joseph K; Pockros, Paul J; Scott, John D; Fevery, Bart; Lambrecht, Tom; Ouwerkerk-Mahadevan, Sivi; Callewaert, Katleen; Symonds, William T; Picchio, Gaston; Lindsay, Karen L; Beumont, Maria; Jacobson, Ira M

2014-11-15

Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. Combined simeprevir and sofosbuvir was efficacious and well tolerated. Janssen. Copyright © 2014 Elsevier Ltd. All rights reserved.

Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study.

PubMed

Mangia, Alessandra; Foster, Graham R; Berg, Christoph P; Curescu, Manuela; Ledinghen, Victor De; Habersetzer, François; Manolakopoulos, Spilios; Negri, Elisa; Papatheodoridis, George; Ahlers, Silke; Castillo, Marco; Bakalos, Georgios; Mauss, Stefan

2017-01-01

The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.

Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data

PubMed Central

Cammà, C; Bruno, S; Schepis, F; Lo Iacono, O; Andreone, P; Gramenzi, A G; Mangia, A; Andriulli, A; Puoti, M; Spadaro, A; Freni, M; Di Marco, V; Cino, L; Saracco, G; Chiesa, A; Crosignani, A; Caporaso, N; Morisco, F; Rumi, M G; Craxì, A

2002-01-01

Background and aims: Retreatment with a combination of α interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. Methods: To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000–1200 mg/daily depending on body weight) was given for 24–60 (mean 39.5) weeks. Results: Biochemical end of treatment and sustained responses were observed in 271/581 (46.6%; 95% confidence interval (CI) 42.6–50.7%) and in 109/581 (18.7%; 95% CI 15.6–22.0%) cases, respectively. Two hundred and six of 532 patients (38.7%; 95% CI 34.6–42.9%) had an end of treatment complete response to retreatment while a complete sustained response occurred in 88 of 559 (15.7%; 95% CI 12.8–18.8%). Fifty four of 581 patients (9.2%; 95% CI 7.0–11.7%) stopped retreatment due to adverse effects. By logistic regression, complete sustained response was predicted independently by age <45 years (p=0.04), by normal pretreatment γ-glutamyltransferase levels (p=0.01), and by a second course total IFN dose of at least 432 mega units (p=0.008). Conclusions: The overall low probability of effectiveness argues against indiscriminate retreatment of all IFN monotherapy non-responders with IFN/ribavirin. Patients less than 45 years old with normal γ-glutamyltransferase levels who were retreated with high dose long course combination therapy had a complete sustained response rate of 30%. PMID:12427791

Regression of esophageal varices and splenomegaly in two patients with hepatitis-C-related liver cirrhosis after interferon and ribavirin combination therapy.

PubMed

Lee, Soon Jae; Cho, Yoo-Kyung; Na, Soo-Young; Choi, Eun Kwang; Boo, Sun Jin; Jeong, Seung Uk; Song, Hyung Joo; Kim, Heung Up; Kim, Bong Soo; Song, Byung-Cheol

2016-09-01

Some recent studies have found regression of liver cirrhosis after antiviral therapy in patients with hepatitis C virus (HCV)-related liver cirrhosis, but there have been no reports of complete regression of esophageal varices after interferon/peg-interferon and ribavirin combination therapy. We describe two cases of complete regression of esophageal varices and splenomegaly after interferon-alpha and ribavirin combination therapy in patients with HCV-related liver cirrhosis. Esophageal varices and splenomegaly regressed after 3 and 8 years of sustained virologic responses in cases 1 and 2, respectively. To our knowledge, this is the first study demonstrating that complications of liver cirrhosis, such as esophageal varices and splenomegaly, can regress after antiviral therapy in patients with HCV-related liver cirrhosis.

Economic evaluation of pegylated interferon plus ribavirin for treatment of chronic hepatitis C in Thailand: genotype 1 and 6.

PubMed

Kapol, Nattiya; Lochid-Amnuay, Surasit; Teerawattananon, Yot

2016-08-05

Pegylated interferon alpha 2a, alpha 2b and ribavirin have been included to the National List of Essential Medicines (NLEM) for treatment of only chronic hepatitis C genotypes 2 and 3 in Thailand. This reimbursement policy has not covered for other genotypes of hepatitis C virus infection (HCV) especially for genotypes 1 and 6 that account for 30-50 % of all HCV infection in Thailand. Therefore, this research determined whether pegylated interferon alpha 2a or alpha 2b plus ribavirin is more cost-effective than a palliative care for treatment of HCV genotype 1 and 6 in Thailand. A cost-utility analysis using a model-based economic evaluation was conducted based on a societal perspective. A Markov model was developed to estimate costs and quality-adjusted life years (QALYs) comparing between the combination of pegylated interferon alpha 2a or alpha 2b and ribavirin with a usual palliative care for genotype 1 and 6 HCV patients. Health-state transition probabilities, virological responses, and utility values were obtained from published literatures. Direct medical and direct non-medical costs were included and retrieved from published articles and Thai Standard Cost List for Health Technology Assessment. The incremental cost-effectiveness ratio (ICER) was presented as costs in Thai baht per QALY gained. HCV treatment with pegylated interferon alpha 2a or alpha 2b plus ribavirin was dominant or cost-saving in Thailand compared to a palliative care. The ICER value was negative with lower in total costs (peg 2a- 747,718vs. peg 2b- 819,921 vs. palliative care- 1,169,121 Thai baht) and more in QALYs (peg 2a- 13.44 vs. peg 2b- 13.14 vs. palliative care- 11.63 years) both in HCV genotypes 1 and 6. As cost-saving results, the Subcommittee for Development of the NLEM decided to include both pegylated interferon alpha 2a and alpha 2b into the NLEM for treatment of HCV genotype 1 and 6 recently. Economic evaluation for these current drugs can be further applied to other novel

Incidence of retinopathy in chronic hepatitis C patients treated with pegylated interferon alpha 2a and ribavirin combination therapy.

PubMed

Kashif, Muhammad; Saleem, Muhammad Khurram; Farooka, Imran Khan; Husnain, Amina; Siddiqui, Arif Mahmood

2015-01-01

The objective of this study was to determine the incidence of retinopathy in chronic hepatitis C patients treated with Pegylated interferon alpha 2a and Ribavirin. This descriptive case series study was conducted in Medical Unit II of the Jinnah Hospital Lahore from September 2012 to February 2013. One hundred chronic hepatitis C patients visiting Medical Unit II outpatient department fulfilling inclusion criteria were selected for this study via non probability purposive sampling. Patients were started on pegylated interferon and ribavirin combination therapy. Subjects were subjected to dilated eye fundoscopic examination at the start of therapy and then after three months of the therapy. One hundred patients were included in this study. Out of these 100 patients 5% developed retinopathy whereas fundus examination was normal in rest of the patients. Interferon therapy can lead to retinopathy. Periodic fundoscopic examinations help in early detection and prevent progression to permanent visual loss.

Virologic response to treatment with Pegylated Interferon alfa-2b and Ribavirin for chronic hepatitis C in children.

PubMed

Pawłowska, Malgorzata; Pilarczyk, Malgorzata; Halota, Waldemar

2010-12-01

This study assessed the efficacy and safety of treatment of chronic hepatitis C in children with pegylated interferon alpha and ribavirin. Investigations were performed on 53 children with chronic hepatitis C, aged 8-17 years. Children were divided into 2 groups: naïve (n=29) and retreated (n=24). All children were administered a combined therapy with pegylated interferon (IFN) alpha-2b 1.5 mcg/kg/wk and ribavirin 15 mg/kg/d for 48 weeks. Mean baseline viral load was 0.456×10(6) IU/mL, mean alanine aminotransferase (ALT) activity was 45.8±24.3 IU/mL. No child had liver disease assessed greater than grade 2, stage 2 according to modified Scheuer scale. Serum hepatitis C virus (HCV) RNA in TW 12-EVR, TW 48-ETR, and W 72-sustained virologic response (SVR) with the polymerase chain reaction (PCR) method (Roche TaqMan) were evaluated. Sustained virologic response was achieved in 47% of children. The prevalence of relapses was 7.5%. The most important predictor of SVR in both groups was undetectable HCV RNA at TW 12. All retreated children who achieved partial EVR - (the HCV RNA level decreased more than 2 logs relative to baseline) were relapsers. In responders from both groups, baseline ALT activity was higher and baseline viral load was lower. In all children who achieved SVR, HCV RNA was undetectable 12 months later. Pegylated IFN and ribavirin are effective in treating chronic hepatitis C in children. Complete EVR is predictive of a sustained viral response. And high rate of relapses in retreated patients may suggest a longer duration of retherapy.

Sustained Virological Response after 8-Week Treatment of Simeprevir with Peginterferon α-2a plus Ribavirin in a Japanese Female with Hepatitis C Virus Genotype 1b and IL28B Minor Genotype

PubMed Central

Kanda, Tatsuo; Nakamura, Masato; Sasaki, Reina; Yasui, Shin; Nakamoto, Shingo; Haga, Yuki; Jiang, Xia; Wu, Shuang; Tawada, Akinobu; Arai, Makoto; Imazeki, Fumio; Yokosuka, Osamu

2015-01-01

Direct-acting antivirals with or without peginterferon α (PEG-IFN α) plus ribavirin are now available for the treatment of hepatitis C virus (HCV) infection. Direct-acting antivirals are potent inhibitors of HCV replication, but some of them occasionally possess serious adverse events. We experienced a 64-year-old female with chronic HCV genotype 1b infection who showed elevated alanine aminotransferase of 528 IU/l at week 9 after the commencement of treatment of simeprevir with PEG-IFN α-2a plus ribavirin. However, she achieved sustained virological response at week 24 after the end of treatment. In Japan, we also have to treat elderly patients infected with HCV and/or advanced hepatic fibrosis. Until an effective interferon-free regimen is established, direct-acting antivirals with PEG-IFN plus ribavirin may still play a role in the treatment for certain patients. To avoid serious results from adverse events, careful attention and follow-up will be needed in the treatment course of simeprevir with PEG-IFN plus ribavirin for chronic HCV infection. PMID:26269697

Incidence of retinopathy in chronic hepatitis C patients treated with pegylated interferon alpha 2a and ribavirin combination therapy

PubMed Central

Kashif, Muhammad; Saleem, Muhammad Khurram; Farooka, Imran Khan; Husnain, Amina; Siddiqui, Arif Mahmood

2015-01-01

Objectives: The objective of this study was to determine the incidence of retinopathy in chronic hepatitis C patients treated with Pegylated interferon alpha 2a and Ribavirin. Methods: This descriptive case series study was conducted in Medical Unit II of the Jinnah Hospital Lahore from September 2012 to February 2013. One hundred chronic hepatitis C patients visiting Medical Unit II outpatient department fulfilling inclusion criteria were selected for this study via non probability purposive sampling. Patients were started on pegylated interferon and ribavirin combination therapy. Subjects were subjected to dilated eye fundoscopic examination at the start of therapy and then after three months of the therapy. Results: One hundred patients were included in this study. Out of these 100 patients 5% developed retinopathy whereas fundus examination was normal in rest of the patients. Conclusion: Interferon therapy can lead to retinopathy. Periodic fundoscopic examinations help in early detection and prevent progression to permanent visual loss. PMID:25878638

Safety of Sofosbuvir and Ribavirin Combination Therapy in a Patient Who Developed Anemia due to Ribavirin.

PubMed

Suii, Hirokazu; Ozeki, Itaru; Tatsumi, Ryoji; Yamaguchi, Masakatsu; Kimura, Mutsuumi; Arakawa, Tomohiro; Nakajima, Tomoaki; Kuwata, Yasuaki; Ohmura, Takumi; Hige, Shuhei; Karino, Yoshiyasu; Toyota, Joji

2017-01-01

Interferon (IFN) and ribavirin (RBV) combination therapy was previously the standard of care for treatment of hepatitis C virus (HCV) genotype 2 infection. But, it often induced hemolytic anemia. In 2014, sofosbuvir (SOF) was approved for the treatment of chronic HCV genotype 2 in Japan. SOF/RBV therapy is more effective against genotype 2 than IFN/RBV therapy. We report a case of a 74-year-old woman with chronic HCV genotype 2b infection. She received five treatments including RBV and IFN therapy before SOF was approved and all of them were ineffective. Therapies that included RBV induced severe anemia and led to discontinuation of treatment. With pegylated IFN/RBV therapy, the maximum change in hemoglobin (Hb) from baseline was -3.7 g/dL. However, SOF/RBV therapy was effective and she achieved sustained virologic response (SVR) with a maximum change in Hb from baseline of only -1.2 g/dL. We also found reticulocyte count was very low during treatment in this case and speculate it was one of the reasons that she developed hemolytic anemia with RBV. In conclusion, SOF/RBV therapy is effective and allowed the patient to achieve SVR. An SOF/RBV regimen is safe and effective for patients who have or are at risk of anemia induced by RBV.

Safety of Sofosbuvir and Ribavirin Combination Therapy in a Patient Who Developed Anemia due to Ribavirin

PubMed Central

Ozeki, Itaru; Tatsumi, Ryoji; Yamaguchi, Masakatsu; Kimura, Mutsuumi; Arakawa, Tomohiro; Nakajima, Tomoaki; Kuwata, Yasuaki; Ohmura, Takumi; Hige, Shuhei; Karino, Yoshiyasu; Toyota, Joji

2017-01-01

Interferon (IFN) and ribavirin (RBV) combination therapy was previously the standard of care for treatment of hepatitis C virus (HCV) genotype 2 infection. But, it often induced hemolytic anemia. In 2014, sofosbuvir (SOF) was approved for the treatment of chronic HCV genotype 2 in Japan. SOF/RBV therapy is more effective against genotype 2 than IFN/RBV therapy. We report a case of a 74-year-old woman with chronic HCV genotype 2b infection. She received five treatments including RBV and IFN therapy before SOF was approved and all of them were ineffective. Therapies that included RBV induced severe anemia and led to discontinuation of treatment. With pegylated IFN/RBV therapy, the maximum change in hemoglobin (Hb) from baseline was −3.7 g/dL. However, SOF/RBV therapy was effective and she achieved sustained virologic response (SVR) with a maximum change in Hb from baseline of only −1.2 g/dL. We also found reticulocyte count was very low during treatment in this case and speculate it was one of the reasons that she developed hemolytic anemia with RBV. In conclusion, SOF/RBV therapy is effective and allowed the patient to achieve SVR. An SOF/RBV regimen is safe and effective for patients who have or are at risk of anemia induced by RBV. PMID:29375917

Determination of ribavirin in chicken muscle by quick, easy, cheap, effective, rugged and safe method and liquid chromatography-tandem mass spectrometry.

PubMed

Wu, Yin-Liang; Chen, Ruo-Xia; Zhu, Lie; Lv, Yan; Zhu, Yong; Zhao, Jian

2016-02-15

A new analytical method for the determination of ribavirin in chicken muscle using a QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method and liquid chromatography-tandem mass spectrometry (LC-MS-MS) was developed and validated. Samples were extracted with acidified methanol (methanol:acetic acid, 99:1, v/v). The extract was further purified by QuEChERS method using primary-secondary amine (PSA) and C18. Finally, the extract was dried by nitrogen under 45°C and reconstituted in water. The separation was performed on a Hypercarb analytical column under a gradient elution. The mobile phase was composed of water buffered with ammonium acetate (2.0mM) and acetonitrile. The proposed method was validated according to the European Commission Decision 2002/657/EC. The values of the decision limit (CCα) and the detection capability (CCβ) were 1.1 and 1.5μg/kg, respectively. The mean recoveries of ribavirin ranged from 94.2% to 99.2%. The repeatability (expressed as coefficient of variation, CVr) of the method ranged from 4.5% to 4.9% and the reproducibility (CVR) of the method ranged from 4.8% to 5.4%. The method is demonstrated to be suitable for the determination of ribavirin in chicken muscle in conformity with the current EU performance requirements through validation. The total time required for the analysis of one sample, including sample preparation, was about 45min. Copyright © 2016 Elsevier B.V. All rights reserved.

Addition of ribavirin to daclatasvir plus asunaprevir for chronic hepatitis C 1b patients with baseline NS5A resistance-associated variants improved response.

PubMed

Hong, Chun-Ming; Liu, Chun-Jen; Yeh, Shiou-Hwei; Chen, Pei-Jer

2017-04-01

Daclatasvir is a nonstructural protein 5A inhibitor with potent activity against hepatitis C virus genotypes 1-6 in vitro, and asunaprevir is a nonstructural protein 3 protease inhibitor with activity against genotypes 1, 4, 5, and 6. Despite a 90% sustained virologic response (SVR) rate, the SVR rate in patients with baseline NS5A-L31/Y93H polymorphisms decreased to around 40%. Therefore, an alternative regimen under the consideration of cost-effectiveness would be important. Whether the addition of ribavirin could improve the SVR rate among this group of patients remains unknown and hence our case series was reported. For six adult chronic hepatitis C 1b patients with a pre-existing NS5A-Y93H (>20%) polymorphism, we added ribavirin (800 mg/d) to daclatasvir/asunaprevir for 24 weeks and followed through 12-weeks post-treatment. Four of these patients received interferon/ribavirin treatment before but relapsed, while the other two were naïve cases. Two of them had liver cirrhosis and one had hepatocellular carcinoma postcurative therapy. The primary efficacy end-point was undetectable hepatitis C virus RNA (hepatitis C virus RNA level of<25 IU/mL) at 12 weeks after the end of the treatment (SVR12). In total, five cases reached SVR12 eventually (SVR rate: 83%; 95% confidence interval: 18.6-99.1%). However, the viral load of one remaining patient rebounded from the 24 th week of treatment. No patients developed significant adverse effects during and after the treatment. In genotype 1b chronic hepatitis C patients with NS5A-Y93H polymorphism, the addition of ribavirin to daclatasvir/asunaprevir may increase the SVR12 rate with minimal side effects, and thus deserves more comprehensive trials in resource-limited areas. Copyright © 2016. Published by Elsevier B.V.

Extended follow-up of anti-HBe-positive patients with chronic hepatitis B retreated with ribavirin and interferon-alpha.

PubMed

Carreño, V; Rico, M A; Pardo, M; Quiroga, J A

2001-11-01

In a pilot study of combination therapy with ribavirin and IFN alpha conducted in anti-HBe-positive individuals with chronic hepatitis B, 21% of patients achieved a sustained ALT normalization and clearance of hepatitis B virus (HBV) DNA as measured by PCR. The present work has assessed whether these sustained responses are lasting long-term. In addition, IFN gamma levels were tested serially in serum as a measure of the immune system activation during treatment. By extending the post-treatment follow-up period 2 years the occurrence of delayed HBV DNA relapses was observed. A low serum level of IFN gamma was detected during and after treatment. IFN gamma demonstrated a multiphasic time-course: the amount of IFN gamma increased in parallel with reductions in HBV DNA but also with ALT flare-ups. In conclusion, the extended follow-up study of anti-HBe-positive patients after combined treatment with ribavirin and IFN alpha has shown that sustained responses are lasting in 17% patients but also that a late onset HBV DNA relapse may occur.

Peripheral lymphocyte subsets in chronic hepatitis C: Effects of 12 weeks of antiviral treatment with interferon-alpha plus ribavirin.

PubMed

Oliveira, Isabela S; Carvalho, Lucas P; Schinoni, Maria Isabel; Paraná, Raymundo; Atta, Ajax M; Atta, Maria Luiza B Sousa

2016-02-01

Chronic infection with hepatitis C virus (HCV) causes a quantitative and functional alteration in innate and adaptative immunity. In the present work, we determined by flow-cytometry the profile of blood lymphocyte of untreated HCV patients and in subjects of this group that achieved or not an early virologic response at 12-weeks of treatment with interferon-α plus ribavirin. Twenty-six untreated HCV patients and 20 control healthy individuals were enrolled in the study. Untreated HCV patients had a higher proportion of B cell and a lower proportion of CD8(+) T cell and NK cells than healthy individuals did, but the proportions of CD4(+) T cells and Treg cells (CD4(+)CD25(+)Foxp3(+)) were similar in these patients and controls. Untreated HCV patients presenting cryoglobulinemia had a lower proportion of Treg cells and a lower Treg/NK cell ratio when compared with those without cryoglobulins. Nineteen out of 26 untreated HCV patients remained in the study and were treated with Interferon-α plus ribavirin. At 12-weeks of treatment, 10 of them achieved early virologic response (EVR), whereas 9 were non-responders (NR). EVR patients differed from NR patients in the increase of their proportion of NK cells at 12 weeks of treatment. In conclusion, untreated HCV patients exhibit an altered profile of blood lymphocyte subsets, including a reduction in the proportion of CD4(+)CD25(+)FoxP3(+)T regulatory cells in patients that present cryoglobulinemia. An early virological response at 12-weeks of treatment with IFN-α plus ribavirin seems to be associated a significant improvement in the proportion of NK cells of HCV treated patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative study to evaluate the anti-viral efficacy of Glycyrrhiza glabra extract and ribavirin against the Newcastle disease virus

PubMed Central

Omer, Muhammad Ovais; AlMalki, Waleed Hassan; Shahid, Imran; Khuram, Shahzada; Altaf, Imran; Imran, Saeed

2014-01-01

Background: The Newcastle disease represents as one of the most infectious viral disease, which afflicts almost every species of the birds. The causative agent of the disease is a single-stranded RNA virus with rapid replication capability. Objective: This study was performed to evaluate the comparative anti-viral efficacy and toxicity of Glycyrrhiza glabra aqueous extract and ribavirin against the Newcastle disease virus. Materials and Methods: The embryonated eggs were divided into six groups (A, B, C, D, E and F). Groups A, B, C, and D were further subdivided into three subgroups. The virus was identified by hemagglutination inhibition test. Spot hemagglutination test and viability of embryos were also evaluated. Three different concentrations i-e., 30 mg/100 ml, 60 mg/100 ml, and 120 mg/100 ml of the Glycyrrhiza aqueous extract and 10 μg/ml, 20 μg/ml, and 40 μg/ml ribavirin in deionized water were evaluated for their toxicity and anti-viral activity in the embryonated eggs. Results: 60 mg/100 ml concentration of Glycyrrhiza extract did not produce any toxicity in the embryonated eggs and showed anti-viral activity against the virus. Similarly, 20 μg/ml ribavirin was non-toxic in the embryonated eggs and contained anti-viral activity. Conclusion: It may conclude from the presented study that 60 mg/100 ml Glycyrrhiza extract inhibits replication of Newcastle disease virus and is non-toxic in the embryonated eggs. So, Glycyrrhiza glabra extract may be further evaluated in future to determine the potentially active compounds for their anti-viral activity against Newcastle disease virus. Furthermore, the mechanism of action of these active phytochemicals as an antiviral agent would be helpful to elucidate the pathogenesis of the disease. PMID:24497736

Ribavirin in Cancer Immunotherapies: Controlling Nitric Oxide Augments Cytotoxic Lymphocyte Function

PubMed Central

Kast, Richard E

2003-01-01

Abstract Either ribavirin (RBV) or cyclophosphamide (CY) can shift an immune response from Th2 toward a Th1 cytokine profile. CY is used in this role in various current cancer immunotherapy attempts but with mixed success. More potent and reliable immunoadjuvants and Th1 response biasing methods are needed. RBV is used today mainly to augment interferon-alpha treatment of hepatitis C. RBV shifts an immune response from Th2 toward Th1 more effectively than CY and may be a safe and useful adjuvant for current cancer immunotherapeutic efforts. RBV is thought to act by inhibition of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is an essential cofactor for all known isoforms of nitric oxide synthase. Lowered nitric oxide favors Th1 development as high levels favor Th2 weighting. PMID:12659664

A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients.

PubMed

Debing, Yannick; Gisa, Anett; Dallmeier, Kai; Pischke, Sven; Bremer, Birgit; Manns, Michael; Wedemeyer, Heiner; Suneetha, Pothakamuri Venkata; Neyts, Johan

2014-11-01

We analyzed blood samples collected from 15 patients with chronic hepatitis E who were recipients of solid-organ transplants. All patients cleared the hepatitis E virus (HEV) except for 2 (nonresponders); 1 patient died. A G1634R mutation in viral polymerase was detected in the HEV RNA of the nonresponders; this mutation did not provide the virus with resistance to ribavirin in vitro. However, the mutant form of a subgenomic replicon of genotype 3 HEV replicated more efficiently in vitro than HEV without this mutation, and the same was true for infectious virus, including in competition assays. Similar results were obtained for genotype 1 HEV. The G1634R mutation therefore appears to increase the replicative capacity of HEV in the human liver and hence reduce the efficacy of ribavirin. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C.

PubMed

Rodriguez-Torres, Maribel; Jeffers, Lennox J; Sheikh, Muhammad Y; Rossaro, Lorenzo; Ankoma-Sey, Victor; Hamzeh, Fayez M; Martin, Paul

2009-01-15

Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. Treatment with peginterferon alfa

Cost utility of telaprevir-PR (peginterferon-ribavirin) versus boceprevir-PR and versus PR alone in chronic hepatitis C in The Netherlands.

PubMed

Vellopoulou, Aikaterini; van Agthoven, Michel; van der Kolk, Annemarie; de Knegt, Robert J; Berdeaux, Gilles; Cure, Sandrine; Bianic, Florence; Lamotte, Mark

2014-12-01

The hepatitis C virus may lead to cirrhosis, liver cancer, liver transplant, and increased mortality. With standard treatment peginterferon-alpha and ribavirin (PR), sustained viral response (SVR) was less than 50 %. SVR rates improve greatly when PR is combined with telaprevir or boceprevir. The aim of this study was to assess the cost utility of telaprevir-peginterferon-ribavirin (TPR) versus PR and boceprevir-peginterferon-ribavirin (BPR) in treatment-naïve (TN) and treatment-experienced (TE) adults with chronic hepatitis C in the Netherlands. A Markov model with a lifelong time horizon and annual cycles was developed. Clinical data stemmed from phase III trials (TPR vs PR, BPR vs PR). A mixed treatment comparison (MTC) was developed to compare TPR and BPR indirectly. Unit costs and utilities based on EQ-5D were established in a Dutch cross-sectional study. Cost per quality-adjusted life-years (QALYs) was calculated according to the societal perspective. Treating TN patients with TPR generates 1.12 additional QALYs with €333 additional cost compared with PR, resulting in an incremental cost-utility ratio of €299/QALY. In TE patients, TPR dominates PR with cost savings (-€7,819) and 1.63 additional QALYs. TPR dominates BPR yielding additional QALYs (0.26 in TN; 0.71 in TE) and cost savings (-€7,296, -€18,144, respectively). TPR seems a cost-effective alternative to PR in TN patients and dominant in TE patients. TPR was a dominant, more effective and less costly alternative to BPR in both patient types. The cost effectiveness of both TPR and BPR is well below generally accepted willingness-to-pay thresholds and may be considered cost effective.

Effectiveness of Sofosbuvir and Ribavirin for Eradicating Hepatitis C Virus in Renal Transplant Recipients in Pakistan: Where Resources Are Scarce.

PubMed

Hanif, Farina Muhammad; Laeeq, S Mudassir; Mandhwani, Rajesh Kumar; Luck, Nasir Hassan; Aziz, Tahir; Mehdi, Syed Haider

2017-02-01

Although direct-acting antiviral agents have revolutionized hepatitis C virus treatment, these novel agents are not widely available in the developing world. Further, no treatment recommendation for renal transplant recipients includes these agents. We aimed to evaluate the effectiveness of sofosbuvir and ribavirin, the only direct-acting antiviral agents available in Pakistan, in renal transplant recipients. All renal transplant recipients receiving sofosbuvir and ribavirin from August 2015 to March 2016 were enrolled in the study. Patients' demographics and baseline laboratory parameters were collected. Rapid virologic response, early virologic response, end-of-treatment response, and sustained virologic response at 12 and 24 weeks were analyzed. Statistical analyses were performed using IBM SPSS Statistics software, version 20.0. Of the 37 renal transplant recipients, the mean age was 37.2 ± 10.7 years and the majority (33 [89.2% ]) were men. Twenty-five patients were treatment naive; of the remaining 12 patients, 10 were responders, 2 were nonresponders, and 5 were relapsers to pretransplant hepatitis C treatment. The genotype most commonly seen posttransplant was genotype 1 (56.8%). Rapid virologic response was achieved in 33 patients (89.2%). Early virologic response, end-oftreatment response, and sustained virologic response at 12 weeks were achieved in all 37 patients (100%). Until the time of data collection, 14 patients had achieved a sustained virologic response at 24 weeks. No complications were noted during therapy. In 2 of 4 patients who developed decompensated cirrhosis, treatment led to the resolution of ascites. Sofosbuvir and ribavirin are well tolerated and effective in renal transplant recipients for eradicating hepatitis C virus. Their effectiveness is not limited to renal transplant recipients with genotypes 1, 2, 3, and 4 but also extends to those with mixed genotype (in this study, genotypes 1 and 3).

Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities.

PubMed

Ho, Samuel B; Monto, Alexander; Peyton, Adam; Kaplan, David E; Byrne, Sean; Moon, Scott; Copans, Amanda; Rossaro, Lorenzo; Roy, Anupma; Le, Hadley; Dvory-Sobol, Hadas; Zhu, Yanni; Brainard, Diana M; Guyer, William; Shaikh, Obaid; Fuchs, Michael; Morgan, Timothy R

2017-02-01

We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. We performed a prospective study of treatment-naive (n = 47) and treatment-experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000-1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%-88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%-97%) and 36 were treatment naive (77%; 95% confidence interval, 62%-88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542. Copyright © 2017 AGA Institute. Published by Elsevier

Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life?

PubMed

Gonçales, Fernando L; Moma, Camila A; Vigani, Aline G; Angerami, Adriana F C F; Gonçales, Eduardo S L; Tozzo, Raquel; Pavan, Maria H P; Gonçales, Neiva S L

2010-07-20

More than 50% of hepatitis C viruses (HCV)-infected patients do not respond to the classical Interferon (IFN)/Ribavirin (RBV) combination therapy. The aim of this study was to evaluate the efficacy of retreatment with Peg-Interferon alpha-2b (PEG-IFN alpha-2b) plus RBV, in patients with HCV, genotypes 1 or 3, who were non-responders to the previous standard treatment with IFN/RBV. In the period 2005-2007, a total of 238 HCV chronic patients were non-responders to previous treatment with IFN plus RBV. Of these 130 agreed to be retreated with PEG-IFN alpha-2b and participated in this evaluation (90 with genotype 1 HCV and 40 with genotype 3 HCV). Patients were retreated at assisted IFN application hubs in compliance with the country's public health system rules. They received subcutaneous PEG-IFN alpha-2b, 1.5 microg, once weekly, associated with RBV, through the oral route, with doses determined according to weight (1,000 mg if weight 75 kg). Patients with genotype 1 HCV were retreated for over 48 weeks and patients with genotype 3 HCV for over 24 weeks. HCV-RNA was tested by polymerase chain reaction (PCR) at baseline, at week 12, at the end of the treatment, and 6 months thereafter. The predictiveness of week 12 in the development of a sustained virologic response (SVR) was also evaluated. Patients with negative HCV-RNA at week 12 were considered as early virologic responders (EVR). EVR was observed in 25% of the patients with genotype 1 HCV and in 64% of the patients genotype 3 HCV (risk = 2.075 and p-value = 0.0414). SVR was observed in 22.2% of the patients with genotype 1 HCV and in 40% with genotype 3 HCV (intention-to-treat analysis). The positive predictive value (PPV) of the HCV-RNA testing at week 12, in order to obtain the SVR, was 65% for genotype 1 and 56% for genotype 3, and the negative predictive value (NPV) was 88% for genotype 1 and 89% for genotype 3. PEG-IFN alpha-2b plus weight-based ribavirin is effective in re

Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life?

PubMed Central

2010-01-01

Background More than 50% of hepatitis C viruses (HCV)-infected patients do not respond to the classical Interferon (IFN)/Ribavirin (RBV) combination therapy. The aim of this study was to evaluate the efficacy of retreatment with Peg-Interferon alpha-2b (PEG-IFN alpha-2b) plus RBV, in patients with HCV, genotypes 1 or 3, who were non-responders to the previous standard treatment with IFN/RBV. Methods In the period 2005-2007, a total of 238 HCV chronic patients were non-responders to previous treatment with IFN plus RBV. Of these 130 agreed to be retreated with PEG-IFN alpha-2b and participated in this evaluation (90 with genotype 1 HCV and 40 with genotype 3 HCV). Patients were retreated at assisted IFN application hubs in compliance with the country's public health system rules. They received subcutaneous PEG-IFN alpha-2b, 1.5 μg, once weekly, associated with RBV, through the oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 kg and 1,250 mg if > 75 kg). Patients with genotype 1 HCV were retreated for over 48 weeks and patients with genotype 3 HCV for over 24 weeks. HCV-RNA was tested by polymerase chain reaction (PCR) at baseline, at week 12, at the end of the treatment, and 6 months thereafter. The predictiveness of week 12 in the development of a sustained virologic response (SVR) was also evaluated. Patients with negative HCV-RNA at week 12 were considered as early virologic responders (EVR). Results EVR was observed in 25% of the patients with genotype 1 HCV and in 64% of the patients genotype 3 HCV (risk = 2.075 and p-value = 0.0414). SVR was observed in 22.2% of the patients with genotype 1 HCV and in 40% with genotype 3 HCV (intention-to-treat analysis). The positive predictive value (PPV) of the HCV-RNA testing at week 12, in order to obtain the SVR, was 65% for genotype 1 and 56% for genotype 3, and the negative predictive value (NPV) was 88% for genotype 1 and 89% for genotype 3. Conclusions PEG-IFN alpha-2b plus weight

IL28B But Not ITPA Polymorphism Is Predictive of Response to Pegylated Interferon, Ribavirin, and Telaprevir Triple Therapy in Patients With Genotype 1 Hepatitis C

PubMed Central

Hayes, C. Nelson; Abe, Hiromi; Miki, Daiki; Ochi, Hidenori; Karino, Yoshiyasu; Toyota, Joji; Nakamura, Yusuke; Kamatani, Naoyuki; Sezaki, Hitomi; Kobayashi, Mariko; Akuta, Norio; Suzuki, Fumitaka; Kumada, Hiromitsu

2011-01-01

Background. Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. Methods. We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. Results. Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. Conclusions. Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy. PMID:21628662

Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment.

PubMed

Scharton, Dionna; Bailey, Kevin W; Vest, Zachary; Westover, Jonna B; Kumaki, Yohichi; Van Wettere, Arnaud; Furuta, Yousuke; Gowen, Brian B

2014-04-01

Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin. Copyright © 2014 Elsevier B.V. All rights reserved.

Early virologic response and IL28B polymorphisms in patients with chronic hepatitis C genotype 3 treated with peginterferon alfa-2a and ribavirin.

PubMed

Scherzer, Thomas-Matthias; Hofer, Harald; Staettermayer, Albert Friedrich; Rutter, Karoline; Beinhardt, Sandra; Steindl-Munda, Petra; Kerschner, Heidrun; Kessler, Harald H; Ferenci, Peter

2011-05-01

Polymorphisms of the IL28B gene (rs12979860 and rs8099917) are associated with high sustained virological response (SVR) rates in HCV genotype 1 patients. This study analyzes the impact of these IL28B polymorphisms on early treatment response (weeks 2 and 4) and SVR in HCV genotype 3 patients. rs12979860 and rs8099917 were analyzed by the Step-OnePlus Real-time PCR system in 71 out of 72 Caucasian HCV genotype 3 patients participating, at our center, in a randomized study comparing 400mg with 800 mg ribavirin/day. HCV RNA was determined at weeks 2 and 4 of 180 μg/week peginterferon alfa-2a/ribavirin treatment. Sixty-nine patients completed the treatment and follow-up. rs12979860 genotyping revealed that 27 (37.5%) patients had C/C, 39 (54.2%) T/C, and 5 (6.9%) T/T. Thirteen patients (18.1%) became HCV RNA negative at week 2 and an additional 30 (41.7%) at week 4 (rapid virologic response; RVR); thus a total of 43 had a RVR (C/C: 77.8%; T/C or T/T: 50.0%). Irrespective of the ribavirin dose, the viral load decline was larger than in those with the T allele (T/C or T/T) (week 2: 4.46; [0.36-6.02] median; [range] vs. 3.50; [0.14-5.62]; log IU HCV-RNA/ml; p<0.001; week 4: 4.97; [1.21-6.20] vs. 4.49; [1.16-6.23]; p=0.003). Despite the faster initial viral response in C/C carriers, SVR rates were not different compared to T-allele carriers. Results of the SNP in the rs8099917 region were similar. IL28B polymorphisms modulate early virologic response to peginterferon/ribavirin treatment. In contrast to HCV genotype 1 patients, no effect on SVR rates was observed in genotype 3 patients. The clinical relevance of an earlier viral decline in C/C patients needs to be determined. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study.

PubMed

Petta, Salvatore; Marzioni, Marco; Russo, Pierluigi; Aghemo, Alessio; Alberti, Alfredo; Ascione, Antonio; Antinori, Andrea; Bruno, Raffaele; Bruno, Savino; Chirianni, Antonio; Gaeta, Giovanni Battista; Giannini, Edoardo G; Merli, Manuela; Messina, Vincenzo; Montilla, Simona; Perno, Carlo Federico; Puoti, Massimo; Raimondo, Giovanni; Rendina, Maria; Silberstein, Francesca Ceccherini; Villa, Erica; Zignego, Anna Linda; Pani, Luca; Craxì, Antonio

2017-06-01

We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83-12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Our findings

Cost-effectiveness analysis of adding low dose ribavirin to peginterferon alfa-2a for treatment of chronic hepatitis C infected thalassemia major patients in iran.

PubMed

Mehrazmay, Alireza; Alavian, Seyed Moayed; Moradi-Lakeh, Maziar; Mokhtari Payam, Mahdi; Hashemi-Meshkini, Amir; Behnava, Bita; Miri, Seyyed Mohammad; Karimi Elizee, Pegah; Tabatabaee, Seyed Vahid; Keshvari, Maryam; Bagheri Lankarani, Kamran

2013-01-01

The prevalence of hepatitis C in Iran is 1% and 18% in general population and thalassemia patients respectively. The cost effectiveness analysis of adding Ribavirin to Peginterferon alfa-2a (PEG IFN alfa-2a) as a combination treatment strategy of chronic hepatitis C in thalassemia patients in comparison with monotherapy could help clinicians and policy makers to provide the best treatment for the patients. In this study we aimed to assess whether adding Ribavirin to PEG IFN alfa-2a is a cost effective strategy in different genotypes and different subgroups of 280 patients with chronic hepatitis C infection from the perspective of society in Iranian setting. A cost effectiveness analysis including all costs and outcomes of treatments for chronic hepatitis C infected thalassemia major patients was conducted. We constructed a decision tree of treatment course in which a hypothetical cohort of 100 patients received "PEG IFN alfa-2a" or "Peg IFN alfa-2a plus Ribavirin." The cost analysis was based on cost data for 2008 and we used 9300 Iranian Rials (IR Rial) as exchange rate declared by the Iranian Central Bank on that time to calculating costs by US Dollar (USD). To evaluate whether a strategy is cost effective, one time and three times of GDP per capita were used as threshold based on recommendation of the World Health Organization. The Incremental Cost Effectiveness Ratio (ICER) for combination therapy in genotype-1 and genotypes non-1 subgroups was 2,673 and 19,211 US dollars (USD) per one Sustain Virological Response (SVR), respectively. In low viral load and high viral load subgroups, the ICER was 5,233 and 14,976 USD per SVR, respectively. The calculated ICER for combination therapy in subgroup of patients with previously resistant to monotherapy was 13,006 USD per SVR. Combination therapy in previously resistant patients to combination therapy was a dominant strategy. Adding low dose of Ribavirin to PEG IFN alfa-2a for treatment of chronic hepatitis C patients

Combined pegylated interferon and ribavirin for the management of chronic hepatitis C in a prison setting.

PubMed

Sabbatani, Sergio; Giuliani, Ruggero; Manfredi, Roberto

2006-08-01

The elevated frequency of chronic hepatitis C virus (HCV) infection found among prison inmates, and the availability of improved pharmacological cure for this potentially life-threatening disorder, make investigations conducted in this somewhat neglected area very relevant, since only a few, open-label experiences have been reported till now. In the metropolitan prison of Bologna (Italy), HCV seroprevalence was found to be over 31% in 2003, so that a pilot feasibility study based on treatment with pegylated interferon plus ribavirin was initiated, after careful counseling carried out by a joint commission of health care personnel of the correctional facility and infectious diseases consultants. Thirty-nine patients were enrolled, and despite expected dropouts due to difficulty in maintaining the same level of counseling pressure over time, and the particularly unfavorable climatic conditions during Summer 2003, a sustained virological response was obtained for 8 out of the 21 patients who remained evaluable after the first three month follow-up, although we need to take into account that a high percentage of subjects (67%) were selected for therapy due to their favorable HCV genotypes (types 2 and 3). Our preliminary experience shows that an intrinsically complicated therapy, such as the administration of pegylated interferon plus ribavirin, can attain a relatively high success rate, even in a very unfavorable and uncomfortable context, such as a prison, where only enforced counseling, active participation of institutional health care operators, and patient's willingness to maintain an elevated level of co-operation and adherence, can overcome most structural and relational difficulties.

Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial.

PubMed

Shiffman, Mitchell L; Cheinquer, Hugo; Berg, Christoph P; Berg, Thomas; de Figueiredo-Mendes, Cláudio; Dore, Gregory J; Ferraz, Maria Lúcia; Mendes-Corrêa, Maria Cássia; Lima, Maria Patelli; Parise, Edison R; Rios, Alma Minerva Perez; Reuter, Tania; Sanyal, Arun J; Shafran, Stephen D; Hohmann, Marc; Tatsch, Fernando; Bakalos, George; Zeuzem, Stefan

2014-10-01

The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR). N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR. Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %). It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than anticipated, and this may have limited the statistical impact of these findings.

Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection

PubMed Central

Ahmed, Ossama A; Elsebaey, Mohamed A; Fouad, Mohamed Hassan A; Elashry, Heba; Elshafie, Ahmed I; Elhadidy, Ahmed A; Esheba, Noha E; Elnaggar, Mohammed H; Soliman, Shaimaa; Abd-Elsalam, Sherief

2018-01-01

Background and aims Treatment of hepatitis C virus (HCV) changed dramatically with the introduction of oral direct-acting antiviral drugs due to their high antiviral potency and safety profile. Sofosbuvir plus daclatasvir combination therapy was extensively investigated in HCV genotypes 1, 2, and 3, while published data regarding its real-life application in the treatment of genotype 4 is lacking. Therefore, we conducted this study to assess the outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Patients and methods This prospective study included 300 Egyptian patients with chronic genotype 4 HCV, treated with sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks. Primary outcome was the number of patients who achieved sustained virologic response (SVR12), and secondary outcome was the occurrence of adverse events. Results A total of 92.67% of all patients achieved SVR12. SVR12 rates of 96.55% and 84.54% were reported in non-cirrhotic and cirrhotic patients, respectively. SVR12 in treatment-naïve and treatment-experienced patients were 94.12% and 87.01%, respectively. A total of 19.7% of patients experienced mild adverse events. Older age, cirrhosis, and low platelet count were the predictors of treatment non-response. Conclusion Based on this multi-center prospective study, sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks appears to have favorable outcomes in the treatment of genotype 4 HCV-infected Egyptian patients. Older age, cirrhosis, especially Child–Pugh class B, and low platelet count are independent risk factors of treatment non-response. PMID:29628768

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia.

PubMed

Isakov, Vasily; Nikitin, Igor; Chulanov, Vladimir; Ogurtsov, Pavel; Lukyanova, Ekaterina; Long, Jianmin; Wahl, Janice; Helmond, Frans A

2016-02-28

To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). Regulatory

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia

PubMed Central

Isakov, Vasily; Nikitin, Igor; Chulanov, Vladimir; Ogurtsov, Pavel; Lukyanova, Ekaterina; Long, Jianmin; Wahl, Janice; Helmond, Frans A

2016-01-01

AIM: To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). METHODS: Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77

[Bilateral non-arteritic ischemic optic neuropathy during treatment of viral hepatitis C with pegylated interferon and Ribavirin].

PubMed

Iferkhass, S; Elasri, F; Chatioui, S; Khoyaali, A; Bargach, T; Reda, K; Oubaaz, A

2015-01-01

Hepatitis C is a serious viral infection, for which the current treatment is based on the combination of pegylated interferon (IFN) and Ribavirin(®). Ophthalmic complications observed with PEG-IFN are infrequent and of variable prognosis. They often include an ischemic retinopathy with typical cotton-wool spots, hemorrhage and retinal edema, and rarely acute non-arteritic anterior ischemic optic neuropathy as illustrated by our report. We report the case of a 51-year-old man followed for chronic active hepatitis C, who presented in the fourth month of treatment with pegylated interferon and vidarabine with a sharp decline in visual acuity secondary to acute bilateral non-arteritic anterior ischemic optic neuropathy. The hepatitis C treatment was discontinued. His course was notable by the third week for a significant regression of papilledema with improvement in visual acuity in the right eye and no change in the left eye, remaining at counting fingers. After regressing for four years, the disease progressed to bilateral temporal optic atrophy without change in visual acuity. Pegylated interferon and Ribavirin(®) are commonly used in the treatment of chronic hepatitis C. They are the source of various ophthalmologic complications of varied severity. The pathophysiology of this ocular toxicity currently remains hypothetical. Non-arteritic ischemic optic neuropathy is still a relatively rare complication with a poor functional prognosis, often requiring discontinuation of treatment. Thus, careful ophthalmologic monitoring before and during antiviral treatment of patients with hepatitis C appears necessary. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for treatment of recurrent chronic hepatitis C genotype 1 infection after liver transplantation: Real-world experience.

PubMed

Yu, Ming-Lung; Chen, Yao-Li; Huang, Chung-Feng; Lin, Kuo-Hua; Yeh, Ming-Lun; Huang, Ching-I; Hsieh, Meng-Hsuan; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Dai, Chia-Yen; Chuang, Wan-Long

2018-06-01

The registered trial has demonstrated that paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) with ribavirin was effective for recurrent hepatitis C virus genotype 1 (HCV-1) infection after liver transplantation in patients with mild fibrosis; however, the real-world efficacy and safety of this regimen have not been determined. The efficacy (sustained virological response, SVR12, undetectable HCV RNA 12 weeks post-treatment) and safety were evaluated in 12 patients with recurrent HCV-1 infection after liver transplantation. Nine patients were treated for 24 weeks, and three patients (two treatment-naïve patients and one interferon-intolerant patient) were treated for 12 weeks. HCV RNA was undetectable at treatment day 1, week 1, week 4, week 12, and at the end of treatment in 8.3% (n = 1), 25% (n = 3), 83.3% (n = 10), 100% (n = 12), and 100% (n = 12) of patients, respectively. All twelve patients achieved SVR12. Treatment was temporarily stopped in one patient because of leucopenia. The other patient with minimal fibrosis experienced an elevation in alanine aminotransferase concentration, which returned to normal levels after dose reduction. Seven (58.3%) patients required RBV dose reduction and two (16.7%) required transient RBV discontinuation during treatment. There were no serious adverse events, and most adverse events were related to ribavirin. No patient developed graft rejection or deterioration in hepatic or renal function during treatment. Treatment efficacy and safety were comparable between patients with and without advanced liver fibrosis. PrOD plus ribavirin had a highly satisfactory real-world efficacy and safety profile in the treatment of recurrent HCV-1 infection after liver transplantation in Asian patients. Copyright © 2017. Published by Elsevier B.V.

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin

PubMed Central

Danilovic, Debora Lucia Seguro; Mendes-Correa, Maria Cassia; Chammas, Maria Cristina; Zambrini, Heverton; Marui, Suemi

2011-01-01

OBJECTIVE: To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C. INTRODUCTION: Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis. METHODS: We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy. RESULTS: Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH) levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns. DISCUSSION: Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis. CONCLUSION: Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels), which occur despite stable free T4 and TSH levels. A thyroid hormonal evaluation

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin.

PubMed

Danilovic, Debora Lucia Seguro; Mendes-Correa, Maria Cassia; Chammas, Maria Cristina; Zambrini, Heverton; Marui, Suemi

2011-01-01

To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C. Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis. We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy. Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH) levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns. Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis. Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels), which occur despite stable free T4 and TSH levels. A thyroid hormonal evaluation, including the analysis of the free T4, TSH, and antithyroid

Financial impact of two different ways of evaluating early virological response to peginterferon-alpha-2b plus ribavirin therapy in treatment-naive patients with chronic hepatitis C virus genotype 1.

PubMed

Buti, Maria; Casado, Miguel A; Fosbrook, Leslie; Esteban, Rafael

2005-01-01

Patients infected with chronic hepatitis C virus (HCV) genotype 1 are the least responsive to peginterferon (pegIFN) and ribavirin therapy. The monitoring of early virological response (EVR) is therefore an important tool for quickly identifying non-responders, permitting therapy discontinuation and avoiding adverse effects and costs. To analyse the financial impact, in treatment-naive patients infected with HCV genotype 1, of two different measurement techniques for evaluating the EVR during pegIFN-alpha-2b plus ribavirin therapy, and to compare the results of a 48-week standard course of therapy with pegIFN-alpha-2b plus ribavirin without measuring EVR. A budget impact model was constructed using a decision-tree analysis. EVR was defined as a >2 log decline in HCV RNA levels at week 12 either tested with two quantitative HCV RNA tests or undetectable HCV core antigen (HCV core Ag) protein levels at week 12 (one HCV core Ag test). Clinical data were taken from multicentre trials and costs from the published literature (euro, 2003 values). The analysis was carried out from the perspective of the Spanish healthcare system and therefore only direct costs were considered. The base-case scenario assumed that a potential study population of 18,504 people in Spain with chronic HCV genotype 1 would be eligible for treatment with pegIFN-alpha-2b plus ribavirin. In the base case, the most effective strategy was testing EVR by HCV core Ag. This resulted in 12,745 patients reaching a sustained virological response (SVR) at an overall cost of 243.98 million euro (19,142 euro per SVR). Conversely, quantitative HCV RNA testing resulted in 11,776 patients with an SVR at a cost of 232.73 million euro ( 19,763 euro per SVR). The incremental cost per successfully treated patient with HCV core Ag testing versus quantitative HCV RNA testing was 11,597 euro. One-way sensitivity analyses demonstrated that changes in the study parameters did not modify the outcomes, except when

Combined etiology for bilateral and simultaneous optic neuropathy in a patient with ciancobalamin deficit and hepatitis C treated with peg-interferon and ribavirin.

PubMed

Pantalon, Anca Delia; Danielescu, Ciprian; Chiseliță, Dorin

2016-01-01

We report the case of a 53-year-old female patient who developed bilateral sudden visual acuity loss after 15 weeks from the initiation of Peg-Interferon and Ribavirin treatment for hepatitis C. Debut was simultaneous and asymmetric, reported in the morning, at awakening. No pain or other symptom was reported by the patient. Results. At presentation, visual acuity was 0.2 in RE and 3/ 50 in LE. Pupillary reflexes were sluggish and severe dyschromatopsia was documented in both eyes (Ishihara plates). Fundus examination revealed bilateral pale optic disc edema, more prominent in LE, with splinter hemorrhages in the RNFL around the optic disk. Visual field exam demonstrated severe defects in 3 quadrants of the RE, whereas in the LE, it was impossible to perform the investigation due to VA<0.1. Neurologic evaluation was normal; other possible causes of systemic vasculitis were excluded by negative lab tests. Acute inflammatory markers (fibrinogen and ESR) and mild pancytopenia were the only documented laboratory changes in this patient. Anamnesis cleared the traditional risk factors for conventional AION (hypertension, diabetes, ischemic heart disease, and hypercholesterolemia). Cranial and orbital CT scan and MRI findings were normal. Patient was withdrawn from the Interferon and Ribavirin treatment and was administered methyl prednisolone pulse therapy (1g/ day) for 3 days, continued with oral Prednisone (60 mg/ day) tapered slowly for over 12 weeks. VA increased to 0.8 during treatment in the RE, but visual recovery in the LE was not as spectacular (0.16) as in the fellow eye. Modified latencies and amplitudes in evoked visual potentials examination during 4 months time emphasized bilateral optic atrophy. Optic nerve sufferance was amplified by a low level of vitamin B12, detected by chance at the last eye visit. Due to the general condition, dietary supplementation was not possible. Conclusion. A case of a patient with bilateral and simultaneous NAION caused by IFN

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

PubMed

Manns, Michael; Marcellin, Patrick; Poordad, Fred; de Araujo, Evaldo Stanislau Affonso; Buti, Maria; Horsmans, Yves; Janczewska, Ewa; Villamil, Federico; Scott, Jane; Peeters, Monika; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; De La Rosa, Guy; Kalmeijer, Ronald; Sinha, Rekha; Beumont-Mauviel, Maria

2014-08-02

Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. 209 (81%) of 257 patients in the simeprevir group and

HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin

PubMed Central

Amador-Cañizares, Yalena; Martínez-Donato, Gillian; Álvarez-Lajonchere, Liz; Vasallo, Claudia; Dausá, Mariacarla; Aguilar-Noriega, Daylen; Valenzuela, Carmen; Raíces, Ivette; Dubuisson, Jean; Wychowski, Czeslaw; Cinza-Estévez, Zurina; Castellanos, Marlén; Núñez, Magdalys; Armas, Anny; González, Yaimé; Revé, Ismariley; Guerra, Ivis; Pérez Aguiar, Ángel; Dueñas-Carrera, Santiago

2014-01-01

AIM: To analyze hepatitis C virus (HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α (IFN-α) plus ribavirin and CIGB-230. METHODS: CIGB-230 was administered in different schedules with respect to IFN-α plus ribavirin therapy. Paired serum and peripheral blood mononuclear cells (PBMC) samples from baseline and end of treatment were analyzed. The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay, neutralizing antibodies were evaluated by cell culture HCV neutralization assays, PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γ secretion was assessed by enzyme-linked immunospot. Data on virological and histological response and their association with immune variables are also provided. RESULTS: From week 12 to week 48, all groups of patients showed a significant reduction in mean leukocyte counts. Statistically significant reductions in antibody titers were frequent, but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response, and the neutralizing antibody response was enhanced only in patients receiving CIGB-230. Cell-mediated immune responses also tended to decline, but significant reductions in IFN-γ secretion and total absence of core-specific lymphoproliferation were exclusive of the control group. Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens. Importantly, it was demonstrated that the quality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy. Specifically, the administration of 6 doses of CIGB-230 as late add-on to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γ secretion, both of which were associated with the sustained virological response. CONCLUSION: CIGB-230, combined with IFN

Successful Management of Graft Reinfection of HCV Genotype 2 in Living Donor Liver Transplantation from a Hepatitis B Core Antibody-Positive Donor with Sofosbuvir and Ribavirin

PubMed Central

Sasaki, Reina; Kanda, Tatsuo; Ohtsuka, Masayuki; Yasui, Shin; Haga, Yuki; Nakamura, Masato; Yokoyama, Masayuki; Wu, Shuang; Nakamoto, Shingo; Arai, Makoto; Maruyama, Hitoshi; Miyazaki, Masaru; Yokosuka, Osamu

2016-01-01

Direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of hepatitis C virus (HCV) in liver transplant recipients. In this case study, we present a female with a graft reinfected with HCV genotype 2 who was treated with a combination of sofosbuvir and ribavirin after living donor liver transplantation (LDLT). Because the graft was from a hepatitis B core antibody-positive donor, passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) and entecavir were also provided to prevent hepatitis B virus (HBV) reactivation. It became clear that the combination of sofosbuvir and ribavirin promptly led to a sustained virologic response and that this combination was safe to treat graft reinfection with HCV genotype 2 after LDLT. Adverse events caused by DAAs were not observed, except for slight anemia. HBIG and entecavir were useful in the prevention of HBV reactivation. In conclusion, the present case indicated that DAA treatment for graft reinfection with HCV is safe and effective in LDLT from hepatitis B core antibody-positive donors. PMID:27721720

Outcome of retinopathy in chronic hepatitis C patients treated with peginterferon and ribavirin.

PubMed

Mehta, Nilesh; Murthy, Uma K; Kaul, Vivek; Alpert, Samuel; Abruzzese, Gerald; Teitelbaum, Charles

2010-02-01

The purpose of this study is to evaluate the incidence and outcome of retinopathy in chronic hepatitis C patients treated with peginterferon and ribavirin. A total of 74 hepatitis C patients with baseline eye exams and eye exams during therapy were included. Retinopathy was defined as development of cotton wool spots and/or intra-retinal hemorrhage. Demographics, hepatitis C viral characteristics, treatment and laboratory data, and eye exam findings were compared in groups with and without retinopathy. Retinopathy developed in 28 (38%), early in therapy. Pre-treatment eye exams did not predict risk of retinopathy. Therapy was continued in all but one; cotton wool spots resolved in 24 of 26. All nine patients with intra-retinal hemorrhage had resolution. No patient had retinopathy-related visual deterioration. Retinopathy is common with peginterferon therapy, but the outcome is favorable. Cessation of therapy for retinopathy is not warranted. Severe visual disturbances and scotomas deserve further evaluation.

Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.

PubMed

DʼAvolio, Antonio; Ciancio, Alessia; Siccardi, Marco; Smedile, Antonina; Baietto, Lorena; Simiele, Marco; Marucco, Diego Aguilar; Cariti, Giuseppe; Calcagno, Andrea; de Requena, Daniel Gonzalez; Sciandra, Mauro; Cusato, Jessica; Troshina, Giulia; Bonora, Stefano; Rizzetto, Mario; Di Perri, Giovanni

2012-04-01

Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 μg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 μg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

Increased duration of dual pegylated interferon and ribavirin therapy for genotype 1 hepatitis C post-liver transplantation increases sustained virologic response: a retrospective review.

PubMed

Wells, Malcolm M; Roth, Lee S; Marotta, Paul; Levstik, Mark; Mason, Andrew L; Bain, Vincent G; Chandok, Natasha; Aljudaibi, Bandar M

2013-01-01

In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence. A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed. A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 ± 0.88 vs. 1.89 ± 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 ± 230 vs. 856 ± 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 ± 13.4 weeks vs. 40.2 ± 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years' post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007). This study identified factors that predict SVR in HCV-positive patients who received dual therapy post-transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one.

Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis.

PubMed

Zeuzem, Stefan; Soriano, Vicente; Asselah, Tarik; Gane, Edward J; Bronowicki, Jean-Pierre; Angus, Peter; Lohse, Ansgar W; Stickel, Felix; Müllhaupt, Beat; Roberts, Stuart; Schuchmann, Marcus; Manns, Michael; Bourlière, Marc; Buti, Maria; Stern, Jerry O; Gallivan, John-Paul; Voss, Florian; Sabo, John P; Böcher, Wulf; Mensa, Federico J

2015-02-01

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.). Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Efficacy and Safety of Faldaprevir, Deleobuvir, and Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Infection and Advanced Liver Fibrosis or Cirrhosis

PubMed Central

Soriano, Vicente; Asselah, Tarik; Gane, Edward J.; Bronowicki, Jean-Pierre; Angus, Peter; Lohse, Ansgar W.; Stickel, Felix; Müllhaupt, Beat; Roberts, Stuart; Schuchmann, Marcus; Manns, Michael; Bourlière, Marc; Buti, Maria; Stern, Jerry O.; Gallivan, John-Paul; Voss, Florian; Sabo, John P.; Böcher, Wulf; Mensa, Federico J.

2014-01-01

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n = 362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.) PMID:25512403

Ledipasvir-Sofosbuvir Plus Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 3 Infection: An Open-Label Study.

PubMed

Feld, Jordan J; Ramji, Alnoor; Shafran, Stephen D; Willems, Bernard; Marotta, Paul; Huchet, Emmanuelle; Vachon, Marie-Louise; Svarovskaia, Evguenia S; Huang, K C; Hyland, Robert H; Yun, Chohee; Massetto, Benedetta; Brainard, Diana M; McHutchison, John G; Tam, Edward; Bailey, Robert; Cooper, Curtis; Yoshida, Eric M; Greenbloom, Susan; Elkhashab, Magdy; Borgia, Sergio; Swain, Mark G

2017-07-01

Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. NCT02413593. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-α-2b and Ribavirin Reduces Sleep Disturbance

PubMed Central

Pennisi, Manuela; Bertino, Gaetano; Gagliano, Caterina; Malaguarnera, Michele; Bella, Rita; Borzì, Antonio Maria; Madeddu, Roberto; Drago, Filippo

2017-01-01

Background: Hepatitis C virus infection and interferon treatment have shown to be risk factors for sleep disorder health-related quality of life. Aim: To determine whether the effects of resveratrol on sleep disorders were associated with different tests in subjects with chronic hepatitis C treated with Peg-IFN-α and RBV. Patients and Methods: In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis received Pegylated-Interferon-α2b (1.5 mg/kg per week), Ribavirin and placebo (N-acetylcysteine 600 mg and lactoferrin 23.6 g), while 30 subjects (Group B) received the same dosage of Pegylated-Interferon-α2b, Ribavirin and association of N-acetylcysteine 600 mg, lactoferrin 23.6 g and Resveratrol 19.8 mg for 12 months. All subjects underwent laboratory exams and questionnaires to evaluate mood and sleep disorders (General Health Questionnaire (GHQ), Profile of Mood States (POMS), Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS)). Results: The comparison between Group A and Group B showed significant differences after six months in C-reactive protein (p < 0.0001); after 12 months in aspartate aminotransferase (AST) (p < 0.0001) Viremia (p < 0.0001), HAI (p < 0.0012) and C-reactive protein (p < 0.0001); and at follow up in AST (p < 0.0001), Viremia (p < 0.0026) and C-reactive protein (p < 0.0001). Significant differences were observed after 12 month and follow-up in General Health Questionnaire, after 1, 6, 12 and follow-up in Profile of Mood States, after 6, 12, follow-up in Pittsburgh Sleep Quality Inventory and Epworth Sleepiness Scale. Conclusions: Supplementation with Resveratrol decreased General Health Questionnaire score and reduced sleep disorders in patients treated with Peg–IFN-α and RBV. PMID:28820468

Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.

PubMed

Freedman, Neal D; Curto, Teresa M; Lindsay, Karen L; Wright, Elizabeth C; Sinha, Rashmi; Everhart, James E

2011-06-01

High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated. Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n=466), and undetectable hepatitis C virus RNA at weeks 20 (n=320), 48 (end of treatment, n=284), and 72 (sustained virologic response; n=157). Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6-3.9) among nondrinkers and 4.0 (IQR, 2.1-4.7) among patients that drank 3 or more cups/day of coffee (P trend<.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1-3.6; P trend=.004) for early virologic response, 2.1 (95% CI: 1.1-3.9; P trend=.005) for week 20 virologic response, 2.4 (95% CI: 1.3-4.6; P trend=.001) for end of treatment, and 1.8 (95% CI: 0.8-3.9; P trend=.034) for sustained virologic response. High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Clinical utility of host genetic IL-28B variants in hepatitis C virus genotype 1 Asian patients retreated with pegylated interferon plus ribavirin.

PubMed

Huang, Chung-Feng; Yeh, Ming-Lun; Hsieh, Meng-Hsuan; Hsieh, Ming-Yen; Lin, Zu-Yau; Chen, Shinn-Cherng; Wang, Liang-Yen; Huang, Jee-Fu; Juo, Suh-Hang Hank; Lin, Yi-Ching; Dai, Chia-Yen; Chuang, Wan-Long; Yu, Ming-Lung

2013-09-01

Host interleukin-28B (IL-28B) genetic variants determine a sustained virological response (SVR) in hepatitis C virus genotype 1 (HCV-1) treatment-naïve patients. Its impact on treatment-experienced Asian patients with peginterferon/ribavirin in is to be elucidated. IL-28B rs8099917 genotype was determined in 70 HCV-1 treatment-experienced patients retreated with 48-week peginterferon/ribavirin. The SVR rate was 60.0% and was significantly higher in previous relapsers than in nonresponders (72.7% and 13.3%, P < 0.001). Multivariate analysis revealed that the most important factor predictive of an SVR was previous relapse (Odds ratio [OR]/95% confidence interval [CI]: 14.76/2.72-80.06, P = 0.002), followed by the carriage of rs8099917 TT genotype (OR/95% C.I.: 7.67/1.27-46.49, P = 0.03). Comparing to patients with TG/GG genotype, those with TT genotype had significantly higher rates of rapid virological response (29.3% vs 0%, P = 0.03), end-of-treatment virological response (86.2% vs 50.0%, P = 0.01), SVR (69.0% vs 16.7%, P = 0.002), and lower relapse rate (22.0 % vs 66.7%, P = 0.04). The SVR rate was similarly low between previous nonresponders with different rs8099917 genotypes (12.5% vs 14.3%, P = 1). On the contrary, previous relapsers with rs8099917 TT genotype had a significantly higher SVR rate than those who carried rs8099917 TG/GG genotype (78.0 % vs 20.0%, P = 0.02). Stepwise logistic regression analysis revealed that the only factor predictive of an SVR in previous relapsers was the carriage of rs809997 TT genotype (OR/95% CI:18.50/1.82-188.39, P = 0.014). Host IL-28B genetic variants played a role in Asian relapsers but not nonresponders retreated with peginterferon/ribavirin. Direct antiviral agents might be possibly avoidable in Asian relapsers with favorable IL-28B genotype. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA.

PubMed

Ferron, François; Subissi, Lorenzo; Silveira De Morais, Ana Theresa; Le, Nhung Thi Tuyet; Sevajol, Marion; Gluais, Laure; Decroly, Etienne; Vonrhein, Clemens; Bricogne, Gérard; Canard, Bruno; Imbert, Isabelle

2018-01-09

Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.

Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1.

PubMed

Jacobson, Ira M; Brown, Robert S; McCone, Jonathan; Black, Martin; Albert, Clive; Dragutsky, Michael S; Siddiqui, Firdous A; Hargrave, Thomas; Kwo, Paul Y; Lambiase, Louis; Galler, Greg W; Araya, Victor; Freilich, Bradley; Harvey, Joann; Griffel, Louis H; Brass, Clifford A

2007-10-01

WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups. Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

Relation of pretreatment sequence diversity in NS5A region of HCV genotype 1 with immune response between pegylated-INF/ribavirin therapy outcomes.

PubMed

de Queiróz, A T L; Maracaja-Coutinho, V; Jardim, A C G; Rahal, P; de Carvalho-Mello, I M V G; Matioli, S R

2011-02-01

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific immune responses and the combination of pegylated interferon (INF)-α and ribavirin therapy. Major histocompatibility complex class I restricted CD8(+) T cells are responsible for the control of viraemia in HCV infection, and several studies suggest protection against viral infection associated with specific HLAs. The reason for low rates of sustained viral response (SVR) in HCV patients remains unknown. Escape mutations in response to cytotoxic T lymphocyte are widely described; however, its influence in the treatment outcome is ill understood. Here, we investigate the differences in CD8 epitopes frequencies from the Los Alamos database between groups of patients that showed distinct response to pegylated α-INF with ribavirin therapy and test evidence of natural selection on the virus in those who failed treatment, using five maximum likelihood evolutionary models from PAML package. The group of sustained virological responders showed three epitopes with frequencies higher than Non-responders group, all had statistical support, and we observed evidence of selection pressure in the last group. No escape mutation was observed. Interestingly, the epitope VLSDFKTWL was 100% conserved in SVR group. These results suggest that the response to treatment can be explained by the increase in immune pressure, induced by interferon therapy, and the presence of those epitopes may represent an important factor in determining the outcome of therapy. © 2010 Blackwell Publishing Ltd.

Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.

PubMed

Ferenci, Peter; Laferl, Hermann; Scherzer, Thomas-Matthias; Gschwantler, Michael; Maieron, Andreas; Brunner, Harald; Stauber, Rudolf; Bischof, Martin; Bauer, Bernhard; Datz, Christian; Löschenberger, Karin; Formann, Elisabeth; Staufer, Katharina; Steindl-Munda, Petra

2008-08-01

This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

Concurrent Autoimmune Hepatitis and Grave's Disease in Hepatitis C during Pegylated Interferon α-2a and Ribavirin Therapy

PubMed Central

Trikudanathan, Guru V.; Ahmad, Imad; Israel, Jonathan L

2011-01-01

Classical interferon-α has been shown to be associated with the development of a variety of autoimmune disorders. A 34-year-old white woman with chronic hepatitis C virus infection who was treated with pegylated interferon α-2a and ribavirin, developed Grave's disease and autoimmune hepatitis (AIH) at 32 and 44 weeks, respectively, following initiation of the therapy. The diagnosis of AIH was made based on the new development of anti-smooth muscle antibodies, anti-mitochondrial antibodies, and liver biopsy findings. It was confirmed by positive response to steroid challenge and was assessed according to the international AIH scoring system. Based on the previous case reports, we review the existing literature. Clinicians should be aware of the possibility of multiple autoimmune disorders during interferon-based therapy for chronic hepatitis. PMID:21912063

Concurrent autoimmune hepatitis and grave's disease in hepatitis C during pegylated interferon α-2a and ribavirin therapy.

PubMed

Trikudanathan, Guru V; Ahmad, Imad; Israel, Jonathan L

2011-01-01

Classical interferon-α has been shown to be associated with the development of a variety of autoimmune disorders. A 34-year-old white woman with chronic hepatitis C virus infection who was treated with pegylated interferon α-2a and ribavirin, developed Grave's disease and autoimmune hepatitis (AIH) at 32 and 44 weeks, respectively, following initiation of the therapy. The diagnosis of AIH was made based on the new development of anti-smooth muscle antibodies, anti-mitochondrial antibodies, and liver biopsy findings. It was confirmed by positive response to steroid challenge and was assessed according to the international AIH scoring system. Based on the previous case reports, we review the existing literature. Clinicians should be aware of the possibility of multiple autoimmune disorders during interferon-based therapy for chronic hepatitis.

Acute hepatitis B in a patient with OLT during treatment with peg-interferon and ribavirin for hepatitis C recurrence.

PubMed

Biliotti, Elisa; Zacharia, Sabu; Grieco, Stefania; Spaziante, Martina; Giusto, Michela; Merli, Manuela; Gallinaro, Valentina; Taliani, Gloria

2012-12-01

The course and outcome of acute viral hepatitis in liver transplanted patients with hepatitis C recurrence are unknown. Here we describe a patient who presented with acute hepatitis B infection while on treatment with peg-interferon and ribavirin for hepatitis C recurrence after liver transplantation. A nucleoside analogue was added (entecavir) and the patient cleared hepatitis C virus (HCV) infection and seroconverted to anti-HBs. In this case, the acute hepatitis B virus (HBV) infection might have contributed to the clearance of HCV, the concomitant immunosuppression might have lead to the slow clearance of HBV infection, and the combined antiviral therapy has helped in the resolution of both infections. Hepatitis B vaccination should be recommended in susceptible patients waiting for liver transplantation.

CTN-194 (PICCO): design of a trial of citalopram for the prevention of depression and its consequences in HIV-hepatitis C co-infected individuals initiating pegylated interferon/ribavirin therapy.

PubMed

Klein, Marina B; Cooper, Curtis; Brouillette, Marie-Josée; Sheehan, Nancy L; Benkelfat, Chawki; Annable, Lawrence; Weston, Francine; Kraus, Deborah; Singer, Joel

2008-07-01

Hepatitis C (HCV)-related end stage liver disease is a primary cause of morbidity and mortality in people with HIV. Despite this, co-infected patients have low rates of HCV treatment initiation and completion. This is in large part due to the risk of pegylated-interferon alpha (PEG-IFN-alpha)-related neuropsychiatric complications. We describe the design of a multicentre randomized, placebo-controlled trial that evaluates whether antidepressant prophylaxis is superior to early detection and treatment of depression in increasing the successful completion of HCV therapy. Seventy-six HIV+ adults with chronic HCV infection requiring therapy and with no contraindications to PEG-IFN-alpha/ribavirin will be randomized in a 1:1 ratio to receive citalopram or placebo starting three weeks prior to HCV treatment. A novel aspect of the trial design is the built-in management of emergent depression while maintaining the blinded treatment assignment. This will permit the comparison of prophylactic versus therapeutic use of citalopram. The primary outcome is the average proportion of prescribed PEG-IFN-alpha and ribavirin doses taken per month at weeks 12 and 24, and will be compared between treatment arms. The study will also compare the development of moderate-to-severe depression between treatment arms. A unique feature of this trial will be the use of Telepsychiatry to standardize observer-administered neuropsychiatric evaluations. Assessments of anxiety, quality of life, and adherence to therapy, as well as pathogenetic studies of neuropsychiatric side effects, will be conducted. Intention-to-treat analyses using random regression modeling will be employed to analyze longitudinal data on prescribed PEG-IFN-alpha and ribavirin doses. Survival analyses will be used to compare the time to the development of depression between the two arms. Effective prevention of a broad range of neuropsychiatric symptoms by citalopram has the potential to diminish PEG-IFN-alpha associated

Coffee Consumption is Associated with Response to Peginterferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

PubMed Central

Freedman, Neal D.; Curto, Teresa M.; Lindsay, Karen L.; Wright, Elizabeth C.; Sinha, Rashmi; Everhart, James E.

2011-01-01

Background & Aims High level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for Hepatitis C virus (HCV) infection has not been evaluated. Methods Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial recorded coffee intake before re-treatment with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000–1200 mg/day). We assessed patients for early virologic response (EVR, 2 log10 reduction in level of HCV RNA at week 12; n=466) and undetectable HCV RNA at week 20 (W20VR; n=320), week 48 (end of treatment, EOT; n=284), and week 72 (sustained virologic response, SVR; n=157). Results The median log10 drop from baseline to week 20 was 2.0 (interquartile range: 0.6–3.9) among non-drinkers and 4.0 (2.1–4.7) among patients that drank ≥3 cup/day of coffee (P-trend <0.0001). In unadjusted models, the odds ratios (OR) and 95% confidence intervals (CI) for drinking ≥3 cups/day vs non-drinking were 3.2 (1.9–5.3) for EVR, 3.1 (1.8–5.1) for W20VR, 3.5 (2.0–5.9) for EOT, and 2.7 (1.4–5.3) for SVR (P-trend<0.0001 for all). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase:alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, the OR (95% CI) for EVR was 2.0 (1.1–3.6; P-trend = 0.004); for W20VR was 2.1 (1.1–3.9; p-trend=0.005); for EOT was 2.4 (1.3–4.6; P-trend=0.001), and for SVR was 1.8 (0.8–3.9; P-trend=0.034). Conclusion High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with Hepatitis C. PMID:21376050

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program.

PubMed

Poynard, Thierry; Munteanu, Mona; Colombo, Massimo; Bruix, Jordi; Schiff, Eugene; Terg, Ruben; Flamm, Steven; Moreno-Otero, Ricardo; Carrilho, Flair; Schmidt, Warren; Berg, Thomas; McGarrity, Thomas; Heathcote, E Jenny; Gonçales, Fernando; Diago, Moises; Craxi, Antonio; Silva, Marcelo; Boparai, Navdeep; Griffel, Louis; Burroughs, Margaret; Brass, Clifford; Albrecht, Janice

2011-02-01

EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p ≤ 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p ≤ 0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Short Communication: Interferon/Ribavirin Treatment for HCV Is Associated with the Development of Hypophosphatemia in HIV/Hepatitis C Virus-Coinfected Patients

PubMed Central

Funk, Emily K.; Shaffer, Ashton; Shivakumar, Bhavana; Sneller, Michael; Polis, Michael A.; Masur, Henry; Heytens, Laura; Nelson, Amy; Kwan, Richard; Kottilil, Shyam

2013-01-01

Abstract One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; χ2=0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; χ2<0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug–drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens. PMID:23701022

Short communication: Interferon/ribavirin treatment for HCV is associated with the development of hypophosphatemia in HIV/hepatitis C virus-coinfected patients.

PubMed

Funk, Emily K; Shaffer, Ashton; Shivakumar, Bhavana; Sneller, Michael; Polis, Michael A; Masur, Henry; Heytens, Laura; Nelson, Amy; Kwan, Richard; Kottilil, Shyam; Kohli, Anita

2013-09-01

One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; χ(2)=0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; χ(2)<0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug-drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens.

Comparative effectiveness and adverse effects of interferon alpha-2b plus ribavirin therapy in hepatitis 'C' for 26 weeks.

PubMed

Ali, Shafqut; Iram, Samia

2009-01-01

Hepatitis C is major emerging challenge for pathologists and treating physicians all over the world. Already 10 million Pakistani population has become anti-HCV positive. It is not only affecting hepatobiliary system but with passage of time research is revealing that Hepatitis C is going to involve almost every organ of the body. With timely diagnosis and treatment, millions of patients can be saved from morbidity and mortality. The nation has to sacrifice initial economic allocations to avoid later millions of mortalities and greater economic losses on affected patients and to support their families. The objective of this study was to evaluate effectiveness of combine therapy of Hepatitis C in local population of Pakistan. This case series study was done at CMH Okara, Kohat, Abbottabad, and PAF Hospital, Shorkot from August 2000 to August 2009. All 1,000 patients from 10 to 60 years of age, confirmed anti-HCV Positive by ELISA and PCR Positive for HCV RNA, were subjected to Interferon alpha-2b and Ribavirin therapy for similar period of time. Response and adverse affects were observed by clinical examination, blood complete picture including platelet count and ALT fortnightly. PCR for HCV RNA and ultrasound abdomen (hepatobilliary system) was done quarterly during treatment and 6 monthly for 2 years after treatment to review the sustained response and relapse. Over all cure rate after 2 years was 855 (85.5%) excluding the 50 (5%) of initial resistant to one year treatment and 95 (9.5%) re-treated relapse cases. One hundred and forty-five (14.5%) patients were found to be resistant to treatment. Hepatitis C must be treated timely after proper diagnosis. Interferon and Ribavirin combination have shown high 'cure' rate in Hepatitis C. In spite of high cure rate of 85.5% with timely and proper treatment, low socio-economic status is a major problem for poor individuals to get treatment. Preventive aspect must be strictly followed and implemented.

Changes in Fasting Plasma Glucose Levels with Ribavirin and Pegylated Interferon Treatment in Normal and Impaired Glucose Tolerant Patients with Chronic Hepatitis C

PubMed Central

Sarasombath, Ongkarn; Suwantarat, Nuntra; Tice, Alan D

2012-01-01

Background Patients with Hepatitis C Virus (HCV) infection have increased rates of glucose intolerance, and studies have shown the improvement of fasting plasma glucose (FPG) levels after clearance of HCV infection with standard ribavirin plus pegylated interferon treatment. The purpose of this study was to examine glycemic changes with standard HCV treatment in patients with impaired fasting glucose (IFG) and normal fasting glucose (NFG). Methods A retrospective study of FPG changes in HCV patients with IFG and NFG treated with standard HCV therapy was conducted. Baseline characteristics and viral responses were assessed; FPG levels before treatment, at the end of treatment, and more than one-month post treatment were compared. Results The mean FPG levels increased by 8.68 mg/dl at the end of treatment in the NFG group but decreased by 9.0 mg/dl in the IFG group, a statistically significant difference (P=0.019). The change in FPG levels remained significantly different after adjusting for weight change (P=0.009) and weight changes and initial weight (P=0.039). FPG change from baseline at more than one month after treatment were similar in both groups (P=0.145). The change in FPG levels was not associated with sustained viral response. Conclusions In HCV-infected patients, standard ribavirin plus pegylated interferon treatment reduced FPG levels in patients with IFG and increased FPG levels in NFG individuals; independent of initial weight, weight change, or viral response. Standard HCV treatment modulates fasting plasma glucose levels which supports the need for a prospective study to determine the clinical significance of this finding. PMID:22737650

Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response.

PubMed

Ferenci, Peter; Laferl, Hermann; Scherzer, Thomas-Matthias; Maieron, Andreas; Hofer, Harald; Stauber, Rudolf; Gschwantler, Michael; Brunner, Harald; Wenisch, Christoph; Bischof, Martin; Strasser, Michael; Datz, Christian; Vogel, Wolfgang; Löschenberger, Karin; Steindl-Munda, Petra

2010-02-01

This randomized multicenter trial evaluated individualization of treatment duration with peginterferon alfa-2a 180 microg/wk plus ribavirin 1000/1200 mg/day in patients with chronic hepatitis C genotype 1/4 based on the rapidity of virologic response (VR). Patients with a rapid VR (RVR; undetectable hepatitis C virus [HCV]-RNA level (<50 IU/mL at week 4) were treated for 24 weeks, those with an early VR (EVR; no RVR but undetectable HCV-RNA level or >or=2-log(10) decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B; peginterferon alfa-2a was reduced to 135 microg/wk after week 48). Patients without an EVR continued treatment until week 72 if they had undetectable HCV-RNA levels at week 24. The primary end point was relapse; sustained VR (SVR; undetectable HCV-RNA level after 24 weeks of follow-up evaluation) was a secondary end point. Of 551 genotype 1/4 patients starting treatment, 289 were randomized to group A (N = 139) or group B (N = 150). The relapse rate was 33.6% in group A (95% confidence interval [CI], 24.8%-43.4%) and 18.5% in group B (95% CI, 11.9%-27.6%; P = .0115 vs group A) and the SVR rate was 51.1% (95% CI, 42.5%-59.6%) and 58.6% (95% CI, 50.3%-66.6%; P > .1), respectively. The overall SVR rate was 50.4% (278 of 551; 95% CI, 46.2%-54.7%), including 115 of 150 patients with an RVR treated for 24 weeks and 4 of 78 patients without an EVR. Extending therapy with peginterferon alfa-2a/ribavirin to 72 weeks decreases the probability of relapse in patients with an EVR. If they can be maintained on extended-duration therapy, SVR rates also may improve.

A multidisciplinary therapeutic approach for reducing the risk of psychiatric side effects in patients with chronic hepatitis C treated with pegylated interferon α and ribavirin.

PubMed

Neri, Sergio; Bertino, Gaetano; Petralia, Antonio; Giancarlo, Crisafulli; Rizzotto, Agostino; Calvagno, Giuseppe Stefano; Mauceri, Barbara; Abate, Giuseppe; Boemi, Patrizia; Di Pino, Antonino; Ignaccolo, Luca; Vadalà, Giuseppe; Misseri, Maria; Maiorca, Daniela; Mastrosimone, Gianluca; Judica, Antonino; Palermo, Filippo

2010-10-01

To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-α and ribavirin among study participants compared with standard clinical monitoring alone. Interferon-α is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy. Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test). At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05). Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment.

Macromolecular prodrugs of ribavirin: towards a treatment for co-infection with HIV and HCV† †Electronic supplementary information (ESI) available: Additional experimental details and figures. See DOI: 10.1039/c4sc02754j Click here for additional data file. ‡A.A.A.S.; K.Z.; M.B.L.K.; B.W. contributed equally to this work.

PubMed Central

Smith, Anton A. A.; Zuwala, Kaja; Kryger, Mille B. L.; Wohl, Benjamin M.; Guerrero-Sanchez, Carlos; Tolstrup, Martin; Postma, Almar

2015-01-01

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) represent tremendous healthcare burdens with a large proportion of patients hosting the two viruses at the same time. An altered hepatic function and immunity as well as cross-interference of drugs make treatment of co-infection increasingly challenging. Herein we report the first design of macromolecular prodrugs (MP) with concurrent success in fighting HIV and alleviating hepatitis (liver inflammation). To achieve this, polymer compositions were systematically screened in a broad range of molar mass and content of ribavirin – a broad spectrum antiviral agent. For the first time, we report that ribavirin is efficacious in fighting HIV and in the form of MP, the treatment is safe, both in terms of lack of association of ribavirin with red blood cells and lack of toxicity upon cellular internalization. The lead polymer compositions were also potent in anti-inflammatory assays with relevance to viral hepatitis – thus making up formulations with potential for treatment of co-infection with HIV and HCV. PMID:28580095

A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3.

PubMed

Ferenci, Peter; Brunner, Harald; Laferl, Hermann; Scherzer, Thomas-Matthias; Maieron, Andreas; Strasser, Michael; Fischer, Gabriele; Hofer, Harald; Bischof, Martin; Stauber, Rudolf; Gschwantler, Michael; Steindl-Munda, Petra; Staufer, Katharina; Löschenberger, Karin

2008-06-01

We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180 mug/week in treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. The results suggest that when administered for 24 weeks with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3.

Assessment of Viral Genotype Impact to the Cost-Effectiveness and Overall Costs of Care for Peg-Interferon-2α + Ribavirine Treated Chronic Hepatitis C Patients

PubMed Central

Jakovljevic, Mihajlo; Mijailovic, Zeljko; Popovska Jovicic, Biljana; Canovic, Predrag; Gajovic, Olgica; Jovanovic, Mirjana; Petrovic, Dejan; Milovanovic, Olivera; Djordjevic, Natasa

2013-01-01

Background Pegylated interferon alfa plus ribavirin protocol is currently considered the most efficient hepatitis C treatment. However, no evidence of costs comparison among common viral genotypes has been published. Objectives We aimed to assess core drivers of hepatitis C medical care costs and compare cost effectiveness of this treatment among patients infected by hepatitis C virus with genotypes 1 or 4 (group I), and 2 or 3 (group II). Patients and Materials Prospective bottom-up cost-effectiveness analysis from societal perspective was conducted at Infectious Diseases Clinic, University Clinic Kragujevac, Serbia, from 2007 to 2010. There were 81 participants with hepatitis C infection, treated with peg alpha-2a interferon plus ribavirin for 48 or 24 weeks. Economic data acquired were direct inpatient medical costs, outpatient drug acquisition costs, and indirect costs calculated through human capital approach. Results Total costs were significantly higher (P = 0.035) in group I (mean ± SD: 12,751.54 ± 5,588.06) compared to group II (mean ± SD: 10,580.57 ± 3,973.02). In addition, both direct (P = 0.039) and indirect (P < 0.001) costs separately were significantly higher in group I compared to group II. Separate comparison within direct costs revealed higher total cost of medical care (P = 0.024) in first compared to second genotype group, while the similar tendency was observed for total drug acquisition (P = 0.072). Conclusion HCV genotypes 1 and 4 cause more severe clinical course require more care and thus incur higher expenses compared to HCV 2 and 3 genotypes. Policy makers should consider willingness to pay threshold differentially depending upon HCV viral genotype detected. PMID:24032044

Pegylated IFN-α-2a and ribavirin in the treatment of hepatitis C infection in children.

PubMed

Pawlowska, Malgorzata

2015-03-01

The epidemiology, natural history and efficacy of treatment for chronic hepatitis C in children are presented. An increase in the number of vertical infections of this etiology is suggested. In children, especially in those vertically infected, spontaneous elimination of hepatitis C virus (HCV) is observed more often than it is in adults. The most common HCV genotype detected in children is genotype 1, but Italian researchers have described an increase of infection with genotypes 3 and 4 HCV in children in recent years. In the context of recent opinions suggesting a more rapid progression of HCV 3 genotype infection, treatment of these children should begin immediately. The high efficacy (sustained viral response > 50%), safety (few adverse events with less intensity as compared to adults) and good tolerance of therapy with pegylated IFN α-2a and ribavirin have been revealed in children. The differences in the efficacy and tolerability of HCV treatment between children and adults are described. A recommendation for inclusion and monitoring parameters of children's physical and mental development during HCV treatment is presented. Regarding new anti-HCV therapies with very high efficacy, including IFN-free treatment, the introduction of these therapies to children is recommended.

Experimental adaptation of human echovirus 11 to ultraviolet radiation leads to resistance to disinfection and ribavirin

PubMed Central

Carratalà, Anna; Shim, Hyunjin; Zhong, Qingxia; Bachmann, Virginie; Jensen, Jeffrey D

2017-01-01

Abstract Ultraviolet light in the UVC range is a commonly used disinfectant to control viruses in clinical settings and water treatment. However, it is currently unknown whether human viral pathogens may develop resistance to such stressor. Here, we investigate the adaptation of an enteric pathogen, human echovirus 11, to disinfection by UVC, and characterized the underlying phenotypic and genotypic changes. Repeated exposure to UVC lead to a reduction in the UVC inactivation rate of approximately 15 per cent compared to that of the wild-type and the control populations. Time-series next-generation sequencing data revealed that this adaptation to UVC was accompanied by a decrease in the virus mutation rate. The inactivation efficiency of UVC was additionally compromised by a shift from first-order to biphasic inactivation kinetics, a form of ‘viral persistence’ present in the UVC resistant and control populations. Importantly, populations with biphasic inactivation kinetics also exhibited resistance to ribavirin, an antiviral drug that, as UVC, interferes with the viral replication. Overall, the ability of echovirus 11 to adapt to UVC is limited, but it may have relevant consequences for disinfection in clinical settings and water treatment plants. PMID:29225923

Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program

PubMed Central

Litwin, Alain H.; Harris, Kenneth A.; Nahvi, Shadi; Zamor, Philippe J.; Soloway, Irene J.; Tenore, Peter L.; Kaswan, Daniel; Gourevitch, Marc. N.; Arnsten, Julia H.

2009-01-01

Injection drug users constitute 60% of the more than 4 million people in the United States with hepatitis C virus (HCV), including many methadone maintenance patients. Few data exist describing clinical outcomes for patients receiving HCV treatment on-site in a methadone maintenance settings. In this retrospective study, we describe clinical outcomes for 73 patients receiving HCV treatment on-site in a methadone maintenance treatment program. Fifty-five percent of patients achieved end-of-treatment response, and 45% achieved sustained viral response. These treatment response rates are nearly equivalent to previously published HCV treatment response rates, despite high prevalences of ongoing drug use (49%), psychiatric comorbidity (67%), and HIV coinfection (32%). These data show that on-site HCV treatment with pegylated interferon and ribavirin is effective in methadone-maintained patients, many of whom are active drug users, psychiatrically ill, or HIV coinfected, and that methadone maintenance treatment programs represent an opportunity to safely treat chronic hepatitis C. PMID:19038524

NS5A resistance leading to failure of 24-week therapy with sofosbuvir/ledipasvir and ribavirin for the treatment of hepatitis C genotype 1a infection in a HIV-1 co-infected patient.

PubMed

Sevastianova, Ksenia; Dean, Jonathan; Bannan, Ciaran; Coghlan, Miriam; Farrell, Gillian; Murray, Catherine; De Gascun, Cillian F; Bergin, Colm

2016-09-01

Herein we report a previously undescribed case of treatment-emergent non-structural protein 5A (NS5A) resistance mutations, Q30H and Y93C, leading to a failure of 24-week course of sofosbuvir/ledipasvir+ribavirin therapy for the treatment of hepatitis C virus (HCV) genotype 1a in interferon-experienced, human immunodeficiency virus type 1 (HIV-1) co-infected patient with cirrhosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Daclatasvir/peginterferon lambda-1a/ribavirin in patients with chronic HCV infection and haemophilia who are treatment naïve or prior relapsers to peginterferon alfa-2a/ribavirin.

PubMed

Santagostino, E; Pol, S; Olveira, A; Reesink, H W; van Erpecum, K; Bogomolov, P; Xu, D; Critelli, L; Srinivasan, S; Cooney, E

2016-09-01

This study explores the potential role of a novel interferon-containing regimen for treatment of patients with chronic hepatitis C (CHC) and underlying haemophilia. This trial (NCT01741545) was an open-label, non-randomized phase 3 study, which included adult haemophiliacs with hepatitis C virus (HCV). Patients with HCV genotypes (GT)-2 or -3 were treated with Lambda-IFN/ribavirin (RBV)/daclatasvir (DCV) for 12 weeks (cohort A). Patients with HCV GT-1b or -4 were treated with Lambda-IFN/RBV/DCV for 12 weeks, followed by Lambda-IFN/RBV for an additional 12 weeks (cohort B). The primary endpoint was the proportion of patients with a sustained virologic response at post-treatment follow-up week 12 (SVR12). Clinical development of Lambda-IFN was discontinued during this trial leading to study termination before a 24-week post-treatment follow-up was obtained for all participants. Overall, 51 patients were treated (cohort A, n = 12; cohort B, n = 39). The proportion of patients achieving SVR12 was 92% in cohort A and 90% in cohort B. Therapy was generally well tolerated. The most common adverse events (AEs) were related to elevations in serum transaminases and/or bilirubin. Five serious AEs, four discontinuations due to AEs, and no deaths were reported. The rate of grade 3-4 bilirubin elevations was 17-18% across cohorts. Lambda-IFN/RBV/DCV treatment demonstrated a high SVR rate and was generally well tolerated with a safety profile consistent with expectations for this special patient population. This study supports use of DCV as part of a combination treatment regimen for haemophiliacs with CHC. © 2016 John Wiley & Sons Ltd.

Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C.

PubMed

Manns, Michael; Zeuzem, Stefan; Sood, Ajit; Lurie, Yoav; Cornberg, Markus; Klinker, Hartwig; Buggisch, Peter; Rössle, Martin; Hinrichsen, Holger; Merican, Ismail; Ilan, Yaron; Mauss, Stefan; Abu-Mouch, Saif; Horban, Andryes; Müller, Thomas H; Welsch, Christoph; Chen, Rongdean; Faruqi, Rab; Pedicone, Lisa D; Wedemeyer, Heiner

2011-09-01

There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5μg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0μg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5μg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5μg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment. Copyright © 2011. Published by Elsevier B.V.

Mutagenic Effects of Ribavirin on Hepatitis E Virus-Viral Extinction versus Selection of Fitness-Enhancing Mutations.

PubMed

Todt, Daniel; Walter, Stephanie; Brown, Richard J P; Steinmann, Eike

2016-10-13

Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials.

PubMed

Lawitz, Eric; Buti, Maria; Vierling, John M; Almasio, Piero L; Bruno, Savino; Ruane, Peter J; Hassanein, Tarek I; Muellhaupt, Beat; Pearlman, Brian; Jancoriene, Ligita; Gao, Wei; Huang, Hsueh-Cheng; Shepherd, Aimee; Tannenbaum, Brynne; Fernsler, Doreen; Li, Jerry J; Grandhi, Anjana; Liu, Hong; Su, Feng-Hsiu; Wan, Shuyan; Dutko, Frank J; Nguyen, Bach-Yen T; Wahl, Janice; Robertson, Michael N; Barr, Eliav; Yeh, Wendy W; Plank, Rebeca M; Butterton, Joan R; Yoshida, Eric M

2017-11-01

There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46

Measurement of Intracellular Ribavirin Mono-, Di- and Triphosphate Using Solid Phase Extraction and LC-MS/MS Quantification

PubMed Central

Jimmerson, Leah C.; Ray, Michelle L.; Bushman, Lane R.; Anderson, Peter L.; Klein, Brandon; Rower, Joseph E.; Zheng, Jia-Hua; Kiser, Jennifer J.

2014-01-01

Ribavirin (RBV) is a nucleoside analog used to treat a variety of DNA and RNA viruses. RBV undergoes intracellular phosphorylation to a mono- (MP), di- (DP), and triphosphate (TP). The phosphorylated forms have been associated with the mechanisms of antiviral effect observed in vitro, but the intracellular pharmacology of the drug has not been well characterized in vivo. A highly sensitive LC-MS/MS method was developed and validated for the determination of intracellular RBV MP, DP, and TP in multiple cell matrix types. For this method, the individual MP, DP, and TP fractions were isolated from lysed intracellular matrix using strong anion exchange solid phase extraction, dephosphorylated to parent RBV, desalted and concentrated and quantified using LC-MS/MS. The method utilized a stable labeled internal standard (RBV-13C5) which facilitated accuracy (% deviation within ±15%) and precision (coefficient of variation of ≤15%). The quantifiable linear range for the assay was 0.50 to 200 pmol/sample. The method was applied to the measurement of RBV MP, DP, and TP in human peripheral blood mononuclear cells (PBMC), red blood cells (RBC), and dried blood spot (DBS) samples obtained from patients taking RBV for the treatment of chronic Hepatitis C virus infection. PMID:25555148

Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C

PubMed Central

Lens, Sabela; Calleja, Jose L; Campillo, Ana; Carrión, Jose A; Broquetas, Teresa; Perello, Christie; de la Revilla, Juan; Mariño, Zoe; Londoño, María-Carlota; Sánchez-Tapias, Jose M; Urbano-Ispizua, Álvaro; Forns, Xavier

2015-01-01

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications. PMID:25954117

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

PubMed Central

Aouri, Manel; Moradpour, Darius; Cavassini, Matthias; Mercier, Thomas; Buclin, Thierry; Csajka, Chantal; Telenti, Amalio; Rauch, Andri

2013-01-01

New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy. PMID:23629707

[Clinical benefit of HCV core antigen assay in patients receiving interferon and ribavirin combination therapy].

PubMed

Higashimoto, Makiko; Takahashi, Masahiko; Jokyu, Ritsuko; Saito, Hidetsugu

2006-02-01

A highly sensitive second generation HCV core antigen assay has recently been developed. We compared viral disappearance and kinetics data between commercially available core antigen assays, Lumipulse Ortho HCV Ag, and a quantitative HCV RNA PCR assay, Cobas Amplicor HCV Monitor Test, Version 2 to estimate the predictive benefit of sustained viral response (SVR) and non-SVR in 59 patients treated with interferon and ribavirin combination therapy. We found a good correlation between HCV core Ag and HCV RNA level regardless of genotype. Although the sensitivity of the core antigen assay was lower than PCR, the dynamic range was broader than that of the PCR assay, so that we did not need to dilute the samples in 59 patients. We detected serial decline of core Ag levels in 24 hrs, 7 days and 14 days after interferon combination therapy. The decline of core antigen levels was significant in SVR patients compared to non-SVR as well as in genotype 2a, 2b patients compared to 1b. Core antigen-negative on day 1 could predict all 10 SVR patients (PPV = 100%), whereas RNA-negative could predict 22 SVR out of 25 on day 14 (PPV = 88.0%). None of the patients who had detectable serum core antigen on day 14 became SVR(NPV = 100%), although NPV was 91.2% on RNA negativity. An easy, simple, low cost new HCV core antigen detecting system seems to be useful for assessing and monitoring IFN treatment for HCV.

Clearance of Hepatitis C Virus Improves Insulin Resistance During and After Peginterferon and Ribavirin Therapy.

PubMed

Chien, Cheng-Hung; Lin, Chih-Lang; Hu, Ching-Chih; Chang, Jia-Jang; Chien, Rong-Nan

2015-12-01

Patients with chronic hepatitis C virus (HCV) infection are at a greater risk of developing insulin resistance (IR). However, little is known about when insulin sensitivity may improve during or after treatment for hepatitis C. In this study, we examined the effect of combination therapy with pegylated interferon-α and ribavirin on IR in patients with chronic HCV infection. We also analyzed factors associated with changes in insulin sensitivity. IR was estimated by homeostasis model assessment (HOMA-IR). HOMA-IR was measured before therapy, during therapy (12 and 24 weeks), and at the end of therapy (EOT; 24 or 48 weeks). We analyzed 78 HCV patients receiving combination therapy. Twenty-two patients (28.2%) exhibited pretreatment IR (HOMA-IR >2.5). In all patients, HOMA-IR was not significantly different from baseline values at 12 weeks (P = 0.823), 24 weeks (P = 0.417), or at EOT (P = 0.158). In patients with pretreatment IR, a significant decrease in HOMA-IR was observed at 12 weeks (P = 0.023), 24 weeks (P = 0.008), and at EOT (P = 0.002). Multivariate analysis using a logistic regression model showed that baseline HOMA-IR is the only factor associated with the decline in HOMA-IR during and after therapy. The eradication of HCV infection was associated with improved insulin sensitivity among patients with pretreatment IR. This significant improvement in insulin sensitivity may occur as early as 12 weeks after the initiation of antiviral therapy.

Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a.

PubMed

Gallegos, Karen M; Drusano, George L; D Argenio, David Z; Brown, Ashley N

2016-10-15

We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). Vero cells were infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log10 following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log10 decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Directly observed therapy of sofosbuvir/ribavirin +/- peginterferon with minimal monitoring for the treatment of chronic hepatitis C in people with a history of drug use in Chennai, India (C-DOT).

PubMed

Solomon, S S; Sulkowski, M S; Amrose, P; Srikrishnan, A K; McFall, A M; Ramasamy, B; Kumar, M S; Anand, S; Thomas, D L; Mehta, S H

2018-01-01

We assessed the feasibility of field-based directly observed therapy (DOT) with minimal monitoring to deliver HCV treatment to people with a history of drug use in Chennai, India. Fifty participants were randomized 1:1 to sofosbuvir+peginterferon alfa 2a+ribavirin (SOF+PR) for 12 weeks (Arm 1) vs sofosbuvir+ribavirin (SOF+R) for 24 weeks (Arm 2). SOF+R was delivered daily at participant chosen venues and weekly peginterferon injections at the study clinic. HCV RNA testing was performed to confirm active HCV infection and sustained virologic response 12 weeks after treatment completion (SVR12). No baseline genotyping or on-treatment viral loads were performed. Median age was 46 years. All were male and 20% had significant fibrosis/cirrhosis. All self-reported history of injection drug use, 18% recent noninjection drug use and 38% alcohol dependence. Six discontinued treatment (88% completed treatment in each arm). Of 22 who completed SOF+PR, all achieved SVR12 (22/25=88%); 15 of 22 who completed SOF+R achieved SVR12 (15/25=60%; P=.05). Among those completing SOF+R, SVR12 was significantly less common in participants reporting ongoing substance use (36% vs 100%) and missed doses. Active substance use and missed doses did not impact SVR with SOF+PR. Field-based DOT of HCV therapy without real-time HCV RNA monitoring was feasible; however, achieving 100% adherence was challenging. SOF+PR appeared superior to SOF+R in achieving SVR12, even when doses were missed with no discontinuations due to side effects. Further exploration of short duration treatment with peginterferon plus direct-acting antivirals is warranted. © 2017 John Wiley & Sons Ltd.

The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil.

PubMed

Artico, Simara; Amaral, Karine Medeiros; Gonçalves, Candice Beatriz Treter; Picon, Paulo Dornelles

2012-12-27

More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR). From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN. The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely. This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored.

The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil

PubMed Central

2012-01-01

Background More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR). Methods From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN. Results The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely. Conclusions This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored. PMID:23270376

Hepatocellular carcinoma or interferon-based therapy history attenuates sofosbuvir/ribavirin for Japanese genotype 2 hepatitis C virus.

PubMed

Yada, Masayoshi; Miyazaki, Masayuki; Tanaka, Kosuke; Masumoto, Akihide; Motomura, Kenta

2018-04-07

To investigate the real-world efficacy and safety of sofosbuvir/ribavirin (SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus (GT2-HCV). A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women (age range: 17-84 years; mean age ± SD: 60.1 ± 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma (HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon (IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9% (intention to treat: 160/182) and 94.1% (per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN-based therapy independently reduced the efficacy of SOF/RBV therapy. SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment.

Safety and Efficacy of Pegylated Interferon Lambda, Ribavirin, and Daclatasvir in HCV and HIV-Coinfected Patients.

PubMed

Nelson, Mark; Rubio, Rafael; Lazzarin, Adriano; Romanova, Svetlana; Luetkemeyer, Annie; Conway, Brian; Molina, Jean-Michel; Xu, Dong; Srinivasan, Subasree; Portsmouth, Simon

2017-03-01

To evaluate the efficacy and safety of pegylated interferon-lambda-1a (Lambda)/ribavirin (RBV)/daclatasvir (DCV) for treatment of patients coinfected with chronic hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Treatment-naive patients were assigned to cohort A [HCV genotype (GT)-2 or -3] or cohort B [HCV GT-1(a or b) or -4]. All patients received Lambda/RBV/DCV for the first 12 weeks; cohort A received Lambda/RBV for an additional 12 weeks, followed by 24 weeks of follow-up, and cohort B received response-guided therapy. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post-treatment week 12 (SVR12). In cohort A (n = 104), 84.6% achieved SVR12 (95.0% in GT-2; 83.1% in GT-3). In cohort B (n = 196), 76.0% achieved SVR12 (71.7% in GT-1a; 86.0% in GT-1b; 70.7% in GT-4). Rates of discontinuation due to adverse events (AEs) (3.8% and 6.1%) and serious AEs (5.8% and 6.1%) were low in cohorts A and B, respectively. In addition, treatment with Lambda/RBV/DCV had little impact on CD4 counts. SVR12 rates with Lambda/RBV/DCV in an HCV/HIV-coinfected population ranged from 71.7% to 95.0%. Treatment was generally well tolerated, with a low proportion of patients discontinuing due to AEs. Clinical trial registration NCT01866930.

Acute pancreatitis associated with interferon and ribavirin therapy in patients with chronic hepatitis C.

PubMed

Chaudhari, Swati; Park, James; Anand, Bhupinderjit S; Pimstone, Neville R; Dieterich, Douglas T; Batash, Steven; Bini, Edmund J

2004-06-01

Acute pancreatitis is a rare complication of interferon (IFN) and ribavirin (RBV) therapy. The aim of this study was to determine the incidence, clinical presentation, and outcome of acute pancreatitis in patients with chronic hepatitis C virus (HCV) infection treated with IFN and RBV combination therapy. We conducted a retrospective review of 1706 HCV-infected patients treated with IFN alpha-2b and RBV. The diagnosis of drug-induced acute pancreatitis was made based on the presence of epigastric pain, elevated amylase and lipase levels, and the absence of other identifiable causes of pancreatitis. Acute pancreatitis was diagnosed in 7 of 1706 HCV-infected patients (0.4%; 95% CI, 0.2 to 0.8%) who were treated with IFN alpha-2b and RBV. The mean age of the patients (four males and three females) was 51.4 +/- 4.7 years and the median duration of therapy prior to development of pancreatitis was 12.0 weeks (range, 4.0-21.0 weeks). All patients presented with epigastric pain associated with nausea, vomiting, and/or fever. The median amylase and lipase values at the time of diagnosis of pancreatitis were 330.0 U/L (range, 182.0-1813.0 U/L) and 500.0 U/L (range, 171.0-2778.0 U/L), respectively. IFN and RBV were discontinued in all patients at the time of diagnosis and six of the seven patients were hospitalized; one patient refused hospital admission. Pancreatitis resolved in all seven patients and none of these individuals had recurrent pancreatitis during a median follow-up of 18.0 months (range, 3.0-27.0 months). In conclusion, IFN and RBV combination therapy is a potential cause of drug-induced pancreatitis in patients with chronic HCV. In these individuals, pancreatitis is often severe enough to warrant hospital admission, although symptoms resolve promptly after discontinuation of antiviral therapy.

Early gene expression profiles of patients with chronic hepatitis C treated with pegylated interferon-alfa and ribavirin.

PubMed

Younossi, Zobair M; Baranova, Ancha; Afendy, Arian; Collantes, Rochelle; Stepanova, Maria; Manyam, Ganiraju; Bakshi, Anita; Sigua, Christopher L; Chan, Joanne P; Iverson, Ayuko A; Santini, Christopher D; Chang, Sheng-Yung P

2009-03-01

Responsiveness to hepatitis C virus (HCV) therapy depends on viral and host factors. Our aim was to assess sustained virologic response (SVR)-associated early gene expression in patients with HCV receiving pegylated interferon-alpha2a (PEG-IFN-alpha2a) or PEG-IFN-alpha2b and ribavirin with the duration based on genotypes. Blood samples were collected into PAXgene tubes prior to treatment as well as 1, 7, 28, and 56 days after treatment. From the peripheral blood cells, total RNA was extracted, quantified, and used for one-step reverse transcription polymerase chain reaction to profile 154 messenger RNAs. Expression levels of messenger RNAs were normalized with six "housekeeping" genes and a reference RNA. Multiple regression and stepwise selection were performed to assess differences in gene expression at different time points, and predictive performance was evaluated for each model. A total of 68 patients were enrolled in the study and treated with combination therapy. The results of gene expression showed that SVR could be predicted by the gene expression of signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signaling-1 in the pretreatment samples. After 24 hours, SVR was predicted by the expression of interferon-dependent genes, and this dependence continued to be prominent throughout the treatment. Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response.

Preparation of high affinity antibody for ribavirin with new haptens and residue analysis in chicken muscle, eggs and duck muscle.

PubMed

Wang, Zhaopeng; Yu, Xuezhi; Ma, Licai; Liu, Hebing; Ding, Shuangyang; Wang, Zhanhui; Zhang, Xiya; Shen, Jianzhong; Wen, Kai

2018-05-23

In this work, high affinity polyclonal antibodies for ribavirin (RBV) from new haptens were prepared and were used to analyse RBV residues in chicken muscle, eggs and duck muscle. The new haptens were synthesised with different spacers, and the best antibody was obtained with an IC 50 value as low as 0.61 ng/mL in indirect competitive enzyme-linked immunosorbent assay (ELISA). The cross-reactivities with another five antiviral drugs including amantadine, rimantadine, moroxydine, zanamivir and oseltamivir were less than 0.1%, which indicated the good specificity of the antibody. An ELISA was developed based on the antibody and applied to detect RBV in multi-food matrices. The sample preparation prior to detection only needed simple dilution after trichloroacetic acid extraction. The limits of detection were 1.07, 1.18 and 1.03 μg/kg in chicken muscle, eggs and duck muscle, respectively. Recoveries ranged from 89.0% to 112.7% with coefficients of variation below 13.0%. Ten blind samples of chicken muscle were analysed simultaneously by ELISA and liquid chromatography-tandem mass spectrometry, and a good correlation between the methods was observed. The results indicated that the high affinity antibody could be applied for the simple and fast detection of RBV in multi-food matrices.

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin.

PubMed

Kast, Richard E; Hill, Quentin A; Wion, Didier; Mellstedt, Håkan; Focosi, Daniele; Karpel-Massler, Georg; Heiland, Tim; Halatsch, Marc-Eric

2017-05-01

Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration- and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

[Cognitive disturbances observed in chronic hepatitis C patients during pegylated interferon alpha and ribavirin therapy].

PubMed

Pawełczyk, Tomasz; Pawełczyk, Agnieszka; Białkowska, Jolanta; Jabłkowski, Maciej; Strzelecki, Dominik; Dworniak, Daniela; Rabe-Jabłońska, Jolanta

2008-01-01

Chronic hepatitis C (CHC) patients treated with peg-interferon alpha and ribavirin (peg-IFNalpha/RBV) complain of irritability, attention and memory disturbances which may indicate cognitive impairment associated with treatment. Assessment of the probable connection between peg-IFNalpha/RBV treatment and the development of cognitive disturbances in CHC patients. 47 CHC patients were divided into two groups: experimental (n=26) and control (n=21). The experimental group patients were given peg-IFNalpha2a (n=18) or peg-IFNalpha2b (n=8) plus RBV in standard doses as recommended by the manufacturers. Control group patients did not receive the above treatment. Both groups underwent a neuropsychological examination consisting of R. Brickenkamp d2 test, Auditory Verbal Learning Test and Hooper Visual Organization Test at the beginning (t=0) and after 12 weeks of treatment or observation (t=1). The experimental group patients showed significant deterioration in all the measured cognitive functions in t=1 comparing to t=0. Cognitive decline was not seen in the control group. The observed cognitive performance changes could not be correlated sufficiently enough with the presence of organic affective disorders diagnosed according to ICD-10 criteria. The findings suggest that peg-IFNalpha/RBV therapy of CHC patients is connected with the deterioration in cognitive functioning including attention, auditory verbal memory and visuo-spatial skills. These changes may be the effect of peg-IFNalpha-induced neurotransmission abnormalities in the dorso-lateral prefrontal cortex, anterior cingulate cortex, hippocampus and parieto-orbital cortical regions and can impair patients' ability to drive a motor vehicle, operate machinery, or their engagement in hazardous activities requiring attention and coordination. Medical professionals should thoroughly inform patients about the possibility of cognitive decline associated with peg-IFNalpha/RBV therapy.

Hepatitis C virus therapy with peg-interferon and ribavirin in Myanmar: A resource-constrained country

PubMed Central

Hlaing, Naomi Khaing Than; Banerjee, Debolina; Mitrani, Robert; Arker, Soe Htet; Win, Kyaw San; Tun, Nyan Lin; Thant, Zaw; Win, Khin Maung; Reddy, K Rajender

2016-01-01

AIM To investigate peg-interferon (peg-IFN) and ribavirin (RBV) therapy in Myanmar and to predict sustained virologic response (SVR). METHODS This single-center, open-label, study was conducted in Myanmar between 2009 and 2014. A total of 288 patients infected with HCV genotypes 1, 2, 3 and 6 were treated with peg-IFN alpha-2a (180 μg/wk) or alpha-2b (50 to 100 μg as a weight-based dose) and RBV as a weight-based dose (15 mg/kg/d). Treatment duration was 48 wk for genotypes 1 and 6, 24 wk for genotype 2, and 24 or 48 wk for genotype 3 based on rapid virologic response (RVR). Those co-infected with hepatitis B received 48 wk of therapy. RESULTS Overall, SVR was achieved for 82% of patients and the therapy was well tolerated. All patients achieved SVR at equivalent rates regardless of HCV genotype (P = 0.314). Low fibrosis scores (P < 0.001), high baseline albumin levels (P = 0.028) and low baseline viral loads (P = 0.029) all independently predicted SVR. On the other hand, IL-28B TT and CC genotypes were not found to significantly predict SVR (P = 0.634; P = 0.618). Among those who completed treatment, the occurrence of RVR showed a > 96% positive predictive value for achieving SVR. Treatment duration did not significantly impact the likelihood of achieving SVR for patients infected with genotype 3 HCV (P = 0.371). The most common adverse events were fatigue (71%) and poor appetite (60%). Among patients with genotype 3 HCV, more patients in the 48-wk treatment group required erythropoietin than in the 24-wk treatment group (61.1% vs 49.2%). CONCLUSION SVR rates were high with peg-IFN and RBV therapy in Myanmar. Fibrosis scores, baseline albumin, HCV RNA levels and RVR independently predicted SVR. PMID:27920482

Hepatitis C virus therapy with peg-interferon and ribavirin in Myanmar: A resource-constrained country.

PubMed

Hlaing, Naomi Khaing Than; Banerjee, Debolina; Mitrani, Robert; Arker, Soe Htet; Win, Kyaw San; Tun, Nyan Lin; Thant, Zaw; Win, Khin Maung; Reddy, K Rajender

2016-11-21

To investigate peg-interferon (peg-IFN) and ribavirin (RBV) therapy in Myanmar and to predict sustained virologic response (SVR). This single-center, open-label, study was conducted in Myanmar between 2009 and 2014. A total of 288 patients infected with HCV genotypes 1, 2, 3 and 6 were treated with peg-IFN alpha-2a (180 μg/wk) or alpha-2b (50 to 100 μg as a weight-based dose) and RBV as a weight-based dose (15 mg/kg/d). Treatment duration was 48 wk for genotypes 1 and 6, 24 wk for genotype 2, and 24 or 48 wk for genotype 3 based on rapid virologic response (RVR). Those co-infected with hepatitis B received 48 wk of therapy. Overall, SVR was achieved for 82% of patients and the therapy was well tolerated. All patients achieved SVR at equivalent rates regardless of HCV genotype ( P = 0.314). Low fibrosis scores ( P < 0.001), high baseline albumin levels ( P = 0.028) and low baseline viral loads ( P = 0.029) all independently predicted SVR. On the other hand, IL-28B TT and CC genotypes were not found to significantly predict SVR ( P = 0.634; P = 0.618). Among those who completed treatment, the occurrence of RVR showed a > 96% positive predictive value for achieving SVR. Treatment duration did not significantly impact the likelihood of achieving SVR for patients infected with genotype 3 HCV ( P = 0.371). The most common adverse events were fatigue (71%) and poor appetite (60%). Among patients with genotype 3 HCV, more patients in the 48-wk treatment group required erythropoietin than in the 24-wk treatment group (61.1% vs 49.2%). SVR rates were high with peg-IFN and RBV therapy in Myanmar. Fibrosis scores, baseline albumin, HCV RNA levels and RVR independently predicted SVR.

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

PubMed Central

Marciano, Sebastián; Borzi, Silvia M; Dirchwolf, Melisa; Ridruejo, Ezequiel; Mendizabal, Manuel; Bessone, Fernando; Sirotinsky, María E; Giunta, Diego H; Trinks, Julieta; Olivera, Pablo A; Galdame, Omar A; Silva, Marcelo O; Fainboim, Hugo A; Gadano, Adrián C

2015-01-01

AIM: To evaluate pre-treatment factors associated with sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 3 treated with peginterferon and ribavirin (RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index, steatosis, INFL3 polymorphism, pre-treatment HCV-RNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1 (± 1.8) wk. Overall, 58% (62/107) of the patients achieved an SVR and 42% (45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/mL (OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis (OR = 0.278, 95%CI: 0.113-0.684, P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥ 600000 UI/mL and advanced fibrosis, the probability of achieving an SVR was 29% (95%CI: 13.1-45.2). In patients with pre-treatment HCV-RNA < 600000 UI/mL and mild to moderate fibrosis, the probability of achieving an SVR was 81% (95%CI: 68.8-93.4). CONCLUSION: In patients with HCV genotype 3 infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agents-based regimes. PMID:25866607

Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness two years after treatment with Ombitasvir/Paritaprevir/Ritonavir ±Dasabuvir ±Ribavirin in the AMBER, real-world experience study.

PubMed

Flisiak, Robert; Janczewska, Ewa; Łucejko, Mariusz; Karpińska, Ewa; Zarębska-Michaluk, Dorota; Nazzal, Khalil; Bolewska, Beata; Białkowska, Jolanta; Berak, Hanna; Fleischer-Stępniewska, Katarzyna; Tomasiewicz, Krzysztof; Karwowska, Kornelia; Simon, Krzysztof; Piekarska, Anna; Tronina, Olga; Tuchendler, Ewelina; Garlicki, Aleksander

2018-06-11

We followed for 2 years patients treated with Direct Acting Agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction of liver stiffness (LS), and risk of hepatocellular carcinoma (HCC).The study included patients from 16 hepatologic centers involved in the AMBER, investigators initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of Ombitasvir/Paritaprevir/ritonavir±Dasabuvir±Ribavirin. A total of 204 patients among 209 from the primary study were enrolled; 200 with available testing at 2 years follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 non-responders retreated). During 2yFU 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses was lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, two-years follow-up confirmed durability of virologic response after treatment of HCV infection with Ombitasvir/Paritaprevir/ritonavir±Dasabuvir±Ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics, that support the need for longer than 2-year monitoring for possible disease progression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pegylated interferon and ribavirin for the recurrence of chronic hepatitis C genotype 1 in transplant patients.

PubMed

Oton, E; Barcena, R; Garcia-Garzon, S; Moreno-Zamora, A; Moreno, A; Garcia-Gonzalez, M; Blesa, C; Foruny, J R; Ruiz, P

2005-11-01

The efficacy of pegylated interferon (p-IFN) and ribavirin (RB) in transplant patients is not well known. Chronic hepatitis C evolves in a more aggressive form after transplantation, causing a worse survival. Twenty-one naïve patients with recurrent chronic hepatitis C demonstrated by biopsy were treated for 48 weeks with p-IFN alpha2b (1.5 microg/kg/wk) and RB (>10.6 mg/kg/d). Quantification of RNA was performed (Amplicor Cobas 2.0 Roche) at baseline, 4, 12, 24, 48, and 72 weeks. A qualitative technique was used when quantitative levels were undetectable. At more than 1 year since liver transplantation we did not detect coinfection with human immunodeficiency virus or use steroid treatment. Among the cohort there were 16 men (76.2%). The mean overall age was 52 +/- 12 years. Time from liver transplant to treatment was 1637 +/- 1030 days. They were all infected with genotype 1. Eight patients received cyclosporine and the others tacrolimus. One patient was coinfected with hepatitis B virus and was receiving lamivudine. The mean initial histological activity index was 6.9 +/- 1.5 and fibrosis, 2.52 +/- 1.8 (Ishak). Two patients needed spleen embolization before the treatment. Two patients had to stop the treatment: one due to clinical intolerance, and the other one due to a cholangitis. In 14%, p-IFN doses were adjusted. In 32% RB was adjusted. Five (23.8%) did not respond at 24 weeks. Fourteen (66.7%) showed end-treatment responses but four relapsed at 72 weeks. A sustained viral response was achieved in 9 (42.8%). One patient died due to arterial thrombosis just after completing the treatment.

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.

PubMed

Manns, Michael; Samuel, Didier; Gane, Edward J; Mutimer, David; McCaughan, Geoff; Buti, Maria; Prieto, Martín; Calleja, José Luis; Peck-Radosavljevic, Markus; Müllhaupt, Beat; Agarwal, Kosh; Angus, Peter; Yoshida, Eric M; Colombo, Massimo; Rizzetto, Mario; Dvory-Sobol, Hadas; Denning, Jill; Arterburn, Sarah; Pang, Phillip S; Brainard, Diana; McHutchison, John G; Dufour, Jean-François; Van Vlierberghe, Hans; van Hoek, Bart; Forns, Xavier

2016-06-01

Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP

Pegylated interferon α-2b plus ribavirin for older patients with chronic hepatitis C

PubMed Central

Kainuma, Mosaburo; Furusyo, Norihiro; Kajiwara, Eiji; Takahashi, Kazuhiro; Nomura, Hideyuki; Tanabe, Yuichi; Satoh, Takeaki; Maruyama, Toshihiro; Nakamuta, Makoto; Kotoh, Kazuhiro; Azuma, Koichi; Shimono, Junya; Shimoda, Shinji; Hayashi, Jun; Group, The Kyushu University Liver Disease Study

2010-01-01

AIM: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) α-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV). METHODS: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 μg/kg per week PEG-IFN α-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk. RESULTS: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN α-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%). CONCLUSION: PEG-IFN α-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage. PMID:20845506

Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction.

PubMed

Sho, Takuya; Suda, Goki; Nagasaka, Atsushi; Yamamoto, Yoshiya; Furuya, Ken; Kumagai, Kenichi; Uebayashi, Minoru; Terashita, Katsumi; Kobayashi, Tomoe; Tsunematsu, Izumi; Onodera, Manabu; Meguro, Takashi; Kimura, Megumi; Ito, Jun; Umemura, Machiko; Izumi, Takaaki; Kawagishi, Naoki; Ohara, Masatsugu; Ono, Yuji; Nakai, Masato; Natsuizaka, Mitsuteru; Morikawa, Kenichi; Ogawa, Koji; Sakamoto, Naoya

2018-06-01

The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction. © 2018 The Japan Society of Hepatology.

Development and validation of a dried blood spot assay for the quantification of ribavirin using liquid chromatography coupled to mass spectrometry

PubMed Central

Jimmerson, Leah C.; Zheng, Jia-Hua; Bushman, Lane R.; MacBrayne, Christine E.; Anderson, Peter L.; Kiser, Jennifer J.

2014-01-01

Efficient, inexpensive and sensitive assays for the measurement of drugs are of interest for pharmacokinetic and pharmacodynamics (PK-PD) analysis. Dried blood spots (DBS) are a unique bioanaltyical matrix with the potential to fulfill this interest for the measurement of numerous analytes. Here we describe the development and validation of a reversed-phase high performance liquid chromatographic (LC), tandem mass spectrometry (MS/MS) assay for the determination of ribavirin (RBV) in DBS. A 3mm punch from spotted and dried whole blood was extracted in methanol utilizing isotopically labeled internal standard for LC-MS/MS analysis. Validation was performed over a range of 0.05 μg/mL to 10.0 μg/mL and the method was shown to be precise (coefficient of variation ≤ 15%) and accurate (within ±15% of control). These acceptance criteria were met for hematocrit ranges of 20-54%, for center versus edge punches and for spot volumes from 10-60 μL. RBV was stable for up to 140 days at room temperature and −20°C as well as for three freeze/thaw cycles. Correlation of RBV in DBS versus in plasma yielded r2 ≥ 0.98 demonstrating that DBS can be used as an alternative to plasma for PK-PD studies in human subjects. PMID:24291608

Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone.

PubMed

Dahmane, A; van Griensven, J; Van Herp, M; Van den Bergh, R; Nzomukunda, Y; Prior, J; Alders, P; Jambai, A; Zachariah, R

2014-03-01

Lassa fever (LF) is an acute viral haemorrhagic infection, endemic in West Africa. Confirmatory diagnosis and treatment (ribavirin) is difficult, expensive, and restricted to specialised hospitals. Among confirmed and suspected LF cases, we report on clinical and laboratory features, timing and administration of ribavirin and the relationship with case fatality. We conducted an audit of patient files of suspected LF cases admitted to a pediatric and obstetric referral hospital in rural Sierra Leone (April 2011 to February 2012). There were 84 suspected LF cases; 36 (43%) were laboratory-confirmed cases, of whom only 20 (56%) received ribavirin after a median duration of eight days (IQR 314 days) of hospital admission. Of 16 patients who did not receive ribavirin, 14 (87%) died before ribavirin treatment could be commenced. Starting ribavirin within six days of admission was associated with a case fatality of 29% (2/7), while starting ribavirin later than six days was associated with a case fatality of 50% (6/12). Among the 48 suspected LF cases without laboratory confirmation, there were 21 (44%) deaths. These findings highlight shortcomings in LF management, including diagnostic and treatment delays. More research and development efforts should be devoted to this 'neglected disease'.

Effectiveness and safety of ledipasvir/sofosbuvir±ribavirin in the treatment of HCV infection: The real-world HARVEST study.

PubMed

Flisiak, Robert; Łucejko, Mariusz; Mazur, Włodzimierz; Janczewska, Ewa; Berak, Hanna; Tomasiewicz, Krzysztof; Mozer-Lisewska, Iwona; Kozielewicz, Dorota; Gietka, Andrzej; Sikorska, Katarzyna; Wawrzynowicz-Syczewska, Marta; Nowak, Krzysztof; Zarębska-Michaluk, Dorota; Musialik, Joanna; Simon, Krzysztof; Garlicki, Aleksander; Pleśniak, Robert; Baka-Ćwierz, Barbara; Olszok, Iwona; Augustyniak, Krystyna; Stolarz, Wojciech; Białkowska, Jolanta; Badurek, Anna; Piekarska, Anna

2017-09-01

To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen in a real-world setting. Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Of the 86 patients, aged 20-80 years, 82.6% were HCV genotype 1b-infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null-responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia. Treatment with LDV/SOF±RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan.

PubMed

Kumada, Hiromitsu; Toyota, Joji; Okanoue, Takeshi; Chayama, Kazuaki; Tsubouchi, Hirohito; Hayashi, Norio

2012-01-01

To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B). HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020). Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required. Copyright © 2011. Published by Elsevier B.V.

Constraints in the diagnosis and treatment of Lassa Fever and the effect on mortality in hospitalized children and women with obstetric conditions in a rural district hospital in Sierra Leone

PubMed Central

Dahmane, A.; van Griensven, J.; Van Herp, M.; Van den Bergh, R.; Nzomukunda, Y.; Prior, J.; Alders, P.; Jambai, A.; Zachariah, R.

2014-01-01

Background Lassa fever (LF) is an acute viral haemorrhagic infection, endemic in West Africa. Confirmatory diagnosis and treatment (ribavirin) is difficult, expensive, and restricted to specialised hospitals. Among confirmed and suspected LF cases, we report on clinical and laboratory features, timing and administration of ribavirin and the relationship with case fatality. Methods We conducted an audit of patient files of suspected LF cases admitted to a pediatric and obstetric referral hospital in rural Sierra Leone (April 2011 to February 2012). Results There were 84 suspected LF cases; 36 (43%) were laboratory-confirmed cases, of whom only 20 (56%) received ribavirin after a median duration of eight days (IQR 314 days) of hospital admission. Of 16 patients who did not receive ribavirin, 14 (87%) died before ribavirin treatment could be commenced. Starting ribavirin within six days of admission was associated with a case fatality of 29% (2/7), while starting ribavirin later than six days was associated with a case fatality of 50% (6/12). Among the 48 suspected LF cases without laboratory confirmation, there were 21 (44%) deaths. Conclusions These findings highlight shortcomings in LF management, including diagnostic and treatment delays. More research and development efforts should be devoted to this ‘neglected disease’. PMID:24535150

Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial.

PubMed

Pianko, Stephen; Flamm, Steven L; Shiffman, Mitchell L; Kumar, Sonal; Strasser, Simone I; Dore, Gregory J; McNally, John; Brainard, Diana M; Han, Lingling; Doehle, Brian; Mogalian, Erik; McHutchison, John G; Rabinovitz, Mordechai; Towner, William J; Gane, Edward J; Stedman, Catherine A M; Reddy, K Rajender; Roberts, Stuart K

2015-12-01

Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01909804). 58 sites in Australia, New Zealand, and the United States. Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. Treatment assignments were not blinded, and no inferential statistics were planned. Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12 weeks was well-tolerated and highly effective in treatment-experienced patients with genotype 1 or 3 HCV infection. Gilead

[Subacute sclerosing panencephalitis (SSPE)].

PubMed

Hosoya, Mitsuaki

2011-11-01

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal central nervous system disorder that results from a persistent SSPE virus infection. The efficacy of inosine pranobex, an antiviral/immunomodulator agent, remains controversial. Intraventricular interferon-alpha combined with oral inosine pranobex slows the progressive course of SSPE, but does not cure the disease. We examined a wide variety of antiviral compounds for their inhibitory effects on SSPE virus strains in vitro and in vivo, and found that ribavirin had potent inhibitory activity against SSPE. We tried to treat SSPE patients first with high-dose intravenous ribavirin therapy, and then with intraventricular ribavirin therapy. Ribavirin therapy seemed to have a certain effect on clinical courses of patients with SSPE. To reach the conclusion that ribavirin therapy is clinically effective, clinical trials on many cases will be required.

Pegylated interferon-alpha2b plus ribavirin therapy in patients with hepatitis C and psychiatric disorders: results of a cohort study.

PubMed

Lang, Jean-Philippe; Melin, Pascal; Ouzan, Denis; Rotily, Michel; Fontanges, Thierry; Marcellin, Patrick; Chousterman, Michel; Cacoub, Patrice

2010-01-01

Hepatitis C antiviral therapies have significant psychiatric side effects. It is therefore believed that they might exacerbate mental illness in patients with pre-existing psychiatric disorders, resulting in poor adherence and response to antiviral treatment. We aimed to assess adherence to treatment, virological outcomes and mental safety in psychiatric patients, compared with non-psychiatric patients, treated for hepatitis C. A cohort study involved unselected hepatitis C patients on scheduled therapy with pegylated interferon-alpha2b and ribavirin, between 2002 and 2005 in France, and followed-up until 6 months after the end of treatment. Virological response was reported by the physician according to standard definitions and adverse events were monitored. Adherence to treatment was assessed by patient report. Among 1,860 patients, 403 (22%) had pre-existing psychiatric disorders, mostly depressive and anxiety disorders. Strict adherence was similar in psychiatric and non-psychiatric patients (35% versus 39%; P=0.20) as was the rate of sustained virological response (52% versus 51%; P=0.75). Conversely the rate of mental adverse events was higher in psychiatric patients (78% versus 57%; P<0.001). Baseline characteristics independently associated with the risk of later mental adverse events were history of depression, initial pegylated interferon-alpha2b dose and female gender. Antiviral therapy in hepatitis C patients with associated psychiatric disease appears as effective as in other patients but results in a higher rate of mental adverse events, emphasizing the need for close monitoring of these psychiatric patients.

Efficacy of and risk of bleeding during pegylated interferon plus ribavirin treatment in HIV/HCV-coinfected patients with pretreatment thrombocytopenia.

PubMed

Mira, J A; Neukam, K; López-Cortés, L F; Rivero-Juárez, A; Téllez, F; Girón-González, J A; de los Santos-Gil, I; Ojeda-Burgos, G; Merino, D; Ríos-Villegas, M J; Collado, A; Torres-Cornejo, A; Macías, J; Rivero, A; Pérez-Pérez, M; Pineda, J A

2015-09-01

The aim of this study was to assess the efficacy of and the risk of major bleeding during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients according to the pretreatment platelet count. Two hundred and seventy-four HCV/HIV-coinfected, previously naïve individuals with compensated cirrhosis enrolled in one Spanish prospective cohort who received peg-IFN/RBV were included in this study. The frequency of severe bleeding and sustained virological response (SVR) rate were compared between patients with a pretreatment platelet count ≤70,000/mm(3) and >70,000/mm(3), respectively. Sixty-one (22 %) patients had a baseline platelet count ≤70,000/mm(3). The median (Q1-Q3) pretreatment platelet count was 58,000 (49,000-65,000) cells/mm(3) in the platelet ≤70,000 group and 129,000 (102,500-166,000) cells/mm(3) in the platelet >70,000 group (p < 0.0001). Seventeen (28 %) subjects of the platelet ≤70,000 group and 71 (33 %) patients of the platelet >70,000 group achieved SVR (p = 0.4). Only 2 (3.2 %) patients in the platelet ≤70,000 group developed a severe hemorrhagic event, specifically esophageal variceal bleeding. The efficacy of therapy with peg-IFN/RBV in HIV/HCV-coinfected patients with low pretreatment platelet counts is comparable to that found in the overall subset of subjects with compensated cirrhosis. The frequency of severe hemorrhagic events related with this therapy is low in this population.

Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study.

PubMed

Terrier, Benjamin; Lapidus, Nathanael; Pol, Stanislas; Serfaty, Lawrence; Ratziu, Vlad; Asselah, Tarik; Thibault, Vincent; Souberbielle, Jean-Claude; Carrat, Fabrice; Cacoub, Patrice

2015-05-14

To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin (PegIFN/RBV) therapy could improve the efficacy of PegIFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection. Genotype 1 or 4 HCV-infected patients with null response to previous PegIFN/RBV treatment and with hypovitaminosis D (< 30 ng/mL) prospectively received cholecalciferol 100000 IU per week for 4 wk [from week -4 (W-4) to W0], followed by 100000 IU per month in combination with PegIFN/RBV for 12 mo (from W0 to W48). The primary outcome was the rate of early virological response defined by an HCV RNA < 12 IU/mL after 12 wk PegIFN/RBV treatment. A total of 32 patients were included, 19 (59%) and 13 (41%) patients were HCV genotype 1 and 4, respectively. The median baseline vitamin D level was 15 ng/mL (range: 7-28). In modified intention-to-treat analysis, 29 patients who received at least one dose of PegIFN/RBV were included in the analysis. All patients except one normalized their vitamin D serum levels. The rate of early virologic response was 0/29 (0%). The rate of HCV RNA < 12 IU/mL after 24 wk of PegIFN/RBV was 1/27 (4%). The safety profile was favorable. Addition of vitamin D to PegIFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1 or 4 HCV infection.

Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

PubMed Central

Wang, K.; Blotner, S.; Magnusson, M. O.; Wilkins, J. J.; Martin, P.; Solsky, J.; Nieforth, K.; Wat, C.; Grippo, J. F.

2013-01-01

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0–12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients. PMID:24080649

Sofosbuvir/Ledipasvir Without Ribavirin Achieved High Sustained Virologic Response for Hepatitis C Recurrence After Liver Transplantation: Two-Center Experience.

PubMed

Elfeki, Mohamed A; Abou Mrad, Rachel; Modaresi Esfeh, Jamak; Zein, Nizar N; Eghtesad, Bijan; Zervos, Xaralambos; Hanouneh, Ibrahim A; O'Shea, Robert; Carey, William D; Alkhouri, Naim

2017-05-01

Current recommended regimens to treat patients with hepatitis C virus (HCV) infection after liver transplantation include the use of ribavirin (RBV). Limited data are available on the efficacy of RBV-free regimens posttransplant, particularly the use of sofosbuvir (SOF)/ledipasvir (LDV) without RBV in this patient population. We aimed to assess the efficacy and safety of SOF/LDV fixed-dose combination without RBV in patients with HCV recurrence posttransplant. This is a retrospective study of 46 patients with HCV recurrence posttransplant. SOF/LDV without RBV was used for 12 weeks in patients with early-stage fibrosis (F0-F2) or for 24 weeks in those with advanced fibrosis (F3-F4) and/or cholestatic hepatitis. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment. Secondary outcomes included relapse after treatment and adverse events. Forty-six patients, with a mean age of 62 ± 8 years, a median duration since time of transplant of 904 days (range, 78-3525 days), an HCV genotype 1, and a mean baseline viral load of 7.79 million IU/mL, were treated. Of these, 32 patients were treated for 12 weeks, and 14 patients were treated for 24 weeks. Twenty-five patients (54%) were treatment experienced (21 with interferon and 4 with SOF). All 46 patients (100%) achieved sustained virological response (SVR) 12. Neither virologic relapses nor serious adverse events were noted. The combination of SOF/LDV without RBV for 12 or 24 weeks produced 100% SVR 12 in patients with HCV recurrence after liver transplantation. The use of RBV may not be necessary to achieve SVR in this patient population.

Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection ▿

PubMed Central

Rivas-Aravena, Andrea; Vallejos-Vidal, Eva; Cortez-San Martin, Marcelo; Reyes-Lopez, Felipe; Tello, Mario; Mora, Patricia; Sandino, Ana María; Spencer, Eugenio

2011-01-01

The infectious salmon anemia virus (ISAV), which belongs to the Orthomyxoviridae family, has been responsible for major losses in the salmon industry, with mortalities close to 100% in areas where Atlantic salmon (Salmo salar) is grown. This work studied the effect of ribavirin (1-β-d-ribofuranosyl-1,2,3-triazole-3-carbaxaide), a broad-spectrum antiviral compound with proven ability to inhibit the replicative cycle of the DNA and RNA viruses. The results show that ribavirin was able to inhibit the infectivity of ISAV in in vitro assays. In these assays, a significant inhibition of the replicative viral cycle was observed with a 50% inhibitory concentration (IC50) of 0.02 μg/ml and an IC90 of 0.4 μg/ml of ribavirin. After ribavirin treatment, viral proteins were not detectable and a reduction of viral mRNA association with ribosomes was observed. Ribavirin does not affect the levels of EF1a, nor its association with polysomes, suggesting that the inhibition of RNA synthesis occurs specifically for the virus mRNAs and not for cellular mRNAs. Moreover, ribavirin caused a significant reduction in genomic and viral RNA messenger levels. The study of the inhibitory mechanism showed that it was not reversed by the addition of guanosine. Furthermore, in vivo assays showed a reduction in the mortality of Salmo salar by more than 90% in fish infected with ISAV and treated with ribavirin without adverse effects. In fact, these results show that ribavirin is an antiviral that could be used to prevent ISAV replication either in vitro or in vivo. PMID:21653663

Type 1 Diabetes Mellitus Associated with Pegylated Interferon-α Plus Ribavirin Treatment for Chronic Hepatitis C: Case Report and Literature Review.

PubMed

Oka, Reiko; Hiroi, Naoki; Shigemitsu, Rika; Sue, Mariko; Oshima, Yasuo; Yoshida-Hiroi, Mayumi

2011-01-01

Combined pegylated interferon (PEG-IFN)+ribavirin (RBV) therapy has been used as a primary treatment for chronic hepatitis C. However, IFN-induced autoimmune disease, including type 1 diabetes mellitus, has been highlighted as one of the problems with this therapy. Here we report the case of a patient who developed type 1 diabetes mellitus during combined PEG-IFN+RBV therapy for hepatitis C but who showed no exacerbation of diabetes despite continued use of IFN. A 63-year-old man with chronic hepatitis C and a nonresponder to previous IFNα treatments, was admitted to our hospital because of excessive thirst, polydipsia, and polyuria 24 weeks after the start of PEG-IFNα+RBV therapy. High levels of blood glucose and glycosylated hemoglobin and low levels of C-peptide and immunoreactive insulin were observed. The serum antiglutamic acid decarboxylase antibody titer was 27,700 U/mL. We diagnosed IFN-induced type 1 diabetes mellitus; however PEG-IFNα+RBV therapy was continued for 48 weeks. Serum HCV remains negative five years after this treatment. Intensive insulin therapy was started immediately after the diagnosis of type 1 diabetes. Although the patient initially required 22 U/day of insulin, the dosage could be gradually reduced after completion of PEG-IFNα+RBV therapy and blood glucose remained well controlled. Prediction of onset of type 1 diabetes mellitus on the basis of baseline measurement of pancreas-associated autoantibodies is difficult. Therefore, it would be advisable to consider the possibility of onset of type 1 diabetes mellitus in all patients receiving IFN+RBV therapy.

Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report.

PubMed

Yamamoto, Takatsugu; Tanaka, Shogo; Uenishi, Takahiro; Kanazawa, Akishige; Kubo, Shoji; Hirohashi, Kazuhiro

2014-12-01

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

Long-term follow-up of previous hepatitis C virus positive nonresponders to interferon monotherapy successfully retreated with combination therapy: are they really cured?

PubMed

Ciancio, Alessia; Smedile, Antonina; Giordanino, Chiara; Colletta, Cosimo; Croce, Guido; Pozzi, Massimo; Cariti, Giuseppe; Macor, Antonio; Biglino, Alberto; Di Napoli, Angelo; Tappero, Gian Franco; Andreoni, Massimo; Manca, Aldo; Prandi, Giancarlo; Calleri, Guido; Orsi, Pier Giulio; Ciccone, Giovannino; Rizzetto, Mario; Saracco, Giorgio

2006-08-01

To evaluate whether in chronic hepatitis C-positive patients who failed to respond to interferon (IFN) monotherapy a sustained response obtained with retreatment using the combination therapy of IFN + ribavirin can be safely considered to reflect eradication of the infection. Prospective follow-up of a cohort of 97 patients who responded to retreatment with different regimens of IFN + ribavirin after failing to respond to a first IFN monotherapy course. The patients were followed throughout 7 yr of follow-up with determinations of HCV viremia every 6 months. At the end of the follow-up, 11 patients (11.3%) showed a viremic reappearance. HCV late relapse rates were 0%, 13%, 20%, and 12% in patients retreated, respectively, with 3 MU IFN + ribavirin for 12 months (Group 1), 5 MU IFN + ribavirin for 12 months (Group 2), 3 MU IFN + ribavirin for 6 months (Group 3), and 5 MU IFN + ribavirin for 6 months (Group 4) (Group 2 vs Group 3, p= 0.005). The virologic relapses occurred within 2 yr from therapy withdrawal. Among patients with genotype 1 and 4, the long-term response was significantly higher in Group 2 than in Group 3 (15%vs 3%, p= 0.03). In patients with genotype 2 and 3, the long-term virological response was not affected by the different regimens. Nonresponders to IFN monotherapy who achieve a sustained virologic response after retreatment with IFN + ribavirin stand a discrete risk of HCV reactivation within 2 yr after therapy.

Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection.

PubMed

Lawitz, Eric; Sullivan, Greg; Rodriguez-Torres, Maribel; Bennett, Michael; Poordad, Fred; Kapoor, Mudra; Badri, Prajakta; Campbell, Andrew; Rodrigues, Lino; Hu, Yiran; Pilot-Matias, Tami; Vilchez, Regis A

2015-02-01

To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naïve, non-cirrhotic adults with chronic HCV genotype 1-3 infection. Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint. Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was

Coadministration of ezetimibe with pegylated interferon plus ribavirin could improve early virological response in chronic hepatitis C obese Egyptian patients.

PubMed

Helal, Gouda K; Gad, Magdy A; Abd-Ellah, Mohamed F; Mahgoup, Elsayed M

2016-05-01

Ezetimibe has been reported to inhibit viral entry and to reduce BMI and has been proposed as a novel therapeutic agent for chronic hepatitis C (CHC), potentiating the effects of pegylated interferon and ribavirin (peg-IFN/RBV). The aim of the study was to assess the effects of ezetimibe coadministration with peg-IFN/RBV combination on the early virological response (EVR) rates in nonobese and obese patients with CHC genotype 4 (CHC-4). A total of 144 CHC-4 patients were divided into two groups; group 1 included nonobese patients (n=76) and group 2 included obese patients (n=68). Each group was further subclassified into equal control and treated groups. The control groups received peg-IFN/RBV combination for 24 weeks, and the treated groups received peg-IFN/RBV plus ezetimibe for 12 weeks and then only peg-IFN/RBV for the remaining 12 weeks. The study revealed that EVR significantly improved in the obese patients (85.3 vs. 64.7% in the treated and control groups, respectively, at P<0.05) without any significant improvement in the nonobese patients. Biochemical responses (defined as normalization of alanine aminotransferase at week 12) were markedly improved in the treated groups in both the nonobese and obese groups compared with their respective controls. The addition of ezetimibe to peg-IFN/RBV combination significantly improves EVR rates in obese patients compared with nonobese patients, and remarkably improves the biochemical responses in both obese and nonobese patients with CHC-4. This may shed light on a new strategy for the treatment of CHC, particularly in obese Egyptian patients.

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

PubMed

Jacobson, Ira M; Brown, Robert S; Freilich, Bradley; Afdhal, Nezam; Kwo, Paul Y; Santoro, John; Becker, Scott; Wakil, Adil E; Pound, David; Godofsky, Eliot; Strauss, Robert; Bernstein, David; Flamm, Steven; Pauly, Mary Pat; Mukhopadhyay, Pabak; Griffel, Louis H; Brass, Clifford A

2007-10-01

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Impact of HIV infection on sustained virological response to treatment against hepatitis C virus with pegylated interferon plus ribavirin.

PubMed

Monje-Agudo, P; Castro-Iglesias, A; Rivero-Juárez, A; Martínez-Marcos, F; Ortega-González, E; Real, L M; Pernas, B; Merchante, N; Cid, P; Macías, J; Merino, M D; Rivero, A; Mena, A; Neukam, K; Pineda, J A

2015-10-01

It is commonly accepted that human immunodeficiency (HIV) coinfection negatively impacts on the rates of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin (PR). However, this hypothesis is derived from comparing different studies. The aim of this study was to determine the impact of HIV coinfection on SVR to PR in one single population. In a multicentric, prospective study conducted between 2000 and 2013, all previously naïve hepatitis C virus (HCV)-infected patients who started PR in five Spanish hospitals were analyzed. SVR was evaluated 24 weeks after the scheduled end of therapy. Of the 1046 patients included in this study, 413 (39%) were coinfected with HIV. Three hundred and forty-one (54%) HCV-monoinfected versus 174 (42%) HIV/HCV-coinfected patients achieved SVR (p < 0.001). The corresponding figures for undetectable HCV RNA at treatment week 4 were 86/181 (47%) versus 59/197 (30%), p < 0.001. SVR was observed in 149 (69%) HCV genotype 2/3-monoinfected subjects versus 91 (68%) HIV/HCV genotype 2/3-coinfected subjects (p = 0.785). In the HCV genotype 1/4-infected population, 188 (46%) monoinfected patients versus 82 (30%) with HIV coinfection (p < 0.001) achieved SVR. In this subgroup, absence of HIV coinfection was independently associated with higher SVR [adjusted odds ratio (95% confidence interval): 2.127 (1.135-3.988); p = 0.019] in a multivariate analysis adjusted for age, sex, baseline HCV RNA load, IL28B genotype, fibrosis stage, and type of pegylated interferon. HIV coinfection impacts on the rates of SVR to PR only in HCV genotype 1/4-infected patients, while it has no effect on SVR in the HCV genotype 2/3-infected subpopulation.

Benefit of hepatitis C virus core antigen assay in prediction of therapeutic response to interferon and ribavirin combination therapy.

PubMed

Takahashi, Masahiko; Saito, Hidetsugu; Higashimoto, Makiko; Atsukawa, Kazuhiro; Ishii, Hiromasa

2005-01-01

A highly sensitive second-generation hepatitis C virus (HCV) core antigen assay has recently been developed. We compared viral disappearance and first-phase kinetics between commercially available core antigen (Ag) assays, Lumipulse Ortho HCV Ag (Lumipulse-Ag), and a quantitative HCV RNA PCR assay, Cobas Amplicor HCV Monitor test, version 2 (Amplicor M), to estimate the predictive benefit of a sustained viral response (SVR) and non-SVR in 44 genotype 1b patients treated with interferon (IFN) and ribavirin. HCV core Ag negativity could predict SVR on day 1 (sensitivity = 100%, specificity = 85.0%, accuracy = 86.4%), whereas RNA negativity could predict SVR on day 7 (sensitivity = 100%, specificity = 87.2%, accuracy = 88.6%). None of the patients who had detectable serum core Ag or RNA on day 14 achieved SVR (specificity = 100%). The predictive accuracy on day 14 was higher by RNA negativity (93.2%) than that by core Ag negativity (75.0%). The combined predictive criterion of both viral load decline during the first 24 h and basal viral load was also predictive for SVR; the sensitivities of Lumipulse-Ag and Amplicor-M were 45.5 and 47.6%, respectively, and the specificity was 100%. Amplicor-M had better predictive accuracy than Lumipulse-Ag in 2-week disappearance tests because it had better sensitivity. On the other hand, estimates of kinetic parameters were similar regardless of the detection method. Although the correlations between Lumipulse-Ag and Amplicor-M were good both before and 24 h after IFN administration, HCV core Ag seemed to be relatively lower 24 h after IFN administration than before administration. Lumipulse-Ag seems to be useful for detecting the HCV concentration during IFN therapy; however, we still need to understand the characteristics of the assay.

Benefit of Hepatitis C Virus Core Antigen Assay in Prediction of Therapeutic Response to Interferon and Ribavirin Combination Therapy

PubMed Central

Takahashi, Masahiko; Saito, Hidetsugu; Higashimoto, Makiko; Atsukawa, Kazuhiro; Ishii, Hiromasa

2005-01-01

A highly sensitive second-generation hepatitis C virus (HCV) core antigen assay has recently been developed. We compared viral disappearance and first-phase kinetics between commercially available core antigen (Ag) assays, Lumipulse Ortho HCV Ag (Lumipulse-Ag), and a quantitative HCV RNA PCR assay, Cobas Amplicor HCV Monitor test, version 2 (Amplicor M), to estimate the predictive benefit of a sustained viral response (SVR) and non-SVR in 44 genotype 1b patients treated with interferon (IFN) and ribavirin. HCV core Ag negativity could predict SVR on day 1 (sensitivity = 100%, specificity = 85.0%, accuracy = 86.4%), whereas RNA negativity could predict SVR on day 7 (sensitivity = 100%, specificity = 87.2%, accuracy = 88.6%). None of the patients who had detectable serum core Ag or RNA on day 14 achieved SVR (specificity = 100%). The predictive accuracy on day 14 was higher by RNA negativity (93.2%) than that by core Ag negativity (75.0%). The combined predictive criterion of both viral load decline during the first 24 h and basal viral load was also predictive for SVR; the sensitivities of Lumipulse-Ag and Amplicor-M were 45.5 and 47.6%, respectively, and the specificity was 100%. Amplicor-M had better predictive accuracy than Lumipulse-Ag in 2-week disappearance tests because it had better sensitivity. On the other hand, estimates of kinetic parameters were similar regardless of the detection method. Although the correlations between Lumipulse-Ag and Amplicor-M were good both before and 24 h after IFN administration, HCV core Ag seemed to be relatively lower 24 h after IFN administration than before administration. Lumipulse-Ag seems to be useful for detecting the HCV concentration during IFN therapy; however, we still need to understand the characteristics of the assay. PMID:15634970

Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens.

PubMed

Vasanthakumar, Aparna; Davis, Justin W; Abunimeh, Manal; Söderholm, Jonas; Zha, Jiuhong; Dumas, Emily O; Cohen, Daniel E; Waring, Jeffrey F; Lagging, Martin

2018-01-01

Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections. To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens. In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV. Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels. Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.

Cost-effectiveness analysis of sofosbuvir plus peginterferon/ribavirin in the treatment of chronic hepatitis C virus genotype 1 infection.

PubMed

Saab, S; Gordon, S C; Park, H; Sulkowski, M; Ahmed, A; Younossi, Z

2014-09-01

Sofosbuvir, an oral NS5B nucleotide polymerase inhibitor, is indicated for the treatment of patients infected with hepatitis C virus (HCV). To evaluate the long-term health economic outcomes of sofosbuvir + pegylated interferon alfa/ribavirin (pegIFN/RBV) compared with current treatments in patients infected with HCV genotype 1 in the US. A decision-analytic Markov model was developed to estimate health outcomes, number needed to treat and short-term and long-term economic outcomes, including incremental cost-effectiveness ratios and cost per sustained virological response (SVR), for several sofosbuvir-comparator regimen pairings for a cohort of 10 000 patients. It considered three patient cohorts: treatment-naïve, treatment-experienced and treatment-naïve human immunodeficiency virus (HIV) co-infected. Subgroup analyses were conducted for treatment-naïve patients with and without cirrhosis. Reductions in the incidence of new cases of liver-disease complications with sofosbuvir + pegIFN/RBV compared with pegIFN/RBV, boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV were 64-82%, 50-68%, 43-58% and 33-56%, respectively. Sofosbuvir + pegIFN/RBV was typically associated with the lowest 1-year cost per SVR. When considering the lifetime incremental cost per quality-adjusted life-year gained, sofosbuvir + pegIFN/RBV was the most cost-effective treatment option assessed. Sofosbuvir + pegIFN/RBV generally dominated (less costly and more effective than) boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV. Sofosbuvir + pegIFN/RBV yields more favourable future health and economic outcomes than current treatment regimens for patients across all levels of treatment experience and cirrhosis stage, as well as for individuals with or without HIV co-infection. © 2014 John Wiley & Sons Ltd.

Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin.

PubMed

Jimenez-Sousa, Maria Angeles; Almansa, Raquel; de la Fuente, Concha; Caro-Paton, Agustín; Ruiz, Lourdes; Sanchez-Antolín, Gloria; Gonzalez, Jose Manuel; Aller, Rocio; Alcaide, Noelia; Largo, Pilar; Resino, Salvador; de Lejarazu, Raul Ortiz; Bermejo-Martin, Jesus F

2010-06-01

Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF

Determination and Therapeutic Exploitation of Ebola Virus Spontaneous Mutation Frequency.

PubMed

Alfson, Kendra J; Worwa, Gabriella; Carrion, Ricardo; Griffiths, Anthony

2015-12-16

Ebola virus (EBOV) is an RNA virus that can cause hemorrhagic fever with high fatality rates, and there are no approved vaccines or therapies. Typically, RNA viruses have high spontaneous mutation rates, which permit rapid adaptation to selection pressures and have other important biological consequences. However, it is unknown if filoviruses exhibit high mutation frequencies. Ultradeep sequencing and a recombinant EBOV that carries the gene encoding green fluorescent protein were used to determine the spontaneous mutation frequency of EBOV. The effects of the guanosine analogue ribavirin during EBOV infections were also assessed. Ultradeep sequencing revealed that the mutation frequency for EBOV was high and similar to those of other RNA viruses. Interestingly, significant genetic diversity was not observed in viable viruses, implying that changes were not well tolerated. We hypothesized that this could be exploited therapeutically. In vitro, the presence of ribavirin increased the error rate, and the 50% inhibitory concentration (IC50) was 27 μM. In a mouse model of ribavirin therapy given pre-EBOV exposure, ribavirin treatment corresponded with a significant delay in time to death and up to 75% survival. In mouse and monkey models of therapy given post-EBOV exposure, ribavirin treatment also delayed the time to death and increased survival. These results demonstrate that EBOV has a spontaneous mutation frequency similar to those of other RNA viruses. These data also suggest a potential for therapeutic use of ribavirin for human EBOV infections. Ebola virus (EBOV) causes a severe hemorrhagic disease with high case fatality rates; there are no approved vaccines or therapies. We determined the spontaneous mutation frequency of EBOV, which is relevant to understanding the potential for the virus to adapt. The frequency was similar to those of other RNA viruses. Significant genetic diversity was not observed in viable viruses, implying that changes were not well

Homozygosity for HLA group 2 alleles predicts treatment failure with interferon-α and ribavirin in chronic hepatitis C virus genotype 1 infection.

PubMed

Collison, Meadhbh; Chin, Jun Liong; Abu Shanab, Ahmed; Mac Nicholas, Ross; Segurado, Ricardo; Coughlan, Suzie; Connell, Jeff; Carr, Michael J; Merriman, Raphael B; McCormick, P Aiden; Hall, William W

2015-02-01

Host genetic factors influence treatment responses to antiviral therapy in chronic hepatitis C virus (HCV) infection. We retrospectively investigated associations between host genetic markers and treatment-induced virologic responses to dual therapy with interferon-α and ribavirin in chronically infected HCV genotype 1 (g1)- and genotype 3 (g3)-infected individuals. A total of 171 patients (89 HCV g1 and 82 HCV g3 infected) were investigated for genetic markers influencing treatment-induced sustained virologic response (SVR). Overall, SVR was observed for 46/89 (52%) HCV g1- and 57/82 (70%) HCV g3-infected patients. Of the 4 interleukin 28B (IL28B) single-nucleotide polymorphisms (SNPs), rs12979860 was the host genetic marker most significantly associated with failure to achieve an SVR in HCV g1-infected individuals [P=3.83×10(-4); odds ratio (OR)=5.61; confidence interval (CI)=2.07-15.18] and gave a positive predictive value for treatment failure of 81.3% for minor homozygotes (TT). Using additive (P=3.54×10(-4)) and dominant models (P=3.83×10(-4)), a dosage effect of the T allele was observed, with the dominance term not significant for this SNP. Logistic regression showed an association between HLA-C1/C1 and rapid virologic response in HCV g1 infections with an OR relative to the heterozygote of 10.0 (95% CI: 1.6-62.5, P=0.014). HLA-C2 homozygosity was a significant predictor of nonresponse to treatment in HCV g1-infected individuals (P=0.023).

The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients.

PubMed

Jung, Hee Jae; Kim, Young Seok; Kim, Sang Gyune; Lee, Yun Nah; Jeong, Soung Won; Jang, Jae Young; Lee, Sae Hwan; Kim, Hong Soo; Kim, Boo Sung

2014-03-01

Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment. In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of β cells (HOMA-β) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx). A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0 ± 11.2 years, mean ± SD; non-SVR, 56.6 ± 9.9 years; P<0.01), there were no significant differences in the baseline characteristics between the SVR and non-SVR groups. In the SVR group, low density lipoprotein-cholesterol (LDL-C) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-β were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group. LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).

In vitro evaluation of the antiviral activity of the synthetic epigallocatechin gallate analog-epigallocatechin gallate (EGCG) palmitate against porcine reproductive and respiratory syndrome virus.

PubMed

Zhao, Chunjian; Liu, Shuaihua; Li, Chunying; Yang, Lei; Zu, Yuangang

2014-02-21

In this study, epigallocatechin gallate (EGCG) palmitate was synthesized and its anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity was studied. Specifically, EGCG palmitate was evaluated for its ability to inhibit PRRSV infection in MARC-145 cells when administered as pre-, post-, or co-treatment. EGCG and ribavirin were used as controls. The results showed that a 50% cytotoxic concentration (CC50) of EGCG, EGCG palmitate, and ribavirin was achieved at 2,359.71, 431.42, and 94.06 μM, respectively. All three drugs inhibited PRRSV in a dose-dependent manner regardless of the treatment protocol. EGCG palmitate exhibited higher cytotoxicity than EGCG, but lower cytotoxicity than ribavirin. EGCG palmitate anti-PRRSV activity was significantly higher than that of EGCG and ribavirin, both as pre-treatment and post-treatment. Under the former conditions and a tissue culture infectious dose of 10 and 100, the selectivity index (SI) of EGCG palmitate in the inhibition of PRRSV was 3.8 and 2.9 times higher than that of ribavirin when administered as a pre-treatment, while the SI of EGCG palmitate in the inhibition of PRRSV was 3.0 and 1.9 times higher than ribavirin when administered as a post-treatment. Therefore, EGCG palmitate is potentially effective as an anti-PRRSV agent and thus of interest to the pharmaceutical industry.

Simeprevir

MedlinePlus

... used along with ribavirin (Copegus, Rebetol) and peginterferon alfa (Pegasys) to treat chronic hepatitis C (an ongoing ... crush them.You will take simeprevir with peginterferon alfa and ribavirin for 12 weeks. Then you will ...

Abacavir, Dolutegravir, and Lamivudine

MedlinePlus

... If you have HCV and are taking interferon alfa with or without ribavirin (Copegus, Rebetol, Ribasphere) and ... are taking abacavir, dolutegravir, and lamivudine and interferon alfa with or without ribavirin, tell your doctor if ...

Sofosbuvir

MedlinePlus

... Rebetol, Ribasphere, others) and sometimes another medication (peginterferon alfa [Pegasys] to treat certain types of chronic hepatitis ... Sofosbuvir must be taken in combination with peginterferon alfa and ribavirin or in combination with ribavirin alone. ...

Telaprevir

MedlinePlus

... two other medications (ribavirin [Copegus, Rebetol] and peginterferon alfa [Pegasys]) to treat chronic hepatitis C (an ongoing ... not successfully be treated with ribavirin and peginterferon alfa alone. Telaprevir is in a class of medications ...

Boceprevir

MedlinePlus

... two other medications (ribavirin [Copegus, Rebetol] and peginterferon alfa [Pegasys]) to treat chronic hepatitis C (an ongoing ... when they were treated with ribavirin and peginterferon alfa alone. Boceprevir is in a class of medications ...

Apolipoprotein B-associated cholesterol is a determinant of treatment outcome in patients with chronic hepatitis C virus infection receiving anti-viral agents interferon-alpha and ribavirin.

PubMed

Sheridan, D A; Price, D A; Schmid, M L; Toms, G L; Donaldson, P; Neely, D; Bassendine, M F

2009-06-15

Hepatitis C virus (HCV) co-opts very-low-density lipoprotein (VLDL) pathways for replication, secretion and entry into hepatocytes and associates with apolipoprotein B (apoB) in plasma. Each VLDL contains apoB-100 and variable amounts of apolipoproteins E and C, cholesterol and triglycerides. To determine whether baseline lipid levels predicted treatment outcome. Retrospective analysis was performed of 250 chronic hepatitis C (CHC) patients who had received anti-viral agents interferon-alpha and ribavirin; 165 had a sustained virological response (SVR). Pre- and post-treatment nonfasting lipid profiles were measured and non-high-density lipoprotein (non-HDL) cholesterol (i.e. apoB-associated) was calculated. Binary logistic regression analysis assessed factors independently associated with treatment outcome. There was an independent association between higher apoB-associated cholesterol (non-HDL-C) and increased odds of SVR (odds ratio 2.09, P = 0.042). In multivariate analysis, non-HDL-C was significantly lower in HCV genotype 3 (g3) than genotype 1 (P = 0.007); this was reversible upon eradication of HCVg3 (pre-treatment non-HDL-C = 2.8 mmol/L, SVR = 3.6 mmol/L, P < 0.001). Higher apoB-associated cholesterol is positively associated with treatment outcome in CHC patients receiving anti-viral therapy, possibly due to competition between apoB-containing lipoproteins and infectious low-density HCV lipo-viral particles for hepatocyte entry via shared lipoprotein receptors.

[Efficacy of combination therapy with pegylated-interferon alfa-2a plus ribavirin in autoantibody-positive chronic hepatitis C patients].

PubMed

Li, Ya-xin; Yang, Yan-jia; Yang, Mei; Chen, Li-yu; Lu, Jia-jie; Ma, Yuan-ji; Liu, Kai; Lei, Xue-zhong; Tang, Hong

2013-05-01

To evaluate the therapeutic efficacy of antiviral combination therapy with pegylated-interferon alpha-2a plus ribavirin (RBV) in patients with autoantibody-positive chronic hepatitis C (CHC) and to investigate the impact of the presence of autoantibodies on the treatment outcome. Eighty-six consecutive CHC patients who underwent a 48-week treatment regimen composed of Peg-IFNa-2a (135 or 180 mug/wk) plus weight-based RBV ( less than or equal to 65 kg, 800 mg/d; 65 to 75 kg, 1000 mg/d; more than or equal to75 kg, 1200 mg/d ). Prior to treatment (baseline) and at end of treatment (EOT; week 48), levels of antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti liver/kidney microsomal antibody type 1 (LKM1), anti-La (SSB), and anti liver cytosolic-1 (LC-1) were detected by indirect immunofluorescence. At baseline, during treatment (weeks 4, 12, 24, and 36), EOT, and 24 weeks after EOT, levels of HCV RNA were assessed by real-time quantitative PCR. Rapid virological response (RVR) was defined as HCV RNA less than 10(3) copy/ml at week 4. Sustained virologic response (SVR) was defined as HCV RNA load below the lower limit of detection at 24 weeks after EOT. Correlation between autoantibodies and treatment-induced reduced HCV RNA load was assessed by univariate analysis of variance or chi-squared tests. Autoantibodies were detected in 24 patients, which included 14 ANA-positive patients, five SMA-positive patients, three LKM1-positive patients, one patient with double-positivity for ANA and SSB, and one patient with double-positivity for ANA and LC-1. The autoantibody-positive patients and autoantibody-negative patients showed similar rates of RVR (70.8% vs. 72.5%, P more than 0.05) and SVR (81.4% vs. 82.2%, P more than 0.05). Antiviral therapy with Peg-IFNa-2a RBV can effectively reduce the HCV RNA load in autoantibody-positive CHC patients; however, the presence of autoantibodies may not be an independent predictor of therapy outcome.

Silybin supplementation during HCV therapy with pegylated interferon-α plus ribavirin reduces depression and anxiety and increases work ability.

PubMed

Malaguarnera, Giulia; Bertino, Gaetano; Chisari, Giuseppe; Motta, Massimo; Vecchio, Michele; Vacante, Marco; Caraci, Filippo; Greco, Carmela; Drago, Filippo; Nunnari, Giuseppe; Malaguarnera, Michele

2016-11-15

Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV). Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg + vitamin E 30 mg + phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI). The comparison between group A and group B showed significant differences after 6 months in ALT (P < 0.001), and viremia (P < 0.05), after 12 months in ALT (P < 0.001), and AST (P < 0.001), at follow up in AST (P < 0.05), and ALT (P < 0.001). Significant difference were observed after 1 month in WAI (p < 0.001) and BDI (P < 0.05), after 6 months in WAI (P < 0.05) and STAI (P < 0.05), after 12 months and at follow up in WAI, STAI and BDI (p < 0.01). The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV. NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).

Sequence diversity of hepatitis C virus 6a within the extended interferon sensitivity-determining region correlates with interferon-alpha/ribavirin treatment outcomes.

PubMed

Zhou, Daniel X M; Chan, Paul K S; Zhang, Tiejun; Tully, Damien C; Tam, John S

2010-10-01

Studies on the association between sequence variability of the interferon sensitivity-determining region (ISDR) of hepatitis C virus and the outcome of treatment have reached conflicting results. In this study, 25 patients infected with HCV 6a who had received interferon-alpha/ribavirin combination treatment were analyzed for the sequence variations. 14 of them had the full genome sequences obtained from a previous study, whereas the other 11 samples were sequenced for the extended ISDR (eISDR). This eISDR fragment covers 192 bp (64 amino acids) upstream and 201 bp (67 amino acids) downstream from the ISDR previously defined for HCV 1b. The comparison between interferon-alpha resistance and response groups for the amino acid mutations located in the full genome (6 and 8 patients respectively) as well as the mutations located in the eISDR (10 and 15 patients respectively) showed that the mutations I2160V, I2256V, V2292I (P<0.05) within eISDR were significantly associated with resistance to treatment. However, the extent of amino acid variations within previously defined ISDR was not associated with resistance to treatment as previously reported. Four amino acid variations I248V (P=0.03-0.06) within E1, R445K (P=0.02-0.05) and S747T (P=0.03) within E2, I861V (P=0.01) within NS2 which located outside the eISDR may also associate with treatment outcome as identified by a prescreening of variations within 14 HCV 6a full genomes. (c) 2010 Elsevier B.V. All rights reserved.

Cost-effectiveness of chronic hepatitis C treatment with thymosin alpha-1.

PubMed

García-Contreras, Fernando; Nevárez-Sida, Armando; Constantino-Casas, Patricia; Abud-Bastida, Fernando; Garduño-Espinosa, Juan

2006-07-01

More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment. We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits. Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon + ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of 1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin 2,277/QALY, peginterferon alone 2,929/QALY, and no treatment 4,204/QALY. Sensitivity analyses confirmed the robustness of the base case. Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option.

Direct-acting Antiviral Agents for the Treatment of Chronic Hepatitis C Virus Infection

PubMed Central

Nakamoto, Shingo; Nakamura, Masato; Jiang, Xia; Miyamura, Tatsuo; Wu, Shuang; Yokosuka, Osamu

2014-01-01

Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan. Therefore, eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals. In 2011, the use of first-generation HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV. Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients. However, this treatment regimen also led to severe adverse events. Second-generation direct-acting antiviral agents (DAAs) for HCV, such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates, with similar adverse events to other peg-interferon and ribavirin treatments. Higher SVR rates in HCV genotype 1- and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin, respectively. For “difficult-to-treat” HCV-infected patients, more therapeutic options are needed. Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments. PMID:26356295

Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US.

PubMed

Zhang, Sai; Bastian, Nathaniel D; Griffin, Paul M

2015-08-05

The standard care of treatment of interferon plus ribavirin (plus protease inhibitor for genotype 1) are effective in 50 % to 70 % of patients with CHC. Several new treatments including Harvoni, Olysio + Sovaldi, Viekira Pak, Sofosbuvir-based regimens characterized with potent inhibitors have been approved by the Food and Drug Administration (FDA) providing more options for CHC patients. Trials have shown that the new treatments increased the rate to 80% to 95%, though with a substantial increase in cost. In particular, current market pricing of a 12-week course of sofosbuvir is approximately US$84,000. We determine the cost-effectiveness of new treatments in comparison with the standard care of treatments. A Markov simulation model of CHC disease progression is used to evaluate the cost-effectiveness of different treatment strategies based on genotype. The model calculates the expected lifetime medical costs and quality adjusted life years (QALYs) of hypothetical cohorts of identical patients receiving certain treatments. For genotype 1, we compare: (1) peginterferon + ribavirin + telaprevir for 12 weeks, followed by 12 or 24 weeks treatment of peginterferon + ribavirin dependent on HCV RNA level at week 12; (2) Harvoni treatment, 12 weeks; (3) Olysio + Sovaldi, 12 weeks for patients without cirrhosis, 24 weeks for patients with cirrhosis; (4) Viekira Pak + ribavirin, 12 weeks for patients without cirrhosis, 24 weeks for patients with cirrhosis; (5) sofosbuvir + peginterferon + ribavirin, 12 weeks for patients with or without cirrhosis. For genotypes 2 and 3, treatment strategies include: (1) peginterferon + ribavirin, 24 weeks for treatment-naïve patients; (2) sofosbuvir + ribavirin, 12 weeks for patients with genotype 2, 24 weeks for genotype 3; (3) peginterferon + ribavirin as initial treatment, 24 weeks for patients with genotype 2/3, follow-up treatment with sofosbuvir + ribavirin for 12/16 weeks are performed

Cost-effectiveness of sofosbuvir plus ribavirin with or without pegylated interferon for the treatment of chronic hepatitis C in Italy.

PubMed

Cure, Sandrine; Guerra, Ines; Cammà, Calogero; Craxì, Antonio; Carosi, Giampiero

2015-01-01

Across Italy up to 7.3% of the population is infected with hepatitis C virus (HCV), with long-term complications resulting in high medical costs and significant morbidity and mortality. Current treatment options have limitations due to side effects, interferon intolerability and ineligibility, long treatment durations and low sustained virological response (SVR) rates, especially for the most severe patients). Sofosbuvir is the first nucleotide polymerase inhibitor with pan-genotypic activity. Sofosbuvir, administered with ribavirin (RBV) and with or without pegylated interferon (PEG-INF), resulted in >90% SVR across treatment-naïve (TN) genotype (GT) 1-6 patients. It is also the first treatment option for patients that are unsuitable for interferon (UI). This analysis evaluates the cost - effectiveness of sofosbuvir for GTs 1-6 in Italy. A Markov model followed a cohort of 10,000 patients until they reached 80 years old. Approximately 20% of naïve and 30% of experienced patients initiated treatment at the cirrhosis stage. Comparators included PEG-INF + RBV for all GTs and plus telaprevir or boceprevir for GT1, or no treatment. Costs and outcomes were discounted at 3% and the cost perspective was that of the National Health Service in Italy. Sofosbuvir was cost-effective with incremental cost-effectiveness ratios (ICERs) below €40,000/QALY in all patient populations, particularly in cirrhotic patients. The exception was for a mixed cohort of GT2 TN patients where the ICER was €68,500/QALY and for a cirrhotic cohort of GT4/5/6 where the ICER was €68,434/QALY. Nevertheless, the prevalence of HCV in this patient population is expected to be low. Results were robust to sensitivity analysis. Sofosbuvir-based regimens are cost-effective in Italy, particular for the most severe patients. The interferon-free regimens are a real treatment option for UI patients. The high cure rates of this breakthrough treatment are expected to substantially reduce the burden of

Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C: AMBER study.

PubMed

Flisiak, R; Janczewska, E; Wawrzynowicz-Syczewska, M; Jaroszewicz, J; Zarębska-Michaluk, D; Nazzal, K; Bolewska, B; Bialkowska, J; Berak, H; Fleischer-Stępniewska, K; Tomasiewicz, K; Karwowska, K; Rostkowska, K; Piekarska, A; Tronina, O; Madej, G; Garlicki, A; Lucejko, M; Pisula, A; Karpińska, E; Kryczka, W; Wiercińska-Drapało, A; Mozer-Lisewska, I; Jabłkowski, M; Horban, A; Knysz, B; Tudrujek, M; Halota, W; Simon, K

2016-11-01

Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies. To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions. Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT. A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child-Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients. The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting. © 2016 John Wiley & Sons Ltd.

Cirrhosis and Rapid Virological Response to Peginterferon Plus Ribavirin Determine Treatment Outcome in HCV-1 IL28B rs12979860 CC Patients

PubMed Central

Aghemo, Alessio; Degasperi, Elisabetta; Rumi, Maria Grazia; Galmozzi, Enrico; Valenti, Luca; De Francesco, Raffaele; De Nicola, Stella; Cheroni, Cristina; Grassi, Eleonora; Colombo, Massimo

2013-01-01

Background. The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. Aim. To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. Methods. Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. Results. 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07–6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (−) (P = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (−) (10/13 (77%) versus 6/17 (35%) P = 0.03). Conclusions. In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy. PMID:23936821

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

PubMed

Zeuzem, S; Flisiak, R; Vierling, J M; Mazur, W; Mazzella, G; Thongsawat, S; Abdurakhmanov, D; Van Kính, N; Calistru, P; Heo, J; Stanciu, C; Gould, M; Makara, M; Hsu, S-J; Buggisch, P; Samuel, D; Mutimer, D; Nault, B; Merz, M; Bao, W; Griffel, L H; Brass, C; Naoumov, N V

2015-10-01

Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens. © 2015 John Wiley & Sons Ltd.

Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor α.

PubMed

Satoh, Shinya; Mori, Kyoko; Onomura, Daichi; Ueda, Youki; Dansako, Hiromichi; Honda, Masao; Kaneko, Shuichi; Ikeda, Masanori; Kato, Nobuyuki

2017-08-01

Ribavirin (RBV) has been widely used as an antiviral reagent, specifically for patients with chronic hepatitis C. We previously demonstrated that adenosine kinase, which monophosphorylates RBV into the metabolically active form, is a key determinant for RBV sensitivity against hepatitis C virus RNA replication. However, the precise mechanism of RBV action and whether RBV affects cellular metabolism remain unclear. Analysis of liver gene expression profiles obtained from patients with advanced chronic hepatitis C treated with the combination of pegylated interferon and RBV showed that the adenosine kinase expression level tends to be lower in patients who are overweight and significantly decreases with progression to advanced fibrosis stages. In our effort to investigate whether RBV affects cellular metabolism, we found that RBV treatment under clinically achievable concentrations suppressed lipogenesis in hepatic cells. In this process, guanosine triphosphate depletion through inosine monophosphate dehydrogenase inhibition by RBV and adenosine monophosphate-activated protein kinase-related kinases, especially microtubule affinity regulating kinase 4, were required. In addition, RBV treatment led to the down-regulation of retinoid X receptor α (RXRα), a key nuclear receptor in various metabolic processes, including lipogenesis. Moreover, we found that guanosine triphosphate depletion in cells induced the down-regulation of RXRα, which was mediated by microtubule affinity regulating kinase 4. Overexpression of RXRα attenuated the RBV action for suppression of lipogenic genes and intracellular neutral lipids, suggesting that down-regulation of RXRα was required for the suppression of lipogenesis in RBV action. Conclusion : We provide novel insights about RBV action in lipogenesis and its mechanisms involving inosine monophosphate dehydrogenase inhibition, adenosine monophosphate-activated protein kinase-related kinases, and down-regulation of RXRα. RBV may be a

Randomized controlled trial of the NS5A inhibitor daclatasvir plus pegylated interferon and ribavirin for HCV genotype-4 (COMMAND-4).

PubMed

Hézode, Christophe; Alric, Laurent; Brown, Ashley; Hassanein, Tarek; Rizzetto, Mario; Buti, Maria; Bourlière, Marc; Thabut, Dominique; Molina, Esther; Rustgi, Vinod; Samuel, Didier; McPhee, Fiona; Liu, Zhaohui; Yin, Philip D; Hughes, Eric; Treitel, Michelle

2015-08-27

Treatment options for HCV genotype-4 (GT4) are limited. This Phase III study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in treatment-naive patients with HCV GT4 infection. Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n=82) or placebo (n=42) once daily plus PEG-IFN 180 µg weekly and RBV 1,000-1,200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus PEG-IFN/RBV; those without eRVR received an additional 24 weeks of PEG-IFN/RBV. All placebo-treated patients received 48 weeks of PEG-IFN/RBV. The primary end point was sustained virological response (SVR) at post-treatment week 12 (SVR12). Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA < lower limit of quantitation [LLOQ]) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus PEG-IFN/RBV versus 43% (18/42) with PEG-IFN/RBV (P<0.0001). In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus PEG-IFN/RBV was comparable to that of PEG-IFN/RBV. Discontinuations due to adverse events occurred in 4.9% of patients receiving DCV plus PEG-IFN/RBV and 7.1% of patients receiving PEG-IFN/RBV. In treatment-naive patients with HCV GT4 infection, DCV plus PEG-IFN/RBV achieved higher SVR12 rates than PEG-IFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals (AI444-042; ClinicalTrials.gov NCT01448044).

DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4.

PubMed

Everson, Gregory; Cooper, Curtis; Hézode, Christophe; Shiffman, Mitchell L; Yoshida, Eric; Beltran-Jaramillo, Teresita; Andreone, Pietro; Bruno, Savino; Ferenci, Peter; Zeuzem, Stefan; Brunda, Michael; Le Pogam, Sophie; Nájera, Isabel; Zhou, Julian; Navarro, Mercidita T; Voulgari, Athina; Shulman, Nancy S; Yetzer, Ellen S

2015-01-01

Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection. Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up). SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R. The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience.

PubMed

Mangia, Alessandra; Susser, Simone; Piazzolla, Valeria; Agostinacchio, Ernesto; De Stefano, Giulio; Palmieri, Vincenzo; Spinzi, Giancarlo; Carraturo, Immacolata; Potenza, Domenico; Losappio, Ruggero; Arleo, Andrea; Miscio, Maria; Santoro, Rosanna; Sarrazin, Christoph; Copetti, Massimiliano

2017-04-01

Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates. SVR12 rates attained in an Italian real life cohort and possible benefits of a duration extended up to 20weeks was investigated in HCV GT2 patients with cirrhosis. The role of 2k/1b chimeras as potential predictor of treatment failure was also analysed. Overall, 291 HCV GT2 infected patients with bridging fibrosis or cirrhosis were evaluated. Median age was 68years (18-87); 163 were treatment naïve. Of 168 cirrhotic patients, 149 had Child-Pugh score A and 19 B, 50 platelets count <100,000/mm 3 and 62 albumin <3.5g/dl. SVR12 were 95.53% overall, with 99.15% in non-cirrhotic patients and 93.06% in cirrhotic patients. In patients who completed treatment, SVR rates for cirrhotic patients resulted in 94.51%, and 94.94% after 16 or 20weeks respectively. Predictors of SVR were low platelet count and esophageal varices (OR 7.2; 95% CI 1.67-31.25; p=0.0022 and OR 0.1; 95% CI 0.01-0.72; p=0.0079, respectively). Anemia was mild in 12.4%, moderate in 3.4%, and severe in 2.4% of cases. Anemia was slightly more frequent among longer duration but not associated with treatment discontinuations. No 2k/1b strains or genotypes different from those at baseline were identified at relapse. In GT2 cirrhotic patients, SOF/RBV for 16 or 20weeks is associated with real life SVR12 rates of 95%. A duration of treatment of 16-20weeks was recommended for treatment of HCV GT2 patients using the combination of sofosbuvir and ribavirin. Real life experiences, where patients received 12weeks of treatment regardless of the severity of liver disease, suggested that response rates are lower than expected, in particular in patients with liver cirrhosis. A misleading genotyping of a 2k/1b

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection.

PubMed

Di Bisceglie, Adrian M; Sulkowski, Mark; Gane, Ed; Jacobson, Ira M; Nelson, David; DeSouza, Cynthia; Alves, Katia; George, Shelley; Kieffer, Tara; Zhang, Eileen Z; Kauffman, Robert; Asmal, Mohammed; Koziel, Margaret J

2014-07-01

To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. VX-222 (100 or 400 mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400 mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400 mg twice daily, respectively). These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

Transient sinus bradycardia during the course of Crimean-Congo hemorrhagic fever in children.

PubMed

Gayretli Aydin, Zeynep Gokce; Tanir, Gonul; Metin, Ozge; Aydin Teke, Turkan; Bayhan, Gulsum Iclal; Oz, Fatma Nur; Caglayik, Dilek Yagci; Gençtürk, Zeynep

2015-03-01

Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne viral zoonotic disease which is endemic in Turkey. Bradycardia has been reported among pediatric and adult patients with CCHF. But, it remains unclear, whether bradycardia is associated with ribavirin treatment or the severity of CCHF. In this study 26 hospitalized CCHF patients were reviewed in terms of age, gender, history of tick bite, duration of hospitalization, presence of bradycardia, laboratory features, ribavirin treatment, and blood products requirement. The demographic, clinical, laboratory and treatment characteristics of CCHF patients with or without bradycardia were compared. The mean age of the patients was 126.42±48.21 months. There were 8 female and 18 male patients. Sinus bradycardia was noted in 15 patients (mean age was 120.20±50.59 months, 5 female). Ribavirin had been administered 18 (69.2%) patients and 11 of them had bradycardia. There was not statistically significant relationships between bradycardia and ribavirin treatment (p=0.683). Furthermore the occurrence of bradycardia was not associated with disease severity according to Swanepoel severity criteria (p=0.683). We concluded that independent of the disease severity and the ribavirin treatment, transient sinus bradycardia might occur during the clinical course of CCHF in pediatric patients. For this reason clinicians should be aware of this finding and all CCHF patients should be monitored closely. Copyright © 2014 Elsevier GmbH. All rights reserved.

A randomized, controlled study of peginterferon lambda-1a/ribavirin ± daclatasvir for hepatitis C virus genotype 2 or 3.

PubMed

Foster, Graham R; Chayama, Kazuaki; Chuang, Wan-Long; Fainboim, Hugo; Farkkila, Martti; Gadano, Adrian; Gaeta, Giovanni B; Hézode, Christophe; Inada, Yukiko; Heo, Jeong; Kumada, Hiromitsu; Lu, Sheng-Nan; Marcellin, Patrick; Moreno, Christophe; Roberts, Stuart K; Strasser, Simone I; Thompson, Alexander J; Toyota, Joji; Paik, Seung Woon; Vierling, John M; Zignego, Anna L; Cohen, David; McPhee, Fiona; Wind-Rotolo, Megan; Srinivasan, Subasree; Hruska, Matthew; Myler, Heather; Portsmouth, Simon D

2016-01-01

Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.

Management of hepatitis C infection in the era of direct-acting antiviral therapy

NASA Astrophysics Data System (ADS)

Zain, L. H.; Sungkar, T.

2018-03-01

Hepatitis C viral infection globally affects millions of people and commonly results in debilitating complications and mortality. Initial mainstay therapy consisted of pegylated interferon α (pegIFNα) with additional ribavirin that showed unsatisfactory cure rate, common side effects and complicated dosing, contributing to high discontinuation rate. Over the last few years, newer antivirals have been extensively studied, that are Direct-Acting Antivirals (DAAs). Specifically targeting viral protein mainly during replication phase, DAAs showed greater cure rate (commonly measured as sustained virologic response), improved safety profile and shorter treatment duration compared to traditional interferon-ribavirin therapy. Current guidelines have also included Interferon-free, often ribavirin-free, DAAs combinations that suggest promising outcomes. The current review highlights development of rapidly growing hepatitis C treatment including DAAs recommendations.

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients.

PubMed

D'Avolio, Antonio; De Nicolò, Amedeo; Cusato, Jessica; Ciancio, Alessia; Boglione, Lucio; Strona, Silvia; Cariti, Giuseppe; Troshina, Giulia; Caviglia, Gian Paolo; Smedile, Antonina; Rizzetto, Mario; Di Perri, Giovanni

2013-10-01

Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients. A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset. All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75×10(-5)) and Hb at baseline (OR=1.51, p=1.21×10(-4)) were independently associated with protection against clinically significant anemia at week 4. All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event. Copyright © 2013 Elsevier B.V. All rights reserved.

The safety and efficacy of ledipasvir/sofosbuvir with or without ribavirin in the treatment of orthotopic liver transplant recipients with recurrent hepatitis C: real-world data.

PubMed

Pyrsopoulos, Nikolaos; Trilianos, Panagiotis; Lingiah, Vivek A; Fung, Phoenix; Punnoose, Merlin

2018-07-01

Recurrent hepatitis C (RHC) in orthotopic liver transplantation (OLT) population is associated with accelerated rates of fibrosis, low efficacy and decreased tolerability with traditional therapies. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir (LED/SOF) with or without ribavirin (RBV) in OLT patients with RHC. Patients at least 3 months post-OLT and with documented RHC were treated with LED/SOF with or without RBV for either 12 or 24 weeks. End-of-treatment and sustained virological response 12 weeks after the completion of treatment were documented. Patients were closely monitored for treatment-related adverse effects and the potential need for adjustment in their immunosuppression. Seventy-one patients were included in the study. Median age was 62 years. Median time from OLT was 55 months. Twenty-six (36.6%) patients were treatment-naive and 45 (63.4%) had previously failed interferon-based therapies. The majority of patients (57.7%) had stage F0-F2 fibrosis. Sixty-seven (94.3%) patients completed 12 weeks of LED/SOF with RBV, three patients completed 12 or 24 weeks of LED/SOF without RBV, and one patient completed only 8 weeks of LED/SOF without RBV owing to severe allograft dysfunction. Sustained virological response was near universal in our cohort (98.5%) regardless of genotype, fibrosis stage, and regimen or treatment duration. Most commonly reported side effects were malaise and gastrointestinal upset. No patient required adjustment in immunosuppression and no episodes of rejection were documented during treatment. The combination of LED/SOF with RBV for 12 weeks or LED/SOF for 24 weeks is very effective and safe in treating OLT recipients with RHC.

A network meta-analysis to compare simeprevir with boceprevir and telaprevir in combination with peginterferon-α and ribavirin in patients infected with genotype 1 Hepatitis C virus.

PubMed

Taieb, Vanessa; Pacou, Maud; Ho, Sophia; Pettré, Ségolène; Van Sanden, Suzy; Pisini, Marta; Ustianowski, Andrew; Mehnert, Angelika

2015-01-01

To conduct a network meta-analysis (NMA) to assess the relative efficacy and safety of simeprevir, a second generation oral protease inhibitor (PI), compared to telaprevir and boceprevir in combination with pegylated interferon-α and ribavirin (PR) in patients with chronic hepatitis C. A systematic literature review and NMA of randomized controlled trials involving anti-virals added to PR were conducted. Electronic database searches and hand searches were conducted to identify relevant publications. Outcomes of interest included sustained virologic response (SVR), incidence of adverse events (AEs), and discontinuation due to AEs. Networks were based on treatment-, dose-, and duration-specific nodes. Sub-group analyses were conducted to investigate heterogeneity, based on Metavir scores, sub-genotypes 1a/1b, and prior response. A total of 15 publications were considered for the base case of the meta-analysis. Simeprevir was associated with higher SVR rates than PR alone. Compared to telaprevir and boceprevir, SVR rates tended to be higher for simeprevir, with odds ratios ranging from 1.27 [0.81-2.00] to 2.61 [1.44-4.74] in treatment-naïve and from 1.04 [0.78-1.38] to 1.74 [0.84-3.61] in treatment-experienced patients, respectively. In terms of safety, the risks of anemia and discontinuations due to AEs were lower for simeprevir compared to PR alone, telaprevir, and boceprevir. The risk of rash was lower for simeprevir compared to telaprevir, and similar compared to PR alone and boceprevir. This NMA in genotype 1 HCV patients suggests a similar or better efficacy and tolerability profile for simeprevir compared to telaprevir and boceprevir.

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study.

PubMed

Fernández-Rodríguez, Conrado M; Morillas, Rosa María; Masnou, Helena; Navarro, José María; Bárcena, Rafael; González, José Manuel; Martín-Martín, Leticia; Poyato, Antonio; Miquel-Planas, Mireia; Jorquera, Francisco; Casanovas, Teresa; Salmerón, Javier; Calleja, José Luis; Solà, Ricard; Alonso, Sonia; Planas, Ramón; Romero-Gomez, Manuel

2014-01-01

Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). To assess the impact of high doses of RBV on SVR in patients with G3 and HVL. Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13). RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609). Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

Sofosbuvir and Simeprevir Combination Therapy for HCV Genotype 1 Infection: Results of a Single-Center VA Experience

PubMed Central

Hernandez, Maria Del Pilar; Vance, Evan; Gilinski, Dani; Youtseff, Helen; Toro, Maribel; Antoine, Marie; Jeffers, Lennox J.; Peyton, Adam

2016-01-01

Treatment of chronic hepatitis C virus (HCV) infection remains a priority in the veterans affairs (VA) health care system nationwide, as there is a high burden of liver disease due to HCV infection among US veterans. The combination of sofosbuvir and simeprevir was the first all-oral antiviral regimen used in clinical practice to treat veterans with HCV infection. In this study, we report a single-center experience showing both the feasibility and effectiveness of this all-oral combination to treat HCV genotype 1 infection. One hundred patients with HCV genotype 1 infection were treated between December 2013 and June 2014. Eighty-six patients were treated with sofosbuvir and simeprevir, with or without ribavirin, for 12 weeks; 12 patients were treated with sofosbuvir, pegylated interferon, and ribavirin for 12 weeks; and 2 patients were treated with sofosbuvir and ribavirin for 24 weeks. Overall, treatment was well tolerated and feasible, with compliance rates over 95% in patients treated with all-oral therapy. The sustained virologic response (SVR) rate for sofosbuvir and simeprevir (88.4%) was superior to the rate for sofosbuvir, pegylated interferon, and ribavirin (50.0%). Subgroup analysis showed diminished SVR rates in cirrhotic patients vs noncirrhotic patients. There were no significant differences in SVR when comparing treatment with or without ribavirin or among genotype subtypes. In conclusion, this study demonstrated excellent completion rates for all-oral treatment of veterans with chronic HCV infection. Additionally, treatment was highly effective, nearing a 90% cure rate. Thus, we recommend that the VA health care system continue to incorporate new HCV medications into its formulary so as to expand HCV treatment for US veterans. PMID:27917084

Simple score to predict risk of hepatocellular carcinoma in chronic hepatitis C patients with advanced fibrosis after pegylated interferon and ribavirin therapy.

PubMed

Hu, Ching-Chih; Weng, Cheng-Hao; Chang, Liang-Che; Lin, Chih-Lang; Chen, Yen-Ting; Hu, Ching-Fang; Hua, Man-Chin; Chen, Li-Wei; Chien, Rong-Nan

2018-01-01

Eradication of chronic hepatitis C virus (HCV) after interferon-based therapy and its association with the reduction of risk of hepatocellular carcinoma (HCC) in HCV-infected patients with advanced fibrosis is controversial. The study is aimed to develop a simple scoring model for HCC prediction among advanced fibrotic chronic hepatitis C (CHC) patients after pegylated interferon (pegIFN) and ribavirin (RBV) therapy. We enrolled 271 biopsy-proven CHC patients with advanced fibrosis between 2003 and 2016, and divided them into non-HCC (n=211) and HCC (n=60) groups. The median observation duration was 6.0 years (range: 0.9-12.6 years). The HCC prevalence after pegIFN and RBV therapy in CHC patients with sustained virologic response (SVR) and without SVR was 14.7% and 32.2%, respectively. Multivariate Cox regression showed age ≥59.5 years old at initiation of therapy (HR: 2.542, 95% CI: 1.390-4.650, P =0.002), pretreatment total bilirubin ≥1.1 mg/dL (HR: 2.630, 95% CI: 1.420-4.871, P =0.002), pretreatment platelet counts <146.5 × 10 3 /μL (HR: 2.751, 95% CI: 1.373-5.511, P =0.004), no achievement of SVR (HR: 2.331, 95% CI: 1.277-4.253, P =0.006), and no diabetes at treatment initiation (HR: 3.085, 95% CI: 1.283-7.418, P =0.012) were significant predictors of HCC development. The scoring model consisted of the five categorical predictors and had an optimal cutoff point of 2.5. The area under receiver operating characteristic (AUROC) of the scoring model was 0.774±0.035 ( P <0.001). The sensitivity and specificity of the cutoff value to detect HCC were 81.3% and 57.5%. The 5-year and 10-year cumulative incidence of HCC was 4.9% and 10.0% in patients with simple score ≤2; and 25.9% and 44.6% in patients with simple score ≥3 ( P <0.001). The simple clinical-guided score has high discriminatory power for HCC prediction in advanced fibrotic CHC patients after pegIFN and RBV therapy.

Evaluation of antiviral efficacy of Chinese traditional medicine Babao Dan in rabbits infected with hepatitis E virus.

PubMed

Gong, Wanyun; Liu, Lin; Li, Manyu; Wang, Lin; Zhang, Mingyu; Luo, Zhengxin; Sridhar, Siddharth; Woo, Patrick C Y; Wang, Ling

2018-06-20

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Patients with chronic hepatitis B superinfected with HEV may progress to liver failure. Babao Dan (BD) is a traditional Chinese medicine widely used as an auxiliary option for the treatment of chronic hepatitis and liver cancer in China. This study aimed to evaluate the effect of BD on the management of HEV infection in a rabbit model. Sixty-two specific-pathogen-free (SPF) rabbits were divided randomly into five groups and treated with BD or placebo for 2 weeks. All rabbits were inoculated intravenously with rabbit HEV after initial administration. Then, rabbits were administered BD or ribavirin or placebo at 2 weeks post-inoculation (wpi) until faecal virus shedding showed negative. The duration of faecal virus shedding and levels of HEV RNA in faeces were reduced, and anti-HEV antibodies were detected in all rabbits in groups treated with BD before or after inoculation. Ribavirin treatment rapidly cleared HEV infection in SPF rabbits, but anti-HEV antibodies remained negative in 50 % of rabbits treated with ribavirin. These results indicate that ribavirin treatment was more effective in clearing HEV infection, while administration of BD before or after inoculation was effective in clearing HEV infection. Further clinical studies are warranted.

Serum apolipoprotein B-100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b.

PubMed

Yoshizawa, Kai; Abe, Hiroshi; Aida, Yuta; Ishiguro, Haruya; Ika, Makiko; Shimada, Noritomo; Tsubota, Akihito; Aizawa, Yoshio

2013-07-01

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b-infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274-24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB-100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. Copyright © 2013 Wiley Periodicals, Inc.

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

PubMed Central

Nakamoto, Shingo; Kanda, Tatsuo; Shirasawa, Hiroshi; Yokosuka, Osamu

2015-01-01

Patients who are infected with hepatitis C virus (HCV) and also have advanced fibrosis or cirrhosis have been recognized as “difficult-to-treat” patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents (DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatment-naïve patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in null-responders and in patients with cirrhosis. Interferon-free regimens in combination with ribavirin and

International Symposium on Epidemic Hemorrhagic Fever (Hemorrhagic Fever with Renal Syndrome) Held in Wuhan, Hubei, China on 31 October - 2 November 1988

DTIC Science & Technology

1989-10-01

15 Song Gan Prophylaxis of Hemorrhagic Fever With Renal Syndrome, Development of Inactivated Cell Culture Vaccine Against HFRS 11:45 END EPIDEMIOLOGYt...Intraveinous Ribavirin or Placebo 11:15 Yang Zhi-cheng Effect of Ribavirin on the White Blood Cell System and the Platelet of the Patients With EHF...from R. nortegicus ias madc by Hlung T. et al (5. A). It %sas a ers brilliant piecc of %;ork. because by observing thin-sections of infected cells in

Shortened therapy of eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection.

PubMed

Martinello, M; Bhagani, S; Gane, E; Orkin, C; Cooke, G; Dore, G J; Petoumenos, K; Applegate, T L; Tu, E; Marks, P; Pagani, N; Grebely, J; Nelson, M; Matthews, G V

2018-04-16

Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks are approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 8 weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12 months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotypes 1a and 1, no subtype) for 8 weeks. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Thirty people (median age 38 years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n = 23) were HIV-positive, 93% (n = 28) had genotype 1a infection and 53% (n = 16) had ever injected drugs. Median maximum ALT in the preceding 12 months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT > 10 x ULN was documented in 83% (n = 25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51), and median HCV RNA was 5.7 log 10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n = 1; per protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks were highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. These data support the use of this shortened duration direct-acting antiviral regimen in this population. © 2018 John Wiley & Sons Ltd.

Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naïve hepatitis C patients with a real-world cohort and database.

PubMed

Tsai, Pei-Chien; Liu, Ta-Wei; Tsai, Yi-Shan; Ko, Yu-Min; Chen, Kuan-Yu; Lin, Ching-Chih; Huang, Ching-I; Liang, Po-Cheng; Lin, Yi-Hung; Hsieh, Ming-Yen; Hou, Nai-Jen; Huang, Chung-Feng; Yeh, Ming-Lun; Lin, Zu-Yau; Chen, Shinn-Cherng; Dai, Chia-Yen; Chuang, Wan-Long; Huang, Jee-Fu; Yu, Ming-Lung

2017-06-01

For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naïve G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naïve G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. We investigated the real-world cost effectiveness data for different subgroups of treatment-naïve HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions

Protein pathway activation associated with sustained virologic response in patients with chronic hepatitis C treated with pegylated interferon (PEG-IFN) and ribavirin (RBV).

PubMed

Younossi, Zobair M; Limongi, Dolores; Stepanova, Maria; Pierobon, Mariaelena; Afendy, Arian; Mehta, Rohini; Baranova, Ancha; Liotta, Lance; Petricoin, Emanuel

2011-02-04

Only half of chronic hepatitis C (CH-C) patients treated with pegylated interferon and ribavirin (PEG-IFN+RBV) achieve sustained virologic response) SVR. In addition to known factors, we postulated that activation of key protein signaling networks in the peripheral blood mononuclear cells (PBMCs) may contribute to SVR due to inherent patient-specific basal immune cell signaling architecture. In this study, we included 92 patients with CH-C. PBMCs were collected while patients were not receiving treatment and used for phosphoprotein-based network profiling. Patients received a full course of PEG-IFN+RBV with overall SVR of 55%. From PBMC, protein lysates were extracted and then used for Reverse Phase Protein Microarray (RPMA) analysis, which quantitatively measured the levels of cytokines and activation levels of 25 key protein signaling molecules involved in immune cell regulation and interferon alpha signaling. Regression models for predicting SVR were generated by stepwise bidirectional selection. Both clinical-laboratory and RPMA parameters were used as predictor variables. Model accuracies were estimated using 10-fold cross-validation. Our results show that by comparing patients who achieved SVR to those who did not, phosphorylation levels of 6 proteins [AKT(T308), JAK1(Y1022/1023), p70 S6 Kinase (S371), PKC zeta/lambda(T410/403), TYK2(Y1054/1055), ZAP-70(Y319)/Syk(Y352)] and overall levels of 6 unmodified proteins [IL2, IL10, IL4, IL5, TNF-alpha, CD5L] were significantly different (P < 0.05). For SVR, the model based on a combination of clinical and proteome parameters was developed, with an AUC = 0.914, sensitivity of 92.16%, and specificity of 85.0%. This model included the following parameters: viral genotype, previous treatment status, BMI, phosphorylated states of STAT2, AKT, LCK, and TYK2 kinases as well as steady state levels of IL4, IL5, and TNF-alpha. In conclusion, SVR could be predicted by a combination of clinical, cytokine, and protein signaling

Postexposure prophylaxis for Lassa fever: Experience from a recent outbreak in Nigeria.

PubMed

Isa, Samson E; Okwute, Attah; Iraoyah, Kelly O; Nathan, Shehu Y; Simji, Gomerep S; Okolo, Mark O; Anejo-Okopi, Joseph; Spicola, Daria; Isa, Daisy E

2016-01-01

Secondary transmission of Lassa fever (LF) occurs in the community and in health-care facilities, and is associated with high fatality in Nigeria. We investigated the role of oral ribavirin postexposure prophylaxis (orPEP) in preventing LF among the primary contacts of confirmed cases from December 2015 to March 2016. Epidemiological and clinical data of LF contacts were prospectively collected. However, information regarding ribavirin adverse effects (AEs) were collected retrospectively through a telephone interview. High-risk contacts were clinically monitored ΁ orPEP. Thirty-five (94.6%) out of the 37 individuals enrolled in the study were contacts of confirmed LF cases, and friends and family members (54%) constituted the largest group. However, only 29 (83%) individuals were classified as high-risk contacts. Twenty-one (60%) of contacts were prescribed ribavirin with 6 (28.6%) of them reporting AEs. Body weakness (33%) was the most frequent AE, but there was no incidence of treatment discontinuation due to AE. Furthermore, there were no reported cases of LF among all respondents (0%), whether they had orPEP or not. Secondary transmission of LF seems uncommon and the benefit of orPEP is uncertain. Although AEs of ribavirin may not be uncommon, they are rarely serious enough to cause treatment interruption. More emphasis should be on supporting persons looking after LF cases adopt measures that minimize the risks of exposure.

Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen.

PubMed

Ikeda, Hiroki; Watanabe, Tsunamasa; Shimizu, Hirohito; Hiraishi, Tetsuya; Kaneko, Rena; Baba, Toshiyuki; Takahashi, Hideaki; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Yasuda, Hiroshi; Okuse, Chiaki; Iwabuchi, Shogo; Suzuki, Michihiro; Itoh, Fumio

2018-03-05

The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4 < 3.25). The SVR24 rate was lower with unfavorable IL28B rs8099917 SNP genotypes; specifically, the TT, TG and GG had SVR24 rates of 78%, 50% and 40%. The SVR24 rate was lower with a poor response to prior DCV plus ASV, where relapse, viral breakthrough and no response had SVR24 rates 71%, 58% and 0%. The SVR24 rate was lower with the number of NS5A resistance-associated substitutions (RAS), where 2, 3, 4 and 5 RAS had SVR24 rates of 78%, 67%, 50% and 0%. A patient with an NS5A-P32 deletion, which shows resistance to next-generation NS5A inhibitors, was retreated with LDV/SOF with RBV and achieved SVR24. The addition of RBV to 12 weeks of LDV/SOF has little therapeutic benefit when retreating patients in whom a prior NS5A inhibitor-containing regimen had failed. © 2018 The Japan Society of Hepatology.

[Cost-effectiveness analysis of sofosbuvir, peginterferon and ribavirin in patients with chronic hepatitis C: Early treatment in the initial stage of fibrosis vs. delayed treatment in advanced fibrosis].

PubMed

Buti, María; Domínguez-Hernández, Raquel; Oyagüez, Itziar; Casado, Miguel Ángel

2016-01-01

Cost-effectiveness analysis of sofosbuvir combined with peginterferon alpha-2a and ribavirin (SOF/Peg-IFN/RBV) in early versus advanced fibrosis in previously untreated patients with chronic hepatitis C genotype 1 (CHC-GT1), from the perspective of the Spanish National Health System (NHS). A Markov model was developed to compare lifetime costs and outcomes (life years gained [LYGs] and quality-adjusted life years [QALYs]) of 2 treatment strategies: SOF/Peg-IFN/RBV administered during early fibrosis (mild-moderate fibrosis; F2-F3) or advanced fibrosis (cirrhosis; F4). Efficacy (sustained virologic response), annual transition probabilities, disease management costs and utilities were obtained from the literature. Costs and outcomes were discounted annually at 3%. Direct costs were considered, expressed in Euros (€, 2014). Probabilistic sensitivity analysis (PSA) was also performed. SOF/Peg-IFN/RBV therapy at F2-F3 was more effective (19.12 LYGs and 14.14 QALYs) compared to F4. In a cohort of 1,000 patients, SOF/Peg-IFN/RBV prevented 66 cases of decompensated cirrhosis, 60 hepatocellular carcinomas and 4 liver transplantations compared with therapy in advanced fibrosis. The total lifetime cost of early therapy (€43,263) was less than the cost of treatment in the advanced stage (€49,018). Early therapy was a dominant strategy, more effective and less costly in all simulations. In the PSA analysis, administration of SOF/PEG-IFN/RBV at F2-F3 was dominant in all simulations. Starting SOF/Peg-IFN/RBV therapy at F2-F3, compared with therapy at F4, reduced the incidence of liver disease complications and was associated with cost savings for the Spanish NHS in CHC-GT1 patients. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

Variation in both IL28B and KIR2DS3 genes influence pegylated interferon and ribavirin hepatitis C treatment outcome in HIV-1 co-infection.

PubMed

Keane, Ciara; O'Shea, Daire; Reiberger, Thomas; Peck-Radosavljevic, Markus; Farrell, Gillian; Bergin, Colm; Gardiner, Clair M

2013-01-01

Pegylated-IFN and ribavirin remains the current treatment for chronic HCV infection in patients co-infected with HIV-1, but this regimen has low efficacy rates, particularly for HCV genotype 1/4 infection, has severe side effects and is extremely costly. Therefore, accurate prediction of treatment response is urgently required. We have recently shown that the NK cell gene, KIR2DS3 and a SNP associated with the IL28B gene synergise to increase the risk of chronic infection in primary HCV mono-infected patients. Identification of SNPs associated with the IL28B gene has also proven very powerful for predicting patient response to treatment. Patients co-infected with HIV-1 are of particular concern given they respond less well to HCV treatment, have more side effects and suffer a more rapid liver disease progression. In this study, we examined both IL28B and KIR2DS3 for their ability to predict treatment response in a cohort of HIV-1/HCV co-infected patients attending two treatment centres in Europe. We found that variation in both host genetic risk factors, IL28B and KIR2DS3, was strongly associated with sustained virological response (SVR) to treatment in our co-infected cohort (n = 149). The majority of patients who achieved a rapid virological response (RVR) achieved a SVR. However, it is currently impossible to predict treatment outcome in patients who fail to achieve an RVR. In our cohort, the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these RVR negative patients (n = 88). Our data suggests that testing for host genetic factors will improve predicting treatment responsiveness in the clinical management of co-infected patients, and provides further evidence of the importance of the innate immune system in the immune response to HCV.

Sofosbuvir and Velpatasvir Combination Improves Patient-reported Outcomes for Patients With HCV Infection, Without or With Compensated or Decompensated Cirrhosis.

PubMed

Younossi, Zobair M; Stepanova, Maria; Feld, Jordan; Zeuzem, Stefan; Sulkowski, Mark; Foster, Graham R; Mangia, Alessandra; Charlton, Michael; O'Leary, Jacqueline G; Curry, Michael P; Nader, Fatema; Henry, Linda; Hunt, Sharon

2017-03-01

The combination of sofosbuvir and velpatasvir is used to treat patients with hepatitis C virus (HCV) infection of different genotypes. We compared the effects of this treatment regimen, with and without ribavirin, on outcomes reported by patients (patient-reported outcomes [PROs]) with HCV infection, with or without cirrhosis. We performed a post hoc analysis of data collected from phase 3 clinical trials (ASTRAL-1, -2, -3, and -4) of 1701 patients infected with HCV of different genotypes treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks (n = 87), sofosbuvir with ribavirin for 12 or 24 weeks (n = 401), and ribavirin-free sofosbuvir and velpatasvir for 12 or 24 weeks (n = 1213). In all trials, participants completed 4 PRO questionnaires (while blinded to their HCV RNA levels): the Short Form-36, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Chronic Liver Disease Questionnaire-HCV Version, and the Work Productivity and Activity Impairment: Specific Health Problem, at multiple time points. We compared baseline PROs and changes in PROs following treatment in patients without cirrhosis (n = 1112), with compensated cirrhosis (n = 338), and with decompensated cirrhosis (n = 251). Baseline PRO scores were as much as 33.5% lower in patients with decompensated cirrhosis than in patients without cirrhosis (P < .05). Following treatment with ribavirin-containing regimens, changes in PRO scores were similar among patients with compensated and decompensated cirrhosis (all P > .01). Treatment with these regimens increased some PRO scores by as much as 11.8% from baseline (P < .05) and reduced others, by as much as 7.1% (P < .05). Despite this, by 12 weeks after cessation of treatment with ribavirin-containing regimens, all PRO decrements resolved; PRO scores increased by as much as 14.2%, and as much as 17.1% at 24 weeks after treatment, regardless of cirrhosis status (all P > .01 between cirrhosis groups). In contrast, treatment with

Sustained virological response and baseline predictors in HIV-HCV coinfected patients retreated with pegylated interferon and ribavirin after failing a previous interferon-based therapy: systematic review and meta-analysis.

PubMed

Basso, Monica; Parisi, Saverio Giuseppe; Mengoli, Carlo; Gentilini, Valeria; Menegotto, Nicola; Monticelli, Jacopo; Nicolè, Stefano; Cruciani, Mario; Palù, Giorgio

2013-01-01

Published data on retreatment with pegylated interferon and ribavirin of previously failing HIV-HCV coinfected patients are sparse and limited to observational study. We aimed to evaluate efficacy and pretreatment predictors. Systematic review and meta-analysis of observational studies. The overall and genotype-related success rate was investigated. A direct comparison was performed between genotypes 1/4 and 2/3 by evaluating the sustained virological response (SVR) rate ratio (RR). The effect of study level variables on the effect size was investigated by meta-regression. Variables that were analyzed included age, gender, advanced hepatic fibrosis, pretreatment of HCV RNA and CD4, and successful antiretroviral treatment (ART). The available evidence was from 5 open-label, cohort studies (275 patients). The overall SVR rate was 0.280 (95% CI,0.171-0.425). The SVR rate in genotype 1/4 infections was 0.174 (95% CI, 0.129-0.230), and in genotype 2/3 infections it was 0.474 (95% CI, 0.286-0.670). The pooled RR comparing the SVR of genotype 1/4 to 2/3 was 0.369 (95% CI, 0.239-0.568), with a decreased probability of response for genotype 1/4 (P < .001). HIV RNA suppression had a significant effect on SVR (P = .005). The other covariates had no effect on the overall SVR rate. The overall SVR rate was 28%, consistent with the rate reported in the retreatment of mono-infected patients with the same schedule. A substantial relative reduction in the SVR rate of about one-third, when treating genotypes 1/4, was found, with a low SVR rate of 17%. Successful HIV suppression by ART predicted a higher rate of treatment success.

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors.

PubMed

Kanda, Tatsuo; Yasui, Shin; Nakamura, Masato; Suzuki, Eiichiro; Arai, Makoto; Ooka, Yoshihiko; Ogasawara, Sadahisa; Chiba, Tetsuhiro; Saito, Tomoko; Haga, Yuki; Takahashi, Koji; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Tawada, Akinobu; Maruyama, Hitoshi; Imazeki, Fumio; Kato, Naoya; Yokosuka, Osamu

2017-04-25

The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.

Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS.

PubMed

Morcos, Peter N; Leong, Ruby; Thommes, James A; DePamphilis, Jean; Grippo, Joseph F; Brennan, Barbara J

2015-01-01

PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 μg/week for 48 weeks or 360 μg/week for 12 weeks followed by 180 μg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 μg and 23.4±11.3 ng/mL for 360 μg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 μg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 μg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 μg to 0.52±0.32 log10 IU/week at 360 μg. Early viral de clines may be enhanced with the 360 μg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

A Patient with Crimean-Congo Hemorrhagic Fever Serologically Diagnosed by Recombinant Nucleoprotein-Based Antibody Detection Systems

PubMed Central

Tang, Qing; Saijo, Masayuki; Zhang, Yuzhen; Asiguma, Muer; Tianshu, Dong; Han, Lei; Shimayi, Bawudong; Maeda, Akihiko; Kurane, Ichiro; Morikawa, Shigeru

2003-01-01

We treated a male patient with Crimean-Congo hemorrhagic fever (CCHF). The diagnosis of CCHF was confirmed by reverse transcription-PCR and recombinant nucleoprotein (rNP)-based immunoglobulin G (IgG) and IgM capture enzyme-linked immunosorbent assays of serially collected serum samples. The patient was treated with intravenous ribavirin and recovered with no consequences. The study indicates that rNP-based CCHF virus antibody detection systems are useful for confirming CCHF virus infections. This case also suggests that intravenous ribavirin therapy may be promising for the treatment of CCHF patients. PMID:12738657

Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection.

PubMed

Foster, Graham R; Afdhal, Nezam; Roberts, Stuart K; Bräu, Norbert; Gane, Edward J; Pianko, Stephen; Lawitz, Eric; Thompson, Alex; Shiffman, Mitchell L; Cooper, Curtis; Towner, William J; Conway, Brian; Ruane, Peter; Bourlière, Marc; Asselah, Tarik; Berg, Thomas; Zeuzem, Stefan; Rosenberg, William; Agarwal, Kosh; Stedman, Catherine A M; Mo, Hongmei; Dvory-Sobol, Hadas; Han, Lingling; Wang, Jing; McNally, John; Osinusi, Anu; Brainard, Diana M; McHutchison, John G; Mazzotta, Francesco; Tran, Tram T; Gordon, Stuart C; Patel, Keyur; Reau, Nancy; Mangia, Alessandra; Sulkowski, Mark

2015-12-31

In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences

A cost utility analysis of simeprevir used with peginterferon + ribavirin in the management of genotype 1 hepatitis C virus infection, from the perspective of the UK National Health Service.

PubMed

Westerhout, Kirsten; Treur, Maarten; Mehnert, Angelika; Pascoe, Katie; Ladha, Imran; Belsey, Jonathan

2015-01-01

Triple therapy using a protease inhibitor (PI) with peginterferon and ribavirin (PR) is increasingly used in patients with chronic hepatitis C virus (HCV) infection. The most recently introduced PI, simeprevir (SMV), offers high levels of viral eradication combined with a reduced overall duration of therapy. The objective of this study was to compare the cost-effectiveness of SMV + PR vs PR alone or in combination with telaprevir (TVR) or boceprevir (BOC) in patients infected with genotype 1 HCV Method: A cost-utility model was constructed, incorporating two phases, capturing the efficacy of therapy in an initial treatment phase, followed by a long-term post-treatment Markov phase, capturing lifetime outcomes according to whether a sustained viral response (SVR) had been achieved on treatment. Dosage regimens were based on the EMA approved label for each treatment. SVR estimates and adverse event rates were derived from a mixed treatment comparison. Baseline characteristics were drawn from an analysis of a UK HCV data-set and clinician opinion. Health state transition probabilities, utilities, and health state costs were drawn from previously published economic analyses. The model considered direct health costs only, and the perspective was that of the UK National Health Service. The model yielded an ICER for SMV + PR vs PR alone of £9725/QALY for treatment-naïve and £7819/QALY for treatment-experienced. Benefit was driven by increased likelihood of achieving SVR, with consequent long-term utility gains. SMV + PR dominated TVR + PR and BOC + PR in both patient groups. This principally reflected the QALY benefit of an increased likelihood of SVR with SMV, combined with lower overall drug costs, due to reduced mean treatment duration. Compared to other currently licensed treatment options, SMV + PR represents a cost effective treatment option for patients with chronic genotype 1 HCV infection.

Customizing treatment to patient populations.

PubMed

Brown, Robert S

2007-01-01

Combination treatment with pegylated interferon plus ribavirin is the most effective therapy for patients with chronic hepatitis C virus (HCV); however, responses are less than optimal in some subpopulations of patients. Emerging insights are suggesting that viral kinetics can be used to predict response. The rapidity of response has been shown to be a more important predictor of sustained virologic response than the duration of therapy. In patients with HCV genotype 2 or 3, shorter durations of treatment might be sufficient in rapid responders and could minimize the risk of toxic effects. Weight-based dosing of ribavirin has emerged as another important consideration. This strategy seems to be most important for difficult-to-treat patients with HCV genotype 1 or advanced fibrosis, and for African-Americans, and is possibly important for patients who have genotype 3 and a high viral load. Re-treatment of nonresponders with interferon-based therapy has been associated with low rates of sustained virologic response. Consensus interferon might offer a new option for patients who do not achieve an early treatment response to standard or pegylated interferon plus ribavirin.

Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program.

PubMed

Gray, E; O'Leary, A; Bergin, C; Cannon, M; Courtney, G; Crosbie, O; De Gascun, C F; Fanning, L J; Feeney, E; Houlihan, D D; Kelleher, B; Lambert, J S; Lee, J; Mallon, Pwg; McConkey, S; McCormick, A; McKiernan, S; McNally, C; Murray, F; Sheehan, G; Stewart, S; Walsh, C; Norris, S

2017-06-01

We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV). Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined. A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%. The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.

Cost-Effectiveness of New Direct-Acting Antivirals to Prevent Post-Liver Transplant Recurrent Hepatitis.

PubMed

Cortesi, P A; Mantovani, L G; Ciaccio, A; Rota, M; Mazzarelli, C; Cesana, G; Strazzabosco, M; Belli, L S

2015-07-01

Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Evaluation of Lassa Antiviral Compound ST-193 in a Guinea Pig Model

PubMed Central

Cashman, Kathleen A.; Smith, Mark A.; Twenhafel, Nancy A.; Larson, Ryan A.; Jones, Kevin F.; Allen, Robert D.; Dai, Dongcheng; Chinsangaram, Jarasvech; Bolken, Tove’ C.; Hruby, Dennis E.; Amberg, Sean M.; Hensley, Lisa E.; Guttieri, Mary C.

2012-01-01

Lassa virus (LASV), a member of the Arenaviridae family, causes a viral hemorrhagic fever endemic to West Africa, where as many as 300,000 infections occur per year. Presently, there are no FDA-approved LASV-specific vaccines or antiviral agents, although the antiviral drug ribavirin has shown some efficacy. A recently identified small-molecule inhibitor of arenavirus entry, ST-193, exhibits submicromolar antiviral activity in vitro. To determine the antiviral utility of ST-193 in vivo, we tested the efficacy of this compound in the LASV guinea pig model. Four groups of strain 13 guinea pigs were administered 25 or 80 mg/kg ST-193, 25 mg/kg of ribavirin, or the vehicle by the intraperitoneal (i.p.) route before infection with a lethal dose of LASV, strain Josiah, and continuing once daily for 14 days. Control animals exhibited severe disease, becoming moribund between days 10 and 15 postinfection. ST-193-treated animals exhibited fewer signs of disease and enhanced survival when compared to the ribavirin or vehicle groups. Body temperatures in all groups were elevated by day 9, but returned to normal by day 19 postinfection in the majority of ST-193-treated animals. ST-193 treatment mediated a 2- to 3-log reduction in viremia relative to vehicle-treated controls. The overall survival rate for the ST-193-treated guinea pigs was 62.5% (10/16) compared with 0% in the ribavirin (0/8) and vehicle (0/7) groups. These data suggest that ST-193 may serve as an improved candidate for the treatment of Lassa fever. PMID:21371508

Acute hepatitis C: a 24-week course of pegylated interferon α-2b versus a 12-week course of pegylated interferon α-2b alone or with ribavirin.

PubMed

Santantonio, Teresa; Fasano, Massimo; Sagnelli, Evangelista; Tundo, Paolo; Babudieri, Sergio; Fabris, Paolo; Toti, Mario; Di Perri, Giovanni; Marino, Nicoletta; Pizzigallo, Eligio; Angarano, Gioacchino

2014-06-01

Therapy of acute hepatitis C (AHC) has not yet been standardized and several issues are still unresolved. This open, randomized, multicenter trial aimed to assess the efficacy and safety of a 24-week course of pegylated IFN (Peg-IFN) alpha-2b versus a 12-week course of Peg-IFN alpha-2b alone or with ribavirin (RBV) in AHC patients. One hundred and thirty HCV acutely infected patients who did not spontaneously resolve by week 12 after onset were consecutively enrolled and randomized to receive Peg-IFN alpha-2b monotherapy (1.5 μg/kg/week) for 24 or 12 weeks (arm 1, n = 44 and arm 2, n = 43, respectively) or in combination with RBV (10.6 mg/kg/day) for 12 weeks (arm 3, n = 43). The primary endpoint was undetectable HCV RNA at 6-month posttreatment follow-up (sustained virological response; SVR). All patients were followed for 48 weeks after therapy cessation. HCV RNA levels were determined by real-time polymerase chain reaction (limit of detection: 15 IU/mL) at the central laboratory at baseline, week 4, end of treatment, and 6 and 12 months posttreatment. Using an intent-to-treat analysis, overall SVR rate was 71.5%. In particular, an SVR was achieved in 31 of 44 (70.5%), 31 of 43 (72.1%), and 31 of 43 (72.1%) patients in arms 1, 2, and 3, respectively (P = 0.898). Sixteen patients (12.3%) prematurely discontinued therapy or were lost to follow-up; thus, sustained response rates with per-protocol analysis were 81.6%, 81.6%, and 81.6% for patients in arms 1, 2, and 3 respectively. With multivariate analysis, virologic response at week 4 of treatment was an independent predictor of SVR. Peg-IFN alpha-2b was well tolerated. Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients. Response rates were not influenced by combination therapy or treatment duration. © 2014 by the American Association for the Study of Liver Diseases.

Safety and effectiveness of a 12-week course of sofosbuvir and simeprevir ± ribavirin in HCV-infected patients with or without HIV infection: a multicentre observational study.

PubMed

Bruno, Giuseppe; Saracino, Annalisa; Fabrizio, Claudia; Scudeller, Luigia; Milano, Eugenio; Dell'Acqua, Raffaele; Ladisa, Nicoletta; Fasano, Massimo; Minniti, Salvatore; Buccoliero, Giovanni; Tartaglia, Alessandra; Giammario, Adele; Milella, Michele; Angarano, Gioacchino

2017-03-01

The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm 3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Impact of Hispanic or Asian ethnicity on the treatment outcomes of chronic hepatitis C: results from the WIN-R trial.

PubMed

Hu, Ke-Qin; Freilich, Bradley; Brown, Robert S; Brass, Clifford; Jacobson, Ira M

2011-09-01

African American ethnicity is a well-described negative predictor of treatment outcome for chronic hepatitis C (CHC); however, less is known about the influence of Hispanic and Asian ethnicity. The aim of this subanalysis of the Weight-based Dosing of PegINterferon α-2b and Ribavirin (WIN-R) study was to assess the impact of Asian (n=118), Hispanic (n=289), and white (n=3919) ethnicity on CHC treatment outcomes. WIN-R was an investigator-initiated trial in which patients with CHC received pegylated interferon α-2b (1.5 μg/kg/wk) plus a fixed ribavirin dose (800 mg/d) or a weight-based ribavirin dose (800 to 1400 mg/d) for 24 or 48 weeks. Sustained virologic response was higher in Asian patients than in white patients (56% vs 46%, P=0.041), and higher in Asian and white patients than in Hispanic patients (56% vs 35%, P=0.0001; and 46% vs 35%, P=0.0002, respectively). In genotype 1 patients, sustained virologic response was higher in white and Asian patients than in Hispanic patients (36% and 45% vs 25%, P<0.001 for both comparisons); however, in genotype 2/3 patients, there were no significant differences among ethnic groups. Psychiatric adverse events were less common and anemia was more common in Asians than in white or Hispanic patients. Ribavirin dose reductions were less frequent in Hispanic patients than in white patients, whereas pegylated interferonα-2b dose reductions were more common in white patients than Hispanic patients. These observations highlight the importance of ethnicity as an integral component of the tailored treatment approach to CHC.

Influence of Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir on Warfarin Dosing Requirements in Four Veterans.

PubMed

Britnell, Sara R; Willets, Amy E; Vanderman, Adam J; Woodard, Catherine L; Britt, Rachel B

2016-11-01

To describe international normalized ratio (INR) trends and warfarin dosage adjustments required for four veterans who were receiving warfarin therapy and started treatment for hepatitis C virus (HCV) with ledipasvir/sofosbuvir with or without ribavirin. Case series. Pharmacist-led anticoagulation clinic in a Veterans Affairs Health Care System. Four patients aged 59-66 years who were receiving warfarin and had stable, therapeutic INRs and started ledipasvir/sofosbuvir therapy with or without ribavirin for HCV infection. All four patients developed subtherapeutic INRs after the addition of ledipasvir/sofosbuvir with or without ribavirin. An increase in weekly warfarin dose ranging from 14-67% was required, with changes in warfarin doses starting 2-3 weeks after ledipasvir/sofosbuvir initiation. Two patients required dose reductions after HCV treatment completion, whereas the other two did not. Use of the Drug Interaction Probability Scale indicated that the interaction between warfarin and ledipasvir/sofosbuvir was doubtful (score of 1 [two patients]) or possible (score of 4 [two patients]). The mechanism of this interaction is unknown but may be related to improvements in hepatic function during HCV treatment. To our knowledge, this is the first case series describing a possible drug interaction between warfarin and ledipasvir/sofosbuvir (with or without ribavirin). Close monitoring is warranted when ledipasvir/sofosbuvir is initiated in patients receiving anticoagulation therapy with warfarin, especially those with evidence of cirrhosis prior to treatment. This is particularly important in the first month after starting treatment and the first month after completion. Failure to monitor and achieve therapeutic INR after HCV therapy completion may have the potential to result in adverse outcomes. © 2016 Pharmacotherapy Publications, Inc.

Guillain-Barre syndrome associated with peginterferon alfa-2a for chronic hepatitis C: A case report

PubMed Central

Niazi, Mumtaz A; Azhar, Ashaur; Tufail, Kashif; Feyssa, Eyob L; Penny, Stephen F; McGregory, Marlene; Araya, Victor; Ortiz, Jorge A

2010-01-01

The recommended therapy for chronic hepatitis C (CHC) infection is the combination of a Pegylated interferon and Ribavirin. Almost all such patients on combination therapy experience one or more adverse events during the course of treatment. Significant neurological side effects are rare. A few cases of Bell’s Palsy, chronic inflammatory demyelinating polyneuropathy and even one case of acute demyelinating polyneuropathy with atypical features for Guillain-Barre syndrome (GBS) associated with Interferon therapy have been reported but no report of GBS with typical features has been published. We present a case report of typical GBS associated with Peginterferon alfa-2a and Ribavirin used for treatment of CHC infection. PMID:21160989

Comparative study of six sequential spectrophotometric methods for quantification and separation of ribavirin, sofosbuvir and daclatasvir: An application on Laboratory prepared mixture, pharmaceutical preparations, spiked human urine, spiked human plasma, and dissolution test.

PubMed

Hassan, Wafaa S; Elmasry, Manal S; Elsayed, Heba M; Zidan, Dalia W

2018-09-05

In accordance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, six novel, simple and precise sequential spectrophotometric methods were developed and validated for the simultaneous analysis of Ribavirin (RIB), Sofosbuvir (SOF), and Daclatasvir (DAC) in their mixture without prior separation steps. These drugs are described as co-administered for treatment of Hepatitis C virus (HCV). HCV is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma) and lymphomas in humans. These techniques consisted of several sequential steps using zero, ratio and/or derivative spectra. DAC was first determined through direct spectrophotometry at 313.7 nm without any interference of the other two drugs while RIB and SOF can be determined after ratio subtraction through five methods; Ratio difference spectrophotometric method, successive derivative ratio method, constant center, isoabsorptive method at 238.8 nm, and mean centering of the ratio spectra (MCR) at 224 nm and 258 nm for RIB and SOF, respectively. The calibration curve is linear over the concentration ranges of (6-42), (10-70) and (4-16) μg/mL for RIB, SOF, and DAC, respectively. This method was successfully applied to commercial pharmaceutical preparation of the drugs, spiked human urine, and spiked human plasma. The above methods are very simple methods that were developed for the simultaneous determination of binary and ternary mixtures and so enhance signal-to-noise ratio. The method has been successfully applied to the simultaneous analysis of RIB, SOF, and DAC in laboratory prepared mixtures. The obtained results are statistically compared with those obtained by the official or reported methods, showing no significant difference with respect to accuracy and precision at p = 0.05. Copyright © 2018 Elsevier B.V. All rights reserved.

Real-World Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir/+Dasabuvir±Ribavirin (OBV/PTV/r/+DSV±RBV) Therapy in Recurrent Hepatitis C Virus (HCV) Genotype 1 Infection Post-Liver Transplant: AMBER-CEE Study.

PubMed

Tronina, Olga; Durlik, Magdalena; Wawrzynowicz-Syczewska, Marta; Buivydiene, Arida; Katzarov, Krum; Kupcinskas, Limas; Tolmane, Ieva; Karpińska, Ewa; Pisula, Arkadiusz; Karwowska, Kornelia Magdalena; Bolewska, Beata; Jabłkowski, Maciej; Rostkowska, Karolina; Jakutiene, Jolita; Simonova, Marieta; Flisiak, Robert

2017-04-07

BACKGROUND The introduction of direct-acting antivirals (DAAs) has considerably improved therapeutic outcomes for patients with chronic hepatitis C virus (HCV) infections. The AMBER-CEE study aimed to assess real-world efficacy and safety of ombitasvir/paritaprevir/ritonavir/+ dasabuvir ±ribavirin (OBV/PTV/r/ +DSV±RBV) in the treatment of post-transplant recurrence of HCV infection. MATERIAL AND METHODS Liver transplant recipients with recurrent HCV genotype 1 infection, scheduled for OBV/PTV/r/+DSV±RBV according to therapeutic guidelines, were eligible. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks after the end of treatment (FU12). Clinical and laboratory adverse events (AEs) were recorded from baseline to FU12. RESULTS A total of 35 patients were included: 91.4% genotype 1b-infected, 94.3% treatment-experienced, and 77.1% at fibrosis stage ≥F2. SVR12 was achieved by all patients (35/35, 100%) including one patient with genotype 1a, one patient with detectable HCV RNA at the end of treatment, two patients with a history of first-generation DAA therapy, and two patients who prematurely discontinued the regimen. AEs were experienced by 22 patients (62.9%) and were mostly mild. No death, graft loss, or acute graft rejections were reported during the therapy. On-treatment hepatic decompensation occurred in three patients (8.6%). Anemia was observed in 29 patients (83.9%), with 21 (60%) requiring RBV dose reduction or discontinuation. CONCLUSIONS OBV/PTV/r/+DSV±RBV has excellent efficacy in post-transplant recurrence of HCV genotype 1-infection treated under real-world conditions. Excellent virologic outcomes were observed irrespective of prior treatment history or the degree of fibrosis, and AEs were mostly mild and transient.

A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C.

PubMed

Flisiak, Robert; Shiffman, Mitchell; Arenas, Juan; Cheinquer, Hugo; Nikitin, Igor; Dong, Yuping; Rana, Khurram; Srinivasan, Subasree

2016-01-01

A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection. Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR. A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm. In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary

Treatment and follow up of children with chronic hepatitis C in Albania

PubMed Central

2012-01-01

Background Treatment of Hepatitis C in children has a better outcome than in adults, and for this reason the treatment had different views. However, in pediatric age hepatitis C is seen to have an evolution towards chronicity. Today is a normal option to treat chronic hepatitis C as early as possible according to certain criteria. The aim of this study is to show the results of treatment with interferon and ribavirin and the follow-up of children diagnosed with chronic hepatitis C in our service. Patients and methods This is a prospective study which has included children 3 up to 15 years old (13 boys and 4 girls) diagnosed with chronic hepatitis C. All patients underwent a certain protocol, including liver biopsy prior to treatment. Treatment consisted in use for 48 weeks of INF α-2b, 3 MIU/m2 three times a week s/c and ribavirin 15 mg/kg orally divided bid. Two patients were treated with PEGINF α-2b with dose 1.5 mcg/kg once a week s/c and ribavirin 15 mg/kg. After the treatment all patients have stayed under our control for an average period of 24 weeks. Results At the end of the treatment we detected a patient with HCV-RNA positive. End Treatment Viral Response was 94%. Six months later we found three patients who showed relapse of disease. Sustained Viral Response was approximately 83% Conclusion The combination therapy of interferon with Ribavirin in treatment of children with chronic hepatitis C provides a higher SVR when treatment is initiated at the earliest stages of hepatic changes. Side effects of therapy are insignificant in comparison with results obtained PMID:22244498

Modeling HCV cure after an ultra-short duration of therapy with direct acting agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goyal, Ashish; Lurie, Yoav; Meissner, Eric G.

In cases of sustained-virological response (SVR or cure) after an ultra-short duration (≤ 27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (V i) and non-infectious virus (V ni) in ordermore » to explain the observation of cure with ultrashort DAA therapy. Established HCV models were compared to the new mathematical model to retrospectively explain cure in 2 patients who achieved cure after 24 or 27 days of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin or sofosbuvir plus ribavirin, respectively. Fitting established models with measured longitudinal HCV viral loads indicated that in both cases, cure would not have been expected without an additional 3–6 weeks of therapy after the actual EOT. In contrast, the new model fits the observed outcome by considering that in addition to blocking V i and V ni production (ε~0.998), these DAA + ribavirin treatments further enhanced the ratio of V ni to V i, thus increasing the log (V ni/V i) from 1 at pretreatment to 6 by EOT, which led to <1 infectious-virus particle in the extracellular body fluid (i.e., cure) prior to EOT. This new model can explain cure after short duration of DAA + ribavirin therapy by suggesting that a minimum 6-fold increase of log (V ni/V i) results from drug-induced enhancement of the V ni/V i.« less

Validation of a questionnaire to monitor symptoms in HIV-infected patients during hepatitis C treatment.

PubMed

Cachay, Edward R; Ballard, Craig; Colwell, Bradford; Torriani, Francesca; Hicks, Charles; Mathews, Wm Christopher

2017-09-20

Clinicians are incorporating patient-reported outcomes in the management of HIV-infected persons co-infected with hepatitis C virus (HCV), but there are no validated inventories to monitor symptoms of patients during HCV therapy. Five-year retrospective cohort analysis of persons living with HIV (PLWH) treated for HCV. The HCV symptom-inventory (HCV-SI) was administered before, during, and after HCV treatment. Discriminant validity was assessed, separately, in mixed model linear regression of HCV-SI T-scores on treatment regimens (pegylated-interferon and ribavirin; pegylated-interferon, ribavirin, and telaprevir; and interferon-free antivirals); and side effect-related premature treatment discontinuation (SE-DC). From the 103 patients who completed the HCV-SI, 7% were female, 26% non-white, 32% cirrhotics and 91% had undetectable HIV viral loads. Most had genotype 1 (83%) and were HCV treatment-naïve (78%). We treated 19% of patients with pegylated-interferon and ribavirin, 22% with pegylated-interferon, ribavirin, and telaprevir and 59% received interferon-free antivirals. Overall, 77% achieved a sustained virologic response, and 6% discontinued HCV treatment due to side effects. In the treatment discrimination model, compared to the no treatment period, HCV-SI scores were significantly (p < 0.01) lower for interferon-free antivirals and higher for interferon-containing regimens. In the SE-DC model, the total HCV-SI, somatic and neuropsychiatric scores significantly predicted those patients who prematurely discontinued HCV treatment (P < 0.05). The HCV-SI effectively differentiated among treatment regimens known to vary by side effect profiles and between patients with and without treatment discontinuation due to side effects. The HCV-SI may have value as a patient-reported outcome instrument predicting the risk of HCV treatment discontinuation.

Modeling HCV cure after an ultra-short duration of therapy with direct acting agents

DOE PAGES

Goyal, Ashish; Lurie, Yoav; Meissner, Eric G.; ...

2017-06-30

In cases of sustained-virological response (SVR or cure) after an ultra-short duration (≤ 27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (V i) and non-infectious virus (V ni) in ordermore » to explain the observation of cure with ultrashort DAA therapy. Established HCV models were compared to the new mathematical model to retrospectively explain cure in 2 patients who achieved cure after 24 or 27 days of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin or sofosbuvir plus ribavirin, respectively. Fitting established models with measured longitudinal HCV viral loads indicated that in both cases, cure would not have been expected without an additional 3–6 weeks of therapy after the actual EOT. In contrast, the new model fits the observed outcome by considering that in addition to blocking V i and V ni production (ε~0.998), these DAA + ribavirin treatments further enhanced the ratio of V ni to V i, thus increasing the log (V ni/V i) from 1 at pretreatment to 6 by EOT, which led to <1 infectious-virus particle in the extracellular body fluid (i.e., cure) prior to EOT. This new model can explain cure after short duration of DAA + ribavirin therapy by suggesting that a minimum 6-fold increase of log (V ni/V i) results from drug-induced enhancement of the V ni/V i.« less

Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Naïve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis

PubMed Central

Sobhonslidsuk, Abhasnee; Thakkinstian, Ammarin; Teerawattananon, Yot

2015-01-01

Background The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs. Aim Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1. Methods Medline and Scopus were searched up to 25th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using ‘pmeta’ command in STATA program. Results Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens

A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients.

PubMed

Braun, Dominique L; Rauch, Andri; Aouri, Manel; Durisch, Nina; Eberhard, Nadia; Anagnostopoulos, Alexia; Ledergerber, Bruno; Müllhaupt, Beat; Metzner, Karin J; Decosterd, Laurent; Böni, Jürg; Weber, Rainer; Fehr, Jan

2015-01-01

The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group. Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin. We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1-2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

PubMed

Wedemeyer, Heiner; Forns, Xavier; Hézode, Christophe; Lee, Samuel S; Scalori, Astrid; Voulgari, Athina; Le Pogam, Sophie; Nájera, Isabel; Thommes, James A

2016-01-01

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.

Lassa fever presenting as acute abdomen: a case series.

PubMed

Dongo, Andrew E; Kesieme, Emeka B; Iyamu, Christopher E; Okokhere, Peter O; Akhuemokhan, Odigie C; Akpede, George O

2013-04-19

Lassa fever, an endemic zoonotic viral infection in West Africa, presents with varied symptoms including fever, vomiting, retrosternal pain, abdominal pain, sore-throat, mucosal bleeding, seizures and coma. When fever and abdominal pain are the main presenting symptoms, and a diagnosis of acute abdomen is entertained, Lassa fever is rarely considered in the differential diagnosis, even in endemic areas. Rather the diagnosis of Lassa fever is suspected only after surgical intervention. Therefore, such patients often undergo unnecessary surgery with resultant delay in the commencement of ribavirin therapy. This increases morbidity and mortality and the risk of nosocomial transmission to hospital staff. We report 7 patients aged between 17 months and 40 years who had operative intervention for suspected appendicitis, perforated typhoid ileitis, intussuception and ruptured ectopic pregnancy after routine investigations. All seven were post-operatively confirmed as Lassa fever cases. Four patients died postoperatively, most before commencement of ribavirin, while the other three patients eventually recovered with appropriate antibiotic treatment including intravenous ribavirin. Surgeons working in West Africa should include Lassa fever in the differential diagnosis of acute abdomen, especially appendicitis. The presence of high grade fever, proteinuria and thrombocytopenia in patients with acute abdomen should heighten the suspicion of Lassa fever. Prolonged intra-operative bleeding should not only raise suspicion of the disease but also serve to initiate precautions to prevent nosocomial transmission.

Lassa fever presenting as acute abdomen: a case series

PubMed Central

2013-01-01

Lassa fever, an endemic zoonotic viral infection in West Africa, presents with varied symptoms including fever, vomiting, retrosternal pain, abdominal pain, sore-throat, mucosal bleeding, seizures and coma. When fever and abdominal pain are the main presenting symptoms, and a diagnosis of acute abdomen is entertained, Lassa fever is rarely considered in the differential diagnosis, even in endemic areas. Rather the diagnosis of Lassa fever is suspected only after surgical intervention. Therefore, such patients often undergo unnecessary surgery with resultant delay in the commencement of ribavirin therapy. This increases morbidity and mortality and the risk of nosocomial transmission to hospital staff. We report 7 patients aged between 17 months and 40 years who had operative intervention for suspected appendicitis, perforated typhoid ileitis, intussuception and ruptured ectopic pregnancy after routine investigations. All seven were post-operatively confirmed as Lassa fever cases. Four patients died postoperatively, most before commencement of ribavirin, while the other three patients eventually recovered with appropriate antibiotic treatment including intravenous ribavirin. Surgeons working in West Africa should include Lassa fever in the differential diagnosis of acute abdomen, especially appendicitis. The presence of high grade fever, proteinuria and thrombocytopenia in patients with acute abdomen should heighten the suspicion of Lassa fever. Prolonged intra-operative bleeding should not only raise suspicion of the disease but also serve to initiate precautions to prevent nosocomial transmission. PMID:23597024

Approved Antiviral Drugs over the Past 50 Years

PubMed Central

2016-01-01

SUMMARY Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2′-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2′-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide. PMID:27281742

[Hepatitis C treatment in special patient groups].

PubMed

Berenguer, Marina; Jorquera, Francisco; Ángel Serra, Miguel; Sola, Ricard; Castellano, Gregorio

2014-07-01

The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects. These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C.

PubMed

Fazel, Yousef; Lam, Brian; Golabi, Pegah; Younossi, Zobair

2015-08-01

The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy. The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available. In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug-drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug-drug interactions.

Reactivation of Herpesvirus in Patients With Hepatitis C Treated With Direct-Acting Antiviral Agents.

PubMed

Perelló M, Christie; Fernández-Carrillo, Carlos; Londoño, María-Carlota; Arias-Loste, Teresa; Hernández-Conde, Marta; Llerena, Susana; Crespo, Javier; Forns, Xavier; Calleja, José Luis

2016-11-01

We performed a case-series analysis of reactivation of herpesvirus in patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents. We collected data from 576 patients with HCV infection treated with DAA combinations at 3 hospitals in Spain, from November 2014 through November 2015. We also collected data from a control population (230 HCV-infected patients, matched for sex and age; 23 untreated and 213 treated with interferon-based regimens). Herpesvirus was reactivated in 10 patients who received DAA therapy (7 patients had cirrhosis and 3 patients had received liver transplants), a median of 8 weeks after the therapy was initiated. None of the controls had herpesvirus reactivation. Patients with herpesvirus reactivation were receiving the DAA agents sofosbuvir with ledipasvir (with or without ribavirin, 7/10), ombitasvir with paritaprevir and ritonavir plus dasabuvir (with or without ribavirin, 2/10), or sofosbuvir with simeprevir plus ribavirin (1/10). Two of the 10 patients developed postherpetic neuralgia and 1 patient developed kerato-uveitis. All 10 patients with herpesvirus reactivation achieved a sustained virologic response. Immune changes that follow clearance of HCV might lead to reactivation of other viruses, such as herpesvirus. Patients with HCV infection suspected of having herpesvirus infection should be treated immediately. Some groups also might be screened for herpesvirus infection. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

PubMed

Kamal, Adina Maria; MitruŢ, Paul; Kamal, Kamal Constantin; Tica, Oana Sorina; Niculescu, Mihaela; Alexandru, Dragoş Ovidiu; Tica, Andrei Adrian

2016-01-01

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

[Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients].

PubMed

Martínez-Rebollar, Maria; Mallolas, Josep; Pérez, Iñaki; González-Cordón, Ana; Loncà, Montserrat; Torres, Berta; Rojas, Jhon-Fredy; Monteiro, Polyana; Blanco, José-Luis; Martínez, Esteban; Gatell, José-María; Laguno, Montserrat

2015-01-01

Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution. This retrospective study includes all HIV patients with AHC in our centre from 2003 to March 2013. AHC was defined by seroconversion of HCV antibodies and detection of serum HCV RNA. 93 episodes of AHC were diagnosed in 89 patients. All but three were MSM with a history of unprotected sex. Thirty-seven (40%) patients had other associated sexually transmitted disease. The 29% (27) had any symptoms suggestive of AHC. HCV genotype 4 was the most common (41%), followed by genotype1. Seventy patients started treatment with interferon-alfa and weight-adjusted ribavirin. Currently 46 have completed treatment and follow-up, reaching 26 of them (56.5%) sustained viral response. The incidence of AHC in HIV MSM patients from our centre has increased exponentially in recent years; sexual transmission remains the main route of infection. Early treatment with interferon-alpha and ribavirin achieved a moderate response in these patients. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Outcomes of chronic hepatitis C therapy in patients treated in community versus academic centres in Canada: final results of APPROACH (a prospective study of peginterferon alfa-2a and ribavirin at academic and community centres in Canada).

PubMed

Myers, Robert P; Cooper, Curtis; Sherman, Morris; Lalonde, Richard; Witt-Sullivan, Helga; Elkashab, Magdy; Harris, Paul; Balshaw, Robert; Usaty, Chistopher; Marrotta, Paul J

2011-09-01

In patients chronically infected with the hepatitis C virus (HCV), it is not established whether viral outcomes or health-related quality of life (HRQoL) differ between individuals treated at academic or community centres. In the present observational study, adults with chronic HCV were treated with peginterferon alfa-2a 180 ìg⁄week plus ribavirin at 45 Canadian centres (16 academic, 29 community). The primary efficacy end point was sustained virological response (SVR). Other outcome measures included HRQoL (assessed using the 36-item Short-Form Health Survey), heath resource use, and workplace productivity and absences within a 60-day interval. In treatment-naive patients infected with HCV genotype 1, significantly higher SVR rates were achieved in those treated at academic (n=54) compared with community (n=125) centres (52% versus 32% [P=0.01]), although rates of dosage reduction and treatment discontinuation were similar across settings. SVR rates among patients infected with genotype 2⁄3 were similar between academic (n=59) and community (n=100) centres (64% versus 67% [P=0.73]). Following antiviral therapy, patients with genotype 1 who achieved an SVR (n=67) had significantly higher mean scores on the physical (P=0.005) and mental components of the 36-item Short-Form Health Survey (P=0.043) compared with those without an SVR (n=111). In contrast, HRQoL scores were similar in HCV genotype 2⁄3 patients with and without an SVR. There were no differences in workplace productivity or absences between patients with and without an SVR. The most frequently used health care resources by all patients were visits and phone calls to hepatitis nurses, and general practice or walk-in clinics. Patients infected with HCV genotype 1 achieved higher SVR rates when treated at academic rather than community centres in Canada. The reasons for this difference require additional investigation.

Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.

PubMed

Mulhall, Brian P; Younossi, Zobair

2005-01-01

Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is

Loukoumasomes Are Distinct Subcellular Structures from Rods and Rings and Are Structurally Associated with MAP2 and the Nuclear Envelope in Retinal Cells

PubMed Central

Noble, Jake W.; Hunter, Diana V.; Roskelley, Calvin D.; Chan, Edward K. L.; Mills, Julia

2016-01-01

“Rods and rings” (RR) and loukoumasomes are similarly shaped, subcellular macromolecular structures with as yet unknown function. RR, so named because of their shape, are formed in response to inhibition in the GTP or CTP synthetic pathways and are highly enriched in the two key enzymes of the nucleotide synthetic pathway. Loukoumasomes also occur as linear and toroidal bodies and were initially inferred to be the same as RR, largely due to their shared shape and size and the fact that it was unclear if they shared the same subcomponents. In human retinoblastoma tissue and cells we have observed toroidal, perinuclear, macromolecular structures of similar size and antigenicity to those previously reported in neurons (neuronal-loukoumasomes). To further characterize the subcomponents of the retinal-loukoumasomes, confocal analysis following immunocytochemical staining for alpha-tubulin, beta-III tubulin and detyrosinated tubulin was performed. These studies indicate that retinal-loukoumasomes are enriched for beta-III tubulin and other tubulins associated with microtubules. Immunofluorescence together with the in situ proximity ligation assay (PLA), confirmed that beta-III tubulin colocalized with detyrosinated tubulin within loukoumasomes. Our results indicate that these tissues contain only loukoumasomes because these macromolecular structures are immunoreactive with an anti-tubulin antibody but are not recognized by the prototype anti-RR/inosine monophosphate dehydrogenase (IMPDH) antibody (It2006). To further compare the RR and retinal-loukoumasomes, retinoblastoma cells were exposed to the IMPDH-inhibitor ribavirin, a drug known to induce the formation of RR. In contrast to RR, the production of retinal-loukoumasomes was unaffected. Coimmunostaining of Y79 cells for beta-III tubulin and IMPDH indicate that these cells, when treated with ribavirin, can contain both retinal-loukoumasomes and RR and that these structures are antigenically distinct. Subcellular

Loukoumasomes Are Distinct Subcellular Structures from Rods and Rings and Are Structurally Associated with MAP2 and the Nuclear Envelope in Retinal Cells.

PubMed

Noble, Jake W; Hunter, Diana V; Roskelley, Calvin D; Chan, Edward K L; Mills, Julia

2016-01-01

"Rods and rings" (RR) and loukoumasomes are similarly shaped, subcellular macromolecular structures with as yet unknown function. RR, so named because of their shape, are formed in response to inhibition in the GTP or CTP synthetic pathways and are highly enriched in the two key enzymes of the nucleotide synthetic pathway. Loukoumasomes also occur as linear and toroidal bodies and were initially inferred to be the same as RR, largely due to their shared shape and size and the fact that it was unclear if they shared the same subcomponents. In human retinoblastoma tissue and cells we have observed toroidal, perinuclear, macromolecular structures of similar size and antigenicity to those previously reported in neurons (neuronal-loukoumasomes). To further characterize the subcomponents of the retinal-loukoumasomes, confocal analysis following immunocytochemical staining for alpha-tubulin, beta-III tubulin and detyrosinated tubulin was performed. These studies indicate that retinal-loukoumasomes are enriched for beta-III tubulin and other tubulins associated with microtubules. Immunofluorescence together with the in situ proximity ligation assay (PLA), confirmed that beta-III tubulin colocalized with detyrosinated tubulin within loukoumasomes. Our results indicate that these tissues contain only loukoumasomes because these macromolecular structures are immunoreactive with an anti-tubulin antibody but are not recognized by the prototype anti-RR/inosine monophosphate dehydrogenase (IMPDH) antibody (It2006). To further compare the RR and retinal-loukoumasomes, retinoblastoma cells were exposed to the IMPDH-inhibitor ribavirin, a drug known to induce the formation of RR. In contrast to RR, the production of retinal-loukoumasomes was unaffected. Coimmunostaining of Y79 cells for beta-III tubulin and IMPDH indicate that these cells, when treated with ribavirin, can contain both retinal-loukoumasomes and RR and that these structures are antigenically distinct. Subcellular

Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program.

PubMed

Bruno, S; Bollani, S; Zignego, A L; Pascasio, J M; Magni, C; Ciancio, A; Caremani, M; Mangia, A; Marenco, S; Piovesan, S; Chemello, L; Babudieri, S; Moretti, A; Gea, F; Colletta, C; Perez-Alvarez, R; Forns, X; Larrubia, J R; Arenas, J; Crespo, J; Calvaruso, V; Ceccherini Silberstein, F; Maisonneuve, P; Craxì, A; Calleja, J L

2015-05-01

In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/μL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile. © 2014 John Wiley & Sons Ltd.

Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison.

PubMed

Andersohn, Frank; Claes, Anne-Kathrin; Kulp, Werner; Mahlich, Jörg; Rockstroh, Jürgen Kurt

2016-01-11

About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. This

Determination of glycated hemoglobin in patients with advanced liver disease

PubMed Central

Lahousen, Theresa; Hegenbarth, Karin; Ille, Rottraut; Lipp, Rainer W.; Krause, Robert; Little, Randie R.; Schnedl, Wolfgang J.

2004-01-01

AIM: To evaluate the glycated hemoglobin (HbA 1c) determination methods and to determine fructosamine in patients with chronic hepatitis, compensated cirrhosis and in patients with chronic hepatitis treated with ribavirin. METHODS: HbA1c values were determined in 15 patients with compensated liver cirrhosis and in 20 patients with chronic hepatitis using the ion-exchange high performance liquid chromatography and the immunoassay methods. Fructosamine was determined using nitroblue tetrazolium. RESULTS: Forty percent of patients with liver cirrhosis had HbA1c results below the non-diabetic reference range by at least one HbA1c method, while fructosamine results were either within the reference range or elevated. Twenty percent of patients with chronic hepatitis (hepatic fibrosis) had HbA1c results below the non -diabetic reference range by at least one HbA1c method. In patients with chronic hepatitis treated with ribavirin, 50% of HbA1c results were below the non-diabetic reference using at least one of the HbA1c methods. CONCLUSION: Only evaluated in context with all liver function parameters as well as a red blood count including reticulocytes, HbA 1c results should be used in patients with advanced liver disease. HbA 1c and fructosamine measurements should be used with caution when evaluating long-term glucose control in patients with hepatic cirrhosis or in patients with chronic hepatitis and ribavirin treatment. PMID:15259084

A Modified Carbon Monoxide Breath Test for Measuring Erythrocyte Lifespan in Small Animals

PubMed Central

Ma, Yong-Jian; Zhang, Hou-De; Ji, Yong-Qiang; Zhu, Guo-Liang; Huang, Jia-Liang; Du, Li-Tao; Cao, Ping; Zang, De-Yue; Du, Ji-Hui; Li, Rong; Wang, Lei

2016-01-01

This study was to develop a CO breath test for RBC lifespan estimation of small animals. The ribavirin induced hemolysis rabbit models were placed individually in a closed rebreath cage and air samples were collected for measurement of CO concentration. RBC lifespan was calculated from accumulated CO, blood volume, and hemoglobin concentration data. RBC lifespan was determined in the same animals with the standard biotin-labeling method. RBC lifespan data obtained by the CO breath test method for control (CON, 49.0 ± 5.9 d) rabbits, rabbits given 10 mg/kg·d−1 of ribavirin (RIB10, 31.0 ± 4.0 d), and rabbits given 20 mg/kg·d−1 of ribavirin (RIB20, 25.0 ± 2.9 d) were statistically similar (all p > 0.05) to and linearly correlated (r = 0.96, p < 0.01) with the RBC lifespan data obtained for the same rabbits by the standard biotin-labeling method (CON, 51.0 ± 2.7 d; RIB10, 33.0 ± 1.3 d; and RIB20, 27.0 ± 0.8 d). The CO breath test method takes less than 3 h to complete, whereas the standard method requires at least several weeks. In conclusion, the CO breath test method provides a simple and rapid means of estimating RBC lifespan and is feasible for use with small animal models. PMID:27294128

Peginterferon Lambda-1a Is Associated with a Low Incidence of Autoimmune Thyroid Disease in Chronic Hepatitis C.

PubMed

Fredlund, Paul; Hillson, Jan; Gray, Todd; Shemanski, Lynn; Dimitrova, Dessislava; Srinivasan, Subasree

2015-11-01

Peginterferon alfa (alfa) increases the risk of autoimmune disease. Peginterferon lambda-1a (Lambda) acts through a receptor with a more liver-specific distribution compared to the alfa receptor. In a phase-2b study, 525 treatment-naive patients with chronic hepatitis C virus (HCV) infection received ribavirin and Lambda interferon (120, 180, or 240 μg) or alfa interferon (180 μg) for 24 (genotypes 2 and 3) or 48 (genotypes 1 and 4) weeks. Retrospective analysis found that adverse events of MedDRA-coded thyroid dysfunction and abnormal levels of thyroid-stimulating hormone (TSH) were significantly more frequent with alfa versus Lambda (12% versus 2.6% and 15.2% versus 3.4%, respectively, both P<0.0001). Most Lambda recipients with abnormal TSH had levels below the lower limit of normal; the frequency of low and high TSH was similar in alfa recipients with abnormal TSH. Blinded review by an endocrinologist found that new-onset primary hypothyroidism or painless thyroiditis was less frequent with Lambda versus alfa (0.5% and 1.8% versus 5.3% and 7.5%, respectively, P<0.0001). Most TSH elevations reflected new-onset hypothyroidism requiring treatment, while most markedly suppressed TSH values reflected probable painless thyroiditis and resolved without sequelae. In conclusion, HCV-infected patients treated with Lambda/ribavirin experienced fewer adverse events of thyroid dysfunction compared with patients treated with alfa/ribavirin.

IFNL4 ss469415590 Variant Is Associated with Treatment Response in Japanese HCV Genotype 1 Infected Individuals Treated with IFN-Including Regimens

PubMed Central

Miyamura, Tatsuo; Kanda, Tatsuo; Nakamoto, Shingo; Arai, Makoto; Nakamura, Masato; Wu, Shuang; Jiang, Xia; Sasaki, Reina; Yasui, Shin; Ooka, Yoshihiko; Imazeki, Fumio; Mikami, Shigeru; Yokosuka, Osamu

2014-01-01

Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens. PMID:25548683

Peginterferon Alfa-2b (PEG-Intron)

MedlinePlus

Peginterferon alfa-2b is used alone or in combination with ribavirin (a medication) to treat chronic (long-term) hepatitis ... treated with interferon alpha (medication similar to peginterferon alfa-2b) in the past. Peginterferon alfa-2b is ...

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies

PubMed Central

Wedemeyer, Heiner; Forns, Xavier; Hézode, Christophe; Lee, Samuel S.; Scalori, Astrid; Voulgari, Athina; Le Pogam, Sophie; Nájera, Isabel; Thommes, James A.

2016-01-01

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. Trial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390 PMID:26752189

Bradycardia seen in children with Crimean-Congo hemorrhagic fever.

PubMed

Oflaz, Mehmet Burhan; Kucukdurmaz, Zekeriya; Guven, A Sami; Karapinar, Hekim; Kaya, Ali; Sancakdar, Enver; Deveci, Koksal; Gul, Ibrahim; Erdem, Alim; Cevit, Omer; Icagasioglu, F Dilara

2013-11-01

Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic viral disease with a high mortality rate. In clinical practice, we observed bradycardia in some pediatric patients with CCHF during the clinical course. So we aimed to report CCHF cases that presented bradycardia during the clinical course and the relation of bradycardia with the clinical findings and ribavirin therapy. Charts of all hospitalized pediatric CCHF patients were reviewed with respect to age, sex, history of tick bite or history of removing a tick, other risk factors for CCHF transmission, and interval between the tick bite and the onset of symptoms. Outcomes and clinical and laboratory findings and medications were recorded for each patient. We searched the patient records for information regarding the existence of bradycardia. Bradycardia was accepted as the heart rate 2 standard deviations (SD) lower than the suspected heart rate based on age. Fifty-two patients (mean age 11.2 ± 4.4 years, 31 female) were enrolled into the study. Bradycardia was seen in seven patients. Six patients with bradycardia were male and only one was female, and the mean age was 13.1 ± 1.6 years. It was observed that male gender is frequent among patients with bradycardia, as compared with those without bradycardia (p=0.01). Bleeding was found to be more frequent in patients with bradycardia (p=0.02). There were significant differences between the bradycardia and nonbradycardia groups with regard to the requirements for fresh frozen plasma transfusion, the number of platelet suspension given, requirement for intravenous immune globulin (IVIG) and in the days of stay in hospital (p=0.01, p=0.03, p=0.03, p=0.04, respectively). Reversible bradycardia might be seen in the clinical course of pediatric CCHF patients, and the clinicians must be aware of this finding. The possibility that ribavirin may potentiate bradycardia cannot be assessed without a placebo-control study. So further studies may help to reveal the cause of the

Systematic review: patient-reported outcomes in chronic hepatitis C--the impact of liver disease and new treatment regimens.

PubMed

Younossi, Z; Henry, L

2015-03-01

Treatment for chronic hepatitis C (CH-C) is rapidly changing and moving away from an interferon and ribavirin-based therapy to interferon-free ribavirin-free all oral regimens. These regimens are simpler and shorter to administer with very high efficacy rates and better side effect profiles. As advances in the treatment of CH-C occur, it is imperative to capture both clinical outcomes (efficacy and safety) as well as patient-reported outcomes (PROs). In fact, PROs assesses and quantifies the impact of these regimens on patient experience. PROs assess patients' health-related quality of life (HRQOL) especially in the realms of fatigue and neuropsychiatric issues such as depression which can affect treatment adherence and work productivity. To review the literature related to PRO's in HCV patients and summarise the impact of CH-C and its treatment on PROs. Databases Ovid MEDLINE and PubMed were searched from 1990 to October 2014 using a combination of MEsh, thesaurus terms and relevant text words: hepatitis C, CH-C, treatment, quality of life, health-related quality of life, fatigue, work productivity, adherence, patient-reported outcomes, direct acting anti-viral agents and second generation direct acting anti-viral agents. Each manuscript was assessed for pertinence to the issue of PROs in CH-C as well as the quality of study design and publications. From the literature, it is evident that CH-C patients have baseline PRO impairment. Furthermore, treatment with interferon with or without ribavirin and first generation DAAs causes additional PRO burden which can negatively impact treatment adherence and indirectly, treatment efficacy and work productivity. The new treatment regimens with interferon- and ribavirin-free regimens not only have very high efficacy, but also result in the improvement of PRO scores as early as 2 weeks into treatment as well as possibly better adherence to treatment regimens. CH-C and its treatment have been associated with patient

Outcomes of chronic hepatitis C therapy in patients treated in community versus academic centres in Canada: Final results of APPROACH (A Prospective study of Peginterferon alfa-2a and Ribavirin at Academic and Community Centres in Canada)

PubMed Central

Myers, Robert P; Cooper, Curtis; Sherman, Morris; Lalonde, Richard; Witt-Sullivan, Helga; Elkashab, Magdy; Harris, Paul; Balshaw, Rob; Usaty, Christopher; Marotta, Paul J

2011-01-01

BACKGROUND: In patients chronically infected with the hepatitis C virus (HCV), it is not established whether viral outcomes or health-related quality of life (HRQoL) differ between individuals treated at academic or community centres. METHODS: In the present observational study, adults with chronic HCV were treated with peginterferon alfa-2a 180 μg/week plus ribavirin at 45 Canadian centres (16 academic, 29 community). The primary efficacy end point was sustained virological response (SVR). Other outcome measures included HRQoL (assessed using the 36-item Short-Form Health Survey), heath resource use, and workplace productivity and absences within a 60-day interval. RESULTS: In treatment-naive patients infected with HCV genotype 1, significantly higher SVR rates were achieved in those treated at academic (n=54) compared with community (n=125) centres (52% versus 32% [P=0.01]), although rates of dosage reduction and treatment discontinuation were similar across settings. SVR rates among patients infected with genotype 2/3 were similar between academic (n=59) and community (n=100) centres (64% versus 67% [P=0.73]). Following antiviral therapy, patients with genotype 1 who achieved an SVR (n=67) had significantly higher mean scores on the physical (P=0.005) and mental components of the 36-item Short-Form Health Survey (P=0.043) compared with those without an SVR (n=111). In contrast, HRQoL scores were similar in HCV genotype 2/3 patients with and without an SVR. There were no differences in workplace productivity or absences between patients with and without an SVR. The most frequently used health care resources by all patients were visits and phone calls to hepatitis nurses, and general practice or walk-in clinics. CONCLUSION: Patients infected with HCV genotype 1 achieved higher SVR rates when treated at academic rather than community centres in Canada. The reasons for this difference require additional investigation. PMID:21912762

Cost-effectiveness of Interferon-free therapy for Hepatitis C in Germany--an application of the efficiency frontier approach.

PubMed

Gissel, Christian; Götz, Georg; Mahlich, Jörg; Repp, Holger

2015-07-30

The approval of direct-acting antivirals for Interferon-free treatment revolutionized the therapy of chronic Hepatitis C infection. As of August 2014, two treatment regimens for genotype 1 infection received conditional approval in the European Union: Sofosbuvir and Ribavirin for 24 weeks and Sofosbuvir and Simeprevir with or without Ribavirin for 12 weeks. We aim to analyze the cost-effectiveness of both regimens in Germany. We set up a Markov model with a lifetime horizon to simulate immediate treatment success and long-term disease progression for treatment-naive patients. The model analyzes both short-term and long-term costs and benefits from the perspective of the German Statutory Health Insurance. We apply the efficiency frontier method, which was suggested by German Institute for Quality and Efficiency in Health Care for cost-effectiveness analysis in Germany. The efficiency frontier is defined by dual therapy and first generation direct-acting antiviral Boceprevir, yielding a maximum of € 1,447.69 per additional percentage point of sustained virologic response gained. Even without rebates, Sofosbuvir/Simeprevir is very close with € 1,560.13 per additional percentage point. It is both more effective and less expensive than Sofosbuvir/Ribavirin. In addition to higher sustained virologic response rates, new direct-acting antivirals save long-term costs by preventing complications such as liver cirrhosis, hepatocellular carcinoma and ultimately liver transplants, thereby offsetting part of higher drug costs. Our findings are in line with the guidance published by German Society for Gastroenterology, Digestive and Metabolic Diseases, which recommends Sofosbuvir/Simeprevir for Interferon ineligible or intolerant patients.

76 FR 14027 - Antiviral Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-15

..., 2011, the committee will discuss a new drug application (NDA) 201-917, telaprevir (a hepatitis C virus... treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated...

76 FR 14026 - Antiviral Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-15

..., 2011, the committee will discuss a new drug application (NDA) 202-258, boceprevir (a hepatitis C virus... chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated liver disease...

Health Care Response to CCHF in US Soldier and Nosocomial Transmission to Health Care Providers, Germany, 2009

PubMed Central

Paolino, Kristopher M.; Osborn, Erik C.; Rusnak, Janice M.; Günther, Stephan; Pool, Jane; Rollin, Pierre E.; Allan, Patrick F.; Schmidt-Chanasit, Jonas; Rieger, Toni; Kortepeter, Mark G.

2015-01-01

In 2009, a lethal case of Crimean–Congo hemorrhagic fever (CCHF), acquired by a US soldier in Afghanistan, was treated at a medical center in Germany and resulted in nosocomial transmission to 2 health care providers (HCPs). After his arrival at the medical center (day 6 of illness) by aeromedical evacuation, the patient required repetitive bronchoscopies to control severe pulmonary hemorrhage and renal and hepatic dialysis for hepatorenal failure. After showing clinical improvement, the patient died suddenly on day 11 of illness from cerebellar tonsil herniation caused by cerebral/cerebellar edema. The 2 infected HCPs were among 16 HCPs who received ribavirin postexposure prophylaxis. The infected HCPs had mild or no CCHF symptoms. Transmission may have occurred during bag-valve-mask ventilation, breaches in personal protective equipment during resuscitations, or bronchoscopies generating infectious aerosols. This case highlights the critical care and infection control challenges presented by severe CCHF cases, including the need for experience with ribavirin treatment and postexposure prophylaxis. PMID:25529825

Hepatitis E-induced severe myositis.

PubMed

Mengel, Annerose M; Stenzel, Werner; Meisel, Andreas; Büning, Carsten

2016-02-01

Hepatitis E virus (HEV) is endemic in Asian and African countries but is rarely reported in Western countries. Although there are some prominent neurological manifestations, HEV is rarely recognized by neurologists. This is a case report of myositis induced by HEV. We report the life-threatening case of a 57-year-old man with flaccid tetraparesis due to myositis, acute hepatitis, and renal failure caused by HEV infection. Muscle biopsy revealed scattered myofiber necrosis with a diffuse, mild lymphomonocytic infiltrate in the endomysium and perimysium. Because the patient suffered from an acute HEV infection with a rapidly progressive course of severe myopathy, we started ribavirin treatment. He recovered partially within 3 weeks and recovered fully within 6 months. This case highlights a neurological manifestation of endemic HEV infection with severe myositis in a patient with alcoholic chronic liver disease. Ribavirin treatment is effective in severe HEV infection and may also lead to rapid neurological recovery. © 2015 Wiley Periodicals, Inc.

Successful treatment of hepatitis C, genotype 3, with sofosbuvir/ledipasvir in decompensated cirrhosis complicated by mixed cryoglobulinaemia

PubMed Central

Flemming, Jennifer A; Lowe, Catherine E

2016-01-01

Advances in the treatment of chronic hepatitis C (HCV) have given HCV providers access to treatment regimens able to achieve sustained virological response (SVR or ‘cure’) in the majority of patients. There are, however, groups of patients in whom HCV treatment outcomes with direct acting antivirals (DAAs) are suboptimal (genotype (GT) 3 patients, decompensated cirrhosis, renal failure) or have not been studied in large cohorts (patients with cryoglobulinaemia (CG)). This case outlines the successful eradication of GT-3 hepatitis C (HCV) in a patient with decompensated cirrhosis and renal failure secondary to mixed CG with DAA failure, using a 12-week course of sofosbuvir, ledipasvir and ribavirin. The achievement of SVR in this patient resulted in significant improvement in hepatic and renal function. Patients with decompensated cirrhosis and GT-3 disease remain a difficult to treat population, and the safety and efficacy of sofosbuvir, ledipasvir and ribavirin in this cohort require further study. PMID:27284099

Successful treatment of hepatitis C, genotype 3, with sofosbuvir/ledipasvir in decompensated cirrhosis complicated by mixed cryoglobulinaemia.

PubMed

Flemming, Jennifer A; Lowe, Catherine E

2016-06-09

Advances in the treatment of chronic hepatitis C (HCV) have given HCV providers access to treatment regimens able to achieve sustained virological response (SVR or 'cure') in the majority of patients. There are, however, groups of patients in whom HCV treatment outcomes with direct acting antivirals (DAAs) are suboptimal (genotype (GT) 3 patients, decompensated cirrhosis, renal failure) or have not been studied in large cohorts (patients with cryoglobulinaemia (CG)). This case outlines the successful eradication of GT-3 hepatitis C (HCV) in a patient with decompensated cirrhosis and renal failure secondary to mixed CG with DAA failure, using a 12-week course of sofosbuvir, ledipasvir and ribavirin. The achievement of SVR in this patient resulted in significant improvement in hepatic and renal function. Patients with decompensated cirrhosis and GT-3 disease remain a difficult to treat population, and the safety and efficacy of sofosbuvir, ledipasvir and ribavirin in this cohort require further study. 2016 BMJ Publishing Group Ltd.

Crimean-Congo Hemorrhagic Fever.

PubMed

Shayan, Sara; Bokaean, Mohammad; Shahrivar, Mona Ranjvar; Chinikar, Sadegh

2015-01-01

Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the Bunyaviridae family and Nairovirus genus. The viral genome consists of 3 RNA segments of 12 kb (L), 6.8 kb (M), and 3 kb (S). Crimean-Congo hemorrhagic fever (CCHF) is the most widespread tickborne viral infection worldwide: it has been reported in many regions of Africa, the Middle East, and Asia. The geographical distribution of CCHFV corresponds most closely with the distribution of members of the tick genera, and Hyalomma ticks are the principal source of human infection. In contrast to human infection, CCHFV infection is asymptomatic in all species. Treatment options for CCHF are limited; immunotherapy and ribavirin are effective in the treatment of CCHF; the efficacy of ribavirin in the treatment of CCHF has not yet been proven. This article reviews the history, epidemiology, clinical symptoms, pathogenesis, diagnosis, and treatment of CCHFV, as well as the development of a vaccine against it.

Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System.

PubMed

Ioannou, George N; Beste, Lauren A; Chang, Michael F; Green, Pamela K; Lowy, Elliott; Tsui, Judith I; Su, Feng; Berry, Kristin

2016-09-01

We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4. We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment. An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%-93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%-87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%-77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%-93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3

Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System

PubMed Central

Ioannou, George N.; Beste, Lauren A.; Chang, Michael F.; Green, Pamela K.; Lowy, Elliott; Tsui, Judith I.; Su, Feng; Berry, Kristin

2017-01-01

BACKGROUND & AIMS We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4. METHODS We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment. RESULTS An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%–93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%–87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%–77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%–93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80

Outcomes of treatment with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation.

PubMed

Honda, Masaki; Sugawara, Yasuhiko; Watanabe, Takehisa; Tateyama, Masakuni; Tanaka, Motohiko; Uchida, Koushi; Kawabata, Seiichi; Yoshii, Daiki; Miura, Kouhei; Isono, Kaori; Hayashida, Shintaro; Ohya, Yuki; Yamamoto, Hidekazu; Sasaki, Yutaka; Inomata, Yukihiro

2017-10-01

The development of direct-acting oral agents has dramatically changed the treatment strategy of hepatitis C virus (HCV) infection. Here we aimed to reveal the efficacy and safety of daclatasvir (DCV) and asunaprevir (ASV) for recurrent HCV genotype 1 infection after liver transplantation (LT). A retrospective study was undertaken on nine patients who underwent a 24-week DCV/ASV treatment regimen for recurrent HCV genotype 1 infection. Five of the patients were men; four had failed treatment with pegylated interferon (Peg-IFN)/ribavirin, two had failed simeprevir/Peg-IFN/ribavirin, one had the resistance-associated variant Y93H in the NS5A region, and one underwent maintenance dialysis. Median time to treatment initiation following LT was 70 months. Of the nine patients treated with DCV/ASV, eight (88.9%) achieved a sustained viral response 12 weeks after completion of therapy (SVR12). The patient with virologic failure had failed simeprevir/Peg-interferon/ribavirin therapy 4 months before undergoing the DCV/ASV treatment regimen. In addition, a resistance-associated variant D168E in the NS3 region was detected in the patient after discontinuation of the DCV/ASV regimen. The trough level of tacrolimus tended to decrease, and renal function showed no significant changes during treatment. Adverse events occurred in two patients (22.2%), but no severe adverse events occurred during treatment. The DCV/ASV regimen was well tolerated, resulting in high rates of sustained viral response 12 weeks after completion of therapy for LT patients with recurrent HCV genotype 1 infection. © 2016 The Japan Society of Hepatology.

Lessons learnt from the management of a case of Lassa fever and follow-up of nosocomial primary contacts in Nigeria during Ebola virus disease outbreak in West Africa.

PubMed

Iroezindu, Michael O; Unigwe, Uche S; Okwara, Celestine C; Ozoh, Gladys A; Ndu, Anne C; Ohanu, Martin E; Nwoko, Ugochukwu O; Okoroafor, Uwadiegwu W; Ejimudo, Esinulo; Tobin, Ekaete A; Asogun, Danny A

2015-11-01

To describe our experiences in the management of a case of Lassa fever (LF) and follow-up of nosocomial primary contacts during the 2014 Ebola outbreak in West Africa. Clinical management of the index case and infection control/surveillance activities for primary contacts are described. Laboratory confirmation was by Lassa virus-specific reverse-transcriptase PCR. A 28-year-old man with a 10-day history of febrile illness was referred to a major tertiary hospital in south-east Nigeria from a city that previously experienced a LF outbreak and was recently affected by Ebola. On observation of haemorrhagic features, clinicians were at a crossroads. Diagnosis of LF was confirmed at a National Reference Centre. The patient died despite initiation of ribavirin therapy. Response activities identified 121 primary contacts comprising 78 (64.5%) hospital staff/interns, 19 (15.7%) medical students, 18 (14.9%) inpatients and 6 (5.0%) relatives. Their mean age was 32.8 ± 6.6 years, and 65.3% were women. Twenty (16.5%) had high-risk exposure and were offered ribavirin as post-exposure prophylaxis. No secondary case of LF occurred. Fatigue (43.8%) and dizziness (31.3%) were the commonest side effects of ribavirin. Response activities contained nosocomial spread of LF, but challenges were experienced including lack of a purpose-built isolation facility, absence of local Lassa virus laboratory capacity, failure to use appropriate protective equipment and stigmatisation of contacts. A key lesson is that the weak health systems of Africa should be comprehensively strengthened; otherwise, we might win the Ebola battle but lose the one against less virulent infections for which effective treatment exists. © 2015 John Wiley & Sons Ltd.

New therapies for chronic hepatitis C infection: a systematic review of evidence from clinical trials.

PubMed

Lee, L Y; Tong, C Y W; Wong, T; Wilkinson, M

2012-04-01

Hepatitis C virus (HCV) affects approximately 3% of the world population. The current standard of care for treatment of HCV is a combination of pegylated interferon and ribavirin. Approximately 10% of patients will stop treatment and 30% of patients require dose reduction because of side effects. For genotype 1 HCV-infected patients, only 40% of patients will achieve undetectable viral load 26 weeks posttreatment. The objectives of this review were to identify new treatments that are in clinical trials. These include boceprevir and telaprevir which are in routine clinical use and form part of the American Association for the Study of Liver Diseases (AASLD) 2011 guidelines as well as drugs based on observational studies, improving/modifying ribavirin or interferon-based therapies, modifying the host response and finally the use of direct-acting antiviral agents (DAA).   MEDLINE and EMBASE databases were searched from 2008 to 2011 for treatments for hepatitis C. Furthermore, abstracts and poster presentations for the annual European Association Study of the Liver, AASLD, Digestive Disease Week and Asian Pacific Association for the study of the Liver were searched for relevant material. All four classes of DAA; NS3/NS4a serine protease inhibitors, cyclophilin inhibitors, NS5b polymerase inhibitors and NS5a inhibitors, show good success rates. Trials have been performed without ribavirin or interferon and demonstrate good antiviral activity with a decreased side effect profile. Combinations of DAA are a promising area of research with a high success rate. Clinical trials show that future HCV therapy could be personalised, achieve higher success rates with decreased adverse incidents. © 2012 Blackwell Publishing Ltd.

Boceprevir: a protease inhibitor for the treatment of hepatitis C.

PubMed

Chang, Mei H; Gordon, Lori A; Fung, Horatio B

2012-10-01

Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment. This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir. Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings. Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P < 0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from

Indirect comparison of the antiviral efficacy of peginterferon alpha 2a plus ribavirin used with or without simeprevir in genotype 4 hepatitis C virus infection, where common comparator study arms are lacking: a special application of the matching adjusted indirect comparison methodology.

PubMed

Van Sanden, Suzy; Pisini, Marta; Duchesne, Inge; Mehnert, Angelika; Belsey, Jonathan

2016-01-01

The need to assess relative efficacy in the absence of comparative clinical trials is a problem that is often encountered in economic modeling. The use of matching adjusted indirect comparison (MAIC) in this situation has been suggested. We present the results of a MAIC used to evaluate the incremental benefit offered by adding simeprevir (SMV) to standard therapy in the treatment of patients infected with genotype 4 hepatitis C virus (HCV). Individual patient data for a single arm study evaluating the use of SMV with peginterferon alfa 2a + ribavirin (PR) in genotype 4 HCV were available (RESTORE study). A systematic literature review was used to identify studies of PR alone used in the same patient group. By applying the inclusion criteria for each study in turn to the RESTORE dataset and then applying the published MAIC covariate matching algorithm, a series of pseudosamples from RESTORE were generated. After assessment of the matching outcomes, the best matched comparisons were used to derive estimates of efficacy for SMV + PR in patients equivalent to those participating in the PR trial. Five potential comparator studies were identified. After applying the matching process, two emerged as offering the greatest equivalence with the generated RESTORE pseudosamples and were used to estimate SMV + PR efficacy, expressed as the percentage of patients achieving sustained viral response (SVR). In one comparison, SVR in the SMV + PR group was 85% versus 63% for PR alone. In the second comparison, the corresponding SVRs were 77% and 44% respectively. After matching for varying baseline characteristics, both comparisons of RESTORE versus studies of PR alone yielded a benefit for SMV + PR vs PR alone in genotype 4 HCV-infected patients. The incremental gain in SVR associated with use of SMV ranged from 22% to 33%. In the absence of direct comparative studies, the MAIC gives a better perspective than simple comparison of absolute SVR from individual

Treatment of HCV infection in Poland at the beginning of the interferon-free era-the EpiTer-2 study.

PubMed

Flisiak, R; Zarębska-Michaluk, D; Janczewska, E; Staniaszek, A; Gietka, A; Mazur, W; Tudrujek, M; Tomasiewicz, K; Belica-Wdowik, T; Baka-Ćwierz, B; Dybowska, D; Halota, W; Lorenc, B; Sitko, M; Garlicki, A; Berak, H; Horban, A; Orłowska, I; Simon, K; Socha, Ł; Wawrzynowicz-Syczewska, M; Jaroszewicz, J; Deroń, Z; Czauż-Andrzejuk, A; Citko, J; Krygier, R; Piekarska, A; Laurans, Ł; Dobracki, W; Białkowska, J; Tronina, O; Pawłowska, M

2018-01-06

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections. © 2018 John Wiley & Sons Ltd.

Management of HCV-Related Liver Disease in Hemophilia and Thalassemia.

PubMed

Rumi, Maria Grazia; Di Marco, Vito; Colombo, Massimo

2018-05-01

Chronic infection with the hepatitis C virus (HCV) has long been the dominant complication of substitution therapy in patients with inherited blood disorders and the cause of anticipated death due to end-stage liver disease. In hemophilia, transmission of HCV with clotting factors concentrates started to be curbed in the mid-1980s following the adoption of procedures of virus inactivation of concentrates based on heat, whereas in the 1990s treatment of HCV infection with interferon monotherapy was attempted, however, with little success. The advent of combination therapy of interferon with ribavirin led to a substantial improvement of treatment outcome (40% rate of cure), that however was still of limited efficacy in patients with advanced liver disease, those with high load of HCV genotype 1, and patients coinfected with the human immunodeficiency virus. In this latter population, while the course of hepatitis C was accelerated as a consequence of immunodeficiency, the advent of highly active antiretroviral therapy led acquired immunodeficiency syndrome (AIDS) to decline and hepatitis C to progressively emerge as a dominant cause of mortality, in parallel. In patients with thalassemia, transfusion-related transmission of HCV was efficiently interrupted in 1992 with the advent of sensitive screening tests for testing donors for HCV, whereas treatment with interferon and ribavirin of infected thalassemics was constrained by an increased risk of anemia due to the hemolytic properties of ribavirin coupled with interferon-induced bone marrow suppression. The advent of safe and potent regimens based on the oral administration of direct antiviral agents has revolutionized therapy of HCV in patients with congenital blood diseases, providing substantial clinical benefits and making elimination of infection in these populations, possible. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Optimization of direct anti-viral agent treatment schedule: Focus on HCV genotype 3.

PubMed

Morisco, Filomena; Granata, Rocco; Camera, Silvia; Ippolito, Antonio; Milella, Michele; Conti, Fabio; Masetti, Chiara; Smedile, Antonella; Tundo, Paolo; Santantonio, Teresa; Valvano, Maria Rosa; Termite, Antonio; Gatti, Pietro; Messina, Vincenzo; Iacobellis, Angelo; Librandi, Marta; Caporaso, Nicola; Andriulli, Angelo

2018-03-01

Direct antiviral agents (DAAs) have led to high sustained virological responses (SVR) in hepatitis C virus (HCV) patients. However, genotype 3 patients respond to treatment in a suboptimal way. This study aims to identify which of the several treatment schedules recommended for genotype 3 would constitute the best option. Twenty-four Italian centers were involved in this real-life study of HCV genotype 3 patients treated with DAAs. To expand the number of cases, we conducted a systematic review of the literature on the outcome of genotype 3 patients treated with DAAs. A total of 233 patients with HCV genotype 3 were enrolled. Cirrhotic patients accounted for 83.7%. Overall, the SVR12 rate was achieved by 205 patients (88.0%); the SVR rates were 78.8% after sofosbuvir/ribavirin, 92.5% after sofosbuvir/daclatasvir ± ribavirin, and 100% after sofosbuvir/ledipasvir (seven patients). No difference in rate of SVR was observed in cirrhotic and non-cirrhotic patients (92.2 vs 94.4) using a combination regimen of NS5A and NS5B inhibitors.The systematic review of the literature provided data of 3311 patients: The mean weighted SVR12 rate was 84.4% (CI: 80.4-87.8); the rates varied from 79.0% (CI: 70.9-85.3) with sofosbuvir/ribavirin, to 83.7% (CI: 66.2-93.1) with sofosbuvir/ledispavir, and to 88.2% (CI: 83.3-91.7) with sofosbuvir/daclatasvir. Our results reinforce the concept that patients with HCV genotype 3 should no longer be considered difficult-to-treat individuals. The optimal therapeutic regimen for these patients appears to be the combination sofosbuvir/daclatasvir, administered for 12 weeks without the use of RBV in non-cirrhotic patients. In cirrhotics the meta-analytic approach suggests extending therapy to 24 weeks.

African Americans Respond Poorly to Hepatitis C Treatment

ERIC Educational Resources Information Center

Black Issues in Higher Education, 2004

2004-01-01

African Americans have a significantly lower response rate to treatment for chronic hepatitis C than non-Hispanic Whites, according to a new study led by Duke University Medical Center researchers. Some African Americans--19 percent--did respond to the drug combination of peginterferon alfa-2b and ribavirin. But in non-Hispanic Whites with the…

A computational method for drug repositioning using publicly available gene expression data.

PubMed

Shabana, K M; Abdul Nazeer, K A; Pradhan, Meeta; Palakal, Mathew

2015-01-01

The identification of new therapeutic uses of existing drugs, or drug repositioning, offers the possibility of faster drug development, reduced risk, lesser cost and shorter paths to approval. The advent of high throughput microarray technology has enabled comprehensive monitoring of transcriptional response associated with various disease states and drug treatments. This data can be used to characterize disease and drug effects and thereby give a measure of the association between a given drug and a disease. Several computational methods have been proposed in the literature that make use of publicly available transcriptional data to reposition drugs against diseases. In this work, we carry out a data mining process using publicly available gene expression data sets associated with a few diseases and drugs, to identify the existing drugs that can be used to treat genes causing lung cancer and breast cancer. Three strong candidates for repurposing have been identified- Letrozole and GDC-0941 against lung cancer, and Ribavirin against breast cancer. Letrozole and GDC-0941 are drugs currently used in breast cancer treatment and Ribavirin is used in the treatment of Hepatitis C.

Factors affecting outcome of treatment of chronic hepatitis C: result of an open label study from eastern India.

PubMed

Ray, Gautam

2016-01-01

Standard treatment of hepatitis C involves the use of pegylated interferon (PEGIFN) and ribavirin but directly acting antiviral agents (DAA) with seemingly greater efficacy have now appeared on the market. Thus closer detail needs to be given to optimise the use of the former. Fifty-two chronic hepatitis C patients (Child class A) were administered PEGIFN and ribavirin in a prospective, open label study in standard dose and duration. Complete therapy was ensured for the best chance of achieving a sustained viral response (SVR) and delineating its controlling factors. Seventy-five percent had genotype 3 virus. Compensated cirrhosis was present in 38.5%. Response overall and in cirrhotics were 65.4% and 30%, respectively, without difference between genotypes 1 and 3. Non-cirrhotics had higher response in all groups, especially genotype 1 (83.3%). The factors associated with positive response were age less than 50 years, absence of cirrhosis and presence of risk factors for transmission. Treatment outcome and factors affecting it are similar to studies from Europe and America. © The Author(s) 2015.

Interferon-based treatment of chronic hepatitis C.

PubMed

Souvignet, Claude; Lejeune, Olivier; Trepo, Christian

2007-01-01

The treatment of patients with chronic hepatitis C has rapidly evolved in the past 10 years centered on the use of interferon alpha 2 as an antiviral and immunomodulatory agent against hepatitis C virus. Firstly used as a monotherapy associated with a deceiving long-term efficacy, interferon alpha was then combined with ribavirin, a nucleoside analog with large antiviral properties. Combination of both drugs dramatically improved the efficacy of treatment with 50% of patients reaching a sustained viral response, characterized by the final eradication of the virus from the infected individual. Surprisingly, this synergistic effect remains greatly unexplained. The third step consisted in the use of pegylated interferon in order to adapt its pharmacokinetics and to allow a better efficacy with a more tolerable dosing schedule: once weekly subcutaneous injection instead of thrice weekly. Pegylated interferon combined with ribavirin during 24-48 weeks of treatment is the current standard of care with nearly 60% of sustained virologic response, overall. Development of new forms of interferon alpha are on the way with promising preliminary results.

The Challenge of Treating Children With Hepatitis C Virus Infection.

PubMed

Indolfi, Giuseppe; Thorne, Claire; El Sayed, Manal H; Giaquinto, Carlo; Gonzalez-Peralta, Regino P

2017-06-01

The development of oral hepatitis C virus (HCV) direct-acting antivirals (DAAs) has revolutionized the therapeutic field. Nowadays, multiple safe and highly effective antiviral regimens are commercially available to treat adults with hepatitis C infection. These new regimens for the first time genuinely raise the prospects of eradicating HCV. Many challenges, however, remain from identifying infected individuals to optimizing treatment and ensuring global access to antiviral therapy to all population groups, including children. Recently, in April 2017, the association of sofosbuvir with ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been approved by the Food and Drug Administration for treatment of children with chronic HCV infection 12 years of age and older. The only drugs currently approved for children younger than 12 years are pegylated interferon and ribavirin. There are 6 registered ongoing pediatric trials assessing safety and efficacy of DAAs, but their current completion timelines are years away. Herein, we summarize the state of the art of DAAs' development for adult and children and highlight the crucial importance of overcoming barriers to treating children with HCV.

Genetic Detection and Isolation of Crimean-Congo hemorrhagic fever virus, Kosovo, Yugoslavia

PubMed Central

Boźović, Bojana; Pavlidou, Vassiliki; Papadimitriou, Evangelia; Pelemis, Mijomir; Antoniadis, Aantonis

2002-01-01

Crimean-Congo hemorrhagic fever virus (C-CHFV) strains were isolated from a fatal case and the attending physician in Kosovo, Yugoslavia. Early, rapid diagnosis of the disease was achieved by reverse transcription-polymerase chain reaction. The physician was successfully treated with oral ribavirin. These cases yielded the first genetically studied C-CHFV human isolates in the Balkans. PMID:12141973

Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis.

PubMed

Muir, Andrew J; Poordad, Fred; Lalezari, Jacob; Everson, Gregory; Dore, Gregory J; Herring, Robert; Sheikh, Aasim; Kwo, Paul; Hézode, Christophe; Pockros, Paul J; Tran, Albert; Yozviak, Joseph; Reau, Nancy; Ramji, Alnoor; Stuart, Katherine; Thompson, Alexander J; Vierling, John; Freilich, Bradley; Cooper, James; Ghesquiere, Wayne; Yang, Rong; McPhee, Fiona; Hughes, Eric A; Swenson, E Scott; Yin, Philip D

2015-05-05

Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. Sustained virologic response at posttreatment week 12 (SVR12). One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the

MassTag Polymerase Chain Reaction for Differential Diagnosis of Viral Hemorrhagic Fevers

DTIC Science & Technology

2006-04-01

fever virus (RVFV), Crimean - Congo hemorrhagic fever virus (CCHFV), and hantaviruses (Bunyaviridae); and...ribavirin may be helpful if given early in the course of Lassa fever (9), Crimean - Congo hemorrhagic fever (10), or hemorrhagic fever with renal...I, Erol S, Erdem F, Yilmaz N, Parlak M, et al. Crimean - Congo hemorrhagic fever in eastern Turkey: clinical fea- tures, risk factors and efficacy

Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy.

PubMed

Gheorghe, Liana; Cotruta, Bogdan; Trifu, Viorel; Cotruta, Cristina; Becheanu, Gabriel; Gheorghe, Cristian

2008-09-01

Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy.

Pericarditis mediated by respiratory syncytial virus in a hematopoietic stem cell transplant patient.

PubMed

Rubach, M P; Pavlisko, E N; Perfect, J R

2013-08-01

We describe a case of pericarditis and large pericardial effusion in a 63-year-old African-American man undergoing autologous hematopoietic stem cell transplant for multiple myeloma. Pericardial tissue biopsy demonstrated fibrinous pericarditis, and immunohistochemistry stains were positive for respiratory syncytial virus. The patient improved with oral ribavirin and intravenous immune globulin infusions. © 2013 John Wiley & Sons A/S.

Novel Approaches for Targeting Antiviral Agents in the Treatment of Arena-, Bunya-, Flavi-, and Retroviral Infections

DTIC Science & Technology

1989-05-22

potentially useful antivirals (e... S-HMPA, selenazole, WIN 5177, arildone, phosphonoformic acid ) are currently under investigation. There are, however...by increasing dosage, this often results in toxicity. For example, a number of antiviral agents (ribavirin, adenine arabinoside, phosphonoformic acid ...Three possibilities exist for the activation of carrier bound drugs: 1) endocytosis and release in acidic endosomes; 2) extracellular activation at cell

Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.

PubMed

Berger, K L; Scherer, J; Ranga, M; Sha, N; Stern, J O; Quinson, A-M; Kukolj, G

2015-10-01

Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure. Copyright © 2015, American Society for

Risk of pure red cell aplasia in patients with hepatitis C receiving antiviral therapy and an erythropoiesis-stimulating agent.

PubMed

Rossert, Jerome; Yue, Susan; Smirnakis, Karen; Mytych, Daniel T; Johnson, Larry; Kouchakji, Elias; Casadevall, Nicole

2014-02-01

Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Cost-effectiveness analysis of simeprevir with daclatasvir for non-cirrhotic genotype-1b-naïve patients plus chronic hepatitis C.

PubMed

Gimeno-Ballester, Vicente; Mar, Javier; San Miguel, Ramón

2016-01-01

The cost of interferon-free combination therapies remains high to provide widespread access to treatment, regardless of fibrosis stage. To estimate the cost-effectiveness of simeprevir/daclatasvir (SMV/DCV) therapy in treatment-naïve chronic hepatitis C genotype-1b patients with moderate fibrosis. A Markov model was developed to simulate the natural history of chronic hepatitis C progression. The model estimated lifetime healthcare costs and quality-adjusted life-years (QALY) for a cohort of patients from the Spanish National Healthcare System perspective. The cost-effectiveness threshold considered was €40,000/QALY. The treatment strategies analyzed were SMV/DCV, peginterferon/ribavirin/telaprevir, and peginterferon/ribavirin/boceprevir. A sensitivity analysis was carried out. The incremental cost-effectiveness ratios of the SMV/DCV strategy were €23,774/QALY and €28,524/QALY compared with that of telaprevir or boceprevir triple therapy, respectively, for genotype-1b patients with moderate fibrosis. SMV/DCV combination compared with the standard of care previous to the arrival of second-generation direct-acting antivirals fell below generally accepted willingness-to-pay threshold. Results obtained should be supported by ongoing clinical trials.

Treatment of Hantavirus Pulmonary Syndrome

DTIC Science & Technology

2007-10-14

of Infectious Diseases, Ft. Detrick, MD, United States c Department of Internal Medicine, University of New Mexico , Albuquerque, NM, United States...Within ours the patient required mechanical ventilation and extracorporeal membrane xygenation (ECMO). Courtesy G. Mertz, University of New Mexico . hea...femoral artery and vein. The bed is versity of New Mexico . . Antiviral therapy Ribavirin was tested for efficacy in HFRS patients in China nd shown to

Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future

PubMed Central

de Bruijn, Winnie; Ibáñez, Cristina; Frisk, Pia; Bak Pedersen, Hanne; Alkan, Ali; Vella Bonanno, Patricia; Brkičić, Ljiljana S.; Bucsics, Anna; Dedet, Guillaume; Eriksen, Jaran; Fadare, Joseph O.; Fürst, Jurij; Gallego, Gisselle; Godói, Isabella P.; Guerra Júnior, Augusto A.; Gürsöz, Hakkı; Jan, Saira; Jones, Jan; Joppi, Roberta; Kerman, Saim; Laius, Ott; Madzikwa, Newman; Magnússon, Einar; Maticic, Mojca; Markovic-Pekovic, Vanda; Massele, Amos; Ogunleye, Olayinka; O'Leary, Aisling; Piessnegger, Jutta; Sermet, Catherine; Simoens, Steven; Tiroyakgosi, Celda; Truter, Ilse; Thyberg, Magnus; Tomekova, Kristina; Wladysiuk, Magdalena; Vandoros, Sotiris; Vural, Elif H.; Zara, Corinne; Godman, Brian

2016-01-01

Background: Infection with the Hepatitis C Virus (HCV) is a widespread transmittable disease with a diagnosed prevalence of 2.0%. Fortunately, it is now curable in most patients. Sales of medicines to treat HCV infection grew 2.7% per year between 2004 and 2011, enhanced by the launch of the protease inhibitors (PIs) boceprevir (BCV) and telaprevir (TVR) in addition to ribavirin and pegylated interferon (pegIFN). Costs will continue to rise with new treatments including sofosbuvir, which now include interferon free regimens. Objective: Assess the uptake of BCV and TVR across Europe from a health authority perspective to offer future guidance on dealing with new high cost medicines. Methods: Cross-sectional descriptive study of medicines to treat HCV (pegIFN, ribavirin, BCV and TVR) among European countries from 2008 to 2013. Utilization measured in defined daily doses (DDDs)/1000 patients/quarter (DIQs) and expenditure in Euros/DDD. Health authority activities to influence treatments categorized using the 4E methodology (Education, Engineering, Economics and Enforcement). Results: Similar uptake of BCV and TVR among European countries and regions, ranging from 0.5 DIQ in Denmark, Netherlands and Slovenia to 1.5 DIQ in Tayside and Catalonia in 2013. However, different utilization of the new PIs vs. ribavirin indicates differences in dual vs. triple therapy, which is down to factors including physician preference and genotypes. Reimbursed prices for BCV and TVR were comparable across countries. Conclusion: There was reasonable consistency in the utilization of BCV and TVR among European countries in comparison with other high priced medicines. This may reflect the social demand to limit the transmission of HCV. However, the situation is changing with new curative medicines for HCV genotype 1 (GT1) with potentially an appreciable budget impact. These concerns have resulted in different prices across countries, with their impact on budgets and patient outcomes

Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir.

PubMed

Moreno-Planas, José María; Larrubia-Marfil, Juan Ramón; Sánchez-Ruano, Juan José; Morillas-Ariño, Julia; Patón-Arenas, Roberto; Sáiz-Chumillas, Rosa María; Tébar-Romero, Emilia; Lucendo-Villarín, Alfredo; Gancedo-Bringas, Pilar; Solera-Muñoz, Mario; Vicente-Gutiérrez, María Del Mar; Martínez-Alfaro, Elisa

2018-05-01

There are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. The objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. Prospective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). 204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin ≥ 4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). The combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C Virus Infection.

PubMed

Lin, Ming V; Sise, Meghan E; Pavlakis, Martha; Amundsen, Beth M; Chute, Donald; Rutherford, Anna E; Chung, Raymond T; Curry, Michael P; Hanifi, Jasmine M; Gabardi, Steve; Chandraker, Anil; Heher, Eliot C; Elias, Nahel; Riella, Leonardo V

2016-01-01

The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34-70 years), median creatinine of 1.2 mg/dL (0.66-1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in post

Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C Virus Infection

PubMed Central

Lin, Ming V.; Sise, Meghan E.; Pavlakis, Martha; Amundsen, Beth M.; Chute, Donald; Rutherford, Anna E.; Chung, Raymond T.; Curry, Michael P.; Hanifi, Jasmine M.; Gabardi, Steve; Chandraker, Anil; Heher, Eliot C.; Elias, Nahel; Riella, Leonardo V.

2016-01-01

The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34–70 years), median creatinine of 1.2 mg/dL (0.66–1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in

Week 4 response predicts sustained virological response to all-oral direct-acting antiviral-based therapy in cirrhotic patients with hepatitis C virus genotype 3 infection.

PubMed

Pineda, J A; Morano-Amado, L E; Granados, R; Macías, J; Téllez, F; García-Deltoro, M; Ríos, M J; Collado, A; Delgado-Fernández, M; Suárez-Santamaría, M; Serrano, M; Miralles-Álvarez, C; Neukam, K

2017-06-01

The aim of this study was to determine the predictive capacity of response at treatment week (TW) 4 for the achievement of sustained virological response 12 weeks after the scheduled end of therapy date (SVR 12 ) to treatment against hepatitis C virus (HCV) genotype 3 (GT3) infection with all-oral direct-acting antiviral (DAA) -based regimens. From a prospective multicohort study, HCV GT3-infected patients who completed a course of currently recommended DAA-based therapy at 33 Spanish hospitals and who had reached the SVR 12 evaluation time-point were selected. TW4 HCV-RNA levels were categorized as target-not-detected (TND), below the lower limit of quantification (LLOQ TD ) and ≥LLOQ. A total of 123 patients were included, 86 (70%) received sofosbuvir/ daclatasvir±ribavirin, 27 (22%) received sofosbuvir/ ledipasvir/ ribavirin and 10 (8.1%) received sofosbuvir/ ribavirin, respectively. In all, 114 (92.7%) of the 123 patients presented SVR 12 in an on-treatment approach, but nine (7.3%) patients relapsed, all of them had presented cirrhosis at baseline. In those who achieved TND, LLOQ TD and ≥LLOQ, SVR 12 was observed in 81/83 (98%; 95% CI 91.5%-99.7%), 24/28 (85.7%; 95% CI 67.3%-96%) and 9/12 (75%; 95% CI 42.8%-94.5%), respectively; p (linear association) 0.001. Corresponding numbers for subjects with cirrhosis were: 52/54 (96.3%; 95% CI 87.3%-95.5%), 14/18 (77.8%; 95% CI 52.4%-93.6%) and 7/10 (70%; 95% CI 34.8%-93.3%); p 0.004. TW4-response indicates the probability of achieving SVR 12 to currently used DAA-based therapy in HCV genotype 3-infected individuals with cirrhosis. This finding may be useful to tailor treatment strategy in this setting. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

PubMed

Reau, Nancy; Kwo, Paul Y; Rhee, Susan; Brown, Robert S; Agarwal, Kosh; Angus, Peter; Gane, Edward; Kao, Jia-Horng; Mantry, Parvez S; Mutimer, David; Reddy, K Rajender; Tran, Tram T; Hu, Yiran B; Gulati, Abhishek; Krishnan, Preethi; Dumas, Emily O; Porcalla, Ariel; Shulman, Nancy S; Liu, Wei; Samanta, Suvajit; Trinh, Roger; Forns, Xavier

2018-04-19

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response for 12 weeks post-treatment (SVR12) across all major HCV genotypes (GT). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months post-transplant. Patients without cirrhosis who were HCV treatment-naïve (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N=98/100; 95% confidence interval, 95.3%-100%), which exceeded the pre-specified historic standard of care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity and laboratory abnormalities were infrequent. Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. ClinicalTrials.gov NCT02692703. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the

Precautionary Practices of Respiratory Therapists and Other Health-Care Practitioners Who Administer Aerosolized Medications

PubMed Central

Tsai, Rebecca J; Boiano, James M; Steege, Andrea L; Sweeney, Marie H

2015-01-01

BACKGROUND: Respiratory therapists (RTs) and other health-care workers are potentially exposed to a variety of aerosolized medications. The National Institute for Occupational Safety and Health (NIOSH) Health and Safety Practices Survey of Healthcare Workers describes current exposure control practices and barriers to using personal protective equipment during administration of selected aerosolized medications. METHODS: An anonymous, multi-module, web-based survey was conducted among members of health-care professional practice organizations representing RTs, nurses, and other health-care practitioners. A module on aerosolized medications included submodules for antibiotics (amikacin, colistin, and tobramycin), pentamidine, and ribavirin. RESULTS: The submodules on antibiotics, pentamidine, and ribavirin were completed by 321, 227, and 50 respondents, respectively, most of whom were RTs. The relatively low number of ribavirin respondents precluded meaningful interpretation of these data and may reflect the rare use of this drug. Consequently, analysis focused on pentamidine, classified by NIOSH as a hazardous drug, and the antibiotics amikacin, colistin, and tobramycin, which currently lack authoritative safe handling guidelines. Respondents who administered pentamidine were more likely to adhere to good work practices compared with those who administered the antibiotics. Examples included training received on safe handling procedures (75% vs 52%), availability of employer standard procedures (82% vs 55%), use of aerosol delivery devices equipped with an expiratory filter (96% vs 53%) or negative-pressure rooms (61% vs 20%), and always using respiratory protection (51% vs 13%). CONCLUSIONS: Despite the availability of safe handling guidelines for pentamidine, implementation was not universal, placing workers, co-workers, and even family members at risk of exposure. Although the antibiotics included in this study lack authoritative safe handling guidelines, prudence

Precautionary Practices of Respiratory Therapists and Other Health-Care Practitioners Who Administer Aerosolized Medications.

PubMed

Tsai, Rebecca J; Boiano, James M; Steege, Andrea L; Sweeney, Marie H

2015-10-01

Respiratory therapists (RTs) and other health-care workers are potentially exposed to a variety of aerosolized medications. The National Institute for Occupational Safety and Health (NIOSH) Health and Safety Practices Survey of Healthcare Workers describes current exposure control practices and barriers to using personal protective equipment during administration of selected aerosolized medications. An anonymous, multi-module, web-based survey was conducted among members of health-care professional practice organizations representing RTs, nurses, and other health-care practitioners. A module on aerosolized medications included submodules for antibiotics (amikacin, colistin, and tobramycin), pentamidine, and ribavirin. The submodules on antibiotics, pentamidine, and ribavirin were completed by 321, 227, and 50 respondents, respectively, most of whom were RTs. The relatively low number of ribavirin respondents precluded meaningful interpretation of these data and may reflect the rare use of this drug. Consequently, analysis focused on pentamidine, classified by NIOSH as a hazardous drug, and the antibiotics amikacin, colistin, and tobramycin, which currently lack authoritative safe handling guidelines. Respondents who administered pentamidine were more likely to adhere to good work practices compared with those who administered the antibiotics. Examples included training received on safe handling procedures (75% vs 52%), availability of employer standard procedures (82% vs 55%), use of aerosol delivery devices equipped with an expiratory filter (96% vs 53%) or negative-pressure rooms (61% vs 20%), and always using respiratory protection (51% vs 13%). Despite the availability of safe handling guidelines for pentamidine, implementation was not universal, placing workers, co-workers, and even family members at risk of exposure. Although the antibiotics included in this study lack authoritative safe handling guidelines, prudence dictates that appropriate exposure

Generic ledipasvir-sofosbuvir for patients with chronic hepatitis C: A real-life observational study.

PubMed

Zeng, Qing-Lei; Xu, Guang-Hua; Zhang, Ji-Yuan; Li, Wei; Zhang, Da-Wei; Li, Zhi-Qin; Liang, Hong-Xia; Li, Chun-Xia; Yu, Zu-Jiang

2017-06-01

Few patients from developing countries can afford brand name direct-acting antiviral agents for treating hepatitis C virus (HCV) infection, and controversy regarding the bioequivalence of generics exists. This study aimed to observe the safety and efficacy of 8 or 12weeks of generic ledipasvir-sofosbuvir with or without ribavirin for Chinese genotype 1b HCV-infected patients. In this open-labelled observational study, 63 cirrhotic (group 1) and 65 non-cirrhotic (group 2) patients were administered generic ledipasvir-sofosbuvir plus 1000-1200mg of ribavirin daily for 12 and 8weeks, respectively; and 64 non-cirrhotic patients (group 3) received ledipasvir-sofosbuvir for 8weeks. The primary efficacy endpoint was undetectable HCV RNA at week 12 (SVR12) after cessation of therapy. Safety and pharmacokinetic data were collected. One hundred and eighty-seven patients completed treatment, and the latest undetectable HCV RNA was observed in three patients with cirrhosis at week 5 during treatment. Intention-to-treat analysis revealed 96.8% (61/63), 96.9% (63/65), and 96.9% (62/64) of SVR12 rates in groups 1, 2, and 3, respectively. One patient in group 3 relapsed at post-treatment week 4. The regimens were generally well-tolerated. The most common adverse events were fatigue (17.8%), diarrhea (10.9%), and headache (9.9%). Four patients discontinued therapy due to diarrhea and vomiting. One patient from group 2 discontinued treatment on day 29 because of drug-unaffordability; fortunately, she achieved SVR12. This study demonstrated that 8 or 12weeks of generic ledipasvir-sofosbuvir with or without ribavirin are safe and effective for patients with genotype 1b HCV infection. The price of Harvoni® has led to restrictions and access limitations in many developing and even developed countries with limited healthcare budgets. Gilead approved generic ledipasvir-sofosbuvir costs far less than Harvoni® and presents a similar cure rate for patients with chronic hepatitis C

HCV IRES-Mediated Core Expression in Zebrafish

PubMed Central

Zhang, Jing-Pu; Hu, Zhan-Ying; Tong, Jun-Wei; Ding, Cun-Bao; Peng, Zong-Gen; Zhao, Li-Xun; Song, Dan-Qing; Jiang, Jian-Dong

2013-01-01

The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism. PMID:23469178

Management of the infant with respiratory syncytial virus.

PubMed

Corey, M A; Clore, E R

1991-04-01

This article examines updated clinical information concerning respiratory syncytial virus (RSV) infection including epidemiology, pathology, clinical manifestations, diagnosis, treatment, nosocomial infection, and prognosis. Also presented is current information on ribavirin therapy, its side effects, and precautions. Research related to the most effective isolation methodology is discussed, as well as nursing diagnoses based on Gordon's Functional Health Patterns and interventions for the infant hospitalized with RSV bronchiolitis and/or pneumonia.

Sequential structures provide insights into the fidelity of RNA replication.

PubMed

Ferrer-Orta, Cristina; Arias, Armando; Pérez-Luque, Rosa; Escarmís, Cristina; Domingo, Esteban; Verdaguer, Nuria

2007-05-29

RNA virus replication is an error-prone event caused by the low fidelity of viral RNA-dependent RNA polymerases. Replication fidelity can be decreased further by the use of mutagenic ribonucleoside analogs to a point where viral genetic information can no longer be maintained. For foot-and-mouth disease virus, the antiviral analogs ribavirin and 5-fluorouracil have been shown to be mutagenic, contributing to virus extinction through lethal mutagenesis. Here, we report the x-ray structure of four elongation complexes of foot-and-mouth disease virus polymerase 3D obtained in presence of natural substrates, ATP and UTP, or mutagenic nucleotides, ribavirin triphosphate and 5-fluorouridine triphosphate with different RNAs as template-primer molecules. The ability of these complexes to synthesize RNA in crystals allowed us to capture different successive replication events and to define the critical amino acids involved in (i) the recognition and positioning of the incoming nucleotide or analog; (ii) the positioning of the acceptor base of the template strand; and (iii) the positioning of the 3'-OH group of the primer nucleotide during RNA replication. The structures identify key interactions involved in viral RNA replication and provide insights into the molecular basis of the low fidelity of viral RNA polymerases.

Clinical Value of Thyrotropin Receptor Antibodies for the Differential Diagnosis of Interferon Induced Thyroiditis.

PubMed

Benaiges, D; Garcia-Retortillo, M; Mas, A; Cañete, N; Broquetas, T; Puigvehi, M; Chillarón, J J; Flores-Le Roux, J A; Sagarra, E; Cabrero, B; Zaffalon, D; Solà, R; Pedro-Botet, J; Carrión, J A

2016-01-01

The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin. Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis. 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (p<0.001). Thyrotropin receptor antibodies determination cannot replace thyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon. © Georg Thieme Verlag KG Stuttgart · New York.

The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes.

PubMed

Loomba, R; Rivera, M M; McBurney, R; Park, Y; Haynes-Williams, V; Rehermann, B; Alter, H J; Herrine, S K; Liang, T J; Hoofnagle, J H; Heller, T

2011-03-01

Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined. To establish natural history and complications of treatment of acute hepatitis C. Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed. Twenty-five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and hepatitis C virus (HCV) RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon-based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4-8 weeks, and all except two (HIV-positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%. Among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Anti-viral treatment with a 24-week course of peginterferon and ribavirin was highly effective, but marked by frequent and severe side effects. Published 2010. This article is a US Government work and is in the public domain in the USA.

The natural history of acute hepatitis C: clinical presentation, laboratory findings, and treatment outcomes

PubMed Central

Loomba, R.; Rivera, M. M.; McBurney, R.; Park, Y.; Haynes-Williams, V.; Rehermann, B.; Alter, H. J.; Herrine, S. K.; Liang, T. J.; Hoofnagle, J. H.; Heller, T.

2017-01-01

Summary Background Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined. Aims To establish natural history and complications of treatment of acute hepatitis C. Methods Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed. Results Twenty-five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and HCV RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon-based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4 to 8 weeks, and all except two (HIV-positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%. Conclusion Thus, among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Antiviral treatment with a 24-week course of peginterferon and ribavirin was highly effective but marked by frequent and severe side effects. PMID:21198704

Cost-Effectiveness of Treatments for Genotype 1 Hepatitis C Virus Infection in non-VA and VA Populations

PubMed Central

Liu, Shan; Barnett, Paul G.; Holodniy, Mark; Lo, Jeanie; Joyce, Vilija R.; Gidwani, Risha; Asch, Steven M.; Owens, Douglas K.; Goldhaber-Fiebert, Jeremy D.

2018-01-01

Background Chronic hepatitis C viral (HCV) infection affects millions of Americans. Healthcare systems face complex choices between multiple highly efficacious, costly treatments. This study assessed the cost-effectiveness of HCV treatments for chronic, genotype 1 HCV monoinfected, treatment-naïve individuals in the Department of Veterans Affairs (VA) and general U.S. healthcare systems. Methods We conducted a decision-analytic Markov model-based cost-effectiveness analysis, employing appropriate payer perspectives and time horizons, and discounting benefits and costs at 3% annually. Interventions included: Sofosbuvir/ledipasvir (SOF-LDV); ombitasvir/paritaprevir/ritonavir/dasabuvir (3D); sofosbuvir/simeprevir (SOF-SMV); sofosbuvir/pegylated interferon/ribavirin (SOF-RBV-PEG); boceprevir/pegylated interferon/ribavirin (BOC-RBV-PEG); and pegylated interferon/ribavirin (PEG-RBV). Outcomes were sustained virologic response (SVR), advanced liver disease, costs, quality adjusted life years (QALYs), and incremental cost-effectiveness. Results SOF-LDV and 3D achieve higher SVR rates compared to older regimens and reduce advanced liver disease (>20% relative to no treatment), increasing QALYs by over 2 years per person. For the non-VA population, at current prices ($5,040 per week for SOF-LDV and $4,796 per week for 3D), SOF-LDV’s lifetime cost ($293,370) is $18,000 lower than 3D’s because of its shorter treatment duration in subgroups. SOF-LDV costs $17,100 per QALY gained relative to no treatment. 3D costs $208,000 per QALY gained relative to SOF-LDV. Both dominate other treatments and are even more cost-effective for the VA, though VA aggregate treatment costs still exceed $4 billion at SOF-LDV prices of $3,308 per week. Drug prices strongly determine relative cost-effectiveness for SOF-LDV and 3D; With sufficient price reductions (approximately 20–30% depending on the health system), 3D could be cost-effective relative to SOF-LDV. Limitations include the lack of

Determination of the In Vitro and In Vivo Activity of Compounds Tested Against Punta Toro Virus.

DTIC Science & Technology

1987-12-29

were performed on 295 AVS compounds in LLC-MK2 cells with inhibition of viral cytopathic effect (CPE) as initial endpoint and reduction of virus...ineffective doses of ribavirin were highly active against the infection. 11. Publications and Presentations: One manuscript describing work performed on...USERS unclassifie 22a N4AME QP RESPONSIBE INDIIDUAL 22b. TELEPHONE WInd Area Code) 22. OFFICE SYMBOL WF ir ginia M. Miller- - DD FORM 1473,s4Mat 83

Development of Real-Time Reverse Transcriptase PCR Assays for the Detection of Punta Toro Virus and Pichinde Virus

DTIC Science & Technology

2016-09-09

Gowen et al., 2006c; Smee et al., 1993) and guinea pigs (Jahrling et al., 1981; Lucia et al., 1989) 91 as LASV infection in humans. Both PICV and...Moe, J.B., 1981. Pathogenesis of a pichinde virus 281 strain adapted to produce lethal infections in guinea pigs . Infect Immun 32, 872-880. 282... guinea pig model: antiviral 286 therapy with recombinant interferon-alpha, the immunomodulator CL246,738 and ribavirin. Antiviral 287 Res 12, 279-292

Tick-borne viruses: a review from the perspective of therapeutic approaches.

PubMed

Lani, Rafidah; Moghaddam, Ehsan; Haghani, Amin; Chang, Li-Yen; AbuBakar, Sazaly; Zandi, Keivan

2014-09-01

Several important human diseases worldwide are caused by tick-borne viruses. These diseases have become important public health concerns in recent years. The tick-borne viruses that cause diseases in humans mainly belong to 3 families: Bunyaviridae, Flaviviridae, and Reoviridae. In this review, we focus on therapeutic approaches for several of the more important tick-borne viruses from these 3 families. These viruses are Crimean-Congo hemorrhagic fever virus (CCHF) and the newly discovered tick-borne phleboviruses, known as thrombocytopenia syndromevirus (SFTSV), Heartland virus and Bhanja virus from the family Bunyaviridae, tick-borne encephalitis virus (TBEV), Powassan virus (POWV), Louping-ill virus (LIV), Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV), and Alkhurma hemorrhagic fever virus (AHFV) from the Flaviviridae family. To date, there is no effective antiviral drug available against most of these tick-borne viruses. Although there is common usage of antiviral drugs such as ribavirin for CCHF treatment in some countries, there are concerns that ribavirin may not be as effective as once thought against CCHF. Herein, we discuss also the availability of vaccines for the control of these viral infections. The lack of treatment and prevention approaches for these viruses is highlighted, and we hope that this review may increase public health awareness with regard to the threat posed by this group of viruses. Copyright © 2014 Elsevier GmbH. All rights reserved.

Hepatitis C virus protease inhibitor-resistance mutations: our experience and review.

PubMed

Wu, Shuang; Kanda, Tatsuo; Nakamoto, Shingo; Imazeki, Fumio; Yokosuka, Osamu

2013-12-21

Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network

PubMed Central

Gaeta, Giovanni Battista; Brunetto, Maurizia Rossana; Di Leo, Alfredo; Iannone, Andrea; Santantonio, Teresa Antonia; Giammario, Adele; Raimondo, Giovanni; Filomia, Roberto; Coppola, Carmine; Amoruso, Daniela Caterina; Blanc, Pierluigi; Del Pin, Barbara; Chemello, Liliana; Cavalletto, Luisa; Morisco, Filomena; Donnarumma, Laura; Rumi, Maria Grazia; Gasbarrini, Antonio; Siciliano, Massimo; Massari, Marco; Corsini, Romina; Coco, Barbara; Madonia, Salvatore; Cannizzaro, Marco; Zignego, Anna Linda; Monti, Monica; Russo, Francesco Paolo; Zanetto, Alberto; Persico, Marcello; Masarone, Mario; Villa, Erica; Bernabucci, Veronica; Taliani, Gloria; Biliotti, Elisa; Chessa, Luchino; Pasetto, Maria Cristina; Andreone, Pietro; Margotti, Marzia; Brancaccio, Giuseppina; Ieluzzi, Donatella; Borgia, Guglielmo; Zappulo, Emanuela; Calvaruso, Vincenza; Petta, Salvatore; Falzano, Loredana; Quaranta, Maria Giovanna; Weimer, Liliana Elena; Rosato, Stefano; Vella, Stefano; Giannini, Edoardo Giovanni

2017-01-01

Background Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. Aim To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Methods Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Results Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5–14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3–12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.

PubMed

Kondili, Loreta A; Gaeta, Giovanni Battista; Brunetto, Maurizia Rossana; Di Leo, Alfredo; Iannone, Andrea; Santantonio, Teresa Antonia; Giammario, Adele; Raimondo, Giovanni; Filomia, Roberto; Coppola, Carmine; Amoruso, Daniela Caterina; Blanc, Pierluigi; Del Pin, Barbara; Chemello, Liliana; Cavalletto, Luisa; Morisco, Filomena; Donnarumma, Laura; Rumi, Maria Grazia; Gasbarrini, Antonio; Siciliano, Massimo; Massari, Marco; Corsini, Romina; Coco, Barbara; Madonia, Salvatore; Cannizzaro, Marco; Zignego, Anna Linda; Monti, Monica; Russo, Francesco Paolo; Zanetto, Alberto; Persico, Marcello; Masarone, Mario; Villa, Erica; Bernabucci, Veronica; Taliani, Gloria; Biliotti, Elisa; Chessa, Luchino; Pasetto, Maria Cristina; Andreone, Pietro; Margotti, Marzia; Brancaccio, Giuseppina; Ieluzzi, Donatella; Borgia, Guglielmo; Zappulo, Emanuela; Calvaruso, Vincenza; Petta, Salvatore; Falzano, Loredana; Quaranta, Maria Giovanna; Weimer, Liliana Elena; Rosato, Stefano; Vella, Stefano; Giannini, Edoardo Giovanni

2017-01-01

Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5-14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3-12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of

All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study.

PubMed

Manns, Michael; Pol, Stanislas; Jacobson, Ira M; Marcellin, Patrick; Gordon, Stuart C; Peng, Cheng-Yuan; Chang, Ting-Tsung; Everson, Gregory T; Heo, Jeong; Gerken, Guido; Yoffe, Boris; Towner, William J; Bourliere, Marc; Metivier, Sophie; Chu, Chi-Jen; Sievert, William; Bronowicki, Jean-Pierre; Thabut, Dominique; Lee, Youn-Jae; Kao, Jia-Horng; McPhee, Fiona; Kopit, Justin; Mendez, Patricia; Linaberry, Misti; Hughes, Eric; Noviello, Stephanie

2014-11-01

An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and

New Opportunities for the Management and Therapy of Hepatitis C in Correctional Settings

PubMed Central

Hostetter, Jeffrey E.; Hagan, John J.

2010-01-01

Hepatitis C in prison populations is now a major public health problem, and large numbers of correctional facilities have no comprehensive management program, often because of formidable projected costs and tightening budget constraints. The North Dakota Department of Corrections and Rehabilitation has operated a management and therapy program since 2002 using consensus interferon and ribavirin with 45% cost savings. The program has provided excellent sustained viral responses: 54.2% for genotype 1 hepatitis C, 75% for genotypes 2 and 3, and 63.6% overall. PMID:20007626

Synthesis and Antiviral Activity of 5-Substituted Cytidine Analogues: Identification of a Potent Inhibitor of Viral RNA-Dependent RNA Polymerases

PubMed Central

Harki, Daniel A.; Graci, Jason D.; Galarraga, Jessica E.; Chain, William J.; Cameron, Craig E.; Peterson, Blake R.

2007-01-01

As part of our studies of lethal viral mutagens, a series of 5-substituted cytidine analogues were synthesized and evaluated for antiviral activity. Among the compounds examined, 5-nitrocytidine was effective against poliovirus (PV) and coxsackievirus B3 (CVB3) and exhibited greater activity than the clinically employed drug ribavirin. Instead of promoting viral mutagenesis, 5-nitrocytidine triphosphate inhibited PV RNA-dependent RNA polymerase (Kd = 1.1 ± 0.1 μM), and this inhibition is sufficient to explain the observed antiviral activity. PMID:17034123

Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients.

PubMed

Navarro, Jordi; Laguno, Montserrat; Vilchez, Helem Haydee; Guardiola, Jose M; Carrion, Jose A; Force, Luis; Cairó, Mireia; Cifuentes, Carmen; Vilaró, Josep; Cucurull, Josep; Marco, Andrés; Roget, Mercè; Erice, Eva; Crespo, Manuel

2017-10-01

New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004). In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were

Effect of discounting on estimation of benefits determined by hepatitis C treatment.

PubMed

Messori, Andrea; Fadda, Valeria; Maratea, Dario; Trippoli, Sabrina

2012-06-21

The combination of either boceprevir or telaprevir with ribavirin and interferon (triple therapy) has been shown to be more effective than ribavirin+interferon (dual therapy) for the treatment of genotype 1 hepatitis C. Since the benefit of these treatments takes place after years, simulation models are needed to predict long-term outcomes. In simulation models, the choice of different values of yearly discount rates (e.g., 6%, 3.5%, 2%, 1.5% or 0%) influences the results, but no studies have specifically addressed this issue. We examined this point by determining the long-term benefits under different conditions on the basis of standard modelling and using quality-adjusted life years (QALYs) to quantify the benefits. In our base case scenario, we compared the long-term benefit between patients given a treatment with a 40% sustained virologic response (SVR) (dual therapy) and patients given a treatment with a 70% SVR (triple therapy), and we then examined how these specific yearly discount rates influenced the incremental benefit. The gain between a 70% SVR and a 40% SVR decreased from 0.45 QALYs with a 0% discount rate to 0.22 QALYs with a 6% discount rate (ratio between the two values = 2.04). Testing the other discounting assumptions confirmed that the discount rate has a marked impact on the magnitude of the model-estimated incremental benefit. In conclusion, the results of our analysis can be helpful to better interpret cost-effectiveness studies evaluating new treatment for hepatitis C.

Identification of Inhibitory Compounds Against Singapore Grouper Iridovirus Infection by Cell Viability-Based Screening Assay and Droplet Digital PCR.

PubMed

Jia, Kuntong; Yuan, Yongming; Liu, Wei; Liu, Lan; Qin, Qiwei; Yi, Meisheng

2018-02-01

Singapore grouper iridovirus (SGIV) is one of the major causative agents of fish diseases and has caused significant economic losses in the aquaculture industry. There is currently no commercial vaccine or effective antiviral treatment against SGIV infection. Annually, an increasing number of small molecule compounds from various sources have been produced, and many are proved to be potential inhibitors against viruses. Here, a high-throughput in vitro cell viability-based screening assay was developed to identify antiviral compounds against SGIV using the luminescent-based CellTiter-Glo reagent in cultured grouper spleen cells by quantificational measurement of the cytopathic effects induced by SGIV infection. This assay was utilized to screen for potential SGIV inhibitors from five customized compounds which had been reported to be capable of inhibiting other viruses and 30 compounds isolated from various marine organisms, and three of them [ribavirin, harringtonine, and 2-hydroxytetradecanoic acid (2-HOM)] were identified to be effective on inhibiting SGIV infection, which was further confirmed with droplet digital PCR (ddPCR). In addition, the ddPCR results revealed that ribavirin and 2-HOM inhibited SGIV replication and entry in a dose-dependent manner, and harringtonine could reduce SGIV replication rather than entry at the working concentration without significant toxicity. These findings provided an easy and reliable cell viability-based screening assay to identify compounds with anti-SGIV effect and a way of studying the anti-SGIV mechanism of compounds.

Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis.

PubMed

Morra, Mostafa Ebraheem; Van Thanh, Le; Kamel, Mohamed Gomaa; Ghazy, Ahmed Abdelmotaleb; Altibi, Ahmed M A; Dat, Lu Minh; Thy, Tran Ngoc Xuan; Vuong, Nguyen Lam; Mostafa, Mostafa Reda; Ahmed, Sarah Ibrahim; Elabd, Sahar Samy; Fathima, Samreen; Le Huy Vu, Tran; Omrani, Ali S; Memish, Ziad A; Hirayama, Kenji; Huy, Nguyen Tien

2018-05-01

Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus. Because of lack of vaccination, various studies investigated the therapeutic efficacy of antiviral drugs and supportive remedies. A systematic literature search from 10 databases was conducted and screened for relevant articles. Studies reporting information about the treatment of MERS coronavirus infection were extracted and analyzed. Despite receiving treatment with ribavirin plus IFN, the case fatality rate was as high as 71% in the IFN-treatment group and exactly the same in patients who received supportive treatment only. Having chronic renal disease, diabetes mellitus and hypertension increased the risk of mortality (P < .05), and chronic renal disease is the best parameter to predict the mortality. The mean of survival days from onset of illness to death was 46.6 (95% CI, 30.5-62.6) for the IFN group compared with 18.8 (95% CI, 10.3-27.4) for the supportive-only group (P = .001). Delay in starting treatment, older age group, and preexisting comorbidities are associated with worse outcomes. In conclusion, there is no difference between IFN treatment and supportive treatment for MERS patients in terms of mortality. However, ribavirin and IFN combination might have efficacious effects with timely administration and monitoring of adverse events. Large-scale prospective randomized studies are required to assess the role of antiviral drugs for the treatment of this high mortality infection. Copyright © 2018 John Wiley & Sons, Ltd.

[Natural history, diagnosis and treatment of chronic hepatitis B and C in hemodialysis patients].

PubMed

Nicolardi, Erica; Grieco, Antonio; Rapaccini, Gian Ludovico; Pompili, Maurizio

2010-01-01

Chronic hepatitis B and C are important causes of liver disease in hemodialysis units. The most important route of transmission is the inapparent parenteral route; known risk factors are the high prevalence of HBV and HCV infections in hemodialysis units, previous blood transfusions, long-term dialysis treatment, frequent changes of hemodialysis unit, and previous renal transplants. The source, time and duration of infection are often difficult to ascertain. The studies investigating the natural history of viral hepatitis in hemodialysis patients are few and limited by a short follow-up, but they show an independent and negative impact on survival due to an increased risk of liver cirrhosis and hepatocellular carcinoma. The treatment options include conventional or pegylated interferon (alone or in association with ribavirin) and the nucleoside/nucleotide analogs. The aim of treatment is viral eradication or persistent suppression of viral replication. The altered pharmacokinetics, the increased risk of drug-related toxicity, and the need for renal transplant complicate the management of antiviral therapy. In patients with chronic HBV infection and active replication the most common approach is persistent suppression of viral replication using nucleoside/nucleotide analogs. As regards hepatitis C, several clinical trials evaluating conventional interferon monotherapy have shown higher sustained virological response and dropout rates in dialysis patients than in patients with normal kidney function. Data about pegylated interferon as monotherapy or in association with ribavirin are promising but limited. Hemodialyzed patients obtaining a sustained virological response often maintain the response after kidney transplantation.

The Effect of Combination Antiviral Therapy in the Treatment of Hepatitis C on the Occurrence of Depressive Disorder in Patients Treated for Hepatitis C in the Republic of Srpska.

PubMed

Banjac, Visnja; Zivlak-Radulovic, Nera; Miskovic, Mirjana

2016-04-01

The current standard treatment of chronic hepatitis C in Bosnia and Herzegovina consists of pegylated interferon alpha in combination with ribavirin. Interferon therapy has many psychiatric side effects, with depressive symptomatology being most prominent. The aim of the study was to establish the frequency and severity of depression in patients with chronic hepatitis C during two months of the aforementioned therapy. The overall sample consisted of 46 subjects, divided into three subgroups, aged 18 to 65. The study population consisted of subjects treated for chronic hepatitis C (n = 15), subjects infected but not treated for chronic hepatitis C (n = 15), and healthy controls (n = 16). The assessment and level of depression were based on the Structural clinical interview (SCID), Montgomery-Asberg Depression Rating Scale and Zung Self-Rating Depression Scale. The assessments were conducted before interferon therapy (on the day 0), after 4 and 8 weeks of therapy. Regarding its frequency, MADRS scoring showed that the number of depressed subjects receiving therapy increased after 8 weeks (46.7%). There was statistical significance between the subgroups after 4 and 8 weeks. Likewise, the ZUNG scale showed that the number of depressed subjects receiving therapy increased after 8 weeks (73.3%). There was statistical significance between the subgroups on the day 0, after 4 and 8 weeks. Depression was significantly more frequent in chronic hepatitis C subjects treated with interferon alpha in combination with ribavirin than in subjects in the group without therapy. Mild depression was most prevalent.

The elderly and direct antiviral agents: Constraint or challenge?

PubMed

Fabrizio, Claudia; Saracino, Annalisa; Scudeller, Luigia; Milano, Eugenio; Dell'Acqua, Raffaele; Bruno, Giuseppe; Lo Caputo, Sergio; Monno, Laura; Milella, Michele; Angarano, Gioacchino

2017-09-01

Direct antiviral agents (DAAs) for chronic hepatitis C showed great effectiveness and good safety profile. So far, few data are available about their use in elderly subjects. To assess management, safety and outcome of DAAs treatments in the elderly. This retrospective, single-centre study enrolled all patients aged ≥65 years, compared by age (group A: 65-74 years, group B: ≥75 years), who completed DAAs between February 2015-November 2016. Variables potentially associated to adverse events (AEs) were analyzed. Sustained virological response (SVR) was evaluated at 12-weeks follow-up. DAAs were administered to 221 patients aged ≥65 years (males: 112; group A: 130, group B: 91). Prescribed regimens were: sofosbuvir-based: 44 patients (19.9%), simeprevir-based: 25 (15%), ledipasvir-based: 49 (22.2%), daclatasvir-based: 12 (5.4%), paritaprevir/ritonavir+ombitasvir±dasabuvir: 91 (41.2%). Ribavirin was used in 121 patients. In 58 subjects co-medications were adjusted due to drug interactions. At least one AE occurred in 130 patients, including 13 SAEs, mainly in older subjects (p=0.04). Female sex (p=0.04), liver stiffness (p=0.023), use of simeprevir (p=0.03) and ribavirin (p=0.009) were associated with AEs. SVR-12 was achieved in 96,9% of subjects. A careful baseline evaluation and a strict monitoring allow to optimise management and outcome of DAAs in elderly. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation.

PubMed

Liu, Rui; Liu, Zhidong; Zhang, Chengui; Zhang, Boli

2011-08-01

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system. Copyright © 2011 Wiley-Liss, Inc.

Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication

USGS Publications Warehouse

Debing, Yannick; Winton, James; Neyts, Johan; Dallmeier, Kai

2013-01-01

Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non-pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2′-C-methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17β-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae.

Hepatitis C Virus Resistance Testing in Genotype 1: The Changing Role in Clinical Utility.

PubMed

Molino, Suzanne; Martin, Michelle T

2017-09-01

To review the role and utility of baseline resistance testing with currently available and pipeline genotype 1 hepatitis C virus (HCV) treatment. Authors reviewed liver meeting abstracts for data on currently-available and pipeline genotype 1 retreatment regimens from January 1, 2015, to March 23, 2017. Additional trials were identified from a review of clinicaltrials.gov using the pipeline medication names. Authors identified reports of current and pipeline genotype 1 retreatment regimens. Seven references were clinical study results presented at the meetings of the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, and 2 studies were from clinicaltrials.gov . Retreatment trial data of currently available salvage regimens indicate that baseline NS5A resistance-associated substitutions (RASs) may decrease sustained virological response (SVR) rates when retreating with ledipasvir/sofosbuvir but are not affected when using elbasvir/grazoprevir + sofosbuvir + ribavirin, paritaprevir/ritonavir/ombitasvir + dasabuvir + sofosbuvir, or sofosbuvir/velpatasvir + ribavirin. Pipeline data indicate that baseline NS5A RASs do not affect SVR rates when retreating with sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir. Baseline resistance testing was used for decisional support for 3 clinical scenarios in patients with HCV genotype 1 infection at the time of manuscript submission. Pending the approval of 2 new direct-acting antiviral regimens in the third quarter of 2017, the rapidly evolving HCV treatment guidelines will likely reflect a decreased clinical utility for resistance testing.

Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir

PubMed Central

Vincent, Corine; Furlan, Valérie; Rosa, Isabelle; Rosenthal, Eric; Cheret, Antoine; Molina, Jean-Michel; Taburet, Anne-Marie; Piroth, Lionel

2015-01-01

Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon–ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir. PMID:26438504

[New treatments for hepatitis C, which targets, what timeline?].

PubMed

Goossens, Nicolas; Negro, Francesco

2011-09-07

The hepatitis C virus (HCV) is a global major health burden, its response to current treatment is unfortunately inadequate, in particular for genotype 1. Two new direct acting antivirals, that inhibit NS3/4A viral protease, will soon be available on the Swiss market: telaprevir and boceprevir. These substances increase the rate of sustained viral response, in HCV genotype 1 infected patients, when coadministered with pegylated interferon and ribavirin. However, these new molecules may lead to serious adverse effects and drug interactions with which the specialist and the primary care physician must be familiar.

Lassa Virus Infection of Rhesus Monkeys: Pathogenesis and Treatment with Ribavirin

DTIC Science & Technology

1980-05-01

virus is a severe, gen- data have suggested that mild or subclinical infec- eralized disease described as Lassa fever [1-31. tions may occur [2...Liberia and Sierra Management of Lassa fever would be facilitated if Leone; serologic data also suggest the presence of an effective antiviral drug...of Laboratory monkey model for human Lassa fever . The results Animal Resources, National Research Council. The facilities are encouraging, suggesting

Mechanism of Action of Ribavirin: An Antiviral Drug of Military Importance,

DTIC Science & Technology

1980-06-01

was suspended in 120 mM Tris, 60 mM sodium ace- tate, 3 mM EDTA (pH 7.4) plus 10% glycerol and 0.1% bromophenol blue. Following electrophoresis, gels ... polyacryl - amide gels . J. Mol. Biol. 26:373-387. 2. Browne, M. J. 1979. Mechanism and specificity of action of ri- bavirin. Antimicrob. Agents...of 10 mM EDTA, 1% sodi- um dodecylsulfate (SDS) and 0.4 N sodium acetate (pH 5.2) then ex- tracted twice with a mixture of 50% phenol, 49% chloroform

Synthesis of the first novel pyrazole thioglycosides as deaza ribavirin analogues.

PubMed

Abu-Zaied, Mamdouh A; Elgemeie, Galal H

2017-12-02

This study reports a novel and efficient method for the synthesis of the first reported novel class of thiopyrazoles and their corresponding thioglycosides. These series of compounds were designed through the reaction of hydrazine derivatives with sodium dithiolate salt 2 in EtOH at ambient temperature to give the corresponding sodium 5-amino-4-cyano-1H-pyrazole-3-thiolates 4a-d. The latter compounds were treated with α-acetobromoglucose 6a and α-acetobromogalactose 6b in DMF at ambient temperature to give in an excellent yields the corresponding pyrazole S-glycosides 7a-h. Ammonolysis of the pyrazole thioglycosides 7a-h afforded the corresponding free thioglycosides 8a-h.

Clinical relevance of total HCV core antigen testing for hepatitis C monitoring and for predicting patients' response to therapy.

PubMed

Maynard, M; Pradat, P; Berthillon, P; Picchio, G; Voirin, N; Martinot, M; Marcellin, P; Trepo, C

2003-07-01

To study the correlation between total Hepatitis C virus (HCV) Core antigen (Ag) and HCV-RNA, and to assess the proficiency of HCV Core Ag testing in monitoring and predicting virologic response during and after pegylated interferon (PEG-IFN) and ribavirin combination therapy. A total of 307 samples from treated and untreated patients were used to assess the correlation between the total HCV Core Ag test and quantitative HCV-RNA assays (Superquant, and Quantiplex branched DNA 2.0 assay). Twenty-four patients received combination therapy for 48 weeks. Blood samples were collected at day 0, and week 2, 4, 12, 24, 48 and 72 for virologic evaluation. A linear relation exists between total HCV Core Ag and HCV-RNA levels. At 3 months the positive predictive value (PPV) of response to therapy was 100% with either HCV Core Ag or HCV-RNA. For HCV Core Ag the negative predictive value (NPV) was 100% whereas for HCV-RNA the NPV was 80% (P > 0.05). At month 1, the PPV was 95% and 100% when determined by HCV Core Ag and HCV-RNA, respectively. The NPV value was 100% for HCV Core Ag and 33% for HCV-RNA (P = 0.005). HCV Core Ag quantification could be useful in clinical practice to predict a sustained virological response early during therapy (4 weeks), reaching an optimal performance at month 3. The determination of total HCV Core Ag levels in serum, constitutes an accurate and reliable alternative to HCV-RNA for monitoring and predicting treatment outcome in patients receiving PEG-IFN/Ribavirin combination therapy.

Sustained response to combination therapy in a patient with chronic hepatitis C and thrombocytopenia secondary to alpha-interferon.

PubMed

Jiménez-Sáenz, M; Rojas, M; Piñar, A; Salas, E; Rebollo, J; Carmona, I; Herrerías-Esteban, J M; Herrerías-Gutiérrez, J M

2000-05-01

Recent data suggest that hepatitis C viral (HCV) infection may induce a significant autoimmune reaction to platelets, but the mechanism is unknown. Many patients with chronic hepatitis C, in fact, have high levels of platelet-associated immunoglobulin G (PAIgG) and HCV-RNA is present in the platelets of 100% of those patients with thrombocytopenia and high PAIgG levels. Hepatitis C virus infection has been associated with the development of thrombocytopenic purpura, sometimes triggered during interferon (IFN) therapy. In such cases, the treatment of the underlying disease is a difficult problem to solve. We report the case of a patient with chronic hepatitis C, who developed life-threatening thrombocytopenic purpura after a prolonged course of IFN-alpha2b over a 4-year period. Treatment with anti-immunoglobulin gammaglobulin (Polyglobin; Química Farmaceutica Bayer, Barcelona, Spain) had a transient effect on the platelet count, but prolonged therapy with prednisone was necessary for definitive relief of the haematological complication. Two years later, the patient was treated with combined therapy, including ribavirin (1200 mg/day) and IFN-alpha2b (5 mU, t.i.w.) for 12 months. This therapy induced a sustained response, both biochemical and virological, without haematological complications. This observation suggests that ribavirin may be of benefit in the treatment of immune-mediated thrombocytopenia in patients with chronic hepatitis C, preventing the harmful effect of IFN-alpha but also allowing both drugs to be combined so as to increase the probability of sustained remission of the liver disease.

Direct-Acting Antivirals in Chronic Hepatitis C Genotype 4 Infection in Community Care Setting.

PubMed

Gayam, Vijay; Khalid, Mazin; Mandal, Amrendra Kumar; Hussain, Muhammad Rajib; Mukhtar, Osama; Gill, Arshpal; Garlapati, Pavani; Shrestha, Binav; Guss, Debra; Sherigar, Jagannath; Mansour, Mohammed; Mohanty, Smruti

2018-04-01

Limited data exists comparing the safety, tolerability, and efficacy of direct-acting antivirals (DAAs) in patients with chronic hepatitis C genotype 4 (HCV GT-4) in the community practice setting. We aim to evaluate the treatment response of DAAs in these patients. All the HCV GT-4 patients treated with DAAs between January 2014 and October 2017 in a community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with sustained virologic response (SVR) at 12 weeks post treatment (SVR12), and adverse reactions were assessed. Fifty-two patients of Middle Eastern (primarily Egyptian) descent were included in the study. Thirty-two patients were treated with ledipasvir/sofosbuvir (Harvoni ® ) ± ribavirin, 12 patients were treated with ombitasvir/paritaprevir/ritonavir/dasabuvir (ViekiraPak ® ) ± ribavirin, and eight patients were treated with sofosbuvir/Velpatasvir (Epclusa ® ). Ten patients (19.2%) had compensated cirrhosis. Overall, SVR at 12 weeks was achieved in 94% in patients who received one of the three DAA regimens (93.8% in Harvoni ® group, 91.7 % in ViekiraPak ® group and 100% in Epclusa ® group). Prior treatment status and type of regimen used in the presence of compensated cirrhosis had no statistical significance on overall SVR achievement (P value = 0.442 and P value = 0.091, respectively). The most common adverse effect was fatigue (27%). In the real-world setting, DAAs are effective and well tolerated in patients with chronic HCV GT-4 infection with a high overall SVR rate of 94%. Large-scale studies are needed to further assess this SVR in these groups.

[Severe acute respiratory syndrome: the first transmissible disease of the 21st century].

PubMed

Nicastri, Emanuele; Petrosillo, Nicola; Macrì, Giulia; Ippolito, Giuseppe

2003-01-01

The Severe Acute Respiratory Syndrome (SARS) is the first severe and easily transmissible disease to emerge in the 21st century. It is caused by the infection with a coronavirus, a single strand RNA capsulated virus, recently found in a small mammalian, the masked palm civet. It is likely to represent the source of human infection. The first cases of SARS have been reported in the Chinese province of Guangdong and, since then, probable cases have been reported world wide. The clinical picture is characterized by nonspecific symptoms such as fever, cough or dyspnea in patients affected by air-space opacities (unifocal involvement in the 54.6% of cases) or distress respiratory syndrome and linked to a recent exposure to a SARS case or to a travel/residence in an affected area. The empirical therapy is based on broad-spectrum antibiotics, steroids and ribavirin, but susceptibility testing have failed to demonstrate direct anti-viral activity of ribavirin against SARS-related coronavirus in vitro. The exposure to respiratory droplets and the contact with biologic fluids (respiratory and gastrointestinal secretions) represent the most efficient transmission modality of the SARS-related coronavirus. Hand hygiene is the most simple and cost effective measure of infection control to prevent contagion, and the use of airborne, contact and droplet precaution is strictly recommended to all health care workers taking care of such patients. The spread of SARS, to less developed country with limited resource for public health programs, represent the emerging alarming threat in the new global scenario.

Extinction of Zika virus and Usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs.

PubMed

Bassi, Maria Rosaria; Sempere, Raquel Navarro; Meyn, Prashansa; Polacek, Charlotta; Arias, Armando

2018-06-18

Flaviviruses constitute an increasing source of public health concern with growing numbers of pathogens causing disease, and a geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there is currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides that have shown mutagenic activity against other RNA viruses - favipiravir, ribavirin and 5-fluorouracil - while they remain unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although both viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin) while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis, and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication, and the design of antiviral therapies based on lethal mutagenesis. Copyright © 2018 Bassi et al.

Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication.

PubMed

Debing, Yannick; Winton, James; Neyts, Johan; Dallmeier, Kai

2013-10-01

Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non-pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2'-C-methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17β-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae. Copyright © 2013 Elsevier B.V. All rights reserved.

In vitro anti-influenza viral activities of constituents from Caesalpinia sappan.

PubMed

Liu, Ai-Lin; Shu, Shi-Hui; Qin, Hai-Lin; Lee, Simon Ming Yuen; Wang, Yi-Tao; Du, Guan-Hua

2009-03-01

Six constituents with neuraminidase (NA) inhibitory activity, namely brazilein, brazilin, protosappanin A, 3-deoxysappanchalcone, sappanchalcone and rhamnetin, were isolated from the hearthwood of Caesalpinia sappan (Leguminosae). Their in vitro anti-influenza virus activities were evaluated with the cytopathic effect (CPE) reduction method. The results showed that 3-deoxysappanchalcone and sappanchalcone exhibited the highest activity against influenza virus (H3N2) with IC50 values of 1.06 and 2.06 microg/mL, respectively, in comparison to the positive control oseltamivir acid and ribavirin with IC50 values of 0.065 and 9.17 microg/mL, respectively.

Crimean-Congo hemorrhagic fever: epidemiological trends and controversies in treatment.

PubMed

Maltezou, Helena C; Papa, Anna

2011-12-08

Crimean-Congo hemorrhagic fever (CCHF) virus has the widest geographic range of all tick-borne viruses and is endemic in more than 30 countries in Eurasia and Africa. Over the past decade, new foci have emerged or re-emerged in the Balkans and neighboring areas. Here we discuss the factors influencing CCHF incidence and focus on the main issue of the use of ribavirin for treating this infection. Given the dynamics of CCHF emergence in the past decade, development of new anti-viral drugs and a vaccine is urgently needed to treat and prevent this acute, life-threatening disease.

Crimean-Congo hemorrhagic fever: epidemiological trends and controversies in treatment

PubMed Central

2011-01-01

Crimean-Congo hemorrhagic fever (CCHF) virus has the widest geographic range of all tick-borne viruses and is endemic in more than 30 countries in Eurasia and Africa. Over the past decade, new foci have emerged or re-emerged in the Balkans and neighboring areas. Here we discuss the factors influencing CCHF incidence and focus on the main issue of the use of ribavirin for treating this infection. Given the dynamics of CCHF emergence in the past decade, development of new anti-viral drugs and a vaccine is urgently needed to treat and prevent this acute, life-threatening disease. PMID:22152109

Cost-effectiveness analysis of triple therapy with protease inhibitors in treatment-naive hepatitis C patients.

PubMed

Blázquez-Pérez, Antonio; San Miguel, Ramón; Mar, Javier

2013-10-01

Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below

Classical and emerging roles of vitamin D in hepatitis C virus (HCV) infection

PubMed Central

Gutierrez, Julio A.; Parikh, Neil; Branch, Andrea D.

2014-01-01

The risk of clinically-significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL, according to the Institute of Medicine. By this standard, most cirrhotic hepatitis C virus (HCV)-positive patients and many non-cirrhotic patients are vitamin D deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin D's beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. The article concludes with information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients. PMID:22189978

Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus.

PubMed

Sepúlveda, Claudia S; García, Cybele C; Damonte, Elsa B

2018-05-01

The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses. © 2018 Wiley Periodicals, Inc.

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin.

PubMed

Coelho-Borges, Silvia; Cheinquer, Hugo; Wolff, Fernando Herz; Cheinquer, Nelson; Krug, Luciano; Ashton-Prolla, Patricia

2012-01-01

Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.

Failed triple therapy in a treatment-experienced patient with genotype 6 hepatitis C infection.

PubMed

Gammal, Roseann S; Spooner, Linda M; Abraham, George M

2014-02-01

The first published report of the use of triple therapy in a patient with hepatitis C virus (HCV) genotype 6 infection-a treatment that was prescribed due to incorrect HCV genotyping and which ultimately failed-is presented. A 70-year-old male U.S. resident of Vietnamese descent requested treatment for chronic HCV infection acquired decades earlier. He reported experiencing hepatitis C treatment failures twice before-13 years prior (interferon alfa monotherapy for six months) and 7 years prior (standard dual therapy with pegylated interferon alfa-2b and ribavirin for nine months). Initial viral genotyping indicated infection with HCV genotypes 1a and 6c (a form of mixed HCV disease amenable to triple therapy), and treatment with pegylated interferon alfa-2a, ribavirin, and boceprevir was initiated. By week 8 of triple therapy, the patient's viral load had decreased from 15,700,000 (7.20 log) to 462,882 (5.67 log) IU/mL, but the viral load subsequently rebounded to baseline levels, and treatment was discontinued at week 16. When repeat HCV genotyping was performed, it was discovered that initial genotyping was incorrect and that the man's infection involved not mixed genotypes but only genotype 6; he was not an appropriate candidate for triple therapy. The case emphasizes the need for clinicians to be cognizant of potential HCV genotyping errors, particularly with regard to patients of Southeast Asian descent. Three courses of interferon-based treatment, including triple therapy with boceprevir, failed to produce a sustained therapeutic response in a 70-year-old ethnic Vietnamese man with genotype 6 HCV infection.

Hepatitis C in the pediatric population: transmission, natural history, treatment and liver transplantation.

PubMed

Khaderi, Saira; Shepherd, Ross; Goss, John A; Leung, Daniel H

2014-08-28

The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is $199-366 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Phase 1 and 2 trials with triple therapy (interferon, ribavirin, and a protease inhibitor) are ongoing. Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survivals are noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe and effective antiviral therapies for recurrent HCV should help increase graft survival.

Direct-Acting Antivirals in Chronic Hepatitis C Genotype 4 Infection in Community Care Setting

PubMed Central

Gayam, Vijay; Khalid, Mazin; Mandal, Amrendra Kumar; Hussain, Muhammad Rajib; Mukhtar, Osama; Gill, Arshpal; Garlapati, Pavani; Shrestha, Binav; Guss, Debra; Sherigar, Jagannath; Mansour, Mohammed; Mohanty, Smruti

2018-01-01

Background Limited data exists comparing the safety, tolerability, and efficacy of direct-acting antivirals (DAAs) in patients with chronic hepatitis C genotype 4 (HCV GT-4) in the community practice setting. We aim to evaluate the treatment response of DAAs in these patients. Methods All the HCV GT-4 patients treated with DAAs between January 2014 and October 2017 in a community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with sustained virologic response (SVR) at 12 weeks post treatment (SVR12), and adverse reactions were assessed. Results Fifty-two patients of Middle Eastern (primarily Egyptian) descent were included in the study. Thirty-two patients were treated with ledipasvir/sofosbuvir (Harvoni®) ± ribavirin, 12 patients were treated with ombitasvir/paritaprevir/ritonavir/dasabuvir (ViekiraPak®) ± ribavirin, and eight patients were treated with sofosbuvir/Velpatasvir (Epclusa®). Ten patients (19.2%) had compensated cirrhosis. Overall, SVR at 12 weeks was achieved in 94% in patients who received one of the three DAA regimens (93.8% in Harvoni® group, 91.7 % in ViekiraPak® group and 100% in Epclusa® group). Prior treatment status and type of regimen used in the presence of compensated cirrhosis had no statistical significance on overall SVR achievement (P value = 0.442 and P value = 0.091, respectively). The most common adverse effect was fatigue (27%). Conclusions In the real-world setting, DAAs are effective and well tolerated in patients with chronic HCV GT-4 infection with a high overall SVR rate of 94%. Large-scale studies are needed to further assess this SVR in these groups. PMID:29707080

Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials.

PubMed

Arias, Ana; Aguilera, Antonio; Soriano, Vicente; Benítez-Gutiérrez, Laura; Lledó, Gemma; Navarro, Daniel; Treviño, Ana; Otero, Esteban; Peña, José M; Cuervas-Mons, Valentín; de Mendoza, Carmen

2017-01-01

Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower. All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure. A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3-F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4. Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.

The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral Treatments for Hepatitis C Virus

PubMed Central

Rein, David B.; Wittenborn, John S.; Smith, Bryce D.; Liffmann, Danielle K.; Ward, John W.

2018-01-01

Background New hepatitis C virus (HCV) treatments deliver higher cure rates with fewer contraindications, increasing demand for treatment and healthcare costs. The cost-effectiveness of new treatments is unknown. Methods We conducted a microsimulation of guideline testing followed by alternative treatment regimens for HCV among the US population aged 20 and older to estimate cases identified, treated, sustained viral response, deaths, medical costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) of different treatment options expressed as discounted lifetime costs and benefits from the healthcare perspective. Results Compared to treatment with pegylated interferon and ribavirin (PR), and a protease inhibitor for HCV genotype (G) 1 and PR alone for G2/3, treatment with PR and Sofosbuvir (PRS) for G1/4 and treatment with Sofosbuvir and ribavirin (SR) for G2/3 increased QALYs by 555 226, reduced deaths by 80 682, and increased costs by $26.2 billion at an ICER of $47 304 per QALY gained. As compared to PRS/SR, treating with an all oral regimen of Sofosbuvir and Simeprevir (SS) for G1/4 and SR for G2/3, increased QALYs by 1 110 451 and reduced deaths by an additional 164 540 at an incremental cost of $80.1 billion and an ICER of $72 169. In sensitivity analysis, where treatment with SS effectiveness was set to the list price of Viekira Pak and then Harvoni, treatment cost $24 921 and $25 405 per QALY gained as compared to PRS/SR. Conclusions New treatments are cost-effectiveness per person treated, but pent-up demand for treatment may create challenges for financing. PMID:25778747

Identification of 2'-deoxy-2'-fluorocytidine as a potent inhibitor of Crimean-Congo hemorrhagic fever virus replication using a recombinant fluorescent reporter virus.

PubMed

Welch, Stephen R; Scholte, Florine E M; Flint, Mike; Chatterjee, Payel; Nichol, Stuart T; Bergeron, Éric; Spiropoulou, Christina F

2017-11-01

Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne orthonairovirus, causes a severe hemorrhagic disease in humans (Crimean-Congo hemorrhagic fever, CCHF). Currently, no vaccines are approved to prevent CCHF; treatment is limited to supportive care and the use of ribavirin, the therapeutic benefits of which remain unclear. CCHF is part of WHO's priority list of infectious diseases warranting further research and development. To aid in the identification of new antiviral compounds, we generated a recombinant CCHFV expressing a reporter protein, allowing us to quantify virus inhibition by measuring the reduction in fluorescence in infected cells treated with candidate compounds. The screening assay was readily adaptable to high-throughput screening (HTS) of compounds using Huh7 cells, with a signal-to-noise ratio of 50:1, and Z'-factors > 0.6 in both 96- and 384-well formats. A screen of candidate nucleoside analog compounds identified 2'-deoxy-2'-fluorocytidine (EC 50  = 61 ± 18 nM) as having 200 × the potency of ribavirin (EC 50  = 12.5 ± 2.6 μM), as well as 17 × the potency of T-705 (favipiravir), another compound with reported anti-CCHFV activity (EC 50  = 1.03 ± 0.16 μM). Furthermore, we also determined that 2'-deoxy-2'-fluorocytidine acts synergistically with T-705 to inhibit CCHFV replication without causing cytotoxicity. The incorporation of this reporter virus into the high-throughput screening assay described here will allow more rapid identification of effective therapeutic options to combat this emerging human pathogen. Published by Elsevier B.V.

Classical and emerging roles of vitamin D in hepatitis C virus infection.

PubMed

Gutierrez, Julio A; Parikh, Neil; Branch, Andrea D

2011-11-01

According to the Institute of Medicine, the risk of clinically significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL. By this standard, most cirrhotic hepatitis C virus- (HCV-) positive patients and many noncirrhotic patients are vitamin D-deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin D's beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. Information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients is provided. © Thieme Medical Publishers.

Revisiting policy on chronic HCV treatment under the Thai Universal Health Coverage: An economic evaluation and budget impact analysis.

PubMed

Rattanavipapong, Waranya; Anothaisintawee, Thunyarat; Teerawattananon, Yot

2018-01-01

Thailand is encountering challenges to introduce the high-cost sofosbuvir for chronic hepatitis C treatment as part of the Universal Health Care's benefit package. This study was conducted in respond to policy demand from the Thai government to assess the value for money and budget impact of introducing sofosbuvir-based regimens in the tax-based health insurance scheme. The Markov model was constructed to assess costs and benefits of the four treatment options that include: (i) current practice-peginterferon alfa (PEG) and ribavirin (RBV) for 24 weeks in genotype 3 and 48 weeks for other genotypes; (ii) Sofosbuvir plus peginterferon alfa and ribavirin (SOF+PEG-RBV) for 12 weeks; (iii) Sofosbuvir and daclatasvir (SOF+DCV) for 12 weeks; (iv) Sofosbuvir and ledipasvir (SOF+LDV) for 12 weeks for non-3 genotypes and SOF+PEG-RBV for 12 weeks for genotype 3 infection. Given that policy options (ii) and (iii) are for pan-genotypic infection, the cost of genotype testing was applied only for policy options (i) and (iv). Results reveal that all sofosbuvir-based regimens had greater quality adjusted life years (QALY) gains compared with the current treatment, therefore associated with lower lifetime costs and more favourable health outcomes. Additionally, among the three regimens of sofosbuvir, SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype are the most cost-effective treatment option with the threshold of 160,000 THB per QALY gained. The results of this study had been used in policy discussion which resulted in the recent inclusion of SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype in the Thailand's benefit package.

Pancreatitis induced by pegylated interferon alfa-2b in a patient affected by chronic hepatitis C.

PubMed

Cecchi, Enrica; Forte, Paolo; Cini, Elisabetta; Banchelli, Grazia; Ferlito, Chiara; Mugelli, Alessandro

2004-01-01

A middle-aged man was admitted to the ED because of nausea and vomiting, abdominal distention and fainting. A blood analysis revealed high levels of serum amylase and lipase, confirming a diagnosis of acute pancreatitis. The history showed that the patient had self-administered a single dose of pegylated interferon alfa-2b and ribavirin daily for 7 days for chronic hepatitis C. The medications were stopped and his condition gradually improved. In agreement with the literature and the Naranjo algorythm result, pegylated interferon alfa-2b is associated with acute pancreatitis. Identification of a few signs and symptoms is the first 'signal' in preventing a serious drug-induced adverse event.

Treatment of Hepatitis C Virus Infection in Children Less than 12 Years of Age in Developing Countries.

PubMed

Aziz, Sina

2014-12-01

The treatment of hepatitis c virus (HCV) infection in children is difficult as few options are available. The standard therapy is combination pegylated interferon (PEG-IFN) α-2a or 2b and ribavirin, and the duration of therapy depends on HCV genotype. New oral drug therapies available for adults have still not been approved for treatment in children. Here, we review the causes of HCV infection in children, the therapeutic options for children, and the side effects of these treatments. The problems faced by physicians managing HCV infection in children less than 12 years of age in a developing country are also discussed.

Glucose abnormalities in Asian patients with chronic hepatitis C.

PubMed

Bo, Qingyan; Orsenigo, Roberto; Wang, Junyi; Griffel, Louis; Brass, Clifford

2015-01-01

Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin.

Glucose abnormalities in Asian patients with chronic hepatitis C

PubMed Central

Bo, Qingyan; Orsenigo, Roberto; Wang, Junyi; Griffel, Louis; Brass, Clifford

2015-01-01

Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin. PMID:26609222

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China.

PubMed

Lu, Yun; Jin, Xiuze; Duan, Cheng-A-Xin; Chang, Feng

2018-01-01

Hepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China. This study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China. A cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted. For HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective. DCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

Lassa fever in post-conflict sierra leone.

PubMed

Shaffer, Jeffrey G; Grant, Donald S; Schieffelin, John S; Boisen, Matt L; Goba, Augustine; Hartnett, Jessica N; Levy, Danielle C; Yenni, Rachael E; Moses, Lina M; Fullah, Mohammed; Momoh, Mambo; Fonnie, Mbalu; Fonnie, Richard; Kanneh, Lansana; Koroma, Veronica J; Kargbo, Kandeh; Ottomassathien, Darin; Muncy, Ivana J; Jones, Abigail B; Illick, Megan M; Kulakosky, Peter C; Haislip, Allyson M; Bishop, Christopher M; Elliot, Deborah H; Brown, Bethany L; Zhu, Hu; Hastie, Kathryn M; Andersen, Kristian G; Gire, Stephen K; Tabrizi, Shervin; Tariyal, Ridhi; Stremlau, Mathew; Matschiner, Alex; Sampey, Darryl B; Spence, Jennifer S; Cross, Robert W; Geisbert, Joan B; Folarin, Onikepe A; Happi, Christian T; Pitts, Kelly R; Geske, F Jon; Geisbert, Thomas W; Saphire, Erica Ollmann; Robinson, James E; Wilson, Russell B; Sabeti, Pardis C; Henderson, Lee A; Khan, S Humarr; Bausch, Daniel G; Branco, Luis M; Garry, Robert F

2014-03-01

Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF.

Point -of -care testing (POCT) in molecular diagnostics: Performance evaluation of GeneXpert HCV RNA test in diagnosing and monitoring of HCV infection.

PubMed

Gupta, Ekta; Agarwala, Pragya; Kumar, Guresh; Maiwall, Rakhi; Sarin, Shiv Kumar

2017-03-01

Molecular testing at the point-of-care may turn out to be game changer for HCV diagnosis and treatment monitoring, through increased sensitivity, reduced turnaround time, and ease of performance. One such assay GeneXpert ® has recently been released. Comparative analysis between performances of GeneXpert ® and Abbott HCV-RNA was done. 174 HCV infected patients were recruited and, one time plasma samples from 154 patients and repeated samples from 20 patients, obtained at specific treatment time-points (0, 4, 12 and 24) weeks were serially re-tested on Xpert ® . Genotype 3 was the commonest, seen in 80 (66%) of the cases, genotype 1 in 34 (28.3%), genotype 4 in 4 (3.3%) and genotypes 2 and 5 in 1 (0.8%) each. Median HCV RNA load was 4.69 log 10 (range: 0-6.98log 10 ) IU/ml. Overall a very good correlation was seen between the two assays (R 2 =0.985), concordance of the results between the assays was seen in 138 samples (89.6%). High and low positive standards were tested ten times on Xpert ® to evaluate the precision and the coefficient of variation was 0.01 for HPC and 0.07 for the LPC. Monitoring of patients on two different regimes of treatment, pegylated interferon plus ribavirin and sofosbuvir plus ribavirin was done by both the systems at baseline, 4, 12 and 24 weeks. Perfect correlation between the assays in the course of therapy at different treatment time- point in genotypes 3 and 1 was seen. The study demonstrates excellent performance of the Xpert ® HCV assay in viral load assessment and in treatment course monitoring consistency. Copyright © 2017 Elsevier B.V. All rights reserved.

The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C virus.

PubMed

Rein, David B; Wittenborn, John S; Smith, Bryce D; Liffmann, Danielle K; Ward, John W

2015-07-15

New hepatitis C virus (HCV) treatments deliver higher cure rates with fewer contraindications, increasing demand for treatment and healthcare costs. The cost-effectiveness of new treatments is unknown. We conducted a microsimulation of guideline testing followed by alternative treatment regimens for HCV among the US population aged 20 and older to estimate cases identified, treated, sustained viral response, deaths, medical costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) of different treatment options expressed as discounted lifetime costs and benefits from the healthcare perspective. Compared to treatment with pegylated interferon and ribavirin (PR), and a protease inhibitor for HCV genotype (G) 1 and PR alone for G2/3, treatment with PR and Sofosbuvir (PRS) for G1/4 and treatment with Sofosbuvir and ribavirin (SR) for G2/3 increased QALYs by 555 226, reduced deaths by 80 682, and increased costs by $26.2 billion at an ICER of $47 304 per QALY gained. As compared to PRS/SR, treating with an all oral regimen of Sofosbuvir and Simeprevir (SS) for G1/4 and SR for G2/3, increased QALYs by 1 110 451 and reduced deaths by an additional 164 540 at an incremental cost of $80.1 billion and an ICER of $72 169. In sensitivity analysis, where treatment with SS effectiveness was set to the list price of Viekira Pak and then Harvoni, treatment cost $24 921 and $25 405 per QALY gained as compared to PRS/SR. New treatments are cost-effectiveness per person treated, but pent-up demand for treatment may create challenges for financing. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study.

PubMed

Marciano, Sebastián; Haddad, Leila; Reggiardo, María V; Peralta, Mirta; Vistarini, Cecilia; Marino, Mónica; Descalzi, Valeria I; D'Amico, Claudia; Figueroa Escuti, Sebastián; Gaite, Luis A; Perez Ravier, Roberto; Longo, Cristina; Borzi, Silvia M; Galdame, Omar A; Bessone, Fernando; Fainboim, Hugo A; Frías, Silvia; Cartier, Mariano; Gadano, Adrián C

2018-05-01

We report the first real-world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir-based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi ® , Gilead Sciences, n = 135) or generic sofosbuvir (Probirase ® , Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86-93%); 91% (95% CI 84-95%) in patients who received Sovaldi ® , and 89% (95% CI 84-93%) in patients who received Probirase ® . Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis-related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi ® or Probirase ® . Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease-inhibitor-free regimes. © 2018 Wiley Periodicals, Inc.

Auto-antibodies and Autoimmune Disease during Treatment of Children with Chronic Hepatitis C

PubMed Central

Molleston, Jean P.; Mellman, William; Narkewicz, Michael R.; Balistreri, William F.; Gonzalez-Peralta, Regino P.; Jonas, Maureen M.; Lobritto, Steven J.; Mohan, Parvathi; Murray, Karen F.; Njoku, Dolores; Rosenthal, Philip; Barton, Bruce A.; Talor, Monica V.; Cheng, Irene; Schwarz, Kathleen B.; Haber, Barbara A.

2012-01-01

Objectives Auto-antibodies were studied in a well-characterized cohort of children with chronic hepatitis C (CHC) during treatment with PEG-IFN and ribavirin to assess the relationship to treatment and development of autoimmune disease. Methods 114 children (5–17 years), previously screened for the presence of high titer autoantibodies, were randomized to Peg-IFN with or without ribavirin. Anti-nuclear (ANA), anti-liver-kidney-microsomal (LKM), anti-thyroglobulin (TG), anti-thyroid peroxidase (TPO), insulin (IA2), anti-glutamic acid decarboxylase (GAD) antibodies were measured after trial completion using frozen sera. Results At baseline,19% had auto-antibodies: ANA (8%), LKM (4%), and GAD (4%). At 24 and 72 weeks (24 weeks after treatment completion), 23% and 26% had auto-antibodies (p=0.50, 0.48 compared to baseline). One child developed diabetes and two hypothyroidism during treatment; none developed autoimmune hepatitis. At 24 weeks, the incidence of flu-like symptoms, gastrointestinal symptoms, and headaches were 42%, 8% and 19% in those with auto-antibodies vs. 52%, 17%, and 26% in those without (p=0.18, 0.36, and 0.20, respectively). In children with negative HCV PCR at 24 weeks, there was no difference in the rate of early virologic response /sustained virologic response respectively in those with auto-antibodies 76%/69%, vs 58%/65% in those without (p=0.48). Conclusions Despite screening, we found autoantibodies commonly at baseline, during treatment for CHC and after. The presence of antibodies did not correlate with viral response, side effects, or autoimmune hepatitis. Neither screening nor archived samples assayed for thyroid and diabetes-related antibodies identified the 3 subjects who developed overt autoimmune disease, diabetes (1) and hypothyroidism (2). PMID:23439301

Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C.

PubMed

Su, Tung-Hung; Liu, Chen-Hua; Liu, Chun-Jen; Chen, Chi-Ling; Ting, Te-Tien; Tseng, Tai-Chung; Chen, Pei-Jer; Kao, Jia-Horng; Chen, Ding-Shinn

2013-05-07

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E

PubMed Central

Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Osborne, Michael J.; Ramteke, Anup; Sun, Qingxiang; Niesman, Ashley; Chook, Yuh Min; Borden, Katherine L. B.

2016-01-01

Regulation of nuclear-cytoplasmic trafficking of oncoproteins is critical for growth homeostasis. Dysregulated trafficking contributes to malignancy, whereas understanding the process can reveal unique therapeutic opportunities. Here, we focus on eukaryotic translation initiation factor 4E (eIF4E), a prooncogenic protein highly elevated in many cancers, including acute myeloid leukemia (AML). Typically, eIF4E is localized to both the nucleus and cytoplasm, where it acts in export and translation of specific methyl 7-guanosine (m7G)–capped mRNAs, respectively. Nuclear accumulation of eIF4E in patients who have AML is correlated with increased eIF4E-dependent export of transcripts encoding oncoproteins. The subcellular localization of eIF4E closely correlates with patients’ responses. During clinical responses to the m7G-cap competitor ribavirin, eIF4E is mainly cytoplasmic. At relapse, eIF4E reaccumulates in the nucleus, leading to elevated eIF4E-dependent mRNA export. We have identified importin 8 as a factor that directly imports eIF4E into the nucleus. We found that importin 8 is highly elevated in untreated patients with AML, leading to eIF4E nuclear accumulation. Importin 8 only imports cap-free eIF4E. Cap-dependent changes to the structure of eIF4E underpin this selectivity. Indeed, m7G cap analogs or ribavirin prevents nuclear entry of eIF4E, which mirrors the trafficking phenotypes observed in patients with AML. Our studies also suggest that nuclear entry is important for the prooncogenic activity of eIF4E, at least in this context. These findings position nuclear trafficking of eIF4E as a critical step in its regulation and position the importin 8–eIF4E complex as a novel therapeutic target. PMID:27114554

Anti-E1E2 antibodies status prior therapy favors direct-acting antiviral treatment efficacy.

PubMed

Virlogeux, Victor; Berthillon, Pascale; Bordes, Isabelle; Larrat, Sylvie; Crouy, Stéphanie; Scholtès, Caroline; Pradat, Pierre; Maynard, Marianne; Zoulim, Fabien; Leroy, Vincent; Chemin, Isabelle; Trépo, Christian; Petit, Marie-Anne

2018-03-15

Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.

PubMed

Lange, Christian M; Moradpour, Darius; Doehring, Alexandra; Lehr, Hans-Anton; Müllhaupt, Beat; Bibert, Stephanie; Bochud, Pierre-Yves; Antonino, Anca T; Pascual, Manuel; Farnik, Harald; Shi, Ying; Bechstein, Wolf Otto; Moench, Christian; Hansmann, Martin-Leo; Sarrazin, Christoph; Lötsch, Jörn; Zeuzem, Stefan; Hofmann, Wolf-Peter

2011-08-01

Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Liver Zonation Index of Drug Transporter and Metabolizing Enzyme Protein Expressions in Mouse Liver Acinus.

PubMed

Tachikawa, Masanori; Sumiyoshiya, Yuna; Saigusa, Daisuke; Sasaki, Kazunari; Watanabe, Michitoshi; Uchida, Yasuo; Terasaki, Tetsuya

2018-05-01

The purpose of the present study was to clarify the molecular basis of zonated drug distributions in mouse liver based on the protein expression levels of transporters and metabolizing enzymes in periportal (PP) and pericentral (PC) vein regions of mouse hepatic lobules. The distributions of sulforhodamine 101 (SR-101), a substrate of organic anion transporting polypeptides (Oatps), and ribavirin, a substrate of equilibrative nucleoside transporter 1 (Ent1), were elucidated in frozen liver sections of mice, to which each compound had been intravenously administered. Regions strongly positive for SR-101 (SR-101 + ) and regions weakly positive or negative for SR-101 (SR-101 - ) were separated by laser microdissection. The zonated distribution of protein expression was quantified in terms of the liver zonation index. Quantitative targeted absolute proteomics revealed the selective expression of glutamine synthetase in the SR-101 + region, indicating predominant distribution of SR-101 in hepatocytes of the PC vein region. The protein levels of Oatp1a1, Oatp1b2, organic cation transporter 1 (Oct1), and cytochrome P450 (P450) 2e1 were greater in the PC vein regions, whereas the level of organic anion transporter 2 (Oat2) was greater in the PP vein regions. Mouse Oatp1a1 mediated SR-101 transport. On the other hand, there were no statistically significant differences in expression of Ent1, Na + -taurocholate cotransporting polypeptide, several canalicular transporters, P450 enzymes, and UDP-glucuronosyltransferases between the PP and PC vein regions. This is consistent with the almost uniform distribution of ribavirin in the liver. In conclusion, sinusoidal membrane transporters such as Oatp1a1, Oatp1b2, Oct1, and Oat2 appear to be determinants of the zonated distribution of drugs in the liver. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

A comparison of the natural history and outcome of treatment for Asian and non-Asian hepatitis C-infected patients.

PubMed

Lawson, A

2011-07-01

Ethnicity is an important host variable, but its impact on disease progression and response to therapy in Hepatitis C infection is unclear. Here we compare the natural history and outcome of therapy in white and Asian (Indian subcontinent) Hepatitis C infected patients. A total of 2123 White and 120 Asian HCV infected patients were identified within the Trent HCV study. Response to therapy was assessed in 224 white and 46 Asian patients with genotype 3 infection who received pegylated interferon and ribavirin. Asian patients were more likely to be older, female, infected with genotype 3 and to consume no alcohol. At time of first biopsy, fibrosis stage was significantly higher in Asian patients than in Whites (3.0 ± 2.3 vs 1.8 ± 2.0, P < 0.001), as were necro-inflammation and steatosis scores. However, in those patients where duration of infection could be estimated, fibrosis progression was similar for both groups (0.25 ± 0.31 vs. 0.16 ± 0.54 Ishak points/year, P = 0.068). 78.3% of Asian and 67.9% of White genotype 3 patients had a sustained virological response following Pegylated Interferon and Ribavirin. Cirrhosis and increased levels of GGT, but not ethnicity were associated with a reduction in the likelihood of a sustained virological response on multivariate analysis. Asian patients with Hepatitis C are more likely to be female, less likely to give a history of risk factors, present to medical services at an older age, and have more severe liver disease at diagnosis, but disease progression and response to treatment are similar to white patients. © 2010 Blackwell Publishing Ltd.

Sofosbuvir, a Significant Paradigm Change in HCV Treatment

PubMed Central

McQuaid, Thomas; Savini, Carolyn; Seyedkazemi, Star

2015-01-01

Nucleotide compounds like sofosbuvir, acyclovir, and tenofovir have proven to be amongst the most potent orally available antiviral treatments. These drugs exhibit high efficacy and a wide therapeutic index, with demonstrated utility in a number of chronic viral infections. The approval of Sovaldi™, brand name for sofosbuvir, by the U.S. Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment. Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977. It was subsequently acquired and advanced through phase 3 development by Gilead Sciences, Inc. In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious. Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR), curing patients in excess of 80% in all genotypes and >90% in treatment-naïve subjects being administered combination therapy with other agents. Harvoni® is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet, and it has demonstrated high SVR rates in patients infected with HCV genotype 1, without the need for exogenous interferon and/or ribavirin. Here, we discuss the discovery, development, pharmacologic characterization, and results from the phase 3 trials of sofosbuvir. Hepatitis C is a chronic disease, for which most patients have been undiagnosed, are unwilling to start treatment, or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy. Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care, thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines. PMID:26357632

The value of cure associated with treating treatment-naïve chronic hepatitis C genotype 1: Are the new all-oral regimens good value to society?

PubMed

Younossi, Zobair M; Park, Haesuk; Dieterich, Douglas; Saab, Sammy; Ahmed, Aijaz; Gordon, Stuart C

2017-05-01

All-oral regimens are associated with high cure rates in hepatitis C virus-genotype 1 (HCV-GT1) patients. Our aim was to assess the value of cure to the society for treating HCV infection. Markov model for HCV-GT1 projected long-term health outcomes, life years, and quality-adjusted life years (QALYs) gained. The model compared second-generation triple (sofosbuvir+pegylated interferon+ribavirin [PR] and simeprevir+PR) and all-oral (ledipasvir/sofosbuvir and ombitasvir+paritaprevir/ritonavir+dasabuvir±ribavirin) therapies with no treatment. Sustained virological response rates were based on Phase III RCTs. We assumed that 80% and 95% of HCV-GT1 patients were eligible for second-generation triple and all-oral regimens. Transition probabilities, utility and mortality were based on literature review. The value of cure was calculated by the difference in the savings from the economic gains associated with additional QALYs. Model estimated 1.52 million treatment-naïve HCV-GT1 patients in the US. Treating all eligible HCV-GT1 patients with second-generation triple and all-oral therapies resulted in 3.2 million and 4.8 million additional QALYs gained compared to no treatment respectively. Using $50,000 as value of QALY, these regimens lead to savings of $185 billion and $299 billion; costs of these regimens were $109 billion and $128 billion. The value of cure with second-generation triple and all-oral regimens was $55 billion and $111 billion, when we conservatively assumed only drug costs. Cost savings were greater for HCV-GT1 patient cured with cirrhosis compared to patients without cirrhosis. The recent evolution of regimens for HCV GT1 has increased efficacy and value of cure. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients.

PubMed

Ferenci, Peter; Aires, Rodrigo; Beavers, Kimberly L; Curescu, Manuela; Abrão Ferreira, Paulo R; Gschwantler, Michael; Ion, Stefan; Larrey, Dominique; Maticic, Mojca; Puoti, Massimo; Schuller, János; Tornai, Istvan; Tusnádi, Anna; Messinger, Diethelm; Tatsch, Fernando; Horban, Andrzej

2014-01-01

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40 KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N = 1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50 IU/mL] by week 4 of treatment (rapid virologic response) and 24 weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p < 0.1 × 10(-30)) was stronger than that between METAVIR (p = 3.86 × 10(-13)) or APRI (p = 5.48 × 10(-6)) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40  KD)/ribavirin.

Inhibitory effects of recombinant manganese superoxide dismutase on influenza virus infections in mice.

PubMed Central

Sidwell, R W; Huffman, J H; Bailey, K W; Wong, M H; Nimrod, A; Panet, A

1996-01-01

The oxygen free-radical scavenger recombinant human manganese superoxide dismutase (MnSOD) was studied for its effects on influenza virus infections in mice when used alone and in combination with ribavirin. Mice challenged with influenza A/NWS/33 (H1N1) virus were treated parenterally in doses of 25, 50, and 100 mg/kg of body weight per day every 8 h for 5 days beginning at 48 h post-virus exposure. An increase in mean day to death, lessened decline in arterial oxygen saturation, and reduced lung consolidation and lung virus titers occurred in the treated animals. To determine the influence of viral challenge, experiments were run in which mice were infected with a 100 or 75% lethal dose of virus and were treated intravenously once daily for 5 days beginning 96 h after virus exposure. Weak inhibition of the mortality rate was seen in mice receiving the high viral challenge, whereas significant inhibition occurred in the animals infected with the lower viral challenge, indicating that MnSOD effects are virus dose dependent. To determine if treatment with small-particle aerosol would render an antiviral effect, infected mice were treated by this route for 1 h daily for 5 days beginning 72 h after virus exposure. A dose-responsive disease inhibition was seen. An infection induced by influenza B/Hong Kong/5/72 virus in mice was mildly inhibited by intravenous MnSOD treatment as seen by increased mean day to death, lessened arterial oxygen saturation decline, and lowered lung consolidation. MnSOD was well tolerated in all experiments. A combination of MnSOD and ribavirin, each administered with small-particle aerosol, resulted in a generally mild improvement of the disease induced by the influenza A virus compared with use of either material alone. PMID:8913477

Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients.

PubMed

Zha, Jiuhong; Ding, Bifeng; Wang, Haoyu; Zhao, Weihan; Yu, Chen; Alves, Katia; Mobashery, Niloufar; Luo, Yan; Menon, Rajeev M

2018-06-16

The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations. Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations. The exposures [maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (< 20% difference) in healthy Chinese subjects residing in China or the United States. In addition, the trough plasma concentrations (C trough ) in HCV GT1b-infected Asian patients were either similar to (ombitasvir) or within 75% of (paritaprevir and dasabuvir) those in Western patients without cirrhosis, or similar to (ombitasvir and paritaprevir) or within 100% of (dasabuvir) those in Western patients with cirrhosis, with widely overlapping ranges of individual values. Generally comparable drug exposures were observed among Chinese, South Korean, and Taiwanese ethnicities for noncirrhotic and cirrhotic patients. Collectively, the results of these pharmacokinetic analyses support the use of the same dose of the 3D regimen for Asian and Western patients. CLINICALTRIALS.GOV: NCT02534870, NCT02517515, NCT02517528.

Prevalence of naturally occurring protease inhibitor resistance-associated variants in hemodialysis and renal transplant patients with hepatitis C virus infection.

PubMed

Tavares, Rita C F; Feldner, Ana C C A; Pinho, João R R; Uehara, Silvia N O; Emori, Christini T; Carvalho-Filho, Roberto J; Silva, Ivonete S S; Santana, Rúbia A F; de Castro, Vanessa F D; Castoli, Gregório T F; Cristovão, Charliana U; Ferraz, Maria L C G

2017-07-01

Background NS3 protease inhibitors (PIs) were the first direct antiviral agents used for the treatment of hepatitis C virus. The combination of second-wave PIs with other direct antiviral agents enabled the use of interferon-free regimens for chronic kidney disease patients on dialysis and renal transplant (RTx) recipients, populations in which the use of interferon and ribavirin is limited. However, the occurrence of PI resistance-associated variants (RAVs), both baseline and induced by therapy, has resulted in the failure of many treatment strategies. Methods The aim of this study was to estimate the prevalence of PI RAVs and of the Q80K polymorphism in chronic kidney disease patients on hemodialysis and RTx recipients. Direct sequencing of the NS3 protease was performed in 67 patients (32 hemodialysis and 35 RTx).Results RAVs to PIs were detected in 18% of the patients: V55A (9%), V36L (1.5%), T54S (1.5%), S122N (1.5%), I170L (1.5%), and M175L (1.5%). Only 1.5% of the patients carried the Q80K polymorphism. The frequency of these mutations was more than two times higher in patients infected with GT1a (25%) than GT1b (9.7%) (P=0.1). The mutations were detected in 20% of treatment-naive patients and in 15.6% of peginterferon/ribavirin-experienced patients (P=0.64). Furthermore, no mutation that would confer high resistance to PIs was detected.Conclusion The Q80K polymorphism was rare in the population studied. The occurrence of RAVs was common, with predominance in GT1a. However, the variants observed were those associated with a low level of resistance to PIs, facilitating the use of these drugs in this special group of patients.

Association between insulin resistance and sustained virologic response in hepatitis C treatment, genotypes 1 versus 2 and 3: systematic literature review and meta-analysis.

PubMed

Laurito, Marcela Pezzoto; Parise, Edison Roberto

2013-01-01

Controversial results have been found in literature for the association between insulin resistance and sustained virologic response to standard chronic hepatitis C treatment. This study aims to provide a systematic literature review with meta-analysis, in order to evaluate if insulin resistance interferes with sustained virologic response in patients infected by the HCV genotype 1 versus HCV genotypes 2 and 3, undergoing treatment with interferon and ribavirin or pegylated interferon and ribavarin. Systematic search was performed on main electronic databases until May 2012. Primary outcome was sustained virologic response, defined as undetectable levels of HCV-RNA six months after the end of treatment. Meta-analytic measure was estimated using Dersimonian and Laird's method, using Stata software. Thirteen studies involving 2238 infected patients were included. There was a statistically significant association between insulin resistance and lower sustained virologic response rate, and this difference occurred in HCV genotype G1 (OR: 2.23; 95% CI: 1.59-3.13) and G2/G3 (OR: 4.45; 95% CI: 1.59-12.49). In addition, a difference was seen in the cut-offs used for defining insulin resistance by Homeostasis Model Assessment of Insulin Resistance. To minimize this limitation, sub-analysis that excluded the studies that did not use 2 as a cut-off value was performed and the results still demonstrated association between insulin resistance and sustained virologic response, for both genotypic groups. This meta-analysis provides evidence that elevated Homeostasis Model Assessment of Insulin Resistance is associated with a lower sustained virologic response rate in patients with hepatitis C treated with interferon and ribavirin or pegylated interferon and ribavarin, regardless of their genotype. Copyright © 2013 Elsevier Editora Ltda. All rights reserved.

(+)- and (-)-Pestaloxazine A, a Pair of Antiviral Enantiomeric Alkaloid Dimers with a Symmetric Spiro[oxazinane-piperazinedione] Skeleton from Pestalotiopsis sp.

PubMed

Jia, Yan-Lai; Wei, Mei-Yan; Chen, Hai-Yan; Guan, Fei-Fei; Wang, Chang-Yun; Shao, Chang-Lun

2015-09-04

A pair of new enantiomeric alkaloid dimers, (+)- and (-)-pestaloxazine A (1), with an unprecedented symmetric spiro[oxazinane-piperazinedione] skeleton, consisting of 22 carbons and 12 heteroatoms, were isolated from a Pestalotiopsis sp. fungus derived from a soft coral. Separation of the enantiomeric alkaloid dimers was achieved by chiral HPLC. Their structures including absolute configurations were elucidated on the basis of a comprehensive analysis of their spectroscopic and X-ray diffraction data and CD calculations. (+)-Pestaloxazine A exhibited potent antiviral activity against EV71 with an IC50 value of 14.2 ± 1.3 μM, which was stronger than that of the positive control ribavirin (IC50 = 256.1 ± 15.1 μM).

Anterior uveitis after treatment of hepatitis C with alpha interferon: the recurrence of a previous inflammatory process due to presumed ocular toxocariasis.

PubMed

Damasceno, Eduardo F; Damasceno, Nadyr A

2012-02-01

To report a case of recurrent unilateral presumed ocular toxocariasis after treatment of hepatitis C. Case study. Clinical findings, ultrasonography, computed tomography, and serological tests were performed. Once diagnosis was made, effective treatment was administered. A 46-year-old woman with a long history of decreased unilateral visual acuity presented with anterior uveitis after the use of interferon alpha and ribavirin for treatment of hepatitis C. A biomicroscopic examination revealed active anterior uveitis, with ultrasonography and computed tomography demonstrating a central granuloma due to partially calcified toxocariasis. After treatment with corticosteroids and cycloplegics, the symptoms were alleviated. immunostimulation could cause a relapse of the inflammatory reaction found in uveitis due to toxocariasis.

Aseptic Meningitis Caused by Lassa Virus: Case Series Report

PubMed Central

Bankole, Idowu A.; Iruolagbe, Christopher O.; Muoebonam, Benard E.; Okonofua, Martha O.; Dawodu, Simeon O.; Akpede, George O.

2016-01-01

The Lassa virus is known to cause disease in different organ systems of the human body, with varying clinical manifestations. The features of severe clinical disease may include bleeding and/or central nervous system manifestations. Whereas Lassa fever encephalopathy and encephalitis are well described in the literature, there is paucity of data on Lassa virus meningitis. We present the clinical description, laboratory diagnosis, and management of 4 consecutive cases of aseptic meningitis associated with Lassa virus infection without bleeding seen in a region of Nigeria known to be endemic for both the reservoir rodent and Lassa fever. The 4 patients recovered fully following intravenous ribavirin treatment and suffered no neurologic complications. PMID:27957363

Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies.

PubMed

Cross, Robert W; Mire, Chad E; Branco, Luis M; Geisbert, Joan B; Rowland, Megan M; Heinrich, Megan L; Goba, Augustine; Momoh, Mambu; Grant, Donald S; Fullah, Mohamed; Khan, Sheik Humarr; Robinson, James E; Geisbert, Thomas W; Garry, Robert F

2016-09-01

Lassa fever is a significant health threat to West African human populations with hundreds of thousands of annual cases. There are no approved medical countermeasures currently available. Compassionate use of the antiviral drug ribavirin or transfusion of convalescent serum has resulted in mixed success depending on when administered or the donor source, respectively. We previously identified several recombinant human monoclonal antibodies targeting the glycoprotein of Lassa virus with strong neutralization profiles in vitro. Here, we demonstrate remarkable therapeutic efficacy using first-in-class human antibodies in a guinea pig model of Lassa infection thereby presenting a promising treatment alternative. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Sofosbuvir treatment and hepatitis C virus infection

PubMed Central

Nakamura, Masato; Kanda, Tatsuo; Haga, Yuki; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Yasui, Shin; Arai, Makoto; Imazeki, Fumio; Yokosuka, Osamu

2016-01-01

Hepatitis C virus (HCV) infection is a serious problem worldwide. The use of interferon-based therapy has made HCV eradication challenging. The recent appearance of direct-acting antiviral agents (DAAs) has changed HCV therapy. Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy. Furthermore, the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety. In particular, sofosbuvir, a nucleotide-based NS5B inhibitor, prevents HCV RNA synthesis by acting as a “chain terminator”. Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response. The current review summarizes the efficacy and safety of sofosbuvir therapy. PMID:26839641

Pegylated interferon de novo-induce autoimmune haemolytic anaemia in chronic hepatitis C patient.

PubMed

Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem

2011-08-11

A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous γ globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case.

Severe acute respiratory syndrome in a doctor working at the Prince of Wales Hospital.

PubMed

Wong, R S M

2003-06-01

Severe acute respiratory syndrome is a new disease that is highly contagious and is spreading in the local community and worldwide. This report is of a hospital medical officer with severe acute respiratory syndrome. He presented with sudden onset of fever, chills, myalgia, headache, and dizziness in early March 2003. He developed progressive respiratory symptoms and bilateral pulmonary infiltrates during the second week of his illness. Blood tests showed lymphopenia, mild thrombocytopenia, and prolonged activated partial thromboplastin time with normal d-dimer level. His chest condition gradually responded to ribavirin and corticosteroids, and serial chest X-ray showed resolving pulmonary infiltrates. The importance of early diagnosis lies in the potential for early treatment, leading to better response.

New 1-indanone thiosemicarbazone derivatives active against BVDV.

PubMed

Finkielsztein, Liliana M; Castro, Eliana F; Fabián, Lucas E; Moltrasio, Graciela Y; Campos, Rodolfo H; Cavallaro, Lucía V; Moglioni, Albertina G

2008-08-01

Identification of new therapeutic agents for the treatment of viral diseases represents an area of active investigation. In an effort to develop new antiviral compounds, a series of 1-indanone thiosemicarbazone derivatives were synthesized. These derivatives were structurally characterized using several spectroscopic techniques and evaluated against bovine viral diarrhoea virus as a surrogate model for hepatitis C virus. Thiosemicarbazone 2m showed potent anti-bovine viral diarrhoea virus activity with a higher selectivity index (SI=80.29) than that of ribavirin (SI=11.64). This result determines the potentiality of these thiosemicarbazones as antiviral agents for the treatment of infections caused by other highly related members of Flaviviridae family, as hepatitis C virus.

Development of Neutralization Assay Using an eGFP Chikungunya Virus.

PubMed

Deng, Cheng-Lin; Liu, Si-Qing; Zhou, Dong-Gen; Xu, Lin-Lin; Li, Xiao-Dan; Zhang, Pan-Tao; Li, Peng-Hui; Ye, Han-Qing; Wei, Hong-Ping; Yuan, Zhi-Ming; Qin, Cheng-Feng; Zhang, Bo

2016-06-28

Chikungunya virus (CHIKV), a member of the Alphavirus genus, is an important human emerging/re-emerging pathogen. Currently, there are no effective antiviral drugs or vaccines against CHIKV infection. Herein, we construct an infectious clone of CHIKV and an eGFP reporter CHIKV (eGFP-CHIKV) with an isolated strain (assigned to Asian lineage) from CHIKV-infected patients. The eGFP-CHIKV reporter virus allows for direct visualization of viral replication through the levels of eGFP expression. Using a known CHIKV inhibitor, ribavirin, we confirmed that the eGFP-CHIKV reporter virus could be used to identify inhibitors against CHIKV. Importantly, we developed a novel and reliable eGFP-CHIKV reporter virus-based neutralization assay that could be used for rapid screening neutralizing antibodies against CHIKV.

Pegylated interferon de novo-induce autoimmune haemolytic anaemia in chronic hepatitis C patient

PubMed Central

Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem

2011-01-01

A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous γ globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case. PMID:22688484

Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model.

PubMed

de Wilde, Adriaan H; Falzarano, Darryl; Zevenhoven-Dobbe, Jessika C; Beugeling, Corrine; Fett, Craig; Martellaro, Cynthia; Posthuma, Clara C; Feldmann, Heinz; Perlman, Stanley; Snijder, Eric J

2017-01-15

Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Potential for all-trans retinoic acid (tretinoin) to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma.

PubMed

Kast, Richard E

2008-10-01

This note mechanistically accounts for recent unexplained findings that all-trans retinoic acid (ATRA, also termed tretinoin) exerts an anti-viral effect against hepatitis C virus (HCV) in chronically infected patients, in whom ATRA also showed synergy with interferon-alpha. How HCV replication was suppressed was unclear. Both effects of ATRA can be accounted for by ATRA's upregulation of RIG protein, an 18 kDa product of retinoic induced gene-1. Increased RIG then couples ATRA to increased Type 1 interferons' production. Details of this mechanism predict that ATRA will similarly augment interferon-a activity in treating chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma and that the addition of ribavirin and/or bexarotene will each incrementally enhance interferon-a responses in these cancers.

The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection.

PubMed

Garrison, Kimberly L; German, Polina; Mogalian, Erik; Mathias, Anita

2018-04-25

Several safe and highly-effective directly-acting antiviral drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of treatment options available to successfully treat HCV infection. However, as treatment regimens contain at least two drugs (e.g., sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir; elbasvir and grazoprevir) and up to five drugs (ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin), the potential for drug-drug interactions (DDI) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as HIV/HCV co-infection or immunosuppression following liver transplantation. This review details the pharmacokinetics and DDI potential of approved DAAs for the treatment of HCV infection. The American Society for Pharmacology and Experimental Therapeutics.

Influence of insulin resistance on the development of hepatocellular carcinoma after antiviral treatment for non-cirrhotic patients with chronic hepatitis C.

PubMed

Hayashi, Takeo; Ogawa, Eiichi; Furusyo, Norihiro; Murata, Masayuki; Hayashi, Jun

2016-01-01

Insulin resistance is considered to be an important factor in the progression of fibrosis and the enhancement of the risk of hepatocellular carcinoma (HCC) for chronic hepatitis C patients. The aim of this study was to assess the effect of insulin resistance on the development of HCC by non-cirrhotic chronic hepatitis C patients treated with pegylated interferon alpha-2b (PEG-IFNα2b) and ribavirin. This retrospective study consisted of 474 Japanese non-cirrhotic patients with chronic hepatitis C. The cumulative incidence of HCC was estimated using the Kaplan-Meier method, according to insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) and treatment outcome. The overall sustained virological response (SVR) rate was 45.1 % (214/474, genotype 1: 35.4 % [129/364] and genotype 2: 77.3 % [85/110]). Twenty-one (4.4 %) patients developed HCC during the follow-up period. The 5-year cumulative incidence of HCC of the SVR group (2.6 %) was significantly lower than that of the non-SVR group (9.7 %) (log-rank test: P = 0.025). In multivariable logistic regression analysis, HOMA-IR (≥2.5) (hazard ratio [HR] 12.8, P = 0.0006), fibrosis status (F3) (HR 8.85, P < 0.0001), and post-treatment alanine aminotransferase (ALT) level (≥40 U/L) (HR 4.33, P = 0.036) were independently correlated to the development of HCC. Receiver operating characteristic analysis to determine the optimal threshold value of HOMA-IR for predicting the development of HCC in the non-SVR group showed that the areas under the curve was high (0.80, cutoff value: 3.0). Only three patients (1.4 %) who achieved SVR developed HCC. Two of them had severe insulin resistance and did not show improvement in HOMA-IR after achieving SVR. Insulin resistance has a strong impact on the development of HCC by non-cirrhotic patients who have PEG-IFNα2b and ribavirin treatment failure.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-03-01

, mycophenolate mofetil, mycophenolic acid sodium salt; Nitisinone; Omalizumab, omapatrilat, ONYX-015, oxaliplatin; Paclitaxel, paclitaxel nanoparticles, panitumumab, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pertuzumab, phosphatidylcholine-rich phospholipid mixture, pimecrolimus, pioglitazone hydrochloride, pramlintide acetate, prasterone; QR-333; Ranelic acid distrontium salt, ranolazine, rasagiline mesilate, RFB4(dsFv)-PE38, ribavirin, rifabutin, risperidone, rituximab, rofecoxib, rosiglitazone maleate, rosiglitazone maleate/metformin hydrochloride, rotavirus vaccine; S-236, salmeterol xinafoate, sarizotan hydrochloride, sildenafil, sildenafil citrate, sunitinib malate; Tadalafil, tegaserod maleate, temozolomide, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipifarnib, trabectedin, treprostinil sodium; Vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, vinflunine, virosome influenza vaccine, voriconazole; Zidovudine. (c) 2006 Prous Science. All rights reserved.

Clinical impact of non-organ-specific autoantibodies on the response to combined antiviral treatment in patients with hepatitis C.

PubMed

Muratori, Paolo; Muratori, Luigi; Guidi, Marcello; Granito, Alessandro; Susca, Micaela; Lenzi, Marco; Bianchi, Francesco B

2005-02-15

Hepatitis C virus (HCV)-related chronic hepatitis is frequently associated with non-organ-specific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients. A total of 143 consecutive adult patients with hepatitis C were studied. Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomal antibody type 1 (LKM1) were detected by indirect immunofluorescence. All patients were treatment naive and received combined antiviral therapy (interferon [IFN]-ribavirin) after enrollment in the study. Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as long-term responders if transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment. Thirty-seven patients (25%) were NOSA positive (SMA was detected in 19 patients, ANA in 10, ANA and SMA in 4, LKM1 in 3, and SMA and LKM1 in 1). The prevalence of long-term response was similar between NOSA-positive patients and NOSA-negative patients (48.6% vs. 56.6%; P=not significant). Compared with HCV genotype 1 (HCV-1), HCV genotypes other than 1 were more often associated with long-term response among NOSA-positive patients (93.3% vs. 30%; P=.0017). The overall rate of long-term response, irrespective of NOSA status, was 54.5%. Detection of HCV-1 and elevated gamma-glutamyl transpeptidase serum levels were independent negative prognostic factors of treatment response (P=.007 and P=.026, respectively). Combined antiviral treatment (IFN-ribavirin) is safe and effective in NOSA-positive patients with hepatitis C, even if long-term response is

Lassa Fever in Post-Conflict Sierra Leone

PubMed Central

Hartnett, Jessica N.; Levy, Danielle C.; Yenni, Rachael E.; Moses, Lina M.; Fullah, Mohammed; Momoh, Mambo; Fonnie, Mbalu; Fonnie, Richard; Kanneh, Lansana; Koroma, Veronica J.; Kargbo, Kandeh; Ottomassathien, Darin; Muncy, Ivana J.; Jones, Abigail B.; Illick, Megan M.; Kulakosky, Peter C.; Haislip, Allyson M.; Bishop, Christopher M.; Elliot, Deborah H.; Brown, Bethany L.; Zhu, Hu; Hastie, Kathryn M.; Andersen, Kristian G.; Gire, Stephen K.; Tabrizi, Shervin; Tariyal, Ridhi; Stremlau, Mathew; Matschiner, Alex; Sampey, Darryl B.; Spence, Jennifer S.; Cross, Robert W.; Geisbert, Joan B.; Folarin, Onikepe A.; Happi, Christian T.; Pitts, Kelly R.; Geske, F. Jon; Geisbert, Thomas W.; Saphire, Erica Ollmann; Robinson, James E.; Wilson, Russell B.; Sabeti, Pardis C.; Henderson, Lee A.; Khan, S. Humarr; Bausch, Daniel G.; Branco, Luis M.; Garry, Robert F.

2014-01-01

Background Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to

Hepatitis C Virus in Kidney Transplant Recipients: A Problem on the Path to Eradication.

PubMed

Suarez Benjumea, A; Gonzalez-Corvillo, C; Sousa, J M; Bernal Blanco, G; Suñer Poblet, M; Perez Valdivia, M A; Gonzalez Roncero, F M; Acevedo, P; Gentil Govantez, M A

2016-11-01

Hepatitis C virus (HCV) still has significant prevalence in kidney transplant (KT) recipients and is related to poor recipient and graft survival. New direct-acting antivirals (DAA) are leading to a radical change in the problem. We studied HCV prevalence at the time of transplantation and in follow-up patients, the way cases are handled, and the results of DAA. A total of 2,001 KT had been performed in our center since 1978. Pre- or post-transplantation HCV serology was present in 1,880 cases and was positive in 13.4%. A total of 1,195 transplant recipients were still being monitored by us, with only 60 (5%) HCV+ and 45 (3.6%) RNA+ cases. Of these 45 HCV+/RNA+, 25 had been or were being treated, 7 were about to begin treatment, 1 was awaiting new DAA treatment owing to low glomerular filtration rate (GFR), 3 were being evaluated, 2 had been excluded owing to high comorbidity, 2 refused to be treated, 2 needed to return to hemodialysis, and 1 was lost to follow-up. Except 1 case where Viekira Pak was used because of low GFR, all cases included sofosbuvir as the main drug associated with either ledipasvir (70%) or daclatasvir (25%). Ribavirin was added as coadjuvant in 35% of cases. Twenty-one patients had completed treatment (84%). Two patients had to interrupt DAA therapy (8%), one because of hepatotoxicity and the other as a result of a liver transplantation. In every case, the graft maintained function and negativization of viral replication occurred. Side effects have been low, anemia related to ribavirin being the main one. Just one case needed to be interrupted at the 7th week of DAA therapy due to hepatotoxicity. It has frequently been necessary to adjust immunosuppression treatment with the use of higher doses of tacrolimus. Copyright © 2016 Elsevier Inc. All rights reserved.

Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis.

PubMed

Poordad, Fred; Nelson, David R; Feld, Jordan J; Fried, Michael W; Wedemeyer, Heiner; Larsen, Lois; Cohen, Daniel E; Cohen, Eric; Mobashery, Niloufar; Tatsch, Fernando; Foster, Graham R

2017-10-01

Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis. Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported. In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2). This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients. Copyright © 2017 European

Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis.

PubMed

Wei, Fang; Liu, Junying; Liu, Fen; Hu, Huaidong; Ren, Hong; Hu, Peng

2014-01-01

Hepatitis C virus (HCV) infection is highly prevalent in renal transplant (RT) recipients. Currently, interferon-based (IFN-based) antiviral therapies are the standard approach to control HCV infection. In a post-transplantation setting, however, IFN-based therapies appear to have limited efficacy and their use remains controversial. The present study aimed to evaluate the efficacy and safety of IFN-based therapies for HCV infection post RT. We searched Pubmed, Embase, Web of Knowledge, and The Cochrane Library (1997-2013) for clinical trials in which transplant patients were given Interferon (IFN), pegylated interferon (PEG), interferon plus ribavirin (IFN-RIB), or pegylated interferon plus ribavirin (PEG-RIB). The Sustained Virological Response (SVR) and/or drop-out rates were the primary outcomes. Summary estimates were calculated using the random-effects model of DerSimonian and Laird, with heterogeneity and sensitivity analysis. We identified 12 clinical trials (140 patients in total). The summary estimate for SVR rate, drop-out rate and graft rejection rate was 26.6% (95%CI, 15.0-38.1%), 21.1% (95% CI, 10.9-31.2%) and 4% (95%CI: 0.8%-7.1%), respectively. The overall SVR rate in PEG-based and standard IFN-based therapy was 40.6% (24/59) and 20.9% (17/81), respectively. The most frequent side-effect requiring discontinuation of treatment was graft dysfunction (14 cases, 45.1%). Meta-regression analysis showed the covariates included contribute to the heterogeneity in the SVR logit rate, but not in the drop-out logit rate. The sensitivity analyses by the random model yielded very similar results to the fixed-effects model. IFN-based therapy for HCV infection post RT has poor efficacy and limited safety. PEG-based therapy is a more effective approach for treating HCV infection post-RT than standard IFN-based therapy. Future research is required to develop novel strategies to improve therapeutic efficacy and tolerability, and reduce the liver-related morbidity and

Living-Donor Liver Transplant Follow-Up: A SingleCenter Experience.

PubMed

Laeeq, Syed Mudassir; Hanif, Farina M; Luck, Nasir Hassan; Mandhwani, Rajesh Kumar; Iqbal, Jawed; Mehdi, Syed Haider

2017-02-01

Liver transplant is a definite treatment of decompensated liver disease. Because of the shortage of livers from deceased donors, living-donor liver transplant is becoming more common. Here, we analyzed our clinical experience in the follow-up care of these patients. Liver transplant recipients seen at the Sindh Institute of Urology and Transplantation (Karachi, Pakistan) were included in this analysis. Baseline characteristics and follow-up events were recorded. Our study population included 76 liver transplant patients registered at our clinic. Median age was 42 years, with 62 patients (81.6%) being males. The most common indication of transplant was hepatitis C virus-related cirrhosis (42 patients; 55%), followed by hepatitis B-hepatitis D virus coinfection (8 patients; 10.5%). Anastomotic biliary stricture developed in 16 patients (21.1%),which required biliary stenting. Biliary leak developed in 5 patients (6.6%), and renal cell carcinoma developed in 1 patient. Two recipients died due to hepatitis C virus-related fibrosing cholestasis hepatitis and pulmonary com plications. Posttransplant diabetes mellitus developed in 36 (47.1%), hypertension in 17 (38.6%), and dyslipidemia in 19 patients (25%). Of 42 patients with hepatitis C virus infection, 26 were treated with pegylated interferon and ribavirin, of which 65.3% achieved sustained virologic response at 24 weeks. The other 16 patients received sofosbuvir com - bined with ribavirin for 24 weeks. A sustained virologic response at 12 weeks was achieved in 5 patients, with not yet determined results in the remaining patients. Seven patients were lost to follow-up. Hepatitis C-related cirrhosis was the most common indication for liver transplant, and infection recurrence was observed in our patients. Biliary anastomotic stricture formation was the most prevalent complication after transplant. As liver transplants are becoming more widely available for Pakistani patients at home and abroad, gastroenterologists and

Real-World Effectiveness of Simeprevir-containing Regimens Among Patients With Chronic Hepatitis C Virus: The SONET Study

PubMed Central

Brown, Kimberley; Donovan, Cynthia; Forlenza, Jamie; Lauwers, Kris; Mah’moud, Mitchell A.; Manch, Richard; Mohanty, Smruti R.; Prabhakar, Avinash; Reindollar, Robert; DeMasi, Ralph; Slim, Jihad; Tandon, Neeta; Villadiego, Shirley; Naggie, Susanna

2017-01-01

Abstract Background. The Simeprevir ObservatioNal Effectiveness across practice seTtings (SONET) study evaluated the real-world effectiveness of simeprevir-based treatment for hepatitis C virus (HCV) infection. Methods. The SONET study was a phase 4, prospective, observational, United States–based study enrolling patients ≥18 years of age with chronic genotype 1 HCV infection. The primary endpoint was the proportion of patients who achieved sustained virologic response 12 weeks after the end of treatment (SVR12), defined as HCV ribonucleic acid undetectable ≥12 weeks after the end of all HCV treatments. Results. Of 315 patients (intent-to-treat [ITT] population), 275 (87.3%) completed the study. Overall, 291 were treated with simeprevir + sofosbuvir, 17 with simeprevir + sofosbuvir + ribavirin, and 7 with simeprevir + peginterferon + ribavirin. The majority of patients were male (63.2%) and white (60.6%); median age was 58 years, 71.7% had genotype/subtype 1a, and 39.4% had cirrhosis. The SVR12 was achieved by 81.2% (255 of 314) of ITT patients (analysis excluded 1 patient who completed the study but was missing SVR12 data); 2 had viral breakthrough and 18 had viral relapse. The SVR12 was achieved by 92.4% (255 of 276) of patients in the modified ITT (mITT) population, which excluded patients who discontinued treatment for nonvirologic reasons before the SVR12 time point or were missing SVR12 assessment data. Among mITT patients, higher SVR12 rates were associated with factors including age ≥65 years, non-Hispanic/Latino ethnicity, and employment status, but not genotype/subtype nor presence of cirrhosis. Simeprevir-based treatment was well tolerated; no serious adverse events were considered related to simeprevir. Conclusions. In the real-world setting, simeprevir + sofosbuvir treatment was common and 92% of mITT patients achieved SVR12. Simeprevir-based treatment was effective and well tolerated in this cohort, including patients with cirrhosis. PMID

Association of sustained virologic response with reduced progression to liver cirrhosis in elderly patients with chronic hepatitis C.

PubMed

Tseng, Chih-Wei; Chang, Ting-Tsung; Tzeng, Shinn-Jia; Hsieh, Yu-Hsi; Hung, Tsung-Hsing; Huang, Hsiang-Ting; Wu, Shu-Fen; Tseng, Kuo-Chih

2016-01-01

We studied the effect of sustained virologic response (SVR) after treatment with pegylated-interferon (PEG-IFN) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis C (CHC). This retrospective study enrolled 145 elderly CHC patients (aged ≥65 years) who were treatment-naïve and were treated with PEG-IFN plus ribavirin for 6 months between January 2005 and December 2011. Abdominal sonography was performed and liver biochemistry was studied at baseline, at the end of treatment, and every 3-6 months thereafter. The development of liver cirrhosis and related complications was evaluated at the follow-ups. The aspartate aminotransferase-to-platelet ratio index was used as a noninvasive maker for fibrosis. The mean patient age was 69.1±3.3 years, and the average follow-up time was 5.5 years (standard deviation: 2.5 years, range: 1.1-12.3 years). Ninety-five patients (65.5%) achieved SVR, and 26 (17.9%) discontinued treatment. Twenty-seven patients (18.6%) developed liver cirrhosis after treatment. Patients without SVR had significantly greater risk of liver cirrhosis than those with SVR (hazard ratio [HR]: 3.39, 95% confidence interval [CI]: 1.312-8.761, P=0.012). The difference in 3-year cumulative incidence of liver cirrhosis was 24.8% greater for patients without SVR (35.2%, 95% CI: 13.0-57.5, P=0.012) compared with those with SVR (10.4%, 95% CI: 3.1-17.7). There was a trend of a higher baseline aspartate aminotransferase-to-platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress (2.1±1.2 vs 1.6±1.3, P=0.055), but the difference failed to reach significance by Cox regression (adjusted HR: 1.285, 95% CI: 0.921-1.791, P=0.14). An SVR following PEG-IFN combination treatment can reduce the risk of liver cirrhosis in elderly CHC patients.

Safety and efficacy of ledipasvir‐sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data

PubMed Central

Jeffers, Lennox J.; Ravendhran, Natarajan; Shiffman, Mitchell L.; Poulos, John; Sulkowski, Mark S.; Gitlin, Norman; Workowski, Kimberly; Zhu, Yanni; Yang, Jenny C.; Pang, Phillip S.; McHutchison, John G.; Muir, Andrew J.; Howell, Charles; Kowdley, Kris; Afdhal, Nezam; Reddy, K. Rajender

2015-01-01

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

PubMed

Vukotic, R; Conti, F; Fagiuoli, S; Morelli, M C; Pasulo, L; Colpani, M; Foschi, F G; Berardi, S; Pianta, P; Mangano, M; Donato, M F; Malinverno, F; Monico, S; Tamè, M; Mazzella, G; Belli, L S; Viganò, R; Carrai, P; Burra, P; Russo, F P; Lenci, I; Toniutto, P; Merli, M; Loiacono, L; Iemmolo, R; Degli Antoni, A M; Romano, A; Picciotto, A; Rendina, M; Andreone, P

2017-10-01

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments. © 2017 John Wiley & Sons Ltd.

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China

PubMed Central

Lu, Yun; Jin, Xiuze; Duan, Cheng-a-xin

2018-01-01

Background Hepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China. Objectives This study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China. Methods A cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted. Results For HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective. Conclusion DCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China. PMID:29634736

In HIV/hepatitis C virus co-infected patients, higher 25-hydroxyvitamin D concentrations were not related to hepatitis C virus treatment responses but were associated with ritonavir use.

PubMed

Branch, Andrea D; Kang, Minhee; Hollabaugh, Kimberly; Wyatt, Christina M; Chung, Raymond T; Glesby, Marshall J

2013-08-01

Among patients with hepatitis C virus (HCV) monoinfection, 25-hydroxyvitamin D [25(OH)D] concentrations are positively associated with a response to peg-interferon/ribavirin. Data on the relation between 25(OH)D concentrations and HCV treatment response in HIV-infected patients are limited. The objective was to determine whether baseline 25(OH)D concentrations predict virologic response in HIV/HCV co-infected patients and to examine variables associated with 25(OH)D concentrations ≥30 ng/mL. Data and samples from 144 HCV genotype 1, treatment-naive patients from a completed HCV treatment trial were examined in this retrospective study. Early virologic response (EVR) was defined as ≥2 log10 reduction in HCV RNA and/or HCV RNA <600 IU/mL at week 12 of peg-interferon/ribavirin treatment. Baseline 25(OH)D was measured by liquid chromatography/tandem mass spectrometry. Compared with the non-EVR control group (n = 68), the EVR group (n = 76) was younger, had fewer cirrhotic subjects, had a higher proportion with the IL28B CC genotype, had a higher albumin concentration, and had a lower HCV viral load at baseline (P ≤ 0.05). The difference in baseline 25(OH)D concentrations between EVR and non-EVR patients was not statistically significant (median: 25 ng/mL compared with 20 ng/mL; P = 0.23). Similar results were found for sustained virologic response (SVR). In multivariable analysis, white and Hispanic race-ethnicity (OR: 6.26; 95% CI: 2.47, 15.88; P = 0.0001) and ritonavir use (OR: 2.68; 95% CI: 1.08, 6.65; P = 0.033) were associated with higher 25(OH)D concentrations (≥30 ng/mL). Baseline 25(OH)D concentrations did not predict EVR or SVR. Because ritonavir impairs the conversion of 25(OH)D to the active metabolite, utilization of 25(OH)D may have been impaired in subjects taking ritonavir. This trial was registered at www.clinicaltrials.gov as NCT00078403.

Mutagenesis-Mediated Decrease of Pathogenicity as a Feature of the Mutant Spectrum of a Viral Population

PubMed Central

Sanz-Ramos, Marta; Rodríguez-Calvo, Teresa; Sevilla, Noemí

2012-01-01

Background RNA virus populations are heterogeneous ensembles of closely related genomes termed quasispecies. This highly complex distribution of variants confers important properties to RNA viruses and influences their pathogenic behavior. It has been hypothesized that increased mutagenesis of viral populations, by treatment with mutagenic agents, can induce alterations in the pathogenic potential of a virus population. In this work we investigate whether mutagenized foot-and-mouth disease virus (FMDV) populations display changes in their virulence in mice. Methodology and Principal Findings FMDV C-S8c1 was passaged in BHK cells in the presence of the mutagenic agent ribavirin. Decline in viral titer and viral RNA progeny was observed in the first passage, fluctuating around a constant value thereafter. Hence, the specific infectivity remained stable during the passages. The viral population harvested from passage 9 (P9 R) showed decreased virulence in mice, with a lethal dose 50 (LD50) >104 PFU, as compared with LD50 of 50 PFU of the parental population FMDV C-S8c1. This decrease in virulence was associated to a 20-fold increase in the mutation frequency of the P9 R population with respect to C-S8c1. Interestingly, individual biological clones isolated from the attenuated population P9 R were as virulent as the parental virus C-S8c1. Furthermore, a mixed population of C-S8c1 and P9 R was inoculated into mice and showed decreased virulence as compared to C-S8c1, suggesting that population P9 R is able to suppress the virulent phenotype of C-S8c1. Conclusion Ribavirin-mediated mutagenesis of an FMDV population resulted in attenuation in vivo, albeit a large proportion of its biological clones displayed a highly virulent phenotype. These results, together with the suppression of C-S8c1 by mutagenized P9 R population, document a suppressive effect of mutagenized viral quasispecies in vivo, and suggest novel approaches to the treatment and prevention of viral diseases

Vaccinols J-S, ten new salicyloid derivatives from the marine mangrove-derived endophytic fungus Pestalotiopsis vaccinii.

PubMed

Wang, Jun-Feng; Liang, Rui; Liao, Sheng-Rong; Yang, Bin; Tu, Zheng-Chao; Lin, Xiu-Ping; Wang, Bin-Gui; Liu, Yonghong

2017-07-01

Ten new salicyloid derivatives, namely vaccinols J-S (1-10), along with five known compounds (11-15) were isolated from Pestalotiopsis vaccinii (cgmcc3.9199) endogenous with the mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae). Their structures including absolute configurations were established on the basis of spectroscopic analysis, optical rotation, CD spectra, quantum ECD calculations. To the best of our knowledge, vaccinol J (1) is the first example of salicyloid derivatives containing 2-methylfuran moiety. All of the new compounds were tested for their anti-enterovirus 7l (EV71) and cytotoxic activities. Among them, vaccinol J (1) exhibited in vitro anti-EV71 with IC 50 value of 30.7μM (IC 50 177.0μM for the positive control ribavirin). Copyright © 2017. Published by Elsevier B.V.

Branch retinal vein thrombosis and visual loss probably associated with pegylated interferon therapy of chronic hepatitis C

PubMed Central

Gonçalves, Luciana Lofego; Farias, Alberto Queiroz; Gonçalves, Patrícia Lofego; D’Amico, Elbio Antonio; Carrilho, Flair José

2006-01-01

Ophthalmological complications with interferon therapy are usually mild and reversible, not requiring the withdrawal of the treatment. We report a case of a patient who had visual loss probably associated with interferon therapy. Chronic hepatitis C virus infection (genotype 1a) was diagnosed in a 33-year old asymptomatic man. His past medical history was unremarkable and previous routine ophthalmologic check-up was normal. Pegylated interferon alpha and ribavirin were started. Three weeks later he reported painless reduction of vision. Ophthalmologic examination showed extensive intraretinal hemorrhages and cotton-wool spots, associated with inferior branch retinal vein thrombosis. Antiviral therapy was immediately discontinued, but one year later he persists with severely decreased visual acuity. This case illustrates the possibility of unpredictable and severe complications during pegylated interferon therapy. PMID:16874884

Interferon and the fear of needles: a case report.

PubMed

López, Maria; Moreno, Laura; Dosal, Angelina; Pujol, Marta Maria; Vergara, Mercedes; Gil, Montserrat

2011-01-01

The treatment of viral hepatitis C infection uses a combination of pegylated interferon and ribavirin. Psychological preparation of the patient is vital to ensure adherence to the treatment. In our center, the nurse prepares this treatment according to an established educative protocol; however, some patients have special needs that require individualized attention. One such situation observed by the nurse is that the patients frequently admit to the fear of needle puncture (the peginterferon treatment is administered subcutaneously) and are unable to inject themselves. We describe a representative case and the care plan to manage the patient's fear so that the patient acquires confidence in his or her ability to self-inject. This facilitates autonomy and coresponsibility for the treatment, and the nurse can develop care approaches to combat the patient's fear of needles.

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals.

PubMed

Côté, Pierre; Baril, Jean-Guy; Hébert, Marie-Nicole; Klein, Marina; Lalonde, Richard; Poliquin, Marc; Rouleau, Danielle; Therrien, Rachel; Vézina, Sylvie; Willems, Bernard; Dion, Harold; Junod, Patrice; Lapointe, Normand; Lévesque, Dominic; Pinault, Lyse; Tremblay, Cécile; Trottier, Benoît; Trottier, Sylvie; Tsoukas, Chris; Piché, Alain

2007-09-01

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.

Structural Dynamics of Picornaviral RdRP Complexes. Implications for the Design of Antivirals

NASA Astrophysics Data System (ADS)

Verdaguer, Núria; Ferrer-Orta, Cristina; Domingo, Esteban

Genome replication in picornavirus is catalyzed by a virally encoded RNA dependent RNA polymerase, termed 3D. These viruses also use a small protein primer, named VPg to initiate RNA replication. Polymerase 3D also catalyzes the covalent linkage of UMP to a N-terminal tyrosine on VPg. Seven different crystal structures of foot-and-mouth disease virus (FMDV) 3D catalytic complexes have enhanced our understanding of template and primer recognition, VPg uridylylation and rNTP binding and catalysis. In addition, the biochemical and structural analyses of six different FMDV 3D ribavirin resistant mutants provided evidences of three different mechanisms of resistance to this mutagenic nucleoside analogue. Such structural information is providing new insights into the fidelity of RNA replication, and for the design of antiviral compounds.

Therapeutic options for diseases due to potential viral agents of bioterrorism.

PubMed

Bronze, Michael S; Greenfield, Ronald A

2003-02-01

The etiologic agents of smallpox and viral hemorrhagic fever have emerged as potential agents of bioterrorism due to their virulence, potential for human to human dissemination and limited strategies for treatment and prevention. Cidofovir has shown significant promise in animal models, and limited case reports in humans are encouraging. Ribavirin is the treatment of choice for certain hemorrhagic fever viral infections, but has no current application to Ebola and Marburg infections. Current vaccine strategies for smallpox are effective, but carry significant risk for complications. Licensed vaccines for hemorrhagic fever viruses are limited to yellow fever, but animal studies are promising. Genomic analysis of the viral pathogen and the animal model response to infection may provide valuable information enabling the development of novel treatment and prevention strategies. Current knowledge of these strategies is reviewed.

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals

PubMed Central

Côté, Pierre; Baril, Jean-Guy; Hébert, Marie-Nicole; Klein, Marina; Lalonde, Richard; Poliquin, Marc; Rouleau, Danielle; Therrien, Rachel; Vézina, Sylvie; Willems, Bernard; Dion, Harold; Junod, Patrice; Lapointe, Normand; Lévesque, Dominic; Pinault, Lyse; Tremblay, Cécile; Trottier, Benoît; Trottier, Sylvie; Tsoukas, Chris; Piché, Alain

2007-01-01

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment. PMID:18923731

Interference of hepatitis C virus RNA replication by short interfering RNAs

NASA Astrophysics Data System (ADS)

Kapadia, Sharookh B.; Brideau-Andersen, Amy; Chisari, Francis V.

2003-02-01

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Current therapy of patients with chronic HCV infection includes treatment with IFN in combination with ribavirin. Because most treated patients do not resolve the infection, alternative treatment is essential. RNA interference (RNAi) is a recently discovered antiviral mechanism present in plants and animals that induces double-stranded RNA degradation. Using a selectable subgenomic HCV replicon cell culture system, we have shown that RNAi can specifically inhibit HCV RNA replication and protein expression in Huh-7 cells that stably replicate the HCV genome, and that this antiviral effect is independent of IFN. These results suggest that RNAi may represent a new approach for the treatment of persistent HCV infection.

Clearance of hepatitis C viral RNA in cirrhotic patients with antiviral therapy.

PubMed

Ono, S K; da Silva, L C; Carrilho, F J; da Fonseca, L E; Mendes, L C; Madruga, C L; Farias, A de Q; Laudanna, A A

1996-01-01

Interferon is indicated in chronic infection by hepatitis C virus (HCV), however, cirrhosis has been reported as a bad response factor to the therapy. Fifteen cirrhotic patients with HCV, undergoing treatment with recombinant interferon-alpha, ribavirin and/or ursodeoxycholic acid were studied. They were followed-up and evaluated with dosages of alanine aminotransferase and HCV RNA investigation by PCR technique. Of the 15 cirrhotic patients, seven were negative for HCV RNA after antiviral treatment, however ALT was normal in only three of them. Of the eight patients who were not negative, two had normal ALT. Biochemical-virological discrepancy in the follow-up of the patients after antiviral treatment observed in this study has also been reported by other authors. These reports show that the criteria for response to the treatment is to be established.

Experience With Intravenous Ribavirin in the Treatment of Hemorrhagic Fever With Renal Syndrome in Korea

DTIC Science & Technology

2009-01-01

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and...education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or...selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post

Heat stabilization of blood spot samples for determination of metabolically unstable drug compounds

PubMed Central

Blessborn, Daniel; Sköld, Karl; Zeeberg, David; Kaewkhao, Karnrawee; Sköld, Olof; Ahnoff, Martin

2014-01-01

Background Sample stability is critical for accurate analysis of drug compounds in biosamples. The use of additives to eradicate the enzymatic activity causing loss of these analytes has its limitations. Results A novel technique for sample stabilization by rapid, high-temperature heating was used. The stability of six commercial drugs in blood and blood spots was investigated under various conditions with or without heat stabilization at 95°C. Oseltamivir, cefotaxime and ribavirin were successfully stabilized by heating whereas significant losses were seen in unheated samples. Amodiaquine was stable with and without heating. Artemether and dihydroartemisinin were found to be very heat sensitive and began to decompose even at 60°C. Conclusion Heat stabilization is a viable technique to maintain analytes in blood spot samples, without the use of chemical additives, by stopping the enzymatic activity that causes sample degradation. PMID:23256470

Acute pancreatitis associated with pegylated interferon-alpha-2a therapy in chronic hepatitis C.

PubMed

Choi, Jong Wook; Lee, June Sung; Paik, Woo Hyun; Song, Tae Jun; Kim, Jung Wook; Bae, Won Ki; Kim, Kyung-Ah; Kim, Jung Gon

2016-03-01

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Combination therapy of pegylated interferon-alpha (PEG-IFN-α) and ribavirin (RBV) is a current standard treatment for chronic HCV infection in Korea, which has considerable adverse effects. Acute pancreatitis is a rare complication of PEG-IFN-α administration. We report a case of a 62-year-old female who experienced acute pancreatitis after 4 weeks of PEG-IFN-α-2a and RBV combination therapy for chronic HCV infection. The main cause of the acute pancreatitis in this case was probably PEG-IFN-α rather than RBV for several reasons. A few cases have been reported in which acute pancreatitis occurred during treatment with PEG-IFN-α-2b. This is the first report of acute pancreatitis associated with PEG-IFN-α-2a in Korea.

Sofosbuvir-based therapy cures hepatitis C virus infection after prior treatment failures in a patient with concurrent lymphoma.

PubMed

Romagnoli, Dante; Marrazzo, Alessandra; Ballestri, Stefano; Lonardo, Amedeo; Bertolotti, Marco

2015-08-01

We report on the first well-tolerated and successful use of sofosbuvir-based therapy in a patient in whom chronic infection with hepatitis C had preceded the development of B-cell non-Hodgkin's lymphoma. The patient had previously failed numerous attempts to clear the hepatitis C virus with traditional antiviral schedules. We demonstrate that sofosbuvir-based therapy resulted in cure of hepatitis C in a patient who had relapsed during combination therapy with an NS5A inhibitor, an NS3 protease inhibitor and ribavirin, as well as treatment failures to multiple courses of interferon-based therapy. This report also suggests that eradication of hepatitis C virus may result in the short-term prevention of B-cell non-Hodgkin's lymphoma relapse. The findings from our case require further validation in future cohorts of patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device

PubMed Central

Varunok, Peter; Lawitz, Eric; Beavers, Kimberly L; Matusow, Gary; Leong, Ruby; Lambert, Nathalie; Bernaards, Coen; Solsky, Jonathan; Brennan, Barbara J; Wat, Cynthia; Bertasso, Anne

2011-01-01

Background Peginterferon alfa-2a (40 kDa) is currently administered using a prefilled syringe. The peginterferon alfa-2a disposable autoinjector is a new safety-engineered device designed to facilitate injection and reduce the risk of needlestick injuries. The analysis of two open-label Phase I trials evaluated the pharmacokinetics, successful administration, and tolerability of peginterferon alfa-2a when using the autoinjector. The studies were performed to support the filing and registration of the autoinjector device. Methods In trial 1, 50 healthy adult subjects received one 180 μg dose of peginterferon alfa-2a via the autoinjector. Serial blood samples were collected predose, up to 336 hours following drug administration, and at follow-up (28 ± 3 days post-dosing) for noncompartmental pharmacokinetic analysis. Trial 2 randomized 60 adult patients with chronic hepatitis C to 180 μg peginterferon alfa-2a once weekly by the autoinjector or prefilled syringe for 3 weeks followed by the alternative device (prefilled syringe or autoinjector, respectively) for 3 weeks. Patients also received ribavirin. Administration by the devices was evaluated under direct observation by a study staff member and by patient subjective assessment. Results In trial 1, following a single dose of peginterferon alfa-2a, the maximum plasma concentration was 16.1 ± 5.3 ng/mL (mean ± standard deviation), and area under the concentration time curve (0–168 hours) was 1996 ± 613 ng · hour/mL, similar to that reported using a vial/syringe or prefilled syringe. In trial 2, few patients showed handling difficulties with either device. Generally, patients were observed to be more satisfied and confident, followed instructions better, and successfully initiated injection with the autoinjector versus the prefilled syringe. Patients reported the autoinjector to be more convenient and easier to use. No pain or discomfort was experienced using the autoinjector. The autoinjector safety profile

Assessment of cost of innovation versus the value of health gains associated with treatment of chronic hepatitis C in the United States: The quality-adjusted cost of care.

PubMed

Younossi, Zobair M; Park, Haesuk; Dieterich, Douglas; Saab, Sammy; Ahmed, Aijaz; Gordon, Stuart C

2016-10-01

New direct-acting antiviral (DAA) therapy has dramatically increased cure rates for patients infected with hepatitis C virus (HCV), but has also substantially raised treatment costs. The aim of this analysis was to evaluate the therapeutic benefit and net costs (i.e. efficiency frontier) and the quality-adjusted cost of care associated with the evolution of treatment regimens for patients with HCV genotype 1 in the United States. A decision-analytic Markov model. Published literature and clinical trial data. Life Time. Third-party payer. This study compared four approved regimens in treatment-naïve genotype 1 chronic hepatitis C patients, including pegylated interferon and ribavirin (PR), first generation triple therapy (boceprevir + PR and telaprevir + PR), second generation triple therapy (sofosbuvir + PR and simeprevir + PR) and all-oral DAA regimens (ledipasvir/sofosbuvir and ombitasvir + paritaprevir/ritonavir + dasabuvir ± ribavirin). Quality-adjusted cost of care (QACC). QACC was defined as the increase in treatment cost minus the increase in the patient's quality-adjusted life years (QALYs) when valued at $50,000 per QALY. All-oral therapy improved the average sustained virologic response (SVR) rate to 96%, thereby offsetting the high drug acquisition cost of $85,714, which resulted in the highest benefit based on the efficiency frontier. Furthermore, while oral therapies increased HCV drug costs by $48,350, associated QALY gains decreased quality-adjusted cost of care by $14,120 compared to dual therapy. When the value of a QALY was varied from $100,000 to $300,000, the quality adjusted cost of care compared to dual therapy ranged from - $21,234 to - $107,861, - $89,007 to - $293,130, - $176,280 to - $500,599 for first generation triple, second generation triple, and all-oral therapies, respectively. Primary efficacy and safety measurements for drug regimens were sourced from clinical trials data rather than a real

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure, an expert review.

PubMed

Mantry, Parvez S; Pathak, Lakshmikant

2016-01-01

Hepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct - acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA - Dasabuvir, a non - nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated

Cost-effectiveness of daclatasvir plus sofosbuvir-based regimen for treatment of hepatitis C virus genotype 3 infection in Canada.

PubMed

Moshyk, A; Martel, M-J; Tahami Monfared, A A; Goeree, R

2016-01-01

New regimens for the treatment of chronic hepatitis C virus (HCV) genotype 3 have demonstrated substantial improvement in sustained virologic response (SVR) compared with existing therapies, but are considerably more expensive. The objective of this study was to evaluate the cost-effectiveness of two novel all-oral, interferon-free regimens for the treatment of patients with HCV genotype 3: daclatasvir plus sofosbuvir (DCV + SOF) and sofosbuvir plus ribavirin (SOF + RBV), from a Canadian health-system perspective. A decision analytic Markov model was developed to compare the effect of various treatment strategies on the natural history of the disease and their associated costs in treatment-naïve and treatment-experienced patients. Patients were initially distributed across fibrosis stages F0-F4, and may incur disease progression through fibrosis stages and on to end-stage liver disease complications and death; or may achieve SVR. Clinical efficacy, health-related quality-of-life, costs, and transition probabilities were based on published literature. Probabilistic sensitivity analysis was performed to assess parameter uncertainty associated with the analysis. In treatment-naive patients, the expected quality-adjusted life years (QALYs) for interferon-free regimens were higher for DCV + SOF (12.37) and SOF + RBV (12.48) compared to that of pINF + RBV (11.71) over a lifetime horizon, applying their clinical trial treatment durations. The expected costs were higher for DCV + SOF ($170,371) and SOF + RBV ($194,776) vs pINF + RBV regimen ($90,905). Compared to pINF + RBV, the incremental cost-effectiveness ratios (ICER) were $120,671 and $135,398 per QALYs for DCV + SOF and SOF + RBV, respectively. In treatment-experienced patients, DCV + SOF regimen dominated the SOF + RBV regimen. Probabilistic sensitivity analysis indicated a 100% probability that a DCV + SOF regimen was cost saving in treatment

Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.

PubMed

Zeuzem, Stefan; Sulkowski, Mark S; Lawitz, Eric J; Rustgi, Vinod K; Rodriguez-Torres, Maribel; Bacon, Bruce R; Grigorescu, Mircea; Tice, Alan D; Lurie, Yoav; Cianciara, Janusz; Muir, Andrew J; Cronin, Patrick W; Pulkstenis, Erik; Subramanian, G Mani; McHutchison, John G

2010-10-01

The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 μg every week, or albIFN 900 or 1200 μg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg because of increased pulmonary adverse events (AEs) in the 1200-μg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. The primary objective of showing noninferiority of albIFN 900 μg (P < .001) and 1200 μg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-μg groups. albIFN 900 μg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

PubMed

Oze, Tsugiko; Hiramatsu, Naoki; Yakushijin, Takayuki; Miyazaki, Masanori; Yamada, Akira; Oshita, Masahide; Hagiwara, Hideki; Mita, Eiji; Ito, Toshifumi; Fukui, Hiroyuki; Inui, Yoshiaki; Hijioka, Taizo; Inada, Masami; Katayama, Kazuhiro; Tamura, Shinji; Yoshihara, Harumasa; Inoue, Atsuo; Imai, Yasuharu; Hayashi, Eijiro; Kato, Michio; Miyagi, Takuya; Yoshida, Yuichi; Tatsumi, Tomohide; Kasahara, Akinori; Hamasaki, Toshimitsu; Hayashi, Norio; Takehara, Tetsuo

2014-07-01

In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. In patients with

Prevalence and detection of neuropsychiatric adverse effects during hepatitis C treatment.

PubMed

Masip, Montserrat; Tuneu, Laura; Pagès, Neus; Torras, Xavier; Gallego, Adolfo; Guardiola, Josep Maria; Faus, María José; Mangues, Maria Antònia

2015-12-01

Current treatment combinations for chronic hepatitis C virus infection still include pegylated interferon and ribavirin despite the new therapeutic options available. Interferon-based treatments are associated with a high incidence of adverse effects. Central nervous system events are among the most frequent adverse drug reactions and their influence on treatment adherence and effectiveness is controversial. The aim of the study was to evaluate neuropsychiatric adverse effects of interferon-based treatment for chronic hepatitis C in standard multidisciplinary clinical practice. Risk factors for these adverse effects and their impact on adherence and sustained viral response were also evaluated. Setting Ambulatory care pharmacy in coordination with the liver unit and the infectious diseases unit at a 650-bed tertiary university hospital. We included all consecutive patients with chronic hepatitis C who completed treatment with pegylated interferon and ribavirin between 2005 and 2013. All patients underwent a multidisciplinary follow-up during treatment. Neuropsychiatric adverse effects were evaluated in relation to severity, management and outcome. The presence of anxiety and depression was evaluated by means of specific tests. A total of 717 treatments in 679 patients were included. During treatment, we detected 1679 neuropsychiatric adverse effects in 618 patients (86.2 %), generating 1737 clinical interventions. Fifty-seven (3.3 %) neuropsychiatric adverse effects were severe and 2 (0.1 %) were life-threatening (suicidal attempts). Most neuropsychiatric adverse effects (1555 events, 92.6 %) resolved without sequelae. Psychiatric medication was required in 289 patients (40.3 %). Sustained viral response was achieved in 400 cases (55.8 %) and was associated with adherence (OR = 1.942, 95 % CI = 1.235-3.052, p = 0.004). A multivariate analysis did not show any relationship between neuropsychiatric adverse effects and treatment adherence or sustained viral response

Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting

PubMed Central

Susser, Simone; Rogalska-Taranta, Magdalena; Petersen, Jörg; Böker, Klaus H. W.; Grigorian, Natalia; Link, Ralph; Naumann, Uwe; John, Christine; Lueth, Stefan; Malfertheiner, Peter; Manns, Michael P.; Wedemeyer, Heiner; Sarrazin, Christoph; Cornberg, Markus

2015-01-01

Background SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. Methods We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). Results Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). Conclusion IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions. PMID:26699619

Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting.

PubMed

Wiegand, Steffen B; Heidrich, Benjamin; Susser, Simone; Rogalska-Taranta, Magdalena; Petersen, Jörg; Böker, Klaus H W; Grigorian, Natalia; Link, Ralph; Naumann, Uwe; John, Christine; Lueth, Stefan; Malfertheiner, Peter; Manns, Michael P; Wedemeyer, Heiner; Sarrazin, Christoph; Cornberg, Markus

2015-01-01

SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.

Synthesis and characterization of chitosan quaternary ammonium salt and its application as drug carrier for ribavirin.

PubMed

Li, Si-Dong; Li, Pu-Wang; Yang, Zi-Ming; Peng, Zheng; Quan, Wei-Yan; Yang, Xi-Hong; Yang, Lei; Dong, Jing-Jing

2014-11-01

N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) is hydro-soluble chitosan (CS) derivative, which can be obtained by the reaction between epoxypropyl trimethyl ammonium chloride (ETA) and CS. The preparation parameters for the synthesis of HTCC were optimized by orthogonal experimental design. ETA was successfully grafted into the free amino group of CS. Grafting of ETA with CS had great effect on the crystal structure of HTCC, which was confirmed by the XRD results. HTCC displayed higher capability to form nanoparticles by crosslinking with negatively charged sodium tripolyphosphate (TPP). Ribavrin- (RIV-) loaded HTCC nanoparticles were positively charged and were spherical in shape with average particle size of 200 nm. More efficient drug encapsulation efficiency and loading capacity were obtained for HTCC in comparison with CS, however, HTCC nanoparticles displayed faster release rate due to its hydro-soluble properties. The results suggest that HTCC is a promising CS derivative for the encapsulation of hydrophilic drugs in obtaining sustained release of drugs.

Acute pancreatitis associated with pegylated interferon-alpha-2a therapy in chronic hepatitis C

PubMed Central

Choi, Jong Wook; Lee, June Sung; Paik, Woo Hyun; Song, Tae Jun; Kim, Jung Wook; Bae, Won Ki; Kim, Kyung-Ah; Kim, Jung Gon

2016-01-01

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Combination therapy of pegylated interferon-alpha (PEG-IFN-α) and ribavirin (RBV) is a current standard treatment for chronic HCV infection in Korea, which has considerable adverse effects. Acute pancreatitis is a rare complication of PEG-IFN-α administration. We report a case of a 62-year-old female who experienced acute pancreatitis after 4 weeks of PEG-IFN-α-2a and RBV combination therapy for chronic HCV infection. The main cause of the acute pancreatitis in this case was probably PEG-IFN-α rather than RBV for several reasons. A few cases have been reported in which acute pancreatitis occurred during treatment with PEG-IFN-α-2b. This is the first report of acute pancreatitis associated with PEG-IFN-α-2a in Korea. PMID:27044768

Characteristics and Factors Associated with Death among Patients Hospitalized for Severe Fever with Thrombocytopenia Syndrome, South Korea, 2013.

PubMed

Shin, Jaeseung; Kwon, Donghyok; Youn, Seung-Ki; Park, Ji-Hyuk

2015-10-01

In South Korea, nationwide surveillance for severe fever with thrombocytopenia syndrome (SFTS) began during 2013. Among 301 surveillance cases, 35 hospitalized case-patients in 25 areas were confirmed by using virologic testing, and 16 (46%) case-patients subsequently died. The SFTS cases occurred during May-November and peaked during June (9 cases, 26%). The incidence of SFTS was higher in the southern regions of South Korea. Age and neurologic symptoms, including decreased level of consciousness and slurred speech, were heavily associated with death; neurologic symptoms during the first week after disease onset were also associated with death. Although melena was common among patients who died, no other hemorrhagic manifestations were substantively more common among those who died. No effective treatments, including ribavirin, were identified. Expansion of SFTS surveillance to include the outpatient sector and development of an antibody test would enhance completeness of SFTS detection in South Korea.

Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen.

PubMed

Spanakis, Nikolaos; Tsiodras, Sotirios; Haagmans, Bart L; Raj, V Stalin; Pontikis, Kostantinos; Koutsoukou, Antonia; Koulouris, Nikolaos G; Osterhaus, Albert D M E; Koopmans, Marion P G; Tsakris, Athanassios

2014-12-01

Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient. Copyright © 2014. Published by Elsevier B.V.

Association of Oral Lichen Planus with Chronic C Hepatitis. Review of the Data in Literature

PubMed Central

GHEORGHE, Carmen; MIHAI, Lelia; PARLATESCU, Ioanina; TOVARU, Serban

2014-01-01

The relationship between chronic hepatitis C virus infection (HCV) and oral lichen planus (OLP) is a current topic in the field of oral medicine. Many studies of this association have been made over time. The geographic variation of the hepatitis C prevalence proved to be an important factor influencing the statistical results of the studies analyzing the association of the oral plan lichen with the hepatitis C virus. Approaching this issue is not to be neglected. Treatment outcomes in patients with oral lichen planus associated with chronic hepatitis C virus are often unsatisfactory compared to patients suffering from idiopathic oral lichen planus. Also, the evolution of oral lesions is often fluctuating, with repeated periods of relapse according to the degree of liver function decompensation. Background therapy for liver disease itself may influence lichen planus lesions. Thus, during therapy with interferon and ribavirin oral lesions may appear or become acute. PMID:25553136

Hantavirus Pulmonary Syndrome in the United States.

PubMed

Fabbri, Marilyn; Maslow, Melanie J.

2001-06-01

Since the first outbreak of hantavirus pulmonary syndrome (HPS) in 1993, understanding of the vast distribution and potential impact of hantaviruses has grown. At least 277 cases of HPS have been documented in the United States. The full clinical spectrum has yet to be elucidated, and one outbreak suggested the possibility of person-to-person transmission. New research has identified the b-3 integrins as cellular receptors for hantaviruses and has determined the pivotal role of the immune system in pathogenesis. Rapid diagnosis has been facilitated by a new immunoblot assay to detect Sin Nombre virus infection. Treatment remains primarily supportive; however, a placebo- controlled trial of ribavirin is ongoing. Extracorporeal membrane oxygenation may be a potential therapy in severe cases; inhaled nitric oxide needs further study. Vaccines developed against hantaviruses associated with hemorrhagic fever and renal syndrome might be effective against HPS-associated strains.

Conceptual framework for outcomes research studies of hepatitis C: an analytical review

PubMed Central

Sbarigia, Urbano; Denee, Tom R; Turner, Norris G; Wan, George J; Morrison, Alan; Kaufman, Anna S; Rice, Gary; Dusheiko, Geoffrey M

2016-01-01

Hepatitis C virus infection is one of the main causes of chronic liver disease worldwide. Until recently, the standard antiviral regimen for hepatitis C was a combination of an interferon derivative and ribavirin, but a plethora of new antiviral drugs is becoming available. While these new drugs have shown great efficacy in clinical trials, observational studies are needed to determine their effectiveness in clinical practice. Previous observational studies have shown that multiple factors, besides the drug regimen, affect patient outcomes in clinical practice. Here, we provide an analytical review of published outcomes studies of the management of hepatitis C virus infection. A conceptual framework defines the relationships between four categories of variables: health care system structure, patient characteristics, process-of-care, and patient outcomes. This framework can provide a starting point for outcomes studies addressing the use and effectiveness of new antiviral drug treatments. PMID:27313473

Microwave-assisted synthesis and anti-YFV activity of 2,3-diaryl-1,3-thiazolidin-4-ones.

PubMed

Sriram, Dharmarajan; Yogeeswari, Perumal; Kumar, T G Ashok

2005-09-01

The purpose of this study was to prepare several 1,3-thaizolidin-4-ones bearing variously substituted diaryl ring at C-2 and N-3 positions and evaluate them for their anti-YFV activity. Several 1,3-thaizolidin-4-ones were prepared by reacting substituted benzaldehyde with equimolar amount of an appropriate substituted aromatic amine in the presence of an excess of mercaptoacetic acid in toluene utilizing microwave irradiation. The synthesized compounds were also evaluated for their inhibitory effects on the replication of YFV in green monkey kidney (Vero) cells (ATCC CCL81), by means of a cytopathic effect reduction assay. The compound DS1 emerged as the most potent anti-YFV agent with EC50 of 6.9 microM and CC50 more than 100 microM making it more potent than ribavirin. 2,3-diaryl-1,3-thiazolidin-4-ones possess anti-YFV potency.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venkatraman, Srikanth; Bogen, Stephane L.; Arasappan, Ashok

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-{alpha} or polyethylene glycol (PEG)-interferon-{alpha} alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitormore » that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.« less

Herpes Zoster reactivation in patients with chronic hepatitis C under treatment with directly acting antiviral agents: A case series.

PubMed

El Kassas, Mohamed; Wifi, Mohamed Naguib; Mahdy, Reem; Afify, Shimaa; Hafez, Enas; El Latif, Yasmeen Abd; Ezzat, Marwa; El Tahan, Adel; Youssef, Naglaa; Esmat, Gamal

2017-03-01

We report a series of cutaneous Herpes Zoster (HZ) reactivation cases in patients with hepatitis C virus (HCV) infection treated with directly acting antiviral (DAA) agents. Five cases were detected among 2133 treated patients with DAAs at one of the specialized viral hepatitis treatment centers in Egypt. A control group including 2300 age and sex matched HCV patients who were previously treated with pegylated interferon and ribavirin did not show any HZ reactivation reports while on treatment. None of cases had an evidence of immunosuppression or a risk factor for HZ reactivation. The DAAs used regimens were sofosbuvir/daclatasvir in 4 cases and sofosbuvir/simeprevir in one case. HCV clearance with antiviral therapy may bring immune changes causing reactivation of other latent viral infections like HZ. A high index of clinical suspicion may be needed to guarantee early and prompt management of such cases. Copyright © 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Emergence of Lassa Fever Disease in Northern Togo: Report of Two Cases in Oti District in 2016.

PubMed

Patassi, Akouda Akessiwe; Landoh, Dadja Essoya; Mebiny-Essoh Tchalla, Agballa; Halatoko, Wemboo Afiwa; Assane, Hamadi; Saka, Bayaki; Naba, Mouchedou Abdoukarim; Yaya, Issifou; Edou, Kossi Atsissinta; Tamekloe, Tsidi Agbeko; Banla, Abiba Kere; Davi, Kokou Mawule; Manga, Magloire; Kassankogno, Yao; Salmon-Ceron, Dominique

2017-01-01

Lassa fever belongs to the group of potentially fatal hemorrhagic fevers, never reported in Togo. The aim of this paper is to report the first two cases of Lassa fever infection in Togo. The two first Lassa fever cases occurred in two expatriate's health professionals working in Togo for more than two years. The symptoms appeared among two health professionals of a clinic located in Oti district in the north of the country. The absence of clinical improvement after antimalarial treatment and the worsening of clinical symptoms led to the medical evacuation. The delayed diagnosis of the first case led to a fatal outcome. The second case recovered under ribavirin treatment. The emergence of this hemorrhagic fever confirms the existence of Lassa fever virus in Togo. After a period of intensive Ebola virus transmission from 2013 to 2015, this is an additional call for the establishment and enhancement of infection prevention and control measures in the health care setting in West Africa.

Cost-effectiveness analysis of therapeutic options for chronic hepatitis C genotype 3 infected patients.

PubMed

Gimeno-Ballester, Vicente; Mar, Javier; O'Leary, Aisling; Adams, Róisín; San Miguel, Ramón

2017-01-01

This study provides a cost-effectiveness analysis of therapeutic strategies for chronic hepatitis C genotype 3 infected patients in Spain. A Markov model was designed to simulate the progression in a cohort of patients aged 50 years over a lifetime horizon. Sofosbuvir (SOF) plus peginterferon and ribavirin for 12 weeks was a cost-effective option when compared to standard of care (SoC) in the treatment of both 'moderate fibrosis' and 'cirrhotic' patients. Incremental cost-effectiveness ratios were €35,276/QALY and €18,374/QALY respectively. ICERs for SOF plus daclatasvir (DCV) regimens versus SoC were over the threshold limit considered, at €56,178/QALY and €77,378/QALY for 'moderate fibrosis' and 'cirrhotic' patients respectively. Addition of SOF to IFN-based regimens for genotype 3 was cost-effective for both 'moderate fibrosis' and 'cirrhotic' patients. IFN-free options including SOF and DCV association required price reductions lower than the list prices to be considered cost-effective.

Antiviral activity of polymethoxylated flavones from "Guangchenpi", the edible and medicinal pericarps of citrus reticulata 'Chachi'.

PubMed

Xu, Jiao-Jiao; Wu, Xia; Li, Man-Mei; Li, Guo-Qiang; Yang, Yi-Ting; Luo, Hu-Jie; Huang, Wei-Huang; Chung, Hau Yin; Ye, Wen-Cai; Wang, Guo-Cai; Li, Yao-Lan

2014-03-12

The present study found that the supercritical fluid extract of "Guangchenpi" possessed in vitro antiviral activity against respiratory syncytial virus (RSV). Bioassay-guided isolation and identification of this extract led to obtain five active polymethoxylated flavones (1-5). Cytopathic effect (CPE) reduction assay exhibited that tangeretin (2) and nobiletin (3), two major polymethoxylated flavones in the extract, possessed better anti-RSV effect comparable to the positive control ribavirin. Plaque reduction assay revealed that tangeretin dose-dependently inhibited RSV-induced plaque formation on the HEp-2 cells. This polymethoxylated flavone mainly affected the intracellular replication of RSV, and it also could inhibit RSV entry into the HEp-2 cells. Further investigations with quantitative real-time PCR and confocal and Western blot assays indicated that tangeretin downregulated the expression of RSV phosphoprotein (P protein). Results suggest the potential application of the supercritical fluid extract of "Guangchenpi" and tangeretin in the treatment and the prevention of RSV infection.

Understanding the hepatitis C virus life cycle paves the way for highly effective therapies

PubMed Central

Scheel, Troels K H; Rice, Charles M

2014-01-01

More than two decades of intense research has provided a detailed understanding of hepatitis C virus (HCV), which chronically infects 2% of the world's population. This effort has paved the way for the development of antiviral compounds to spare patients from life-threatening liver disease. An exciting new era in HCV therapy dawned with the recent approval of two viral protease inhibitors, used in combination with pegylated interferon-α and ribavirin; however, this is just the beginning. Multiple classes of antivirals with distinct targets promise highly efficient combinations, and interferon-free regimens with short treatment duration and fewer side effects are the future of HCV therapy. Ongoing and future trials will determine the best antiviral combinations and whether the current seemingly rich pipeline is sufficient for successful treatment of all patients in the face of major challenges, such as HCV diversity, viral resistance, the influence of host genetics, advanced liver disease and other co-morbidities. PMID:23836234

[Cost-effectiveness of hepatitis C treatment in slow virologic responders coinfected with HIV].

PubMed

Rodrigues, Marcus Paulo da Silva; Vianna, Cid Manso de Mello; Mosegui, Gabriela Bittencourt Gonzalez; Costa e Silva, Frances Valéria; Peregrino, Antonio Augusto de Freitas; Jardim, Fernando Nagib

2013-11-01

Recent evidence has demonstrated that slow responders may benefit from antiviral treatment in HCV/HIV coinfection. This study aimed to evaluate the cost-effectiveness of HCV treatment in individuals with genotype 1 coinfected with HIV, with peg-interferon in combination with ribavirin, compared to the inclusion (versus non-inclusion) of slow responders. A Markov model was developed that simulated the progression of liver disease in a hypothetical cohort of one thousand men over 40 years of age, considering the Brazilian Unified National Health System (SUS) perspective and a 30-year timeline. The extension of treatment to slow responders provided a 60% increase in the number of individuals who eliminated HCV and an incremental cost-effectiveness ratio of 44,171 BRL/QALY, below the acceptability threshold proposed by World Health Organization. Sensitivity analysis did not alter the results. The inclusion of HCV/ HIV-coinfected slow virologic responders in the treatment protocol is shown to be a cost-effective strategy for the SUS.

An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver

PubMed Central

Myers, Robert P; Shah, Hemant; Burak, Kelly W; Cooper, Curtis; Feld, Jordan J

2015-01-01

Chronic hepatitis C remains a significant medical and economic burden in Canada, affecting nearly 1% of the population. Since the last Canadian consensus conference on the management of chronic hepatitis C, major advances have occurred that warrant a review of recommended management approaches for these patients. Specifically, direct-acting antiviral agents with dramatically improved rates of virological clearance compared with standard therapy have been developed and interferon-free, all-oral antiviral regimens have been approved. In light of this new evidence, an update to the 2012 Canadian Association for the Study of the Liver consensus guidelines on the management of hepatitis C was produced. The present document reviews the epidemiology of hepatitis C in Canada, preferred diagnostic testing approaches and recommendations for the treatment of chronically infected patients with the newly approved antiviral agents, including those who have previously failed peginterferon and ribavirin-based therapy. In addition, recommendations are made regarding approaches to reducing the burden of hepatitis C in Canada. PMID:25585348

Numerical detection, measuring and analysis of differential interferon resistance for individual HCV intra-host variants and its influence on the therapy response.

PubMed

Skums, Pavel; Campo, David S; Dimitrova, Zoya; Vaughan, Gilberto; Lau, Daryl T; Khudyakov, Yury

Hepatitis C virus (HCV) is a major cause of liver disease world-wide. Current interferon and ribavirin (IFN/RBV) therapy is effective in 50%-60% of patients. HCV exists in infected patients as a large viral population of intra-host variants (quasispecies), which may be differentially resistant to interferon treatment. We present a method for measuring differential interferon resistance of HCV quasispecies based on mathematical modeling and analysis of HCV population dynamics during the first hours of interferon therapy. The mathematical models showed that individual intra-host HCV variants have a wide range of resistance to IFN treatment in each patient. Analysis of differential IFN resistance among intra-host HCV variants allows for accurate prediction of response to IFN therapy. The models strongly suggest that resistance to interferon may vary broadly among closely related variants in infected hosts and therapy outcome may be defined by a single or a few variants irrespective of their frequency in the intra-host HCV population before treatment.

Role of Carbamazepine in the Symptomatic Treatment of Subacute Sclerosing Panencephalitis: A Case Report and Review of the Literature

PubMed Central

Ravikumar, Sandhya; Crawford, John Ross

2013-01-01

We describe the clinical presentation and clinical course of subacute sclerosing panencephalitis in a 13-year-old previously healthy boy who recently immigrated to the United States from Iraq. He presented with macular retinopathy, followed by progressive myoclonus and encephalopathy. After extensive workup, a diagnosis of subacute sclerosing panencephalitis was suspected by the presence of period epileptiform discharges on electroencephalogram and confirmed by elevated measles titers in the cerebrospinal fluid. Combination immunomodulatory therapy with isoprinosine, ribavirin, and intra-Ommaya interferon alpha did not result in clinical improvement. Within days following the administration of carbamazepine, there was remarkable improvement in the myoclonus and he was able to ambulate independently for a period of 4 months at which time he unfortunately progressed to a vegetative state. This case highlights the importance of carbamazepine as a potential first line symptomatic treatment of subacute sclerosing panencephalitis and provides a review of the literature on the subject. PMID:23533854

Grazoprevir/elbasvir for the treatment of adults with chronic hepatitis C: a short review on the clinical evidence and place in therapy.

PubMed

Sulejmani, Nimisha; Jafri, Syed-Mohammed

2018-01-01

Chronic hepatitis C virus (HCV) infection impacts approximately 71 million people and approximately 400,000 deaths are attributed to HCV-related liver disease annually worldwide. Mainstay of treatment for over 25 years has been pegylated interferon until the advent of protease inhibitors, which has led to all-oral HCV treatment regimens that have changed the outlook of hepatitis C treatment. Grazoprevir/elbasvir provides high rates of efficacy and tolerability and is an all-oral once daily treatment option for HCV infection. Efficacy of grazoprevir/elbasvir has been proven in patients with cirrhosis, patients who have previously failed treatment with peginterferon and ribavirin (RBV), patients with end-stage renal disease and patients with HIV co-infection. Data have shown a high barrier to resistance despite the presence of resistance-associated substitutions. Grazoprevir/elbasvir represents a very promising regimen for treatment of HCV infection. This review provides a summary of pharmacology, efficacy, and safety of grazoprevir/elbasvir for the treatment of HCV infection.

Study of prevalence and effects of insulin resistance in patients with chronic hepatitis C genotype 4.

PubMed

Amer, A F; Baddour, M M; Elshazly, M A; Fadally, G; Hanafi, N F; Assar, S L

2016-02-01

There is strong epidemiological evidence linking hepatitis C virus (HCV) infection and diabetes. Our aim was to evaluate the prevalence of insulin resistance in Egyptian patients with chronic HCV genotype 4 infection, to assess factors associated with insulin resistance and to test the impact of insulin resistance on outcomes of treatment with pegylated interferon/ribavirin. Insulin resistance [homeostasis model assessmentinsulin resistance (HOMA-IR) score > 3.0] was detected in 31 of 100 nondiabetic patients. The relationship between elevated HOMA-IR and baseline viral load and degree of fibrosis was statistically significant (r = 0.218 and r = 0.223). Follow-up of patients with complete early virological response until the end of treatment showed a statistically significant decrease in HOMA-IR score. Out of 29 liver tissue sections examined, 14 had a low level of expression of insulin receptor type 1 by immunohistochemical studies. This study confirms that insulin resistance affects treatment outcome, and thus HOMA-IR testing before initiation of therapy may be a cost-effective tool.

Multifunctionality of a Picornavirus Polymerase Domain: Nuclear Localization Signal and Nucleotide Recognition

PubMed Central

Ferrer-Orta, Cristina; de la Higuera, Ignacio; Caridi, Flavia; Sánchez-Aparicio, María Teresa; Moreno, Elena; Perales, Celia; Singh, Kamalendra; Sarafianos, Stefan G.; Sobrino, Francisco; Domingo, Esteban

2015-01-01

ABSTRACT The N-terminal region of the foot-and-mouth disease virus (FMDV) 3D polymerase contains the sequence MRKTKLAPT (residues 16 to 24) that acts as a nuclear localization signal. A previous study showed that substitutions K18E and K20E diminished the transport to the nucleus of 3D and 3CD and severely impaired virus infectivity. These residues have also been implicated in template binding, as seen in the crystal structures of different 3D-RNA elongation complexes. Here, we report the biochemical and structural characterization of different mutant polymerases harboring substitutions at residues 18 and 20, in particular, K18E, K18A, K20E, K20A, and the double mutant K18A K20A (KAKA). All mutant enzymes exhibit low RNA binding activity, low processivity, and alterations in nucleotide recognition, including increased incorporation of ribavirin monophosphate (RMP) relative to the incorporation of cognate nucleotides compared with the wild-type enzyme. The structural analysis shows an unprecedented flexibility of the 3D mutant polymerases, including both global rearrangements of the closed-hand architecture and local conformational changes at loop β9-α11 (within the polymerase motif B) and at the template-binding channel. Specifically, in 3D bound to RNA, both K18E and K20E induced the opening of new pockets in the template channel where the downstream templating nucleotide at position +2 binds. The comparisons of free and RNA-bound enzymes suggest that the structural rearrangements may occur in a concerted mode to regulate RNA replication, processivity, and fidelity. Thus, the N-terminal region of FMDV 3D that acts as a nuclear localization signal (NLS) and in template binding is also involved in nucleotide recognition and can affect the incorporation of nucleotide analogues. IMPORTANCE The study documents multifunctionality of a nuclear localization signal (NLS) located at the N-terminal region of the foot-and-mouth disease viral polymerase (3D). Amino acid

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

PubMed

Anty, R; Favre, G; Coilly, A; Rossignol, E; Houssel-Debry, P; Duvoux, C; De Ledinghen, V; Di Martino, V; Leroy, V; Radenne, S; Kamar, N; Canva, V; D'Alteroche, L; Durand, F; Dumortier, J; Lebray, P; Besch, C; Tran, A; Canivet, C M; Botta-Fridlund, D; Montialoux, H; Moreno, C; Conti, F; Silvain, C; Perré, P; Habersetzer, F; Abergel, A; Debette-Gratien, M; Dharancy, S; Esnault, V L M; Fougerou-Leurent, C; Cagnot, C; Diallo, A; Veislinger, A; Danjou, H; Samuel, D; Pageaux, G-P; Duclos-Vallée, J-C

2018-06-01

In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m 2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m 2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising

Immunosuppressive and antiviral treatment of hepatitis C virus-associated glomerular disease: A long-term follow-up.

PubMed

Fabrizi, Fabrizio; Aghemo, Alessio; Lampertico, Pietro; Fraquelli, Mirella; Cresseri, Donata; Moroni, Gabriella; Passerini, Patrizia; Donato, Francesca M; Messa, Piergiorgio

2018-06-01

The evidence in the medical literature on the treatment of hepatitis C virus-associated glomerular disease is extremely limited. The advent of nonconventional immunosuppressive agents and direct-acting antivirals promises high efficacy and safety. We conducted an open-label, single-arm clinical study to examine the efficacy and safety of a combined approach for hepatitis C virus-associated glomerular disease. In the first phase of the study, patients with hepatitis C virus-associated glomerular disease received interferon-based antiviral therapy and immunosuppressive agents; since 2013, interferon-free antiviral therapy was adopted and novel immunosuppressants (including B-cell depleting agents and mycophenolate mofetil) or immunomodulators (ribavirin) were choiced. Virological and clinical responses were evaluated over a long observation period (median follow-up of 60 weeks and 46.5 months after the end of treatment with interferon and direct-acting antiviral agents, respectively). We enrolled 25 consecutive patients with hepatitis C virus-associated glomerular disease, 8 being liver transplant recipients for hepatitis C. A total of 13 patients received therapy with direct-acting antivirals and experienced sustained viral response (serum hepatitis C virus RNA <12 IU/mL, 12 weeks after treatment ended, sustained viral response12). The mean (±standard deviation) proteinuria decreased from 2.61 ± 1.01 at baseline to 1.71 ± 1.43 (g/day) at sustained viral response 48, p = 0.031; microscopic hematuria and serum cryoglobulins disappeared in six (50%) and seven (64%) patients, respectively, after sustained viral response by direct-acting antivirals. Adverse events occurred in 69% (9/13) of patients and were mild, with four cases of ribavirin-related anemia requiring blood transfusions (no drop-outs). After sustained viral response by direct-acting antivirals, immunosuppressive and immunomodulatory agents were initiated in clinical relapsers ( n = 2) and nonresponders

How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation

PubMed Central

Waghmare, Alpana; Englund, Janet A.

2016-01-01

The widespread use of multiplex molecular diagnostics has led to a significant increase in the detection of respiratory viruses in patients undergoing cytotoxic chemotherapy and hematopoietic cell transplantation (HCT). Respiratory viruses initially infect the upper respiratory tract and then progress to lower respiratory tract disease in a subset of patients. Lower respiratory tract disease can manifest itself as airflow obstruction or viral pneumonia, which can be fatal. Infection in HCT candidates may require delay of transplantation. The risk of progression differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been described, which may allow targeting treatment to high-risk patients. Ribavirin is the only antiviral treatment option for noninfluenza respiratory viruses; however, high-quality data demonstrating its efficacy and relative advantages of the aerosolized versus oral form are lacking. There are significant unmet needs, including data defining the virologic characteristics and clinical significance of human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new treatment and preventative options. PMID:26968533

The Changing Face of Hepatitis C: Recent Advances on HCV Inhibitors Targeting NS5A

PubMed

Rai, Diwakar; Wang, Liu; Jiang, Xuemei; Zhan, Peng; Jia, Haiyong; De Clercq, Erik; Liu, Xinyong

2015-05-05

Current treatment for HCV infections consists of approved direct acting antivirals (DAAs), viz. the protease inhibitors (boceprevir, telaprevir, and simeprevir), NS5B polymerase inhibitors (sofosbuvir) and NS5A inhibitor (ledipasvir) in combination with pegylated interferon α and ribavirin). These treatments have made a great improvement in the treatment of chronic HCV infections in recent years, but their adverse side effects, emergence of resistant mutants, high cost, and increased pill burden have limited their clinical use. Recently, with the increasing knowledge in understanding the HCV life cycle, more targets have been recognized. NS5A protein plays a critical role in assembly of infectious HCV particles and offering potential for HCV therapies. Therefore, discovery and development of novel DAAs targeting NS5A with novel mechanisms of action, is of great necessity to improve the quality of existing HCV treatments. In the present review, we discuss recent advances with NS5A inhibitors with potent anti-HCV activity, and the potential for the development of HCV NS5A inhibitors to combat HCV infections.

The hepatitis C virus enigma.

PubMed

Myrmel, Helge; Ulvestad, Elling; Asjø, Birgitta

2009-05-01

Hepatitis C virus (HCV) has a high propensity to establish chronic infection with end-stage liver disease. The high turnover of virus particles and high transcription error rates due to lack of proof-reading function of the viral polymerase imply that HCV exists as quasispecies, thus enabling the virus to evade the host immune response. Clearance of the virus is characterized by a multispecific, vigorous and persistent T-cell response, whereas T-cell responses are weak, narrow and transient in patients who develop chronic infection. At present, standard treatment is a combination of pegylated interferon-alpha and ribavirin, with a sustained viral response rate of 40-80%, depending on genotype. The mechanisms for the observed synergistic effects of the two drugs are still not known in detail, but in addition to direct antiviral mechanisms, the immunomodulatory effects of both drugs seem to be important, with a shift from Th2- to Th1-cytokine profiles in successfully treated patients. This article describes virus-host relations in the natural course of HCV infection and during treatment.

Imported Lassa fever: a report of 2 cases in Ghana.

PubMed

Kyei, Nicholas N A; Abilba, Mark M; Kwawu, Foster K; Agbenohevi, Prince G; Bonney, Joseph H K; Agbemaple, Thomas K; Nimo-Paintsil, Shirley C; Ampofo, William; Ohene, Sally-Ann; Nyarko, Edward O

2015-05-29

Lassa fever is a potentially fatal acute viral illness caused by Lassa virus which is carried by rodents and is endemic in some West African countries. Importation of emerging infections such as Lassa fever, Ebola Virus Disease and other viral hemorrhagic fevers into non endemic regions is a growing threat particularly as international travel and commitments in resolving conflicts in endemic countries in the West Africa sub-region continue. We report the first two recorded imported cases of Lassa fever among Ghanaian Peace keepers in rural Liberia, who became ill while on Peace keeping mission. They were subsequently evacuated to the UN level IV hospital in Accra, where their illnesses were laboratory confirmed. One of the patients recovered with ribavirin treatment and supportive therapy. No secondary clinical cases occurred in Ghana. Healthcare providers at all levels of care should thus have a high index of suspicion for these infectious diseases and adopt standard infection control measures when treating patients in endemic regions or returning travelers from an endemic region with a febrile illness even of a known etiology.

NIOSH health and safety practices survey of healthcare workers: training and awareness of employer safety procedures.

PubMed

Steege, Andrea L; Boiano, James M; Sweeney, Marie H

2014-06-01

The Health and Safety Practices Survey of Healthcare Workers describes current practices used to minimize chemical exposures and barriers to using recommended personal protective equipment for the following: antineoplastic drugs, anesthetic gases, high level disinfectants, surgical smoke, aerosolized medications (pentamidine, ribavirin, and antibiotics), and chemical sterilants. Twenty-one healthcare professional practice organizations collaborated with NIOSH to develop and implement the web-based survey. Twelve thousand twenty-eight respondents included professional, technical, and support occupations which routinely come in contact with the targeted hazardous chemicals. Chemical-specific safe handling training was lowest for aerosolized antibiotics (52%, n = 316), and surgical smoke (57%, n = 4,747). Reported employer procedures for minimizing exposure was lowest for surgical smoke (32%, n = 4,746) and anesthetic gases (56%, n = 3,604). Training and having procedures in place to minimize exposure to these chemicals is one indication of employer and worker safety awareness. Safe handling practices for use of these chemicals will be reported in subsequent papers. © 2014 Wiley Periodicals, Inc.

Tangeretin from Citrus reticulate Inhibits Respiratory Syncytial Virus Replication and Associated Inflammation in Vivo.

PubMed

Xu, Jiao-Jiao; Liu, Zhong; Tang, Wei; Wang, Guo-Cai; Chung, Hau Yin; Liu, Qiu-Ying; Zhuang, Ling; Li, Man-Mei; Li, Yao-Lan

2015-11-04

Human respiratory syncytial virus (RSV) is a common pathogen that causes pneumonia and bronchiolitis in infants and young children. Our previous study showed that tangeretin from Citrus reticulate possessed potent in vitro anti-RSV effects comparable to that of ribavirin. Therefore, in this study, we investigated the in vivo anti-RSV activity of tangeretin in 3-week-old male BALB/c mice. A plaque reduction assay and fluorescence quantitative polymerase chain reaction (FQ-PCR) showed that tangeretin inhibited RSV replication in the lung of mice. Moreover, a luminex assay indicated tangeretin relieved RSV-induced lung inflammation by attenuating interleukin (IL)-1β secretion. Possible anti-inflammatory mechanisms of tangeretin were preliminarily explored using a RSV-infected macrophage model. A FQ-PCR, enzyme-linked immunosorbent assay (ELISA), and luciferase assay revealed that tangeretin inhibited RSV-induced inflammation by suppressing nuclear factor-κB (NF-κB) activation. This study demonstrates that tangeretin inhibited RSV replication and RSV-induced lung inflammation in vivo and may be useful in preventing and treating RSV infections and inflammation.

Interferon-alpha-induced destructive thyroiditis followed by Graves' disease in a patient with chronic hepatitis C: a case report.

PubMed

Kim, Bu Kyung; Choi, Young Sik; Park, Yo Han; Lee, Sang Uk

2011-12-01

Interferon-induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon-alpha (IFN-α) therapy. But, destructive thyroiditis followed by Graves' disease associated with IFN-α therapy is very rarely reported. Herein, we report a rare case of pegylated IFN-α (pegIFN-α) induced destructive thyroiditis followed by Graves' disease in a patient with HCV infection. A 31-yr-old woman suffered from chronic active hepatitis C and was treated with pegIFN-α and ribavirin for 12 months. Results of a thyroid function test and autoantibody levels were normal before IFN-α therapy was initiated. Destructive thyrotoxicosis appeared seven months after the initiation of IFN-α therapy, followed by Graves' thyrotoxicosis two months after the cessation of therapy. The diagnoses of destructive thyroiditis and Graves' disease were confirmed by the presence of TSH receptor antibodies in addition to Tc-99m scintigraphy findings. The patient's antithyroglobulin antibody titer increased gradually during IFN-α therapy and remained weakly positive after IFN-α therapy was discontinued.

Triazole nucleoside derivatives bearing aryl functionalities on the nucleobases show antiviral and anticancer activity.

PubMed

Xia, Yi; Qu, Fanqi; Peng, Ling

2010-08-01

Synthetic nucleoside mimics are important candidates in the searing for antiviral and anticancer drugs. Ribavirin, the first antiviral nucleoside drug, is unique in its antiviral activity with mutilple modes of action, which are mainly due to its special triazole heterocycle as nucleobase. Additionally, introducing aromatic functionalities to the nucleobase is able to confer novel mechanisms of action for nucleoside mimics. With the aim to combine the special characteristics of unnatural triazole heterocycles with those of the appended aromatic groups on the nucleobases, novel 1,2,4-triazole nucleoside analogs bearing aromatic moieties were designed and developed. The present short review summarizes the molecular design, chemical synthesis and biological activity of these triazole nucleoside analogs. Indeed, the discovery of antiviral and anticancer activities shown by these triazole nucleosides as well as the new mechanism underlying the biological activity by one of the anticancer leads has validated the rationale for molecular design and impacted us to further explore the concept with the aim of developing structurally novel nucleoside drug candidates with new modes of action.