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Sample records for nrti didanosine lamivudine

  1. Didanosine

    MedlinePlus

    ... a substance that is bloody or looks like coffee grounds, or dark stools.Ask your doctor about the safe use of alcohol while you are taking didanosine. Drinking alcohol can increase the risk that you will develop serious side effects of ...

  2. Oligonucleotide Ligation Assay for Detecting Mutations in the Human Immunodeficiency Virus Type 1 pol Gene That Are Associated with Resistance to Zidovudine, Didanosine, and Lamivudine

    PubMed Central

    Edelstein, Reva E.; Nickerson, Deborah A.; Tobe, Vincent O.; Manns-Arcuino, Laura A.; Frenkel, Lisa M.

    1998-01-01

    This report describes the detection of mutations in the pol gene of human immunodeficiency virus type 1 associated with resistance to zidovudine, didanosine, and lamivudine by genotyping by an oligonucleotide ligation assay specific codons in the pol gene amplified by PCR. Our studies demonstrate the sensitivity, simplicity, and specificity of this genotyping system. PMID:9466779

  3. The nucleoside reverse transcriptase inhibitors didanosine, lamivudine, stavudine and zidovudine show little effect on the virulence of Candida albicans in vitro.

    PubMed

    Ahmadou Ahidjo, Bintou; Veale, Rob; Dusé, Adriano G; Becker, Piet; Marais, Else

    2008-08-01

    Nucleoside reverse transcriptase inhibitors (NRTIs) are used in the treatment of human immunodeficiency virus (HIV). Since the analogue 5-fluorouracil increases Candida albicans virulence in vitro, and zidovudine therapy is associated with enhanced C. albicans adherence and biofilm formation, we investigated the effects of commonly used NRTIs on the virulence of C. albicans isolated from 21 antiretroviral-naïve HIV/AIDS patients. The isolates were exposed to didanosine, lamivudine, stavudine and zidovudine at their expected patient serum peak levels and at one-half and two times these levels for 24h and 72 h. Assays assessing changes in adherence, proliferation, biofilm formation and antifungal susceptibility were performed. No differences in these virulence characteristics of isolates exposed to NRTIs were noted in most cases. However, at 24h and 72 h a significant increase in the rate of proliferation was observed in response to two-fold the peak concentration of lamivudine. The results suggest a limited effect of NRTIs on C. albicans virulence.

  4. Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903.

    PubMed

    Berenguer, Juan; González, Juan; Ribera, Esteban; Domingo, Pere; Santos, Jesús; Miralles, Pilar; Angels Ribas, M; Asensi, Víctor; Gimeno, Juan Luis; Pérez-Molina, José Antonio; Terrón, José Alberto; Santamaría, Juan Miguel; Pedrol, Enric

    2008-10-15

    The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis. Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003). At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity. NCT00256828.

  5. Lamivudine

    MedlinePlus

    ... Although lamivudine does not cure HIV, it may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) ... sex and making other life-style changes may decrease the risk of transmitting (spreading) the HIV or ...

  6. Risk of cancer in children exposed to didanosine in utero.

    PubMed

    Hleyhel, Mira; Goujon, Stéphanie; Delteil, Clémence; Vasiljevic, Alexandre; Luzi, Stéphanie; Stephan, Jean-Louis; Reliquet, Véronique; Jannier, Sarah; Tubiana, Roland; Dollfus, Catherine; Faye, Albert; Mandelbrot, Laurent; Clavel, Jacqueline; Warszawski, Josiane; Blanche, Stéphane

    2016-05-15

    Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine. Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population. A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)]. There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.

  7. Proximal tubular dysfunction associated with tenofovir and didanosine causing Fanconi syndrome and diabetes insipidus: a report of 3 cases.

    PubMed

    Irizarry-Alvarado, Joan M; Dwyer, Jamie P; Brumble, Lisa M; Alvarez, Salvador; Mendez, Julio C

    2009-03-01

    We report 3 cases of patients with HIV/AIDS in whom Fanconi syndrome and nephrogenic diabetes insipidus developed secondary to use of an antiretroviral regimen containing tenofovir disoproxil fumarate and didanosine. These patients presented with a history of polydipsia, polyuria, weight loss, anorexia, and wasting. Interestingly, 1 patient was not taking protease inhibitors. This response is a well-documented yet uncommon complication of tenofovir use in the HIV population. We recommend continued monitoring for renal toxicity when using NRTI combination of tenofovir and didanosine.

  8. Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir▿

    PubMed Central

    Pruvost, Alain; Negredo, Eugènia; Théodoro, Frédéric; Puig, Jordi; Levi, Mikaël; Ayen, Rafaela; Grassi, Jacques; Clotet, Bonaventura

    2009-01-01

    Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC0-4), the maximum concentration of the drug (Cmax), and the residual concentration of the drug at the end of the dosing interval (Ctrough) for plasma and the AUC0-4 and Ctrough for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC0-4 was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and Ctrough values for

  9. Bioretrosynthetic construction of a didanosine biosynthetic pathway

    PubMed Central

    Birmingham, William R.; Starbird, Chrystal A.; Panosian, Timothy D.; Nannemann, David P.; Iverson, T. M.; Bachmann, Brian O.

    2014-01-01

    Concatenation of engineered biocatalysts into multistep pathways dramatically increases their utility, but development of generalizable assembly methods remains a significant challenge. Herein we evaluate ‘bioretrosynthesis’, which is an application of the retrograde evolution hypothesis, for biosynthetic pathway construction. To test bioretrosynthesis, we engineered a pathway for synthesis of the antiretroviral nucleoside analog didanosine (2,3-dideoxyinosine). Applying both directed evolution and structure-based approaches, we began pathway construction with a retro-extension from an engineered purine nucleoside phosphorylase and evolved 1,5-phosphopentomutase to accept the substrate 2,3-dideoxyribose 5-phosphate with a 700-fold change in substrate selectivity and 3-fold increased turnover in cell lysate. A subsequent retrograde pathway extension, via ribokinase engineering, resulted in a didanosine pathway with a 9,500-fold change in nucleoside production selectivity and 50-fold increase in didanosine production. Unexpectedly, the result of this bioretrosynthetic step was not a retro-extension from phosphopentomutase, but rather the discovery of a fortuitous pathway-shortening bypass via the engineered ribokinase. PMID:24657930

  10. Didanosine Population Pharmacokinetics in West African Human Immunodeficiency Virus-Infected Children Administered Once-Daily Tablets in Relation to Efficacy after One Year of Treatment▿ †

    PubMed Central

    Hirt, Déborah; Bardin, Christophe; Diagbouga, Serge; Nacro, Boubacar; Hien, Hervé; Zoure, Emmanuelle; Rouet, François; Ouiminga, Adama; Urien, Saik; Foulongne, Vincent; Van De Perre, Philippe; Tréluyer, Jean-Marc; Msellati, Philippe

    2009-01-01

    Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (Cmax), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and Cmax (P ≤ 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter·h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing. PMID:19581461

  11. Abacavir, Lamivudine, and Zidovudine

    MedlinePlus

    Trizivir®(as a combination product containing Abacavir, Lamivudine, and Zidovudine) ... HIV) infection. Abacavir, lamivudine and zidovudine are in a class of medications called nucleoside reverse transcriptase inhibitors ( ...

  12. Determination of didanosine in human serum by on-line solid-phase extraction coupled to high-performance liquid chromatography with electrospray ionization tandem mass spectrometric detection: application to a bioequivalence study.

    PubMed

    Estrela, Rita de Cassia E; Salvadori, Myriam C; Raices, Renata S L; Suarez-Kurtz, Guilherme

    2003-04-01

    A method based on solid-phase extraction coupled to liquid chromatography with positive ion electrospray ionization and tandem mass spectrometric detection was developed for the determination of didanosine in human serum, using lamivudine as internal standard. The acquisition was performed in the multiple reaction monitoring mode, monitoring the transitions m/z 237 --> 136.7 for didanosine and m/z 230 --> 111.7 for lamivudine. The method was linear over the range studied (10-1500 ng ml(-1)), with r(2) > 0.98, and the run time was 5 min. The intra- and inter-assay precisions were < or =10% and the intra- and inter-assay accuracies were >95%. The absolute recoveries were 99.8% (10 ng ml(-1)), 98.4% (30 ng ml(-1)), 91.5% (700 ng ml(-1)) and 94.7% (1200 ng ml(-1)). The limits of detection and quantitation were 5 and 10 ng ml(-1), respectively. The method was applied to a bioequivalence study, in which 24 healthy adult volunteers (12 men) received single oral doses (200 mg) of reference and test didanosine formulations (buffered powder for oral solutions), in an open, two-way, randomized, crossover protocol. The 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak serum concentration) and AUC(0-inf) (area under the serum concentration versus time curve from time zero to infinity) were within the range 80-125%, which supports the conclusion that the two formulations are bioequivalent regarding the rate and extent of didanosine absorption.

  13. Long-term CD4+ T-cell count evolution after switching from regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitors to regimens containing NRTI plus non-NRTI or only NRTI

    PubMed Central

    2011-01-01

    Background Data regarding CD4+ recovery after switching from protease inhibitor (PI)-based regimens to regimens not containing PI are scarce. Methods Subjects with virological success on first-PI-regimens who switched to NNRTI therapy (NNRTI group) or to nucleoside reverse transcriptase (NRTI)-only (NRTI group) were studied. The effect of the switch on the ongoing CD4+ trend was assessed by two-phase linear regression (TPLR), allowing us to evaluate whether a change in the CD4+ trend (hinge) occurred and the time of its occurrence. Furthermore, we described the evolution of the frequencies in CD4-count classes across four relevant time-points (baseline, before and immediately after the switch, and last visit). Finally, we explored whether the CD4+ counts evolved differently in patients who switched to NNRTI or NRTI-only regimens by considering: the overall CD4+ trends, the time to CD4+≥ 500/mm3 after the switch, and the area-under-the-curve (AUC) of the CD4+ after the switch. Results Eight hundred and ninety-six patients, followed for a median of 2,121 days, were included. At TPLR, hinges occurred in 581/844 (68.9%), but in only 40/581 (6.9%) within a time interval (180 days) compatible with a possible relationship to the switch; furthermore, in 19/40 cases, CD4+ counts appeared to decrease after the hinges. In comparison with the NNRTI group, the NRTI group showed CD4+ count greater at baseline (P = 0.0234) and before the switch (P ≤ 0.0001), superior CD4+ T-cell increases after HAART was started, lower probability of not achieving CD4+ ≥ 500/mm3 (P = 0.0024), and, finally, no significant differences in the CD4+ T-cell AUC after the switch after adjusting for possible confounders (propensity score and pre-switch AUC). Persistence at CD4+ < 200/mm3 was observed in 34/435 (7.5%) patients, and a decrease below this level was found in only 10/259 (3.9%) with baseline CD4+ ≥ 350/mm3. Conclusions Switching from first-line PI to NNRTI- or NRTI-based regimens did

  14. In vivo absorption of didanosine formulated in pellets composed of chitosan microspheres.

    PubMed

    Severino, Patrícia; Da Silva, Classius Ferreira; Dalla Costa, Teresa Cristina T; Silva, Heloisa; Chaud, Marco V; Santana, Maria Helena A; Souto, Eliana B

    2014-01-01

    The in vivo absorption of didanosine was studied, focusing on the performance of a novel pharmaceutical formulation for didanosine, composed of chitosan granules containing didanosine incorporated in chitosan microspheres. This novel formulation is aimed at oral administration in AIDS therapy. The experimental results in male adult dogs showed controlled delivery of didanosine along 36 h, with a 2-fold increase in the absorption time of didanosine compared to the commercial granules, gastro-resistant didanosine and tablets. The higher absorption is due to adhesion to the intestinal membrane, improving absorption through increase of residence time, permeation and release. Furthermore, the novel formulation facilitates handling and deglutition, especially in the elderly and children, as well as enhances the taste and reduces the frequency of doses and collateral effects associated with a high concentration of the buffer agents usually used in other formulations.

  15. Zidovudine and Lamivudine for HIV Infection.

    PubMed

    Anderson, Peter L; Rower, Joseph E

    2010-01-01

    Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

  16. Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

    PubMed

    Greig, Sarah L; Deeks, Emma D

    2015-04-01

    A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

  17. Impact of HIV-1 reverse transcriptase polymorphism at codons 211 and 228 on virological response to didanosine.

    PubMed

    Marcelin, Anne-Genevieve; Flandre, Philippe; Furco, Andre; Wirden, Marc; Molina, Jean-Michel; Calvez, Vincent

    2006-01-01

    To determine the potential impact of reverse transcriptase (RT) mutations, other than those currently known to confer nucleoside reverse transcriptase inhibitors (NRTIs) resistance, on the virological response to didanosine (ddl). In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddl (n=111) or placebo (n=57) in addition to their currently failing regimen for 4 weeks. The virological response was a reduction of HIV-1 RNA from baseline to week 4. In an univariate analysis, we investigated the impact on the virological response to ddl of all the mutations in the RT gene (codons 21-236), except those known to confer NRTI resistance. Using the removing procedure, with a test for trend (Jonckheere's test), a new potential score was calculated incorporating all potential mutations associated to the week 4 virological response. Two RT polymorphisms were associated with a reduced virological response to ddl, R211A/D/G/K/S and L228H/M/R, and one with a better virological response: F214L. A mutation score (M41L+D67N+T69D-K70R +L74V-M 1 84V/I+T21 5Y/F+ K219Q/E+ R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddl resistance (211 and 228) and RT mutations previously described, was associated with a continuum of virological response and increased the predictability of virological response to ddl. RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddl.

  18. Is the Recommended Once-Daily Dose of Lamivudine Optimal in West African HIV-Infected Children?▿

    PubMed Central

    Bouazza, Naïm; Hirt, Déborah; Bardin, Christophe; Diagbouga, Serge; Nacro, Boubacar; Hien, Hervé; Zoure, Emmanuelle; Rouet, François; Ouiminga, Adama; Blanche, Stephane; Van De Perre, Philippe; Tréluyer, Jean-Marc; Msellati, Philippe; Urien, Saik

    2010-01-01

    We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter·h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P = 0.01). The target mean AUC of 8.9 mg/liters·h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed. PMID:20516271

  19. Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single- and three dual-NRTI treatments.

    PubMed

    Note, Reine; Maisonneuve, Caroline; Lettéron, Philippe; Peytavin, Gilles; Djouadi, Fatima; Igoudjil, Anissa; Guimont, Marie-Christine; Biour, Michel; Pessayre, Dominique; Fromenty, Bernard

    2003-11-01

    Although treatments with nucleoside reverse transcriptase inhibitors (NRTIs) can modify fat metabolism and fat distribution in humans, the mechanisms of these modifications and the roles of diverse NRTIs are unknown. We studied the mitochondrial and metabolic effects of stavudine (d4T), zidovudine (AZT), didanosine (ddI), lamivudine (3TC), zalcitabine (ddC), and three combinations (AZT-3TC, d4T-3TC, and d4T-ddI) in mice treated for 2 weeks with daily doses equivalent to the human dose per body area. Concentrations of AZT and d4T in plasma were lower when these drugs were administered with 3TC or ddI. Whatever the treatment, mitochondrial DNA was not significantly decreased in muscle, heart, brain, or white adipose tissue but was moderately decreased in liver tissue after the administration of AZT, 3TC, or d4T alone. Blood lactate was unchanged, even when NRTIs were administered at supratherapeutic doses. In contrast, the level of plasma ketone bodies increased with the administration of AZT or high doses of d4T but not with ddC, 3TC, or ddI, suggesting that the thymine moiety could be involved. Indeed, the levels of plasma ketone bodies increased in mice treated with beta-aminoisobutyric acid, a thymine catabolite. Treatment with AZT, d4T, or beta-aminoisobutyric acid increased hepatic carnitine palmitoyltransferase I (CPT-I) mRNA expression and the mitochondrial generation of ketone bodies from palmitate. In conclusion, therapeutic doses of NRTIs have no or moderate effects on mitochondrial DNA and no effects on plasma lactate in mice. However, AZT and high doses of d4T increase the levels of hepatic CPT-I, mitochondrial fatty acid beta-oxidation, and ketone bodies, and these catabolic effects are reproduced by beta-aminoisobutyric acid, a thymine metabolite.

  20. Lamivudine-Induced Liver Injury

    PubMed Central

    Olaniyan, Lamidi W. B.; Maduagwu, Emmanuel N.; Akintunde, Olalekan Wasiu; Oluwayelu, Oladimeji O.; Brai, Bartholomew I. C.

    2015-01-01

    BACKGROUND: Lamivudine is a nucleoside analogue antiretroviral drug, known for its low toxicity at clinically prescribed dose. However, the toxicity or mechanism of toxicity and target tissue effects during prolonged administration of higher doses were hardly given sufficient laboratory attention. AIM: The present work was designed to investigate the biochemical and histopathological changes in the liver of rat administered with prolonged doses of lamivudine. MATERIAL AND METHODS: Lamivudine in multiple doses of five ranging from 4 mg/kg to 2500 mg/kg were administered, in vitro, by injection into the air-sac of 10–day old fertile embryonated eggs of Gallus domesticus. Also, female rats of the Wistar strain received oral doses, up to 500 mg/kg singly or repeatedly for 15 or 45 days, respectively. Spectrophotometric techniques were employed to monitor activities of the aminotransferases (ALT and AST), γ–glutamyltransferase (GGT) and total protein concentration in serum while activities of glutathione S–transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein were determined in liver. Histopathological studies were carried out on liver. Data were analysed using ANOVA and were considered significant when p < 0.05. RESULTS: The LD50 for the drug calculated from the incubation experiment was 427 mg/kg. Total serum protein concentration significantly reduced while enzymes activities significantly increased at 500 mg/kg only among the repeat-dosed rats. Hepatic GGT, GST and SOD activities as well as MDA concentration were significantly elevated at 20 mg/kg. Histopathological studies showed multifocal lymphoid cell population in the liver sinusoid of the chicken and hydropic degeneration of hepatocytes were recorded among rats repeatedly exposed to the drug respectively at doses ≥ 100 mg/kg. CONCLUSION: Lamivudine toxicity in rat liver appeared to be mediated by oxidative stress. PMID:27275285

  1. Lamivudine-Induced Liver Injury.

    PubMed

    Olaniyan, Lamidi W B; Maduagwu, Emmanuel N; Akintunde, Olalekan Wasiu; Oluwayelu, Oladimeji O; Brai, Bartholomew I C

    2015-12-15

    Lamivudine is a nucleoside analogue antiretroviral drug, known for its low toxicity at clinically prescribed dose. However, the toxicity or mechanism of toxicity and target tissue effects during prolonged administration of higher doses were hardly given sufficient laboratory attention. The present work was designed to investigate the biochemical and histopathological changes in the liver of rat administered with prolonged doses of lamivudine. Lamivudine in multiple doses of five ranging from 4 mg/kg to 2500 mg/kg were administered, in vitro, by injection into the air-sac of 10-day old fertile embryonated eggs of Gallus domesticus. Also, female rats of the Wistar strain received oral doses, up to 500 mg/kg singly or repeatedly for 15 or 45 days, respectively. Spectrophotometric techniques were employed to monitor activities of the aminotransferases (ALT and AST), γ-glutamyltransferase (GGT) and total protein concentration in serum while activities of glutathione S-transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein were determined in liver. Histopathological studies were carried out on liver. Data were analysed using ANOVA and were considered significant when p < 0.05. The LD50 for the drug calculated from the incubation experiment was 427 mg/kg. Total serum protein concentration significantly reduced while enzymes activities significantly increased at 500 mg/kg only among the repeat-dosed rats. Hepatic GGT, GST and SOD activities as well as MDA concentration were significantly elevated at 20 mg/kg. Histopathological studies showed multifocal lymphoid cell population in the liver sinusoid of the chicken and hydropic degeneration of hepatocytes were recorded among rats repeatedly exposed to the drug respectively at doses ≥ 100 mg/kg. Lamivudine toxicity in rat liver appeared to be mediated by oxidative stress.

  2. Co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection and AIDS.

    PubMed

    Shey, Muki S; Kongnyuy, Eugene J; Alobwede, Samuel M; Wiysonge, Charles Shey

    2013-03-28

    . Overall, there was no significant difference in virological suppression between co-formulated abacavir-lamivudine-zidovudine and NNRTI- or PI-based therapy (4 trials; 2247 participants: RR 0.73, 95% CI 0.39 to 1.36). However, the results showed significant heterogeneity (I(2)=79%); with co-formulated abacavir-lamivudine-zidovudine inferior to NNRTI (1 trial, 1147 participants: RR 0.35, 95%CI 0.26 to 0.49) but with a trend towards co-formulated abacavir-lamivudine-zidovudine being superior to PI (3 trials, 1110 participants: RR 1.07, 95%CI 1.00 to 1.16; I(2)=0%). We found no significant differences between co-formulated abacavir-lamivudine-zidovudine and either PI or NNRTI on CD4+ cell counts (3 trials, 1687 participants: MD -0.01, 95%CI -0.11 to 0.09; I(2)=0%), severe adverse events (4 trials: RR 1.22, 95%CI 0.78 to 1.92; I(2)=62%) and hypersensitivity reactions (4 trials: RR 4.04, 95% CI 0.41 to 40.02; I(2)=72%). Only two studies involving PIs reported data on the lipid profile. One study found that the mean increase in total cholesterol from baseline to 96 weeks was significantly lower with co-formulated abacavir-lamivudine-zidovudine than with nelfinavir, but there were no differences with triglyceride levels. The second study found the fasting lipid profile to be comparable in both co-formulated abacavir-lamivudine-zidovudine and atazanavir arms at 48 weeks.The significant heterogeneity of effects for most outcomes evaluated was largely due to differences in the control therapy used in the included trials (i.e. NNRTIs or PIs). Using the GRADE approach, we rated the overall quality of the evidence on the relative effects of co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection as moderate. The main reason for downgrading the quality of the evidence was imprecision of the findings. The estimate of the treatment effect for each outcome has wide confidence intervals, which extend from the fixed-dose NRTI combination regimen being appreciably

  3. A Reduction Grade of Lipodystrophy and Limited Side Effects after HAART Regimen with Raltegravir, Lamivudine, Darunavir and Ritonavir in an HIV-1 Infected Patient after Six Years of Antiretroviral Therapy

    PubMed Central

    Antoni, A Degli; Weimer, LE; Fragola, V; Giacometti, A; Sozio, F

    2015-01-01

    ABSTRACT HIV-associated lipodystrophy commonly presents with fat loss in the face, buttocks, arms and legs, hypocomplementaemia, glomerulonephritis and autoimmune disorders. The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating that it can be caused by both antiretroviral medications and HIV infection in the absence of antiretroviral medication. Lipodystrophy seems to be mainly due to HIV-1 protease inhibitors. Interference with lipid metabolism is postulated as pathophysiology. Also, the development of lipodystrophy is associated with specific nucleoside reverse transcriptase inhibitors (NRTI). Mitochondrial toxicity is postulated to be involved in the pathogenesis associated with NRTI. Here, we analyse the side effects and examine the impact of the highly active antiretroviral therapy (HAART) regimen including raltegravir, lamivudine, darunavir and ritonavir in an HIV-1 infected patient with severe lipodystrophy after six years of antiretroviral therapy. PMID:26426188

  4. Changes in Proteinuria and Albuminuria with Initiation of Antiretroviral Therapy: Data from a Randomized Trial Comparing Tenofovir Disoproxil Fumarate/Emtricitabine versus Abacavir/Lamivudine

    PubMed Central

    Wyatt, Christina M; Kitch, Douglas; Gupta, Samir K; Tierney, Camlin; Daar, Eric S; Sax, Paul E; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A

    2014-01-01

    Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods We examined changes in urine protein:creatinine (UPCR) and albumin:creatinine (UACR) ratios in 245 ART-naïve participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n=124 or TDF/emtricitabine, TDF/FTC, n=121) with open-label protease inhibitor (PI) atazanavir/ritonavir (ATV/r) or non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV). Results At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥ 200 mg/g) and 11% had clinically significant albuminuria (UACR ≥ 30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold-change in UPCR (p=0.011) and UACR (p=0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold-change in UPCR (p=0.23) or UACR (p=0.88), and no significant interactions between NRTI and NNRTI/PI components. Conclusion In this pre-specified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings. PMID:25117929

  5. Method development and validation for the analysis of didanosine using micellar electrokinetic capillary chromatography.

    PubMed

    Mallampati, Swapna; Leonard, Stefanie; De Vulder, Sabine; Hoogmartens, Jos; Van Schepdael, Ann

    2005-11-01

    A selective MEKC method was developed for the analysis of didanosine in bulk samples. Successful separation of didanosine from 13 of its potential impurities, derived from the various synthetic preparation procedures, was achieved. As CZE gave poor separation selectivity, MEKC was preferable. The use of EKC allowed achievement of the separation in a significantly shorter time than conventional HPLC. An anionic long-chain surfactant, lithium dodecyl sulfate (LiDS), was used as the pseudostationary phase and sodium tetraborate buffer as the aqueous phase. In order to obtain the optimal conditions and to test the method robustness, a central composite response surface modeling experiment was performed. The optimized electrophoretic conditions include the use of an uncoated fused-silica capillary with a total length of 40 cm and an ID of 50 microm, a BGE containing 40 mM sodium tetraborate and 110 mM LiDS at pH 8.0, an applied voltage of 18.0 kV, and the capillary temperature maintained at 15 degrees C. The method was found to be robust. The parameters for validation such as linearity, precision, and sensitivity are also reported. Three commercial bulk samples were analyzed with this system.

  6. Regulating the alky chain length of fatty acid-didanosine prodrugs and evaluating its role in albumin binding.

    PubMed

    Chen, Hongxiang; Wang, Gang; Sun, Lanzhen; Zhang, Huicong; Sun, Mengchi; Sun, Jin; Shang, Lei; Luo, Cong

    2017-09-24

    Rational design of prodrugs for efficient albumin binding shows distinct advantages in drug delivery in terms of drug availability, systemic circulation, and potential targeting effect. And fatty acids are good candidates due to their high affinity to albumin. However, how the alkyl chain length of fatty acids affects the binding dynamics between prodrugs and albumin, despite its importance, is still unclear. In the present study, three prodrugs of didanosine (DDI) and fatty acids were designed and synthesized to evaluate the effect of the alkyl chain length on prodrug-albumin binding process, including capric acid-didanosine (CA-DDI), myristic acid-didanosine (MA-DDI), and stearic acid-didanosine (SA-DDI). The binding dynamics between these prodrugs with bovine serum albumin (BSA) were studied by fluorometry, circular dichroism (CD), UV analysis, and molecular docking. It turned out that DDI itself showed poor binding affinity to BSA. In contrast, CA-DDI, MA-DDI, and SA-DDI demonstrated significantly improved binding affinity. Interestingly, the binding affinity between DDI prodrugs and BSA was correlated with the alkyl chain length of fatty acids, and the binding constant significantly increased with the extension of alkyl chain length (KCA-DDI = 5.86 × 103 M(-1), KMA-DDI = 8.57 × 103 M(-1), and KSA-DDI = 11.42 × 103 M(-1) at 298 K).

  7. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).

    PubMed

    Molina, Jean-Michel; Journot, Valérie; Furco, André; Palmer, Pierre; De Castro, Nathalie; Raffi, François; Morlat, Philippe; May, Thierry; Rancinan, Corinne; Chêne, Geneviève

    2007-01-01

    Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

  8. A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

    PubMed

    Sprenger, H G; Langebeek, N; Mulder, P G H; Ten Napel, C H H; Vriesendorp, R; Hoepelman, A I M; Legrand, J C; Koopmans, P P; Bravenboer, B; Ten Kate, R W; Groeneveld, Php; Bierman, Wfw; van der Werf, Ts; Gisolf, Eh; Richter, C

    2015-02-01

    The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/μL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/μL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI

  9. Improvement of endothelial function after switching previously treated HIV-infected patients to an NRTI-sparing bitherapy with maraviroc.

    PubMed

    Bernal, Enrique; Verdú, Jose Miguel Gomez; Vera, Francisco; Martinez, Onofre; Bravo, Joaquin; Galera, Carlos; Muñoz, Angeles; Garcia, Eva; Serrano, Jose; Perez, Ana; Vera, Carmen; Marín, Irene; Cano, Alfredo

    2014-01-01

    Nucleoside reverse transcriptase inhibitor (NRTI) is associated with endothelial dysfunction and proinflammatory effects. Maraviroc (MVC) is an antagonist of CCR5 receptor. CCR5 is the receptor of RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), a mediator of chronic inflammation and endothelial function. Our aim was to evaluate the maintenance of viral suppression and improvement of endothelial function in virologically suppressed HIV-infected patients switched to an NRTI-sparing combined antiretroviral therapy (cART) with MVC. This observational, non-interventional, multicenter study was performed at the Infectious Diseases Service of Santa Lucia, Morales Meseguer, Virgen de la Arrixaca and Reina Sofía University Hospital (Murcia, Spain). The selection criteria were to be asymptomatic on a regimen with undetectable viral load (<50 HIV-RNA copies/mL) for at least six months, no previous treatment with R5 antagonists, no evidence of previous protease inhibitor (PI) failure and available R5 tropism test. Twenty-one HIV-infected patients were selected after the treatment regimen was changed to Maraviroc 150 mg/once daily plus ritonavir-boosted PI therapy. Endothelial function was prospectively evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline and at weeks 24. We included 21 patients on treatment with PI in combination with 2 NRTI. The mean cART exposition was 133±68.9 months. Fourteen (66.6%) were males, aged 49±9 years, 15 (71.4%) smokers, 4 (19.04%) family history of coronary heart disease, 1 (5.76%) type 2 diabetes and 3 (14.28%) hypertensive, mean total cholesterol was 185.5±35 mg/dL, c-LDL 100.2±37 mg/dL, tryglicerides 170.42±92.03 mg/dL, cHDL 52.6±15.5 mg/dL, CD4 779,5±383.28 cells/mL, nadir CD4 187,96±96 cells/mL. After 24 weeks of follow-up of a switch to an NRTI-sparing regimen, 95.2% of HIV-patients on viral suppressive cART maintained viral suppression and CD4+ T cell count. This cART switch

  10. Improvement of endothelial function after switching previously treated HIV-infected patients to an NRTI-sparing bitherapy with maraviroc

    PubMed Central

    Bernal, Enrique; Miguel Gomez Verdú, Jose; Vera, Francisco; Martinez, Onofre; Bravo, Joaquin; Galera, Carlos; Muñoz, Angeles; Garcia, Eva; Serrano, Jose; Perez, Ana; Vera, Carmen; Marín, Irene; Cano, Alfredo

    2014-01-01

    Introduction Nucleoside reverse transcriptase inhibitor (NRTI) is associated with endothelial dysfunction and proinflammatory effects. Maraviroc (MVC) is an antagonist of CCR5 receptor. CCR5 is the receptor of RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), a mediator of chronic inflammation and endothelial function. Our aim was to evaluate the maintenance of viral suppression and improvement of endothelial function in virologically suppressed HIV-infected patients switched to an NRTI-sparing combined antiretroviral therapy (cART) with MVC. Materials and Methods This observational, non-interventional, multicenter study was performed at the Infectious Diseases Service of Santa Lucia, Morales Meseguer, Virgen de la Arrixaca and Reina Sofía University Hospital (Murcia, Spain). The selection criteria were to be asymptomatic on a regimen with undetectable viral load (<50 HIV-RNA copies/mL) for at least six months, no previous treatment with R5 antagonists, no evidence of previous protease inhibitor (PI) failure and available R5 tropism test. Twenty-one HIV-infected patients were selected after the treatment regimen was changed to Maraviroc 150 mg/once daily plus ritonavir-boosted PI therapy. Endothelial function was prospectively evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline and at weeks 24. Results We included 21 patients on treatment with PI in combination with 2 NRTI. The mean cART exposition was 133±68.9 months. Fourteen (66.6%) were males, aged 49±9 years, 15 (71.4%) smokers, 4 (19.04%) family history of coronary heart disease, 1 (5.76%) type 2 diabetes and 3 (14.28%) hypertensive, mean total cholesterol was 185.5±35 mg/dL, c-LDL 100.2±37 mg/dL, tryglicerides 170.42±92.03 mg/dL, cHDL 52.6±15.5 mg/dL, CD4 779,5±383.28 cells/mL, nadir CD4 187,96±96 cells/mL. After 24 weeks of follow-up of a switch to an NRTI-sparing regimen, 95.2% of HIV-patients on viral suppressive cART maintained viral

  11. Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery.

    PubMed

    Jain, Sanjay K; Gupta, Yashwant; Jain, Anekant; Saxena, Asheesh R; Khare, Piush; Jain, Aviral

    2008-03-01

    The present investigation was aimed at developing and exploring the use of mannosylated gelatin nanoparticles for the selective delivery of an anti-HIV drug, didanosine, to the target organs. The mannosylated gelatin nanoparticles (MN-G-NPs) were prepared using a two-step desolvation technique and coupled with mannose using the amino group of gelatin present on the surface of nanoparticles. The mannosylation was confirmed using infrared and nuclear magnetic resonance spectroscopy. MN-G-NPs were characterized for shape, particle size, zeta potential, and percentage drug entrapment. The size of nanoparticles was found to be in range of 248-325 nm, and maximum drug payload was found to be 40.2% to 48.5%. Average size was found to be more, but drug payload was less in the case of MN-G-NPs as compared with unconjugated nanoparticles (G-NPs). The results of the in vitro release profile demonstrated that G-NPs release a comparatively higher percentage of drug than MN-G-NPs. Cellular uptake by MN-G-NPs was 2.7 times more as compared with G-NPs. Fluorescence studies revealed the enhanced uptake of MN-G-NPs in the macrophage tissues when compared with unmodified G-NPs. Intravenous administration of free-drug solution resulted in a high concentration of drug in serum, whereas it was much less in the case of G-NPs. Coupling of the nanoparticles with mannose significantly enhanced the lung, liver, and lymph nodes uptake of drug, which is reflected in the recovery of a higher percentage of the dose from these organs following administration of MN-G-NPs in comparison to noncoupled G-NPs or free drug.

  12. Investigating the effect of Aloe vera gel on the buccal permeability of didanosine.

    PubMed

    Ojewole, Elizabeth; Mackraj, Irene; Akhundov, Kamil; Hamman, Josias; Viljoen, Alvaro; Olivier, Eugene; Wesley-Smith, James; Govender, Thirumala

    2012-03-01

    The buccal mucosal route offers several advantages but the delivery of certain drugs can be limited by low membrane permeability. This study investigated the buccal permeability properties of didanosine (ddI) and assessed the potential of Aloe vera gel (AVgel) as a novel buccal permeation enhancer. Permeation studies were performed using Franz diffusion cells, and the drug was quantified by UV spectroscopy. Histomorphological evaluations were undertaken using light and transmission electron microscopy. The permeability of ddI was concentration-dependent, and it did not have any adverse effects on the buccal mucosae. A linear relationship (R² = 0.9557) between the concentrations and flux indicated passive diffusion as the mechanism of drug transport. AVgel at concentrations of 0.25 to 2 %w/v enhanced ddI permeability with enhancement ratios from 5.09 (0.25 %w/v) to 11.78 (2 %w/v) but decreased permeability at 4 and 6 %w/v. Ultrastructural analysis of the buccal mucosae treated with phosphate buffer saline pH 7.4 (PBS), ddI/PBS, and ddI/PBS/AVgel 0.5 %w/v showed cells with normal plasmalemma, well-developed cristae, and nuclei with regular nuclear envelopes. However, cells from 1, 2, and 6 %w/v AVgel-treated mucosae showed irregular nuclear outlines, increased intercellular spacing, and plasmalemma crenulations. This study demonstrates the potential of AVgel as a buccal permeation enhancer for ddI to improve anti-HIV and AIDS therapy.

  13. Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine.

    PubMed

    Benito, José Miguel; López, Mariola; Ballesteros, Celia; Lozano, Sara; Capa, Laura; Barreiro, Pablo; Sempere, José; Gonzalez-Lahoz, Juan; Soriano, Vincent

    2006-08-01

    Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.

  14. Biowaiver monographs for immediate release solid oral dosage forms: lamivudine.

    PubMed

    Strauch, S; Jantratid, E; Dressman, J B; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2011-06-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfills the BCS dissolution criteria for very rapidly dissolving; a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.

  15. Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study.

    PubMed

    Landman, R; Descamps, D; Peytavin, G; Trylesinski, A; Katlama, C; Girard, P M; Bonnet, B; Yeni, P; Bentata, M; Michelet, C; Benalycherif, A; Brun Vezinet, F; Miller, M D; Flandre, P

    2005-01-01

    To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA < 400 copies/mL or rebound of > or = 0.7 log10. 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA > 50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels < 4, 4-5, and > 5 log10 copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma Cmin for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (< 50 copies/mL; median follow-up 48 weeks). Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.

  16. Lamivudine treatment in patients with chronic hepatitis B and cirrhosis.

    PubMed

    Haché, Chantal; Villeneuve, Jean-Pierre

    2006-09-01

    Chronic hepatitis B is a common disease and approximately 20% of infected patients with compensated cirrhosis will decompensate over 5 years. If untreated, the survival of decompensated cirrhosis is poor (15% at 5 years). The extent of hepatitis B virus (HBV) replication, as assessed by serum HBV-DNA level, is a strong predictor of the risk of disease progression and hepatocellular carcinoma. This provides a rationale for antiviral therapy to arrest progression of liver disease. Lamivudine is a pyrimidine analogue that inhibits HBV-DNA reverse transcriptase. It decreases HBV replication, normalises alanine aminotransferase levels and reduces hepatic inflammation and fibrosis in patients with chronic hepatitis B. This article will focus on the use of lamivudine in patients with HBV-cirrhosis. In patients with compensated HBV-cirrhosis, a randomised, placebo-controlled trial has shown that lamivudine significantly reduced the rate of disease progression and hepatocellular carcinoma development over a 3-year period. In patients with decompensated cirrhosis, treatment with lamivudine can produce spectacular improvements of liver function, but the improvement is slow and a clinical benefit is usually not observed until after at least 3-6 months of treatment. A major drawback of lamivudine treatment is the development of resistance, observed in 15-20% of patients after 1 year and up to 70% after 5 years of continued treatment. Thus, patients with HBV-cirrhosis treated with lamivudine should have regular monitoring of serum HBV-DNA levels and prompt institution of additional antiviral therapy if viral breakthrough is observed. Adefovir, tenofovir and entecavir have demonstrated efficacy in patients with lamivudine resistance. In patients with decompensated cirrhosis, in whom the development of resistance can be fatal, combination therapy (such as lamivudine plus adefovir) may prove more effective than monotherapy and this issue needs further study.

  17. High-Level Cross-Resistance to Didanosine Observed in South African Children Failing an Abacavir- or Stavudine-Based 1st-Line Regimen

    PubMed Central

    Steegen, Kim; Levin, Leon; Ketseoglou, Irene; Bronze, Michelle; Papathanasopoulos, Maria A.; Carmona, Sergio; Stevens, Wendy

    2014-01-01

    Background The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure. Methods A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions. Results Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%). Conclusion Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens. PMID:24816790

  18. Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis

    SciTech Connect

    Divi, Rao L.; Doerge, Daniel R.; Twaddle, Nathan C.; Shockley, Marie E.; St Claire, Marisa C.; Harbaugh, Jeffrey W.; Harbaugh, Steven W.; Poirier, Miriam C.

    2008-01-15

    Because of their similarity to humans, non-human primates constitute useful preclinical models in which to examine potential human drug toxicities. Antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) toxicity is currently under investigation in Erythrocebus patas monkeys, and whereas NRTI pharmacokinetics have been studied in other monkey species, pharmacokinetics for Zidovudine plus Lamivudine (AZT/3TC) dosing have not been reported in the patas. Here we present 24 h serum pharmacokinetic parameters after a single oral exposure to the combination of AZT (40 mg) and 3TC (24 mg), doses equivalent to a human daily dose of Combivir (registered) . The patas (n = 3) AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations (C{sub max}) for AZT and 3TC were 2.35 and 2.65 {mu}g/ml, respectively, and were observed at 0.83 h (T{sub max}). C{sub max} was 13.34 {mu}g/ml for the AZT-glucuronide (AZT-G) and was 0.023 {mu}g/ml for the potentially toxic minor metabolite 3'-amino-3'-deoxythymidine (AMT), both occurring at about 1 h after dosing. Similar elimination half-times, 0.70 and 0.68 h{sup -1}, were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h{sup -1}) resulting in AUC{sub (0-{infinity})} values of 6.97 {mu}g/ml h for 3TC, 2.99 {mu}g/ml h for AZT, 20.5 {mu}g/ml h for AZT-G and 0.002 for AMT 6.97 {mu}g/ml h. This study shows similar metabolism and pharmacokinetics for oral administration of AZT/3TC in the adult patas monkey, other primate species and humans. The data validate the use of the patas monkey for studies of NRTI toxicity.

  19. Connection Subdomain Mutations in HIV-1 Subtype-C Treatment-Experienced Patients Enhance NRTI and NNRTI Drug Resistance

    PubMed Central

    Delviks-Frankenberry, Krista A.; Lengruber, Renan B.; Santos, Andre F.; Silveira, Jussara M.; Soares, Marcelo A.; Kearney, Mary F.; Maldarelli, Frank; Pathak, Vinay K.

    2012-01-01

    Mutations in the connection subdomain (CN) and RNase H domain (RH) of HIV-1 reverse transcriptase (RT) from subtype B-infected patients enhance nucleoside and nonnucleoside RT inhibitor (NRTI and NNRTI) resistance by affecting the balance between polymerization and RNase H activity. To determine whether CN mutations in subtype C influence drug sensitivity, single genome sequencing was performed on Brazilian subtype C-infected patients failing RTI therapy. CN mutations identified were similar to subtype B, including A376S, A400T, Q334D, G335D, N348I, and A371V, and increased AZT resistance in the presence of thymidine analog mutations. CN mutations also enhanced NNRTI resistance in the presence of classical NNRTI mutations: etravirine resistance was enhanced 6- to 11-fold in the presence of L100I/K103N/Y181C. These results indicate that selection of CN mutations in treatment-experienced patients also occurs in subtype-C-infected patients and are likely to provide valuable information in predicting clinical RTI resistance. PMID:23068886

  20. Tropical spastic paraparesis treated with Combivir (lamivudine-zidovudine).

    PubMed

    Hassan, Syed; Amer, Syed; Zervos, Marcus

    2013-05-01

    Tropical spastic paraparesis (TSP) or human T-cell leukemia virus-type 1 (HTLV-I)-associated myelopathy is caused by human T-lymphotropic virus type 1. It is a slow, progressive spastic paraparesis with significant morbidity and causing profound repercussions on quality of life. No therapies have been found to persistently improve the outcome in these patients. We present a patient with HTLV-1-associated myelopathy/TSP (HAM/TSP) who was treated with Combivir (lamivudine-zidovudine, GlaxoSmithKline, London, UK). She was walker-dependent for several years but, soon after treatment with lamivudine-zidovudine, was able to walk using only a cane. The role of lamivudine-zidovudine should be investigated further in this patient population. Published by Elsevier Ltd.

  1. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.

    PubMed

    Villeneuve, J P; Condreay, L D; Willems, B; Pomier-Layrargues, G; Fenyves, D; Bilodeau, M; Leduc, R; Peltekian, K; Wong, F; Margulies, M; Heathcote, E J

    2000-01-01

    The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)-DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV-DNA in serum. Ten had Child-Pugh class B and 25 had Child-Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean = 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 +/- 13 to 30 +/- 4 micromol/L (P <.05, baseline vs. 9 months), an increase in serum albumin from 27 +/- 1 to 34 +/- 1g/L (P <.05), and a decrease in Child-Pugh score from 10.3 +/- 0.4 to 7.5 +/- 0.5 (P <.05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long-term benefits remain uncertain.

  2. Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study

    PubMed Central

    Logan, Sarah; Rodger, Alison; Maynard-Smith, Laura; O’Beirne, James; Fernandez, Thomas; Ferro, Filippo; Smith, Colette; Bhagani, Sanjay

    2016-01-01

    AIM To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients. METHODS Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment. RESULTS Ninety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis (n = 6), normal architecture (n = 4) and NRH (n = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%). CONCLUSION A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population. PMID:28083085

  3. Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study.

    PubMed

    Logan, Sarah; Rodger, Alison; Maynard-Smith, Laura; O'Beirne, James; Fernandez, Thomas; Ferro, Filippo; Smith, Colette; Bhagani, Sanjay

    2016-12-28

    To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients. Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment. Ninety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis (n = 6), normal architecture (n = 4) and NRH (n = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%). A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population.

  4. Evaluation of the Activity of Lamivudine and Zidovudine against Ebola Virus

    PubMed Central

    Hart, Brit J.; DeWald, Lisa Evans; Johnson, Joshua C.; Postnikova, Elena; Zhou, Huanying; Gross, Robin; Rojas, Oscar; Alexander, Isis; Josleyn, Nicole; Zhang, Tengfei; Michelotti, Julia; Janosko, Krisztina; Glass, Pamela J.; Flint, Mike; McMullan, Laura K.; Spiropoulou, Christina F.; Mierzwa, Tim; Guha, Rajarshi; Shinn, Paul; Michael, Sam; Klumpp-Thomas, Carleen; McKnight, Crystal; Thomas, Craig; Eakin, Ann E.; O’Loughlin, Kathleen G.; Green, Carol E.; Catz, Paul; Mirsalis, Jon C.; Honko, Anna N.; Olinger, Gene G.; Bennett, Richard S.; Holbrook, Michael R.; Hensley, Lisa E.; Jahrling, Peter B.

    2016-01-01

    In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD

  5. Evaluation of the Activity of Lamivudine and Zidovudine against Ebola Virus.

    PubMed

    Cong, Yu; Dyall, Julie; Hart, Brit J; DeWald, Lisa Evans; Johnson, Joshua C; Postnikova, Elena; Zhou, Huanying; Gross, Robin; Rojas, Oscar; Alexander, Isis; Josleyn, Nicole; Zhang, Tengfei; Michelotti, Julia; Janosko, Krisztina; Glass, Pamela J; Flint, Mike; McMullan, Laura K; Spiropoulou, Christina F; Mierzwa, Tim; Guha, Rajarshi; Shinn, Paul; Michael, Sam; Klumpp-Thomas, Carleen; McKnight, Crystal; Thomas, Craig; Eakin, Ann E; O'Loughlin, Kathleen G; Green, Carol E; Catz, Paul; Mirsalis, Jon C; Honko, Anna N; Olinger, Gene G; Bennett, Richard S; Holbrook, Michael R; Hensley, Lisa E; Jahrling, Peter B

    2016-01-01

    In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD.

  6. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine.

    PubMed

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-25

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm(-1) represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  7. Effects of OCT2 c.602C > T genetic variant on the pharmacokinetics of lamivudine.

    PubMed

    Choi, Chang-Ik; Bae, Jung-Woo; Keum, Seul-Ki; Lee, Yun-Jeong; Lee, Hye-In; Jang, Choon-Gon; Lee, Seok-Yong

    2013-07-01

    1. The renal excretion of organic cation drugs, including lamivudine, is mostly mediated by OCT2 in vitro. To date, three putatively relevant single nucleotide polymorphisms (SNPs), including c.596C > T (p.Thr199Ile), c.602C > T (p.Thr201Met), and c.808G > T (p.Ala270Ser) have been observed in Asians. The effects of the SLC22A2 c.602C > T genetic variant on the pharmacokinetics of lamivudine were studied with healthy Korean subjects. 2. Nineteen healthy subjects carrying either the SLC22A2 c.602CC (n = 12) or c.602CT (n = 7) genotype volunteered for this study. A single 100 mg dose of lamivudine was orally administered to each subject. Blood samples were collected for up to 24 h and the plasma concentrations of lamivudine were measured using liquid chromatography-tandem mass spectrometry. 3. The mean plasma concentration-time profiles of lamivudine in the c.602CC and c.602CT genotype groups were similar. There was no significant difference in the overall pharmacokinetic parameters of lamivudine between the c.602CC and c.602CT genotype groups. Differences in renal clearance and tubular secretion clearance were also not statistically significant between the two genotype groups. 4. The SLC22A2 c.602C > T genotype did not affect the pharmacokinetics of lamivudine in humans in vivo. Dose adjustment of lamivudine is not required between individuals with c.602CC and c.602CT genotypes.

  8. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine

    NASA Astrophysics Data System (ADS)

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-01

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm-1 represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  9. High Dose of Lamivudine and Resistance in Patients with Chronic Hepatitis B

    PubMed Central

    Wani, Hamid Ullah; Al Kaabi, Saad; Singh, Rajvir; John, Anil; Derbala, Moutaz; Al-Mohannadi, Muneera J.

    2014-01-01

    Background. Lamivudine is the most affordable drug used for chronic hepatitis B and has a high safety profile. With the daily dose of 100 mg there is progressive appearance of resistance to lamivudine therapy. In our study we used 150 mg of lamivudine daily as a standard dose which warrants further exploration for the efficacy of the drug. Aims of the Study. To assess the efficacy of lamivudine 150 mg daily on resistance in patients with chronic hepatitis B. Methods. This retrospective study consists of 53 patients with chronic hepatitis B treated with 150 mg of lamivudine daily. The biochemical and virological response to the treatment were recorded at a 1-year and 2-, 3-, 4-, and 5-year period and time of emergence of resistance to the treatment was noted. Results. The mean age of the patients was 54 years with 80% being males. The resistance to lamivudine 150 mg daily at 1 year and 2, 3, and 5 years was 12.5%, 22.5%, 37.5%, and 60%, respectively, which is much less compared to the standard dose of 100 mg of lamivudine. Conclusions. Lamivudine is safe and a higher dose of 150 mg daily delays the resistance in patients with chronic hepatitis B. PMID:25349729

  10. High dose of Lamivudine and resistance in patients with chronic hepatitis B.

    PubMed

    Wani, Hamid Ullah; Al Kaabi, Saad; Sharma, Manik; Singh, Rajvir; John, Anil; Derbala, Moutaz; Al-Mohannadi, Muneera J

    2014-01-01

    Background. Lamivudine is the most affordable drug used for chronic hepatitis B and has a high safety profile. With the daily dose of 100 mg there is progressive appearance of resistance to lamivudine therapy. In our study we used 150 mg of lamivudine daily as a standard dose which warrants further exploration for the efficacy of the drug. Aims of the Study. To assess the efficacy of lamivudine 150 mg daily on resistance in patients with chronic hepatitis B. Methods. This retrospective study consists of 53 patients with chronic hepatitis B treated with 150 mg of lamivudine daily. The biochemical and virological response to the treatment were recorded at a 1-year and 2-, 3-, 4-, and 5-year period and time of emergence of resistance to the treatment was noted. Results. The mean age of the patients was 54 years with 80% being males. The resistance to lamivudine 150 mg daily at 1 year and 2, 3, and 5 years was 12.5%, 22.5%, 37.5%, and 60%, respectively, which is much less compared to the standard dose of 100 mg of lamivudine. Conclusions. Lamivudine is safe and a higher dose of 150 mg daily delays the resistance in patients with chronic hepatitis B.

  11. Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

    PubMed Central

    Ceckova, Martina; Reznicek, Josef; Ptackova, Zuzana; Cerveny, Lukas; Müller, Fabian; Kacerovsky, Marian; Fromm, Martin F.; Glazier, Jocelyn D.

    2016-01-01

    Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport. PMID:27401571

  12. Seroclearance of Hbsag in Chronic Hepatitis B Virus Patients on Lamivudine Therapy: A 10 Year Experience

    PubMed Central

    Sali, Shahnaz; Merza, Muayad A.; Saadat, Sina; Mustafa, Nazik H.; Queiky, Farzam; Yadegarynia, Davood

    2015-01-01

    Introduction: The aim of this study was to determine hepatitis B surface antigen (HBsAg) seroclearance rate among patients treated with lamivudine at a specialized tertiary care referral hospital in Tehran, Iran. Methods: All patients on lamivudine (biovudin®) therapy at a dose of 100 mg/day, who showed seroclearnace between March 2001 and September 2011 were recruited. The main evaluation parameters were duration of HBsAg seroclearance and duration of HBsAg seroconversion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using standard methods. HBsAg seroclearance was defined as two consecutive negative serums HBsAg at least 6 months apart, whereas HBsAg seroconversion was defined as the disappearance of serum HBsAg and the presence of anti-HBs for >6 months. Results: A total of 203 chronic HBV patients treated with lamivudine at a dose of 100 mg/day were included in the study. HBsAg seroclearance and seroconversion were observed in 11 patients after the initiation of the lamivudine therapy. Overall, in lamivudine responder patients, the mean time to HBsAg seroclearance was 26.90±10.93 months (range: 12-48 months). Furthermore, the responders showed seroconversion after a mean time of 26.90±11.08 months from the initiation of lamivudine therapy. When comparing the characteristics of those who have responded to lamivudine and those who have not responded, baseline HBV-DNA levels was significantly lower in responder than non responder patients (p<0.001). Meantime, there was no difference in age, sex, baseline ALT, AST and liver biopsy score between lamivudine responder and lamivudine non-responder patients. Conclusion: Despite introduction of tenofovir and entecavir as first line treatment for chronic HBV infection, lamivudine remains to be a low cost, safe and effective drug for HBsAg seroclearnace. PMID:26153167

  13. Design and study of lamivudine oral controlled release tablets.

    PubMed

    Ravi, Punna Rao; Ganga, Sindhura; Saha, Ranendra Narayan

    2007-12-07

    The objective of this study was to design oral controlled release matrix tablets of lamivudine using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, and compression force on the in vitro release of drug. In vitro release studies were performed using US Pharmacopeia type 1 apparatus (basket method) in 900 mL of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using the zero-order model equation, Higuchi's square-root equation, and the Ritger-Peppas empirical equation. Compatibility of the drug with various excipients was studied. In vitro release studies revealed that the release rate decreased with increase in polymer proportion and viscosity grade. Increase in compression force was found to decrease the rate of drug release. Matrix tablets containing 60% HPMC 4000 cps were found to show good initial release (26% in first hour) and extended the release up to 16 hours. Matrix tablets containing 80% HPMC 4000 cps and 60% HPMC 15,000 cps showed a first-hour release of 22% but extended the release up to 20 hours. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets was dependent on drug diffusion and polymer relaxation and therefore followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of lamivudine, with good initial release (20%-25% in first hour) and extension of release up to 16 to 20 hours, can overcome the disadvantages of conventional tablets of lamivudine.

  14. Azvudine, A Novel Nucleoside Reverse Transcriptase Inhibitor Showed Good Drug Combination Features and Better Inhibition on Drug-Resistant Strains than Lamivudine In Vitro

    PubMed Central

    Wang, Rui-Rui; Yang, Qing-Hua; Luo, Rong-Hua; Peng, You-Mei; Dai, Shao-Xing; Zhang, Xing-Jie; Chen, Huan; Cui, Xue-Qing; Liu, Ya-Juan; Huang, Jing-Fei; Chang, Jun-Biao; Zheng, Yong-Tang

    2014-01-01

    Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC50s ranging from 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range. PMID:25144636

  15. Effect of coadministration of neurovite and Lamivudine on the histomorphology of the cerebellum of wistar rats.

    PubMed

    Peter, A I; Ekong, M B; Davies, K; Azu, O O; Bassey, R B; Ugwu, L O; Umoh, I U

    2014-01-01

    Introduction. Lamivudine is a nucleoside reverse transcriptase inhibitor antiretroviral agent used in the treatment of human immunodeficiency virus type 1 infection. This study was to investigate the effects of coadministration of neurovite and lamivudine on the histomorphology of the cerebellum of Wistar rats. Materials and Methods. Twenty Wistar rats were divided equally into four groups. Group A animals were the control treated with distilled water. Groups B, C, and D animals were treated, respectively, with therapeutic dose of lamivudine (4.28 mg/kg), a combination of lamivudine (4.28 mg/kg) and neurovite (7.05 mg/kg), and neurovite (7.05 mg/kg) alone, daily. The rats were sacrificed using chloroform inhalation, processed, and stained using H&E method. Results. There was severe cellular degeneration with dystrophic changes, vacuolization in the molecular and granular layers, and aggregation of swollen Purkinje cells in group B animals compared with group C animals which showed only slight cellular dystrophy and inflammation. The mean cellular population was significantly (P < 0.05) higher in the treatment groups compared with the control. Conclusion. There was amelioration of damage of the cerebellum in the animals treated with neurovite and lamivudine combination compared to animals treated with only lamivudine. Therefore, there is need to give neurovite to patients on lamivudine therapy.

  16. Effect of Coadministration of Neurovite and Lamivudine on the Histomorphology of the Cerebellum of Wistar Rats

    PubMed Central

    Peter, A. I.; Ekong, M. B.; Davies, K.; Azu, O. O.; Bassey, R. B.; Ugwu, L. O.; Umoh, I. U.

    2014-01-01

    Introduction. Lamivudine is a nucleoside reverse transcriptase inhibitor antiretroviral agent used in the treatment of human immunodeficiency virus type 1 infection. This study was to investigate the effects of coadministration of neurovite and lamivudine on the histomorphology of the cerebellum of Wistar rats. Materials and Methods. Twenty Wistar rats were divided equally into four groups. Group A animals were the control treated with distilled water. Groups B, C, and D animals were treated, respectively, with therapeutic dose of lamivudine (4.28 mg/kg), a combination of lamivudine (4.28 mg/kg) and neurovite (7.05 mg/kg), and neurovite (7.05 mg/kg) alone, daily. The rats were sacrificed using chloroform inhalation, processed, and stained using H&E method. Results. There was severe cellular degeneration with dystrophic changes, vacuolization in the molecular and granular layers, and aggregation of swollen Purkinje cells in group B animals compared with group C animals which showed only slight cellular dystrophy and inflammation. The mean cellular population was significantly (P < 0.05) higher in the treatment groups compared with the control. Conclusion. There was amelioration of damage of the cerebellum in the animals treated with neurovite and lamivudine combination compared to animals treated with only lamivudine. Therefore, there is need to give neurovite to patients on lamivudine therapy. PMID:24967314

  17. Efficacy and safety of one-month postpartum zidovudine and didanosine to prevent HIV-resistance mutations following intrapartum single-dose nevirapine

    PubMed Central

    Lallemant, Marc; Ngo-Giang-Huong, Nicole; Jourdain, Gonzague; Traisaithit, Patrinee; Cressey, Tim R.; Collins, Intira J.; Jarupanich, Tapnarong; Sukhumanant, Thammanoon; Achalapong, Jullapong; Sabsanong, Prapan; Chotivanich, Nantasak; Winiyakul, Narong; Ariyadej, Surabon; Kanjanasing, Annop; Ratanakosol, Janyaporn; Hemvuttiphan, Jittapol; Kengsakul, Karun; Wannapira, Wiroj; Sittipiyasakul, Veerachai; Pornkitprasarn, Witaya; Liampongsabuddhi, Prateung; McIntosh, Kenneth; Van Dyke, Russell B.; Frenkel, Lisa M.; Koetsawang, Suporn; Le Coeur, Sophie

    2009-01-01

    Background Intrapartum single-dose-nevirapine along with third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child HIV transmission in resource-limited settings. The persistence of nevirapine in the plasma for three weeks postpartum risks selection of resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTI). We hypothesized that a one-month zidovudine-plus-didanosine course initiated at the same time as single-dose nevirapine would prevent the selection of nevirapine resistance mutations. Methods PHPT-4 HIV-infected pregnant women with CD4 counts above 250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, single-dose nevirapine during labor and one-month zidovudine-plus-didanosine postpartum. These women were matched on baseline viral load (VL), CD4 count and duration of antepartum zidovudine to women who received single-dose nevirapine in the PHPT-2 trial (controls). Consensus sequencing and the more sensitive oligonucleotide ligation assay (OLA) were performed on samples drawn at 7–10, 37–45 and 120 days postpartum (if VL>500 copies/mL) to detect K103N/Y181C/G190A mutations. Results The 222 PHPT-4 subjects did not differ from their matched controls in baseline characteristics except for age. Combined groups median CD4 count was 421 cells/mm3 [IQR: 322–549], VL 3.45 log10 copies/mL [2.79–4.00] and ZDV prophylaxis 10.4 weeks [9.1–11.4]. Using consensus sequencing, major NNRTI resistance mutations were detected postpartum in 0% of PHPT-4 subjects versus 10.4% of PHPT-2 controls. OLA detected resistance in 1.8% of PHPT-4 subjects versus 18.9% controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects versus 20.7% in controls (p<10−10). Conclusions One-month postpartum zidovudine-plus-didanosine prevented the selection of vast majority NNRTI resistance mutations. PMID:20158398

  18. Formulation and evaluation of ethosomes for transdermal delivery of lamivudine.

    PubMed

    Jain, Subheet; Tiwary, Ashok K; Sapra, Bharti; Jain, Narendra K

    2007-12-21

    The purpose of the present research was to investigate the mechanism for improved intercellular and intracellular drug delivery from ethosomes using visualization techniques and cell line study. Ethosomal formulations were prepared using lamivudine as model drug and characterized in vitro, ex vivo and in vivo. Transmission electron microscopy, scanning electron microscopy, and fluorescence microscopy were employed to determine the effect of ethosome on ultrastructure of skin. Cytotoxicity and cellular uptake of ethosome were determined using T-lymphoid cell line (MT-2). The optimized ethosomal formulation showed 25 times higher transdermal flux (68.4 +/- 3.5 microg/cm(2)/h) across the rat skin as compared with that of lamivudine solution (2.8 +/- 0.2 microg/cm(2)/h). Microscopic studies revealed that ethosomes influenced the ultrastructure of stratum corneum. Distinct regions with lamellar stacks derived from vesicles were observed in intercellular region of deeper skin layers. Results of cellular uptake study showed significantly higher intracellular uptake of ethosomes (85.7% +/- 4.5%) as compared with drug solution (24.9% +/- 1.9%). The results of the characterization studies indicate that lipid perturbation along with elasticity of ethosomes vesicles seems to be the main contributor for improved skin permeation.

  19. Lamivudine treatment for hepatitis B in dialysis population : case reports and literature review.

    PubMed

    Fabrizi, F; Mangano, S; Stellato, T; Martin, P; Messa, P

    2013-12-01

    It is well known that chronic hepatitis B plays a detrimental role on survival in patients on long-term dialysis and after kidney transplantation. The advent of nucleos(t)ide analogues offers the opportunity to change the natural history of hepatitis B in patients with chronic kidney disease. We report our experience on lamivudine use in two patients with HBV-related liver disease on long-term dialysis. At the beginning, both the patients were HBsAg positive and HBeAg positive with high viral load; after long-term lamivudine therapy, clearance of HBV viremia from serum was observed in both. Raised aminotransferase levels fell into the normal range and one patient experienced clearance of HBsAg by anti-HBV therapy. Tolerance to lamivudine was satisfactory and lamivudine resistance was not detected. Information on antiviral therapy with lamivudine in HBsAg positive patients on regular dialysis is extremely limited; we identified by an extensive review of the literature five studies with a total of 38 unique patients, most of them being renal transplant candidates. Lamivudine proved to be effective as the clearance of HBV viraemia from serum ranged between 56% and 100% ; the clearance of HBeAg from serum was less evident (between 37.5% and 100%). No significant side-effects due to lamivudine were observed and emergence of lamivudine-resistant strains was observed in two (5%) patients. Only a minority of patients experienced HBsAg loss (13%). We conclude that anti-HBV treatment with a nucleoside analogue such as lamivudine gives satisfactory results in some patients on long-term dialysis. Clinical trials are in progress to assess efficacy and safety of last-generation nucleos(t)ide analogues for anti-HBV therapy in dialysis population.

  20. Development and validation of an oligonucleotide ligation assay to detect lamivudine resistance in hepatitis B virus.

    PubMed

    Beck, Ingrid A; Payant, Rachel; Ngo-Giang-Huong, Nicole; Khamduang, Woottichai; Laomanit, Laddawan; Jourdain, Gonzague; Frenkel, Lisa M

    2016-07-01

    Treatment of chronic hepatitis B virus (HBV) infection with lamivudine-monotherapy rapidly selects mutant variants in a high proportion of individuals. Monitoring lamivudine resistance by consensus sequencing is costly and insensitive for detection of minority variants. An oligonucleotide ligation assay (OLA) for HBV lamivudine-resistance was developed and compared to consensus sequencing. Both assays detected drug resistance mutations in 35/64 (54.7%) specimens evaluated, and OLA detected minority mutants in an additional six (9.4%). OLA may offer a sensitive and inexpensive alternative to consensus sequencing for detection of HBV drug resistance in resource-limited settings.

  1. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food.

    PubMed

    Weller, Stephen; Chen, Shuguang; Borland, Julie; Savina, Paul; Wynne, Brian; Piscitelli, Stephen C

    2014-08-01

    The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.

  2. Lamivudine is not effective in primary Sjögren's syndrome

    PubMed Central

    Gescuk, B; Wu, A; Whitcher, J; Daniels, T; Lund, S; Fye, K; Davis, J

    2005-01-01

    Background: Retroviral infection has been implicated in the pathogenesis of primary Sjögren's syndrome. Objective: To examine the efficacy of the reverse transcriptase inhibitor lamivudine in patients with this syndrome. Methods: 16 patients with primary Sjögren's syndrome were randomised to receive either lamivudine 150 mg twice daily or placebo for three months. Measures of lacrimal and salivary function, including minor salivary gland biopsies, were obtained before and after treatment. Results: Treatment with lamivudine did not result in significant improvement in the primary outcome measure of unstimulated whole salivary flow or other secondary measures, including minor salivary gland biopsy focus scores. Conclusion: Lamivudine is not effective in patients with primary Sjögren's syndrome, suggesting either that a retroviral aetiology is not present or that it may be important only in early disease. PMID:15708886

  3. Lactic acidosis in HIV infected patients: a systematic review of published cases

    PubMed Central

    Arenas-Pinto, A; Grant, A; Edwards, S; Weller, I

    2003-01-01

    Methods: Systematic review of cases reported in the medical literature. Results: 217 published cases were identified, 90 of which fulfilled the study definition and had sufficient individual data on potential risk factors to be included. The 90 patients had a mean age of 40.1 years (range 16–69) and 53% were female. All 90 patients were taking nucleoside reverse transcriptase inhibitors (NRTI) at the time of the episode. Among the 83 patients with details of their antiretroviral therapy (ART) regimen 51 patients were taking stavudine, 29 zidovudine, 27 didanosine, and 25 lamivudine. Around 50% of the patients had abdominal pain, nausea, or vomiting. Hepatic steatosis was consistently reported (53/90) and in 36 (68%) there was histological evidence. The case fatality rate was 48%. Six cases were rechallenged with NRTI and three developed a further LA episode. Using data on the numbers of HIV infected individuals receiving care in the United States, we estimate that the risk of LA could be 2.5 times higher for women than men. Conclusions: NRTI use and female sex appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include duration of NRTI therapy, specific drug use, and genetic predisposition. A case-control study is needed to better define risk factors for severe LA. PMID:12902594

  4. Selective extraction of lamivudine in human serum and urine using molecularly imprinted polymer technique.

    PubMed

    Shekarchi, Maryam; Pourfarzib, Mojgan; Akbari-Adergani, Behrouz; Mehramizi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul

    2013-07-15

    In this work, a novel technique is described for determination of lamivudine in biological fluids by molecularly imprinted polymers (MIPs) as the sample clean-up method joint with high performance liquid chromatography (HPLC). MIPs were prepared using methacrylic acid as functional monomer, ethylene glycol dimethacrylate as crosslinker, acetonitrile and tetrahydrofuran as porogen and lamivudine as the template molecule. The new imprinted polymer was used as a molecular sorbent for the separation of lamivudine from human serum and urine. Molecular recognition properties, binding capacity and selectivity of the MIPs were evaluated and the results showed that the obtained MIPs have a high affinity for lamivudine in aqueous medium. HPLC analyses showed that the extraction of lamivudine from serum and urine by MIPs had a linear calibration curve in the range of 60-700μg/L with excellent precisions of 2.73% for serum and 2.60% for urine. The limit of detection and quantization of lamivudine was 19.34 and 58.6μg/L in serum and 7.95 and 24.05μg/L in urine respectively. MIP extraction provided about 10 fold LOQ improvement in serum and 5 fold LOQ improvement in urine samples. The recoveries of lamivudine in serum and urine samples were found to be 84.2-93.5% and 82.5-90.8% respectively. Due to the high precision and accuracy, this method may be the UV-HPLC choice with MIP extraction for bioequivalence analysis of lamivudine in serum and urine.

  5. Cathodic adsorptive stripping voltammetric studies on lamivudine: an antiretroviral drug.

    PubMed

    Jain, Rajeev; Jadon, Nimisha; Radhapyari, Keisham

    2007-09-01

    The electrochemical reduction and adsorption of lamivudine, a systemic antiviral drug, were studied in a phosphate buffer medium at a hanging mercury drop electrode (HMDE). Cyclic voltammetry studies showed one well-defined reduction peak in the potential range from -1.2 to -1.8 V under different pH conditions, but the best results were obtained at pH 3.4. The reduction was irreversible and exhibited diffusion-controlled adsorption. The response was evaluated with respect to preconcentration time, pH effect, accumulation potential, accumulation time, and scan rate. The number of electrons transferred in the reduction process was calculated and the probable reduction mechanism was proposed. A systemic study of the experimental parameters that affect the square-wave stripping response was carried out and experimental conditions were optimized.

  6. [Hepatitis B virus genotypes and the response to lamivudine therapy].

    PubMed

    Zalewska, Małgorzata; Domagała, Małgorzata; Simon, Krzysztof; Gładysz, Andrzej

    2005-12-01

    Hepatitis B virus (HBV) can be classified into eight major genotypes (A-H) that have mainly a geographic distribution. The HBV genotype may influence disease progression, HBeAg seroconversion rates, response to antiviral treatment. The aim of study was to analyze the distribution and frequency of genotypes in patients with chronic hepatitis B. Response to lamivudine 100 mg daily therapy was examined in respect to genotype. Sixty six patients (45 (68,2%) male, 21 (31,8%) female) with chronic hepatits B were enrolled. HBV genotypes were assigned before treatment with INNO-LiPA HBV Genotyping, Innogenetics, N. V., Ghent assay, which is a line probe test based on the reverse hybridization principle. In baseline and after 12 months of treatment serological markers of HBV infection, alanine aminotransferase (ALT) activities and HBV DNA serum levels were tested. Patients with chronic hepatitis B were infected predominantly with genotype A. HBV genotype distribution was: 78,8% for genotype A, 13,6% for genotype D, 1,5% for mixed infection with genotypes A and D. Distribution of genotypes A and D was asymmetrically regardless of sex, HBeAg status, ALT and HBV DNA levels. Four (6,1%) specimens had indeterminate A results by LiPA. There were no significant differences between patients with genotypes A and D regarding age and sex. There were also no significant differences between these two groups regarding rates of HBeAg and anti-HBe positivity, ALT activity and viral load. Twenty months of lamivudine (100 mg daily) therapy resulted in significant decreases in serum HBV DNA and ALT activities in patients with genotype A as well as with genotype D. After 12 months of treatment there were no statistical differences in HBeAg seroconversion rates, ALT activities, viral loads, frequency of HBeAg and anti-HBe between genotypes A and D.

  7. Dutrebis (lamivudine and raltegravir) for use in combination with other antiretroviral products for the treatment of HIV-1 infection.

    PubMed

    Casado, José Luis; Bañón, Sara

    2015-01-01

    Raltegravir and lamivudine have been part of highly active therapy regimens throughout the past years of antiretroviral therapy. A fixed-dose, single-tablet regimen comprising a non-poloxamer formulation of the integrase inhibitor raltegravir and the transcriptase inhibitor lamivudine (raltegravir/lamivudine; Dutrebis(®)) has been recently licensed for the treatment of HIV-1 infection. In several Phase I pharmacokinetic studies, one Dutrebis (150 mg lamivudine/300 mg raltegravir) fixed-dose combination tablet showed a higher bioavailability but comparable lamivudine and 400 mg raltegravir poloxamer exposures. Thus, the co-administration of raltegravir together with lamivudine created a potent, effective, well-tolerated antiretroviral combination, which could be more convenient for the patient. However, the disadvantage of twice a day administration, and the existence of other fixed-dose combinations limit its widespread clinical use. This article reviews pharmacokinetics data and appraises their potential use in current and future HIV therapy.

  8. [Effects of lamivudine on growth of intestinal characteristic bacteria by microcalorimetry in vitro].

    PubMed

    Zhang, Cong-En; Wang, Jia-Yi; Hao, Jun-Jie; Yan, Dan; Wang, Rui-Lin; Li, Rui-Sheng; Li, Jian-Yu; Xiao, Xiao-He

    2013-10-01

    The study is aimed to investigate the effect of lamivudine on growth and metabolism of three intestinal characteristic bacteria (namely, Bifidobacterium adolescentis, Escherichia coli and Shigella dysenteriae). The growth condition of the three bacteria was quantitatively evaluated by microcalorimetry with four characteristic parameters of the thermal power-time curves, including the growth rate constant (k), thermal power (p), time to peak (t) and calorific value (Q). The results showed that the IC50 value of lamivudine on B. adolescentis was 200 microg x mL(-1), and the IC50 values of lamivudine on S. dysenteriae and E. coli were higher than 3 000 microg x mL(-1) and 6 000 microg x mL(1), respectively. Therefore, lamivudine made different inhibitory effects on the three bacteria, in which the B. adolescentis was most susceptible to lamivudine. This work showed that taking lamivudine chronically is likely to affect the balance of good flora in the intestinal tract, and might increase endotoxin release, leading to inflammation and disease progression in hepatopathy.

  9. Cytokine and sex hormone effects on zidovudine- and lamivudine-triphosphate concentrations in vitro

    PubMed Central

    Anderson, Peter L.; King, Tracy; Zheng, Jia-Hua; MaWhinney, Samantha

    2008-01-01

    Introduction Elevated zidovudine- and lamivudine-triphosphates have been observed in peripheral blood mononuclear cells (PBMCs) from females versus males and in patients with high inflammatory states versus lower inflammatory states. Consistent with high triphosphate exposures, these same patient groups also experience elevated rates of toxicity, including lipoatrophy. The purpose of this study was to evaluate the effects of oestradiol, progesterone and testosterone as well as tumour necrosis factor (TNF)-α and interferon (IFN)-α on zidovudine- and lamivudine-triphosphates in PBMCs and, for the cytokines, in 3T3-L1 adipocytes. Methods Multiple replicates of adipocytes and human PBMCs were incubated with experimental versus control conditions using several cytokine and sex hormone doses. Zidovudine- and lamivudine-triphosphate concentrations were determined with validated LC-MS-MS assays. A mixed effects, cell means model that accounted for experiment number was used to evaluate the effects of experimental conditions relative to control. Results In adipocytes, TNF-α doses below 2 ng/mL increased zidovudine-triphosphate by 18% (5–31%). Lamivudine-triphosphate was not detectable in adipocytes. In PBMCs, pooled IFN-α doses (0.1–10 U/mL) decreased zidovudine-triphosphate 26% (10–42%); 100 and 1000 ng/mL of progesterone decreased lamivudine-triphosphate by 22% (1–43%) and 47% (25–68%), respectively. Pooled testosterone doses (10–1000 ng/mL) decreased lamivudine-triphosphate by 24% (7–41%). No other statistically significant effects were observed. Conclusions We found evidence that sex hormones and cytokines influence zidovudine-triphosphate and lamivudine-triphosphate slightly in PBMCs and adipocytes in vitro. These findings provide insight and scientific direction to address inflammation-dependent and sex-dependent phosphorylation and responses in patients. PMID:18567572

  10. Pharmacokinetic interactions between lersivirine and zidovudine, tenofovir disoproxil fumarate/emtricitabine and abacavir/lamivudine.

    PubMed

    Vourvahis, Manoli; Davis, John; Langdon, Grant; Layton, Gary; Fang, Juanzhi; Choo, Heng Wee; Hansson, Arne G; Tawadrous, Margaret

    2013-01-01

    To investigate pharmacokinetic interactions associated with coadministration of lersivirine with zidovudine, tenofovir disoproxil fumarate (DF)/emtricitabine (Truvada(®)) or abacavir/lamivudine (Epzicom(®)/Kivexa(®)). Three Phase I, open, crossover studies with two (studies 1 and 3) or three (study 2) treatment periods were conducted in healthy individuals. In study 1, individuals received zidovudine and placebo or zidovudine and lersivirine on days 1-14. In study 2, individuals received lersivirine and tenofovir DF/emtricitabine, lersivirine and placebo or tenofovir DF/emtricitabine and placebo on days 1-10. In study 3, individuals received abacavir/lamivudine only in period 1 (5 days) and abacavir/lamivudine and lersivirine in period 2 (10 days). Blood samples were taken on days 1-14 (study 1) or day of final dose (studies 2 and 3) and analysed using high performance liquid chromatography/dual mass spectrometry. Pharmacokinetic parameters were calculated by standard non-compartmental methods. When coadministered with lersivirine, zidovudine exposure increased by 35%, and exposure of its metabolite zidovudine-glucuronide decreased by 19%. Following coadministration of lersivirine and tenofovir DF/emtricitabine, tenofovir exposure increased by 30%, and lersivirine exposure decreased by 12%. Coadministration of lersivirine and abacavir/lamivudine increased abacavir exposure by 27% and decreased lamivudine exposure by 8%. Adverse events were predominantly mild in these Phase I studies. Coadministration of lersivirine with zidovudine, tenofovir DF/emtricitabine or abacavir/lamivudine influenced the systemic exposure of all nucleoside reverse transcriptase inhibitor agents investigated (except for lamivudine; emtricitabine pharmacokinetics were not assessed). Changes were not considered clinically meaningful for zidovudine and abacavir. The clinical relevance of the effect on tenofovir pharmacokinetics is currently unknown.

  11. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

    PubMed Central

    Boni, C; Bertoletti, A; Penna, A; Cavalli, A; Pilli, M; Urbani, S; Scognamiglio, P; Boehme, R; Panebianco, R; Fiaccadori, F; Ferrari, C

    1998-01-01

    High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection. PMID:9727065

  12. Quantum chemical and experimental studies on polymorphism of antiviral drug Lamivudine

    NASA Astrophysics Data System (ADS)

    Ramkumaar, G. R.; Srinivasan, S.; Bhoopathy, T. J.; Gunasekaran, S.

    2012-12-01

    Lamivudine, is chemically known as [4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one], is an anti-HIV agent belonging to the class of the non-nucleoside inhibitors of the HIV-1 virus reverse transcriptase. Spectral characteristics of Lamivudine have been studied by methods of FTIR, NMR and quantum chemistry. The FTIR and spectra of Lamivudine was recorded in the regions 4000-400 cm-1. The thermal stability of Lamivudine was studied by the thermogravimetric analysis (TGA). The isotropic 13C-nuclear magnetic shielding constants of this compound were calculated by employing the direct implementation of the gauge including-atomic-orbital (GIAO) method at the HF and B3LYP density functional theory using 6-31G(d,p) basis set. The optimized molecular geometry, bond orders, harmonic vibrational spectrum of anhydrous and hydrated Lamivudine were calculated by restricted Hartree Fock and density functional B3LYP method with the 6-31G(d,p) basis set using Gaussian 03W program.

  13. Cost-effectiveness of telbivudine versus lamivudine for chronic hepatitis B.

    PubMed

    Wiens, Astrid; Venson, Rafael; Correr, Cassyano Januário; Pontarolo, Roberto

    2011-01-01

    Chronic hepatitis B is a highly prevalent disease worldwide, leading to serious consequences if not properly treated. Six treatment options for chronic hepatitis B are currently provided by the Brazilian public health system. Telbivudine is a nucleoside analogue that is neither included in the Brazilian clinical protocol nor in the therapeutic guidelines for chronic hepatitis B. The aim of this study was to evaluate the cost-effectiveness of telbivudine for the viewpoint of the Brazilian public system, comparing it to lamivudine. A Markov model was used to project lifetime complications and costs of treatment with lamivudine or telbivudine for chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. To evaluate disease progression, probabilities and utilities of virologic response, virologic resistance, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, treatment, interruption of treatment, death and seroconversion were collected in systematic reviews. Costs were collected in DATASUS, ABC da Saúde and scientific literature. Higher rate of virologic response and seroconversion was obtained with telbivudine, and also higher values of quality adjusted life years. However lamivudine is associated with lower costs and also lower cost-effectiveness values. The incremental cost-effectiveness ratios for telbivudine, when compared with lamivudine, were US$ 30,575 and US$ 40,457, respectively for HBeAg-positive and HBeAg-negative patients. In chronic hepatitis B lamivudine is a more cost-effective or even cost-saving strategy when compared with telbivudine.

  14. Quantum chemical and experimental studies on polymorphism of antiviral drug Lamivudine.

    PubMed

    Ramkumaar, G R; Srinivasan, S; Bhoopathy, T J; Gunasekaran, S

    2012-12-01

    Lamivudine, is chemically known as [4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one], is an anti-HIV agent belonging to the class of the non-nucleoside inhibitors of the HIV-1 virus reverse transcriptase. Spectral characteristics of Lamivudine have been studied by methods of FTIR, NMR and quantum chemistry. The FTIR and spectra of Lamivudine was recorded in the regions 4000-400 cm(-1). The thermal stability of Lamivudine was studied by the thermogravimetric analysis (TGA). The isotropic (13)C-nuclear magnetic shielding constants of this compound were calculated by employing the direct implementation of the gauge including-atomic-orbital (GIAO) method at the HF and B3LYP density functional theory using 6-31G(d,p) basis set. The optimized molecular geometry, bond orders, harmonic vibrational spectrum of anhydrous and hydrated Lamivudine were calculated by restricted Hartree Fock and density functional B3LYP method with the 6-31G(d,p) basis set using Gaussian 03W program. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Abacavir + dolutegravir + lamivudine for the treatment of HIV.

    PubMed

    Comi, Laura; Maggiolo, Franco

    2016-10-01

    Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients. In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies. Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration. In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.

  16. Breastfeeding while taking lamivudine or tenofovir disoproxil fumarate: a review of the evidence.

    PubMed

    Ehrhardt, Stephan; Xie, Chan; Guo, Nan; Nelson, Kenrad; Thio, Chloe L

    2015-01-15

    Lamivudine and tenofovir disoproxil fumarate (TDF) are both active against hepatitis B virus (HBV). Due to its potency, high genetic barrier to resistance, and safety during pregnancy, TDF may be useful to prevent HBV transmission from mother to child, which is the leading cause of transmission globally. Despite the safety record of lamivudine and TDF in pregnancy, the labels for both of these drugs recommend against their use during breastfeeding. In this review, we discuss the data regarding lamivudine and TDF use during pregnancy and breastfeeding and find that the exposure to the drug is lower from breastfeeding than from in utero exposure. Thus, the data do not support the contraindication to their use during breastfeeding.

  17. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir: ACTG A5224 s, A5202 substudy

    PubMed Central

    McComsey, Grace A.; Kitch, Douglas; Daar, Eric S.; Tierney, Camlin; Jahed, Nasreen C; Melbourne, Kathleen; Ha, Belinda; Brown, Todd T.; Bloom, Anthony; Fedarko, Neal; Sax, Paul E.

    2012-01-01

    Background The effect of specific antiretrovirals on inflammation is unclear. Methods A5224 s was a substudy of A5202, which randomized HIV-infected treatment-naïve subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r. Results Analyses included 244 subjects (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/mL, CD4 240 cells/µL. TNF-α, sTNFR-I and -II, sVCAM-1 and sICAM-1 decreased significantly at weeks 24 and 96, without significant differences between components (p ≥ 0.44). At week 24, ABC/3TC had a greater hsCRP mean fold change than TDF/FTC (1.43 vs. 0.88, estimated mean fold change percent difference (Δ) 61.5% [95% CI 13.6%, 129.5%]; p = 0.008). Similar results were seen at week 96 (p = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r (1.41 vs. 0.88; Δ = 60.2% [12.6%, 127.7%]; p = 0.009). IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components p = 0.019). At week 96, IL-6 decreased significantly in both NRTI components (between-components p = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (p ≥ 0.89). Conclusions Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r. PMID:22546988

  18. Antiviral and cellular metabolism interactions between Dexelvucitabine and lamivudine.

    PubMed

    Hernandez-Santiago, Brenda I; Mathew, Judy S; Rapp, Kim L; Grier, Jason P; Schinazi, Raymond F

    2007-06-01

    Studies on cellular drug interactions with antiretroviral agents prior to clinical trials are critical to detect possible drug interactions. Herein, we demonstrated that two 2'-deoxycytidine antiretroviral agents, dexelvucitabine (known as beta-d-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, DFC, d-d4FC, or RVT) and lamivudine (3TC), combined in primary human peripheral blood mononuclear (PBM) cells infected with human immunodeficiency virus 1 strain LAI (HIV-1(LAI)), resulted in additive-to-synergistic effects. The cellular metabolism of DFC and 3TC was studied in human T-cell lymphoma (CEM) and in primary human PBM cells to determine whether this combination caused any reduction in active nucleoside triphosphate (NTP) levels, which could decrease with their antiviral potency. Competition studies were conducted by coincubation of either radiolabeled DFC with different concentrations of 3TC or radiolabeled 3TC with different concentrations of DFC. Coincubation of radiolabeled 3TC with DFC at concentrations up to 33.3 microM did not cause any marked reduction in 3TC-triphosphate (TP) or any 3TC metabolites. However, a reduction in the level of DFC metabolites was noted at high concentrations of 3TC with radiolabeled DFC. DFC-TP levels in CEM and primary human PBM cells decreased by 88% and 94%, respectively, when high concentrations of 3TC (33.3 and 100 microM) were added, which may influence the effectiveness of DFC-5'-TP on the HIV-1 polymerase. The NTP levels remained well above the median (50%) inhibitory concentration for HIV-1 reverse transcriptase. These results suggest that both beta-d- and beta-l-2'-deoxycytidine analogs, DFC and 3TC, respectively, substrates of 2'-deoxycytidine kinase, could be used in a combined therapeutic modality. However, it may be necessary to decrease the dose of 3TC for this combination to prove effective.

  19. Lamivudine and interferon versus lamivudine monotherapy for HBeAg-positive hepatitis B treatment: a meta-analysis of randomized, controlled trials.

    PubMed

    Rudin, Dan

    2007-01-01

    The suboptimal outcomes of current chronic hepatitis B treatments have prompted the notion of combination therapy as a means of augmenting the therapeutic response. In this study, investigators compared lamivudine monotherapy versus its combination with conventional or pegylated interferon-alpha, pooling data from all pertinent randomized controlled studies into the meta-analysis. The studies were evaluated for methodologic quality and heterogeneity. Rates of sustained virologic and biochemical responses and of hepatitis B e antigen clearance and seroconversion were used as primary efficacy measures. Quantitative metaanalyses were conducted to assess differences between groups for conventional and pegylated interferon, and overall. Analysis yielded greater sustained virologic, biochemical, and seroconversion rates with the addition of conventional (odds ratio [OR]=4.5, 95% confidence interval [CI]=2.2-9.4, P<.001; OR=2.1, 95% CI=1.3-3.2, P=.002; and OR=2.6, 95% CI=1.4-4.8, P=.001, respectively) and pegylated (OR=2.0, 95% CI=1.1-3.6, P=.02; OR=1.8, 95% CI=1.3-2.6, P<.001; and OR=1.6, 95% CI=1.1-2.3, P=.03, respectively) interferon-alpha to lamivudine, with the former also yielding greater hepatitis B e antigen clearance rates (OR=2.6, 95% CI=1.3-5.2, P=.008). As previous studies suggested that pegylated interferon monotherapy and its combination with lamivudine were comparable, the use of this combination is not justified. In contrast, when conventional interferon-a is used, its combination with lamivudine should be considered.

  20. Abacavir/Lamivudine Versus Tenofovir/Emtricitabine in Virologically Suppressed Patients Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir

    PubMed Central

    d'Albuquerque, Polyana M.; Pérez, Ignacio; Pich, Judit; Gatell, José M.

    2013-01-01

    Abstract There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA ≥50 copies/ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI −17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference −2.33%; 95% CI −16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events (p=0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults. PMID:22916715

  1. Curative effect of combined lamivudine, adefovir dipivoxil, and stem cell transplantation on decompensated hepatitis B cirrhosis.

    PubMed

    Liu, L; Yan, Y; Zhou, J; Huang, L W; He, C P; Ling, K; Zhou, H C; Wen, Q M; Wang, X M

    2014-02-21

    This study assessed the clinical efficacy of lamivudine and adefovir dipivoxil combined with autologous bone marrow stem cell transplantation as treatment for patients with hepatitis B and decompensated liver cirrhosis. In total, 77 patients with hepatitis B and decompensated liver cirrhosis were randomly divided into two groups. Under general symptomatic and supportive treatment, the patients in group A (37 cases) were treated with lamivudine and adefovir dipivoxil, whereas those in group B (40 cases) were treated with autologous bone marrow stem cell transplantation in combination with lamivudine and adefovir dipivoxil. After 4 weeks of treatment, the liver function indicators and clinical signs and symptoms of the patients in group B improved more significantly than those of patients in group A. Lamivudine and adefovir dipivoxil in combination with autologous bone marrow stem cell transplantation effectively prevented hepatitis B virus infection and bone marrow stem cell damage. This combination treatment facilitates the differentiation of bone marrow stem cells into normal liver cells to restore liver structure and improve liver function, thereby improving the quality of life of patients.

  2. Comparative studies of lamivudine-zidovudine nanoparticles for the selective uptake by macrophages.

    PubMed

    Sankar, V; Nareshkumar, Parmar Nilaykumar; Ajitkumar, Gohel Nishit; Penmetsa, Shalini Devi; Hariharan, Sivaram

    2012-09-01

    The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGA-Poloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs.

  3. Photolysis of three antiviral drugs acyclovir, zidovudine and lamivudine in surface freshwater and seawater.

    PubMed

    Zhou, Chengzhi; Chen, Jingwen; Xie, Qing; Wei, Xiaoxuan; Zhang, Ya-nan; Fu, Zhiqiang

    2015-11-01

    Photodegradation is an important elimination process for many pharmaceuticals in surface waters. In this study, photodegradation of three antiviral drugs, acyclovir, zidovudine, and lamivudine, was investigated in pure water, freshwater, and seawater under the irradiation of simulated sunlight. Results showed that zidovudine was easily transformed via direct photolysis, while acyclovir and lamivudine were mainly transformed via indirect photolysis. We found that in freshwater, nitrate enhanced the photodegradation of the three antiviral drugs, bicarbonate promoted the photodegradation of acyclovir, and dissolved organic matter (DOM) accelerated the photolysis of acyclovir and lamivudine. In seawater, the photolysis of acyclovir was not susceptible to Cl(-), Br(-) and ionic strength; however, the photolysis of zidovudine was inhibited by Cl(-) and Br(-), and the photolysis of lamivudine was enhanced by Cl(-), Br(-) and ionic strength. Second-order reaction rate constants for the three antiviral drugs with (1)O2 (k1O2) and OH (kOH) were also measured. These results are important for fate and ecological risk assessment of the antiviral drugs in natural waters. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. An extended two-year trial of lamivudine in Chinese patients with chronic hepatitis B.

    PubMed

    Yao, Guangbi; Cui, Zhenyu; Wang, Baoen; Yao, Jilu; Zeng, Minde

    2002-12-01

    To evaluate the long-term efficacy and safety of lamivudine therapy for the treatment of chronic hepatitis B and the clinical influence of emergence of tyrosine methionine aspartic acid (YMDD) motif mutation of hepatitis B virus (HBV). This multicenter, double-blind, randomized, placebo controlled trial began in 1996. A total of 429 patients with HBsAg, HBeAg and HBV CNA positives were enrolled. They were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) on 3 : 1 ratio for the first 12 weeks. Thereafter all patients were offered open label lamivudine treatment and assessed every 4 weeks for a total of 104 weeks. After 1 year treatment 72.7% patients (285/392) had a sustained serum HBV DNA response. HBV DNA continued to be substantially suppressed at the second year, except in patients with the emergence of YMDD mutation whose mean HBV DNA levels increased to 86 Meq/ml (bDNA assay) but were much more lower than that of pre-treatment baseline level. lamivudine therapy resulted in increased HBeAg loss and HBeAg/anti-HBe seroconversion, which were correlated with both baseline alanine transaminase (ALT) levels and also with duration of lamivudine treatment. HBeAg loss was achieved in 26.8% of patients with ALT > 1-fold upper limit of normal at 2 yeas and in 35.6% and 55.6% of patients with ALT > 2-fold upper limit of normal and ALT > 5-fold upper limit of normal, respectively. For HBeAg seroconversion, these figures were 17.4%, 22.2%, and 33.3% respectively. By the end of 2 years, ALT levels were remained in normal ranges in 50.3% whose ALT were abnormal before treatment, and in 83% whose ALT were mormal before treatment. YMDD mutation were developed in 49.7% of the patients. Their serum HBV DNA levels were slightly increased to bDNA median level 86 Meq/ml and 15% of the patients they were ALT exceeded baseline levels. Four patients clinically flared-up and recovered after stop treatment. The adverse drug reactions (ADRs) of lamivudine

  5. Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China

    PubMed Central

    Li, Yijia; Zhu, Ting; Song, Xiaojing; Huang, Ying; Yang, Feifei; Guan, Shuo; Xie, Jing; Gohda, Jin; Hosoya, Noriaki; Kawana-Tachikawa, Ai; Liu, Wenjun; Gao, George Fu; Iwamoto, Aikichi; Li, Taisheng; Ishida, Takaomi

    2015-01-01

    In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15–20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV. PMID:26288093

  6. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial.

    PubMed

    Cahn, Pedro; Andrade-Villanueva, Jaime; Arribas, José R; Gatell, José M; Lama, Javier R; Norton, Michael; Patterson, Patricia; Sierra Madero, Juan; Sued, Omar; Figueroa, Maria Inés; Rolon, Maria José

    2014-07-01

    Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy. The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age ≥18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100,000 vs ≥100,000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than -12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444. Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral

  7. Decompensated lamivudine-resistant hepatitis B virus-related cirrhosis treated successfully with adefovir dipivoxil allowing surgery for hepatocellular carcinoma.

    PubMed

    Takamura, Masaaki; Ichida, Takafumi; Ohkoshi, Shogo; Tsubata, Shunsuke; Osaki, Akihiko; Aoyagi, Tomoya; Nomoto, Minoru; Uehara, Kazuhiro; Terada, Haruo; Aoyagi, Yutaka

    2007-01-01

    We describe a 64-year-old man with decompensated hepatitis B virus (HBV)-related cirrhosis who became resistant to lamivudine. He was started on adefovir at 10 mg daily while continuing lamivudine therapy. Several months later, his liver function improved and subsequently his ascites disappeared. The serum HBV-DNA level became undetectable 11 months later. Twenty months after the start of additional treatment with adefovir, one hepatocellular carcinoma (HCC) was detected, and the patient underwent a successful hepatectomy. Our findings suggest that the addition of adefovir to ongoing lamivudine therapy is useful for improving liver function in patients with decompensated lamivudine-resistant HBV-related cirrhosis, allowing surgery for HCC.

  8. Cost-effectiveness analysis of prophylactic lamivudine use in preventing vertical transmission of hepatitis B virus infection.

    PubMed

    Hung, Hui-Fang; Chen, Hsiu-Hsi

    2011-12-01

    As neonates born to mothers with positive hepatitis B e antigen may not be completely protected by hepatitis B vaccination, prophylactic lamivudine use in mothers with high viraemia has been proposed. However, the overall effectiveness and the balance between cost and benefit for such a prophylactic strategy have rarely been addressed. Using a review of recent literature, we aimed to assess the cost effectiveness, from the Taiwanese societal perspective, of administering prophylactic lamivudine to mothers to reduce vertical transmission of hepatitis B virus and its long-term sequelae in neonates. A meta-analysis of three randomized controlled trials was conducted to evaluate the efficacy of lamivudine versus placebo. A Markov decision model was constructed in which in both treatment arms infants received active and passive immunoprophylaxis. An economic evaluation was performed to calculate costs, acute infections averted, and QALYs gained. Probabilistic sensitivity analyses were conducted and a cost-effectiveness acceptability curve drawn. All these analyses were from the societal perspective. Costs ($US) were valued in year 2008 prices. Supplemental lamivudine use gained an additional 0.0024 QALYs and averted 0.23 acute infections per birth compared with the routine active-passive immunization without lamivudine. The cost-effectiveness analysis suggested that the use of additional prophylactic lamivudine dominated the routine strategy. The acceptability curve suggested that the probability of being cost effective under the willingness-to-pay threshold of $US20,000 was 94%. This analysis suggests that supplemental use of lamivudine in mothers with high hepatitis B viraemia is effective in reducing vertical transmission and may be cost effective, from a Taiwanese societal perspective, compared with the routine active-passive immunization without lamivudine.

  9. Simultaneous And Extended Delivery Of Stavudine, Lamivudine And Nevirapine In Fixed Dose Combination Using Sandwiched Osmotic Tablets For Hiv Therapy.

    PubMed

    Priya, M Ranga; Rajendran, N N

    2015-01-01

    Current HIV-therapy recommends combination of stavudine, lamivudine and nevirapine. Stavudine and lamivudine are administered as fixed combination while nevirapine as separate dosage form which often results in poor compliance and adherence to therapy by patients and therefore, there is a need to develop dosage forms that can overcome the problems of currently available dosage forms for treatment of HIV infection. The present study developed a single unit osmotic system for simultaneous and extended delivery of stavudine, lamivudine and nevirapine that can ensure patients compliance and adherence to HIV-therapy. Sandwich osmotic pump tablets (SOPTs) of stavudine, lamivudine and nevirapine in fixed dose combination were designed and evaluated for the effect of variables such as PEO (polymer), KCl (osmogen), and orifice diameter on the physicochemical characteristics and the release behavior of the drugs. A 24 h zero order release of stavudine, lamivudine and nevirapine from the formulations was observed and the release rate of the drugs was found to be affected by PEO, KCl, and orifice diameter. The in vitro release data of SOPT correlated with in vivo predictions by super - position method. The results of the study propose that a single unit osmotic system (SOPT) of stavudine, lamivudine and nevirapine is beneficial to overcome the disadvantages of currently available dosage forms for effective control of HIV infection.

  10. Liver fibrosis progression and clinical outcomes are intertwined: role of CD4+ T-cell count and NRTI exposure from a large cohort of HIV/HCV-coinfected patients with detectable HCV-RNA

    PubMed Central

    Focà, Emanuele; Fabbiani, Massimiliano; Prosperi, Mattia; Quiros Roldan, Eugenia; Castelli, Francesco; Maggiolo, Franco; Di Filippo, Elisa; Di Giambenedetto, Simona; Gagliardini, Roberta; Saracino, Annalisa; Di Pietro, Massimo; Gori, Andrea; Sighinolfi, Laura; Pan, Angelo; Postorino, Maria Concetta; Torti, Carlo

    2016-01-01

    Abstract Introduction: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) suffer from faster progression of liver fibrosis (LF) and have greater risk of worse clinical outcomes. We evaluated predictors and incidence of these events in a large multicentre cohort. Methods: We selected all HIV-infected patients starting a first-line combination antiretroviral therapy (cART), with detectable HCV-RNA, without exposure to interferon/ribavirin, with ≥2 fibrosis-4 index (FIB-4) classifications before cART. Kaplan–Meier analysis was used to estimate incidence of clinical events (AIDS, non-AIDS related, deaths) and LF progression (via transitions: from FIB-4 class 1 to 2 or 3, from class 2 to class 3, and worsening by 0.5 point). Multivariate Cox regression was used to assess predictors, baseline, or time updated. Results: One thousand four hundred thirty-three patients were selected. Overall, 745 clinical events occurred, with an incidence of 7.6% over 9811 person-year of follow-up (PYFU) and a median survival time of 9.36 years. Incidence of LF progression from FIB-4 class 1 to 2 or 3 was 12.4%, and from FIB-4 class 2 to 3 was 7% with a median survival time of 5.67 and 10.35 years, respectively. At multivariate analyses, intravenous drug use and time-updated gamma-glutamyl transferase (γGT) were negative predictors for any outcomes, either clinical or FIB-4 progression. Higher CD4+ T-cell protected from clinical events, and lower HIV-RNA and higher CD4+ T-cell appeared to protect from FIB-4 transitions. Moreover, independently from the viro-immunological status, current FIB-4 class 3 predicted clinical events. Occurrence of AIDS and cardiovascular/kidney events were significant predictors of 0.5 point worsening and transitions of FIB-4, respectively. Prolonged exposure to nucleos(t)ide reverse transcriptase inhibitors (NRTI) was a negative predictor for any outcomes. Conclusion: Both clinical and LF progression in HIV

  11. Abacavir/lamivudine combination in the treatment of HIV: a review

    PubMed Central

    Sivasubramanian, Geetha; Frempong-Manso, Emmanuel; MacArthur, Rodger D

    2010-01-01

    Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the “recommended” category to the “alternative” category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs. PMID:20234788

  12. Matrix metalloproteinases and their tissue inhibitors in children with chronic hepatitis B treated with lamivudine.

    PubMed

    Lebensztejn, D M; Skiba, E; Sobaniec-Łotowska, M E; Kaczmarski, M

    2007-01-01

    To evaluate if measurements of MMP-2, MMP-9, TIMP-1 and TIMP-2 have clinical applicability as markers of liver fibrosis and to assess the effect of long-term lamivudine treatment on liver fibrosis in children with chronic hepatitis B (chB). The observation was carried out on 41 children with biopsy proven chB (HBe/+/, HBVDNA/+/) who were nonresponders to previous IFNalpha therapy. Lamivudine was administered in the group of 29 children (3 mg/kg/day, maximum 100 mg/daily). The serum concentration of examined markers was measured with ELISA before and after 24 months of therapy. ROC analysis was used to calculate the power of the assays to detect advanced liver fibrosis (score >2 according to Batts & Ludwig). Serum TIMP-1 and TIMP-2 levels were significantly higher and MMP-9 lower in children with chB compared to controls. There was a significant positive correlation between serum MMP-2 and negative correlation between MMP-9 level and the stage of liver fibrosis. The ability of serum MMP-9 to differentiate children with mild fibrosis from those with advanced fibrosis was significant (AUC = 0.75; p = 0.03). Other serum markers did not allow a useful prediction. 2-year lamivudine treatment did not improve histological fibrosis but it caused significant decrease of serum TIMP-2 (p = 0.01) and increase of MMP-9 level (p = 0.00005). MMP-9 is a better serum fibrosis marker than MMP-2, TIMP-1 and TIMP-2 to diagnose children with advanced liver fibrosis. The significant decrease of TIMP-2 and increase of MMP-9 level during therapy suggest antifibrotic effect of lamivudine in children with chB.

  13. Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines.

    PubMed

    Chen, Xuan; Wang, Cong; Guan, Shanghui; Liu, Yuan; Han, Lihui; Cheng, Yufeng

    2016-07-01

    Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer.

  14. Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

    PubMed Central

    Pereira-Gómez, Marianoel; Bou, Juan-Vicente; Andreu, Iván; Sanjuán, Rafael

    2016-01-01

    The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10−5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses. PMID:27649318

  15. Lamivudine/telbivudine-associated neuromyopathy: neurogenic damage, mitochondrial dysfunction and mitochondrial DNA depletion

    PubMed Central

    Xu, Hongliang; Wang, Zhaoxia; Zheng, Lemin; Zhang, Wei; Lv, He; Jin, Suqin; Yuan, Yun

    2014-01-01

    Aims Myopathy or neuropathy has been associated with lamivudine/telbivudine therapy in hepatitis B patients. We aim to describe the pathological changes of lamivudine/telbivudine-associated neuromyopathy. Methods We retrospectively recruited six patients who were diagnosed with nucleotide analogues-associated myopathy or neuropathy. Muscle and nerve biopsy were performed, and the specimens were prepared for the light microscopy and electron microscopy. Genomic DNA was extracted from frozen muscle specimens, and the mitochondrial DNA (mtDNA) content was quantified by real-time PCR. Results Recovery of the myopathy can be achieved after the discontinuation or changing the drugs to entecavir. Muscle and nerve biopsy revealed similar changes under either the light or electronic microscopy in all the subjects. Quantitative real-time PCR revealed decrease of mtDNA content in the affected muscle. Conclusions MtDNA depletion results in mitochondrial dysfunction in the lamivudine/telbivudine-associated neuromyopathy. Myopathy was characterised by mitochondrial dysfunction accompanied with neurogenic damage due to axonal neuropathy. Ultrastructure changes of mitochondria included vacuolisation, simplification of the cristae and homogenised matrix. PMID:25190818

  16. Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers

    PubMed Central

    Abel, Samantha; Russell, Deborah; Whitlock, Lyndsey A; Ridgway, Caroline E; Muirhead, Gary J

    2008-01-01

    Aims To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive. Methods Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 μg ethinyloestradiol/150 μg levonorgestrel (Microgynon®). Results The geometric mean ratios for Cmax and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in Tmax, t1/2 or CLR (where measured) for any of the compounds. Conclusions Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel. PMID:18333862

  17. Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial.

    PubMed

    Wiegand, J; Wedemeyer, H; Franke, A; Rößler, S; Zeuzem, S; Teuber, G; Wächtler, M; Römmele, U; Ruf, B; Spengler, U; Trautwein, C; Bock, C T; Fiedler, G M; Thiery, J; Manns, M P; Brosteanu, O; Tillmann, H L

    2014-10-01

    Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 μm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 μm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 μm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

  18. Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study.

    PubMed

    Cahn, Pedro; Rolón, María José; Figueroa, María Inés; Gun, Ana; Patterson, Patricia; Sued, Omar

    2017-05-09

    A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm(3) (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in

  19. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine.

    PubMed

    Müller, Fabian; König, Jörg; Hoier, Eva; Mandery, Kathrin; Fromm, Martin F

    2013-09-15

    The antiviral lamivudine is cleared predominantly by the kidney with a relevant contribution of renal tubular secretion. It is not clear which drug transporters mediate lamivudine renal secretion. Our aim was to investigate lamivudine as substrate of the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins MATE1 and MATE2-K. Uptake experiments were performed in OCT2, MATE1, or MATE2-K single-transfected human embryonic kidney 293 (HEK) cells. Transcellular transport experiments were performed in OCT2 and/or MATE1 single- or double-transfected Madin-Darby canine kidney II (MDCK) cells grown on transwell filters. Lamivudine uptake was significantly increased in HEK-OCT2, HEK-MATE1, and HEK-MATE2-K cells compared to control cells. In transcellular experiments, OCT2 located in the basolateral membrane had no effect on transcellular lamivudine transport. MATE1 located in the apical membrane decreased intracellular concentrations and increased transcellular transport of lamivudine from the basal to the apical compartment. MATE1- or MATE2-K-mediated transport was increased by an oppositely directed pH gradient. Several simultaneously administered drugs inhibited OCT2- or MATE2-K-mediated lamivudine uptake. The strongest inhibitors were carvedilol for OCT2 and trimethoprim for MATE2-K (inhibition by 96.3 and 83.7% at 15 μM, respectively, p<0.001). Trimethoprim inhibited OCT2- and MATE2-K-mediated lamivudine uptake with IC₅₀ values of 13.2 and 0.66 μM, respectively. Transcellular lamivudine transport in OCT2-MATE1 double-transfected cells was inhibited by trimethoprim with an IC₅₀ value of 6.9 μM. Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K. Concomitant administration of drugs that inhibit these transporters could decrease renal clearance of lamivudine.

  20. Hepatitis B virus variants in an HIV-HBV co-infected patient at different periods of antiretroviral treatment with and without lamivudine

    PubMed Central

    Santos, Eneida A; Sucupira, Michel VF; Arabe, Juçara; Gomes, Selma A

    2004-01-01

    Background Lamivudine inhibits replication of both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and is commonly used as part of antiretroviral therapy. The main limitation in the use of lamivudine is resistant mutation selection. Most of these mutations affect the YMDD motif of the HBV DNA polymerase. The resistance occurs through M550V or M550I aminoacid replacements. The M550V variation may be accompanied by L526M mutation, notably in HIV-HBV co-infected patients. The aim of this study was to investigate mutations associated with lamivudine resistance in a hemodialysis patient chronically co-infected with HIV-1 and HBV, who was submitted to several antiretroviral treatments. Methods HBV isolates derived from three blood samples collected at different times of antiretroviral therapies with and without lamivudine, were titred and submitted to nucleotide sequencing. Results HBV isolate derived from a sample collected in 1999 during an antiretroviral treatment with lamivudine showed the lamivudine resistant double mutation (L526M, M550V). However, no mutation associated with lamivudine resistance was observed in the HBV genome derived from the sample collected during a period of treatment without lamivudine (2001). After reinstitution of lamivudine (2002), the predominant HBV population exhibited a rare triple mutation (V519L, L526M, M550V), which has previously been associated with an in vitro reduction of virus antigenicity (escape mutant). HBV DNA was detected at high levels (108–109 copies/ml) in the three blood samples. Conclusions Reintroduction of lamivudine as part of antiretroviral treatment in a patient who had developed lamivudine resistant HBV strains favored the predominance of an HBV isolate with reduced antigenicity. The absence of hepatitis acute exacerbation in this patient may be correlated to the absence of significant variations of the viral load, which was independent of the presence of mutations in the HBV DNA polymerase

  1. Clinical impact and efficacy of lamivudine therapy in de novo hepatitis B infection after liver transplantation.

    PubMed

    Castells, Lluís; Vargas, Víctor; Rodríguez, Francisco; Allende, Helena; Buti, Maria; Sánchez-Avila, José F; Jardí, Rosendo; Margarit, Carlos; Pumarola, Tomás; Esteban, Rafael; Guardia, Jaime

    2002-10-01

    De novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) in patients negative for hepatitis B surface antigen (HBsAg) is between 1.7% and 3.5% in areas with a low prevalence of HBV infection. The importance of this problem and the efficacy of lamivudine treatment has not been defined in areas with a high prevalence of positivity to antibody to hepatitis B core antigen (Anti-HBc). To define the characteristics and the clinical impact of de novo HBV infection in OLT recipients and to evaluate the efficacy of lamivudine treatment in this context, 229 HBsAg (-) donors (145 men, 84 women) were retrospectively evaluated between June 1994 and June 2000. Forty-eight recipients were excluded for various reasons. The final study population included 181 patients that were prospectively followed up for more than 6 months after OLT. When de novo HBV infection was detected, liver allograft biopsy was performed and treatment with lamivudine was indicated if patients were HBV-DNA-positive with elevated ALT levels. Survival time was defined as the interval between diagnosis of HBV infection and death or last follow-up visit. Thirty-one of 229 liver donors (13.5%) were anti-HBc(+). After a mean follow-up of 54.4+/-30 months, 9 of the 181 recipients (5%) developed de novo HBV infection; 8 of 27 recipients (29.6%) of livers from anti-HBc(+) donors as compared with only one of 154 recipients (0.6%) of livers from anti-HBc(-) donors P < 0.005). Liver biopsies performed in 8 of 9 cases showed chronic active hepatitis in 7 patients and acute hepatitis in one patient who cleared HBV spontaneously during the first 3 months. Seven patients were treated with lamivudine for a mean period of 24.5 months; HBV-DNA became negative in 5 of 7 (71.4%), and HBeAg became undetectable in 3 of 6 patients (50%). Patient actuarial survival rates at 1, 3, and 5 years were 100%, 94.7%, and 81.2% for recipients of anti-HBc (+) livers and 95.2%, 83%, and 77.3% for recipients of

  2. Synthesis of N4 donor macrocyclic Schiff base ligands and their Ru (II), Pd (II), Pt (II) metal complexes for biological studies and catalytic oxidation of didanosine in pharmaceuticals

    NASA Astrophysics Data System (ADS)

    Ravi krishna, E.; Muralidhar Reddy, P.; Sarangapani, M.; Hanmanthu, G.; Geeta, B.; Shoba Rani, K.; Ravinder, V.

    2012-11-01

    A series of tetraaza (N4 donor) macrocyclic ligands (L1-L4) were derived from the condensation of o-phthalaldehyde (OPA) with some substituted aromatic amines/azide, and subsequently used to synthesize the metal complexes of Ru(II), Pd(II) and Pt(II). The structures of macrocyclic ligands and their metal complexes were characterized by elemental analyses, IR, 1H &13C NMR, mass and electronic spectroscopy, thermal, magnetic and conductance measurements. Both the ligands and their complexes were screened for their antibacterial activities against Gram positive and Gram negative bacteria by MIC method. Besides, these macrocyclic complexes were investigated as catalysts in the oxidation of pharmaceutical drug didanosine. The oxidized products were further treated with sulphanilic acid to develop the colored products to determine by spectrophotometrically. The current oxidation method is an environmentally friendly, simple to set-up, requires short reaction time, produces high yields and does not require co-oxidant.

  3. Hepatitis B-related serological events in hematopoietic stem cell transplant patients and efficacy of lamivudine prophylaxis against reactivation.

    PubMed

    Gupta, Alok; Punatar, Sachin; Gawande, Jayant; Bagal, Bhausaheb; Mathew, Libin; Bhat, Vivek; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    Reactivation of remote hepatitis B infection (RHBI) is an important cause of morbidity in hematopoietic cell transplant (HCT) patients. We analyzed the prevalence of RHBI in 205 patients who underwent HCT in our centre, serological events related to hepatitis B virus (HBV) reactivation and role of lamivudine prophylaxis in HCT patients with RHBI. The prevalence of RHBI was 14% (28/205 patients). Of these 28 patients, 15 received lamivudine prophylaxis (14 anti-HBcIgG positive and 1 only anti-HBs positive) while 13 did not receive lamivudine prophylaxis (12 anti-HBs positive and 1 anti-HBcIgG positive). None in prophylaxis group developed HBV reactivation while 12 of 13 in no-prophylaxis group reactivated (P < 0.001). The rate of HBV reactivation was 10% (21/205 patients), which included 9 patients with no evidence of RHBI pre-transplant. We conclude that lamivudine prophylaxis protects against HBV reactivation in HCT patients with evidence of RHBI. Lamivudine prophylaxis should be used not only in patients with anti-HBcIgG positivity but also in those with isolated anti-HBs positivity pre-transplant given the high rate of HBV reactivation in these patients. HBV serology cannot identify all cases with RHBI and therefore does not preclude HBV reactivation post-transplant. Copyright © 2015 John Wiley & Sons, Ltd.

  4. Lamivudine compared with newer antivirals for prophylaxis of hepatitis B core antibody positive livers: a cost-effectiveness analysis.

    PubMed

    Wright, A J; Fishman, J A; Chung, R T

    2014-03-01

    There is concern over the development of de novo hepatitis B in patients receiving liver transplants from hepatitis B surface antigen negative, hepatitis B core antibody positive donors. Current practice is to place such patients on indefinite lamivudine prophylaxis; however, there is a small risk of breakthrough infection and newer antivirals for hepatitis B are available. The objective of this study was to determine the cost-effectiveness of lamivudine compared with the newer agents, tenofovir and entecavir, in the prophylaxis setting using a Markov model. Three strategies were examined which consisted of either lamivudine or entecavir monoprophylaxis with tenofovir add-on therapy after breakthrough or tenofovir monoprophylaxis with emtricitabine add-on therapy after breakthrough. In the base case scenario, lamivudine was the most cost-effective option at a threshold of $100 000 per quality-adjusted life-year and this remained robust despite parameter uncertainty. Tenofovir had an incremental cost-effectiveness ratio of $3 540 194.77 while other strategies were superior to entecavir therapy. Until drug costs decrease, lamivudine remains the most cost-effective option for hepatitis B prophylaxis in the liver transplant setting. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

  5. Virological Response to Tenofovir Disoproxil Fumarate in HIV-Positive Patients with Lamivudine-Resistant Hepatitis B Virus Coinfection in an Area Hyperendemic for Hepatitis B Virus Infection

    PubMed Central

    Huang, Yu-Shan; Chang, Sui-Yuan; Sheng, Wang-Huei; Sun, Hsin-Yun; Lee, Kuan-Yeh; Chuang, Yu-Chung; Su, Yi-Ching; Liu, Wen-Chun; Hung, Chien-Ching; Chang, Shan-Chwen

    2016-01-01

    Background Sequential addition of tenofovir disoproxil fumarate (TDF) is often needed for patients coinfected with HIV and hepatitis B virus (HBV) who develop HBV resistance to lamivudine after combination antiretroviral therapy (cART) containing only lamivudine for HBV. We aimed to assess the virological response of HBV to add-on TDF in patients coinfected with lamivudine-resistant HBV. Methods Between November 2010 and December 2014, 33 HIV/HBV-coinfected patients with lamivudine-resistant HBV and 56 with lamivudine-susceptible HBV were prospectively included. TDF plus lamivudine was used to substitute zidovudine or abacavir plus lamivudine contained in cART in patients with lamivudine-resistant HBV infection, while patients with lamivudine-susceptible HBV infection received TDF plus lamivudine as backbone of cART. Serial determinations of plasma HBV DNA load, HBV serologic markers, and liver and renal functions were performed after initiation of TDF-containing cART. Results Of 89 patients included, 38.6% tested positive for HBV envelope antigen (HBeAg) at baseline. The plasma HBV DNA level at enrollment of lamivudine-resistant and lamivudine-susceptible group were 6.1 ± 2.2 log10 and 6.0 ± 2.2 log10 copies/mL, respectively (p = 0.895). The cumulative percentage of HBV viral suppression in lamivudine-resistant and lamivudine-susceptible group was 81.8% and 91.1% at 48 weeks, respectively (p = 0.317), which increased to 86.7% and 96.2% at 96 weeks, respectively (p = 0.185). At 48 weeks, 11 patients testing HBeAg-positive at baseline failed to achieve viral suppression. In multivariate analysis, the only factor associated with failure to achieve viral suppression at 48 weeks was higher HBV DNA load at baseline (odds ratio, per 1-log10 copies/mL increase, 1.861; 95% CI, 1.204–2.878). At 48 weeks, HBeAg seroconversion was observed in 5 patients (1 in the lamivudine-resistant group and 4 in the lamivudine-susceptible group; p = 0.166). During the study period, HBs

  6. Pure red cell aplasia induced by lamivudine without the influence of zidovudine in a patient infected with human immunodeficiency virus.

    PubMed

    Nakamura, Kiwamu; Tateyama, Masao; Tasato, Daisuke; Haranaga, Shusaku; Tamayose, Maki; Yara, Satomi; Higa, Futoshi; Fujita, Jiro

    2014-01-01

    We herein report the case of a patient with human immunodeficiency virus infection and acquired immune deficiency syndrome who was diagnosed with drug-induced pure red cell aplasia consequent to lamivudine treatment. The patient was admitted to our hospital for treatment of increasing shortness of breath following physical effort. Upon admission, routine blood tests revealed a hemoglobin level of 7.6 g/dL and a hematocrit proportion of 21.2%, with normal leukocyte and platelet counts. After stopping the lamivudine treatment, the patient's hemoglobin concentration and hematocrit level returned to normal. A bone marrow examination showed an exclusive reduction in erythrocyte formation. This case indicates that lamivudine can induce severe anemia without the influence of zidovudine.

  7. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.

    PubMed

    Xu, W-M; Cui, Y-T; Wang, L; Yang, H; Liang, Z-Q; Li, X-M; Zhang, S-L; Qiao, F-Y; Campbell, F; Chang, C-N; Gardner, S; Atkins, M

    2009-02-01

    This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.

  8. Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance.

    PubMed

    Tanaka, Eiji; Matsumoto, Akihiro; Suzuki, Fumitaka; Kobayashi, Mariko; Mizokami, Masashi; Tanaka, Yasuhito; Okanoue, Takeshi; Minami, Masahito; Chayama, Kazuaki; Imamura, Michio; Yatsuhashi, Hiroshi; Nagaoka, Shinya; Yotsuyanagi, Hiroshi; Kawata, Sumio; Kimura, Tatsuji; Maki, Noboru; Iino, Shiro; Kiyosawa, Kendo

    2006-02-01

    The clinical usefulness of hepatitis B virus core-related antigen (HBVcrAg) assay was compared with that of HBV DNA assay in predicting the occurrence of lamivudine resistance in patients with chronic hepatitis B. Of a total of 81 patients who were treated with lamivudine, 25 (31%) developed lamivudine resistance during a median follow-up period of 19.3 months. The pretreatment positive rate of HBe antigen, or pretreatment levels of HBVcrAg or HBV DNA did not differ between patients with and without lamivudine resistance. Levels of both HBVcrAg and HBV DNA decreased after the initiation of lamivudine administration; however, the level of HBVcrAg decreased significantly more slowly than that of HBV DNA. The occurrence of lamivudine resistance was significantly less frequent in the 56 patients whose HBV DNA level was less than 2.6 log copy/ml at 6 months of treatment than in the remaining 25 patients. The cumulative rate of lamivudine resistance was as high as 70% within 2 years in the latter group, while it was only 28% in the former group. Lamivudine resistance did not occur during the follow-up period in the 19 patients whose HBVcrAg level was less than 4.6 log U/ml at 6 months of treatment, while it did occur in 50% of the remaining patients within 2 years. These results suggest that measurement of HBV DNA is valuable for identifying patients who are at high risk of developing lamivudine resistance, and that, conversely, measurement of HBVcrAg is valuable for identifying those who are at low risk of lamivudine resistance.

  9. Entecavir plus adefovir combination therapy versus lamivudine add-on adefovir for lamivudine-resistant chronic hepatitis B: A meta-analysis.

    PubMed

    Zeng, Teng; Xu, Hua; Liu, Jun-Ying; Lei, Yu; Zhong, Shan; Zhou, Zhi

    2014-09-01

    To determine whether adefovir (ADV) in combination with entecavir (ETV) is more effective than with lamivudine (LAM) in patients with lamivudine-resistant chronic HBV infection, electronic databases were searched through May 10th, 2013 to obtain relevant trials which met the inclusion criteria. Meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies. Four trials containing a total of 323 patients were included. Serum HBV DNA reductions after 3 and 6 months of treatment in the ETV + ADV group were greater than that of LAM + ADV group (mean difference (MD) = 0.90, 95% confidence interval (CI): 0.74-1.07, P < 0.00001; MD = 0.81, 95% CI: 0.57-1.06, P < 0.00001). The rate of 6 months HBV DNA undetectability with ETV and ADV was higher than that of LAM and ADV (relative risk (RR) = 1.63, 95% CI: 1.14-2.34, P < 0.007). There were higher rates of serum ALT normalization than those in LAM + ADV group after 6 months of treatment (RR = 1.40, 95% CI: 1.11-1.77, P < 0.005). The ETV + ADV group had lower viral breakthrough and genotypic mutation rates than LAM + ADV group after 12 months of treatment (RR = 0.24, 95% CI: 0.10-0.58, P = 0.002). The combination of ETV plus ADV is a more effective rescue therapy than LAM add-on ADV in patients with LAM-resistant HBV.

  10. The Effect of Prophylactic Lamivudine plus Adefovir Therapy Compared with Lamivudine Alone in Preventing Hepatitis B Reactivation in Lymphoma Patients with High Baseline HBV DNA during Chemotherapy

    PubMed Central

    Wu, Shaoxu; Geng, Qirong; Huang, Huiqiang; Lin, Tongyu; Jiang, Wenqi; Xia, Zhongjun; Duan, Huaxin; Rao, Huilan; Yao, Mengfei; Hu, Liyang

    2016-01-01

    Prophylactic antiviral therapy is essential for lymphoma patients with high baseline HBV DNA who undergo cytotoxic chemotherapy. However, there are limited data on the optimal options. The present study was designed to compare the efficacy of prophylactic lamivudine (LAM) with lamivudine plus adefovir dipivoxil (LAM+ADV) in preventing hepatitis B virus (HBV) reactivation in lymphoma with, pre-chemotherapy HBV DNA load ≥2000 IU/ml. We retrospectively analyzed the medical records of 86 lymphoma patients with baseline HBV DNA load ≥2000 IU/ml during chemotherapy and received LAM or LAM+ADV as prophylaxis between January 1, 2008 and November 30, 2014 at Sun Yat-sen University Cancer Center, China. Sixty-five patients received LAM and 21 received LAM+ADV. The rate was significantly lower in the LAM+ADV group compared with the LAM group for HBV reactivation (23.8% vs 55.4%; p = 0.012), while no difference was observed between the two groups in patients for HBV-related hepatitis (21.3% vs 33.3%; p   =  0.349), and chemotherapy disruption (10.9% vs 19.0%; p = 0.337). In a multivariate analysis of factors associated with HBV reactivation in these patients, LAM+ADV treatment and HBeAg negative were the independent protective factors. Therefore, LAM+ADV should be considered for antiviral prophylaxis in lymphoma patients with pre-chemotherapy HBV DNA load ≥2000 IU/ml. Further study is warranted to confirm these findings. PMID:27711135

  11. Histopathological effects of sub-chronic lamivudine-artesunate co-administration on the liver of diseased adult Wistar rats

    PubMed Central

    Olurishe, Temidayo Olutoyin; Kwanashie, Helen Ochuko; Anuka, Joseph; Muktar, Haruna; Bisalla, Mohammed

    2011-01-01

    Background: Lamivudine and artesunate are sometimes co administered in HIV-malaria co morbidity. Both drugs are used concurrently in presumptive malaria treatment and simultaneous HIV post exposure prophylaxis. Aim: The aim of this study was to investigate the effect of lamivudine-artesunate co administration on the histology of the liver of diseased adult Wistar rats. Materials and Methods: Five groups of rats of both sexes were used for the study and placed on feed and water ad libitum. Disease state consisted of immunosuppression with cyclophosphamide, and infection with Plasmodium berghei. Group 1 animals served as vehicle control, while group 2 were the diseased controls. Group 3 animals received 20 mg/kg lamivudine for three weeks, while group 4 similarly received 20 mg/kg Lamivudine but also received 10 mg/kg artesunate from day 12. Animals in group 5 received 10 mg/kg artesunate from day 12. All drugs were administered intraperitoneally. The animals were treated for twenty-one days, at the end of which they were sacrificed and their livers fixed in 10% formalin for histological studies. Result: Results from the study show the presence of regions of focal necrosis and perivascular cuffing with animals that received artesunate. Hemosiderosis was a common feature in all the parasitized groups, while fatty degeneration was observed in the group that received artesunate alone. Conclusion: Concurrent lamivudine-artesunate administration resulted in some histopathological changes in the liver. This study suggests there may be considerable histological changes with repeated occurrence of malaria and immunosuppression that may warrant intermittent lamivudine-artesunate administration, and may require evaluation as well as monitoring of liver function during such therapeutic interventions. PMID:22540106

  12. An observational comparison of first-line combination antiretroviral treatment (cART) with 2NRTI and ATV/r or DRV/r in HIV-infected patients in Italy

    PubMed Central

    Cozzi-Lepri, Alessandro; Antinori, Andrea; Bonora, Stefano; Cingolani, Antonella; Cassola, Giovanni; Angarano, Gioacchino; Vullo, Vincenzo; Mussini, Cristina; Gori, Andrea; Maggiolo, Franco; Castagna, Antonella

    2014-01-01

    Introduction In a recent clinical trial (ACTG 5257), no difference in viral failure (VF) of a first-line cART containing atazanavir/r (ATV/r) or darunavir/r (DRV/r) was found [1]. For the endpoint of discontinuation due to intolerance, the regimen with DRV/r was superior to that of ATV/r (49% of the stops of ATV/r were attributed to jaundice or hyperbilirubinemia). These and other intolerances to ATV/r remain a concern for clinicians. Methods Participants in the ICONA Foundation Study who started cART with 2NRTI+ ATV/r or DRV/r while ART-naïve were included. Several endpoints were evaluated: confirmed VF>200 copies/mL after six months of therapy, discontinuation of DRV/r or ATV/r for any reasons or because of intolerance/toxicity (as reported by the treating physician) and the combined endpoint of VF or stop. Survival analysis with Kaplan–Meier curves and Cox regression model stratified by clinical site was used. Patients' follow-up accrued from cART initiation to the date of the event or to the date of last available visit/viral load. Results 894 patients starting 2NRTI+ATV/r and 686 2NRTI+DRV/r when ART-naïve on average in 2011 (IQR: 2010–2012) were studied. Most common NRTIs used were FTC/TDF (84%) and ABC/3TC (12%). Median age was 40 years, 22% females, 44% heterosexuals. Patients starting ATV/r were more likely to be hepatitis B/C infected (2% and 14% vs 1% and 9%, p=0.001), they started one year earlier (2011 vs 2012, p=0.001), were more likely to be enrolled in sites located in the north of Italy (63% vs 54%, p=0.04), started cART less promptly after HIV diagnosis (5 vs 2 months, p=0.02) and less likely to have started TDF/FTC (83% vs 85%, p=0.02). By two years of cART, 9.8% (95% CI 7.6–12.0) of those starting ATV/r experienced discontinuation due to intolerance/toxicity vs 6.5% in DRV/r group (95% CI 4.2–8.8, p=0.04). After controlling for several potential confounders (age, gender, nation of birth, mode of HIV transmission, hepatitis co

  13. An observational comparison of first-line combination antiretroviral treatment (cART) with 2NRTI and ATV/r or DRV/r in HIV-infected patients in Italy.

    PubMed

    Cozzi-Lepri, Alessandro; Antinori, Andrea; Bonora, Stefano; Cingolani, Antonella; Cassola, Giovanni; Angarano, Gioacchino; Vullo, Vincenzo; Mussini, Cristina; Gori, Andrea; Maggiolo, Franco; Castagna, Antonella

    2014-01-01

    In a recent clinical trial (ACTG 5257), no difference in viral failure (VF) of a first-line cART containing atazanavir/r (ATV/r) or darunavir/r (DRV/r) was found [1]. For the endpoint of discontinuation due to intolerance, the regimen with DRV/r was superior to that of ATV/r (49% of the stops of ATV/r were attributed to jaundice or hyperbilirubinemia). These and other intolerances to ATV/r remain a concern for clinicians. Participants in the ICONA Foundation Study who started cART with 2NRTI+ ATV/r or DRV/r while ART-naïve were included. Several endpoints were evaluated: confirmed VF>200 copies/mL after six months of therapy, discontinuation of DRV/r or ATV/r for any reasons or because of intolerance/toxicity (as reported by the treating physician) and the combined endpoint of VF or stop. Survival analysis with Kaplan-Meier curves and Cox regression model stratified by clinical site was used. Patients' follow-up accrued from cART initiation to the date of the event or to the date of last available visit/viral load. 894 patients starting 2NRTI+ATV/r and 686 2NRTI+DRV/r when ART-naïve on average in 2011 (IQR: 2010-2012) were studied. Most common NRTIs used were FTC/TDF (84%) and ABC/3TC (12%). Median age was 40 years, 22% females, 44% heterosexuals. Patients starting ATV/r were more likely to be hepatitis B/C infected (2% and 14% vs 1% and 9%, p=0.001), they started one year earlier (2011 vs 2012, p=0.001), were more likely to be enrolled in sites located in the north of Italy (63% vs 54%, p=0.04), started cART less promptly after HIV diagnosis (5 vs 2 months, p=0.02) and less likely to have started TDF/FTC (83% vs 85%, p=0.02). By two years of cART, 9.8% (95% CI 7.6-12.0) of those starting ATV/r experienced discontinuation due to intolerance/toxicity vs 6.5% in DRV/r group (95% CI 4.2-8.8, p=0.04). After controlling for several potential confounders (age, gender, nation of birth, mode of HIV transmission, hepatitis co-infection status, AIDS diagnosis, nucleoside

  14. HLA-DQ polymorphisms with HBV infection: different outcomes upon infection and prognosis to lamivudine therapy.

    PubMed

    Zhang, X; Jia, J; Dong, J; Yu, F; Ma, N; Li, M; Liu, X; Liu, W; Li, T; Liu, D

    2014-07-01

    Two recent genome-wide studies showed that the single-nucleotide polymorphisms in the HLA-DQ region (rs2856718 and rs9275572) were associated with chronic hepatitis B virus infection and chronic hepatitis C virus-associated hepatocellular carcinoma in Japanese patients. We tested the effects of the two single-nucleotide polymorphisms for all major HBV outcomes and lamivudine treatment in Han Chinese. A total of 1649 samples were enrolled, and peripheral blood samples were collected in this study. The single-nucleotide polymorphisms in the HLA-DQ region were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Our study demonstrated the clear relevance of HLA-DQ rs2856718 and rs9275572 with HBV susceptibility, natural clearance and HBV-associated HCC. HLA-DQ rs2856718G and rs9275572A were strongly associated with decreased risk of chronic HBV infection (odds ratio = 0.641; P = 2.64 × 10(-4) ; odds ratio = 0.627, P = 7.22 × 10(-5) ) and HBV natural clearance (odds ratio = 0.610; P = 4.80 × 10(-4) ; odds ratio = 0.714, P = 0.013). Moreover, rs9275572A was also associated with development of cirrhosis and hepatocellular carcinoma (odds ratio = 0.632, P = 0.008). In addition, we showed for the first time to our knowledge that rs9275572 was a predictor for lamivudine therapy (viral response: odds ratio = 2.599, P = 4.43 × 10(-4) ; biochemical response: odds ratio = 2.279, P = 4.23 × 10(-4) ). Our study suggested that HLA-DQ loci were associated with both HBV clearance and HBV-related diseases and outcomes of lamivudine treatment in Han Chinese.

  15. Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir

    PubMed Central

    Kakuda, Thomas N.; Page, Linda M.; Anderson, Peter L.; Henry, Keith; Schacker, Timothy W.; Rhame, Frank S.; Acosta, Edward P.; Brundage, Richard C.; Fletcher, Courtney V.

    2001-01-01

    Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted. PMID:11120972

  16. Determination of lamivudine in human plasma by HPLC and its use in bioequivalence studies.

    PubMed

    Kano, Eunice Kazue; dos Reis Serra, Cristina Helena; Koono, Eunice Emiko Mori; Andrade, Simone Schramm; Porta, Valentina

    2005-06-13

    A simple, accurate, precise and sensitive high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed to quantificate lamivudine (3-TC) in human plasma samples from bioequivalence studies. 3-TC and stavudine (internal standard, I.S.) were extracted from 0.5 ml of human plasma by acetonitrile protein precipitation. The method was validated over a concentration range of 0.05-3.00 microg/ml and used in a bioequivalence trial between two lamivudine formulations, to assess its usefulness in this kind of study. FURP-lamivudine (Fundação para o Remédio Popular, Brazil, as test formulation) and Epivir (GlaxoSmithKline, Brazil, as reference formulation) were evaluated following a single 150 mg oral dose to 24 healthy volunteers of both genders. The dose was administered after an overnight fast according to a two-way crossover design. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals for the ratio of Cmax (0.86-1.06), AUC0-t (0.96-1.04) and AUC0-inf (0.97-1.05) values for the test and reference products are within the 0.80-1.25 interval proposed by FDA and EMEA. It was concluded that the two 3-TC formulations are bioequivalent in their rate and extent of absorption, and thus, may be used interchangeably.

  17. Vibrational and thermal analyses of multicomponent crystal forms of the anti-HIV drugs lamivudine and zalcitabine.

    PubMed

    Martins, Felipe T; Guimarães, Freddy Fernandes; Honorato, Sara B; Ayala, Alejandro P; Ellena, Javier

    2015-06-10

    The vibrational and thermal characterizations of four multicomponent molecular crystals of lamivudine, namely, lamivudine hydrochloride anhydrate (1), lamivudine hydrochloride monohydrate (2), lamivudine duplex I (3), with a 8:2:2:1:4 lamivudine:maleic acid:HCl:(CH3)2CHOH:H2O stoichiometry, being all three more soluble in water than the commercial solid form of lamivudine, and lamivudine maleate (4), have been performed here by infrared (IR) and Raman spectroscopy, differential scanning calorimetry (DSC), and thermogravimetry (TG). Furthermore, the vibrational spectra of zalcitabine hydrochloride (5), isostructural to 1 but with a methylene moiety in the 3'-position of the five-membered ring instead of sulfur in lamivudine, have also been measured in order to point out the role of this molecular substitution and conformation in the vibrational modes of the salts. In fact, scattering bands at the high frequency range relative to CH stretching modes are not superimposable in the Raman spectra of 1 and 5, even though these crystal forms are assembled with the same molecular conformation and intermolecular packing. At the same time, the structural similarity between 1 and 5 can be reflected in their IR spectra, as in the carbonyl and iminium stretching bands shifted to lower frequencies as consequence of their hydrogen bonding engagement. Furthermore, a scattering band at 3057 cm(-1) is observed only in the Raman spectra of crystal forms present with their 5'-CH2OH moiety in-gauche conformation, namely, 2-4. It is absent in the Raman spectra of 1 and 5 whose 5'-CH2OH moiety adopts (+)gauche conformation. In-gauche conformation, the 5'-OH oxygen is pointed toward one of the two aromatic CH hydrogens. Consequently, there is formation of an intramolecular hydrogen bond between them, shifting the aromatic CH stretching band to a lower frequency. The DFT calculations have also revealed in-phase and out-of-phase couplings of the two aromatic CH stretchings in the Raman

  18. Determination of lamivudine and stavudine in pharmaceutical preparations using chemometrics-assisted spectrophotometry.

    PubMed

    Mohamed, Abd El-Maaboud I; Mikre, Workalemahu

    2009-10-01

    A simple chemometrics-assisted spectrophotometric method for the simultaneous determination of lamivudine and stavudine in pharmaceutical tablets is described. The UV absorption spectra of the studied drugs, in the range of 200-310 nm, showed a considerable degree of spectral overlapping ([Di ](0.5) = 94.9%). Resolution of the mixture has been accomplished by using classical least-squares regression analysis (CLS) and principle components regression analysis methods (PCR). Beer's law was obeyed for both drugs in the general concentration ranges of 2-12 and 3-15 μg ml(-1) for lamivudine and stavudine, respectively. The proposed methods were successfully applied for the determination of the two drugs in laboratory prepared mixtures. The overall recoveries percent were found 98.58 ± 1.53-101.30 ± 1.35 (CLS) and 98.62 ± 1.65-101.13 ± 1.04 (PCR) for lamivudine and 98.43 ± 1.62-99.42 ± 1.55 (CLS) and 98.23 ± 1.97-101.20 ± 1.79 (PCR) for stavudine, respectively. The commercial tablets percentage content was found 98.10 ± 2.5-102.47 ± 2.94 (CLS) and 99.12 ± 1.71-100.92 ± 1.54 (PCR) for lamivudine and 96.00 ± 2.94-98.17 ± 1.72 (CLS) and 97.40 ± 1.55-97.80 ± 1.92 (PCR) for stavudine, respectively. Good percentage recoveries and proper statistical data obtained with both the laboratory prepared mixtures and the commercial tablets proved the suitability and efficiency of the proposed procedures for routine analysis and quality control purposes with quite satisfactory precision. A comparison of the obtained results from CLS and PCR were also performed with those obtained from reported method. The obtained F- and t-values obtained indicating no significant differences between the results of the proposed and reported methods.

  19. Dolutegravir–lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study

    PubMed Central

    Cahn, Pedro; Rolón, María José; Figueroa, María Inés; Gun, Ana; Patterson, Patricia; Sued, Omar

    2017-01-01

    Abstract Introduction: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. Methods: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Results: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand

  20. [The HBeAg/antiHBe seroconversion as a result of lamivudine treatment in children with chronic hepatitis B unresponsive to previous interferon alpha therapy].

    PubMed

    Lebensztejn, Dariusz Marek; Skiba, Elzbieta; Sobaniec-Lotowska, Maria; Kaczmarski, Maciej

    2004-06-01

    The aim of the study was evaluation the HBeAg/antiHBe seroconversion frequency as a result of lamivudine treatment in children who are nonresponders to previous IFN-alpha therapy. The observation was carried out on 41 children, aged 4-17 years, with biopsy-proven chronic hepatitis B (HBeAg+) treated with lamivudine 3-4 mg/kg/d (max. 100 mg/d) for 12 months. After 6 months of lamivudine therapy 59.3% children normalized GPT activity and only 1 child (2.5%) lost HBeAg. At the end of 12 months of therapy 81.5% normalized GPT activity and 4 of them (10%) lost HBeAg and seroconverted to antiHBe. None of treated children lost HBsAg. The age, sex, pretreatment GPT activity and active histological disease were not predictors of lamivudine-induced HBeAg loss. There were no side effects of lamivudine therapy except one boy who had severe thrombocytopenia. The HBeAg/antiHBe seroconversion rate after one year trial of lamivudine in children with chronic hepatitis B unresponsive to previous IFN alpha therapy was 10%. The age, sex, pretreatment GPT activity and active histologic disease were not predictors of lamivudine-induced HBeAg loss.

  1. Glycyrrhizin conjugated chitosan nanoparticles for hepatocyte-targeted delivery of lamivudine.

    PubMed

    Mishra, Deepak; Jain, Nivrati; Rajoriya, Vaibhav; Jain, Ashish K

    2014-08-01

    The present study was focused to prepare controlled release glycyrrhizin (GL) conjugated low molecular weight chitosan nanoparticles (CS-NPs) for liver targeting. The hydrophilic antiretroviral drug lamivudine was chosen as a model drug and encapsulated within glycyrrhizin conjugated low molecular weight chitosan nanoparticles (GL-CS-NPs) for liver specificity. First, the low molecular weight chitosan (CS) was synthesized through depolymerization method. The low molecular weight chitosan nanoparticles were prepared by inotropic gelation method. Then glycyrrhizin was conjugated with previously prepared low molecular weight chitosan nanoparticles (CS-NPs) and conjugation was confirmed by Fourier transform infrared (FT-IR) spectroscopy. The prepared GL-CS-NPs were characterized using dynamic light scattering, transmission electron microscopy and FT-IR. The encapsulation efficiency and in-vitro drug release behaviour of drug-loaded GL-CS-NPs were studied using ultra violet spectroscopy and high performance liquid chromatographic methods. Release of lamivudine from the nanoparticles exhibited a biphasic pattern, initial burst release and consequently sustained release. In-vivo biodistribution study suggested the target ability of GL-CS-NPs is better and haematological study shows decline of the tissue damage in comparison with plain drug solution. The experimental results show that the glycyrrhizin conjugated LMWC nanoparticles may be used as a potential drug delivery system with hepatocyte-targeting characteristics. © 2014 Royal Pharmaceutical Society.

  2. Rapid determination of lamivudine in human plasma by high-performance liquid chromatography.

    PubMed

    Alebouyeh, Mahmoud; Amini, Hossein

    2015-01-15

    A simple and rapid high-performance liquid chromatographic method with spectrophotometric detection was developed for the determination of lamivudine in human plasma. Sample preparation was accomplished through protein precipitation with acetonitrile followed by aqueous phase separation using dichloromethane. Lamivudine and the internal standard acyclovir were well separated from endogenous plasma peaks on a Chromolith RP-18e column under isocratic elution with 50 mM sodium dihydrogen phosphate-triethylamine (996:4, v/v), pH 3.2 at 20 °C. Total run time at a flow-rate of 1.5 ml/min was less than 5 min. Detection was made at 278 nm. The method was specific and sensitive, with a lower quantification limit of 40 ng/ml and a detection limit of 10 ng/ml. The absolute recovery was 97.7%, while the within- and between-day coefficient of variation and percent error values of the assay method were all less than 7%. The linearity was assessed in the range of 40-2560 in plasma, with a correlation coefficient of greater than 0.999. The method was successfully applied to a bioequivalence study in healthy volunteers.

  3. Adherence to combined Lamivudine + Zidovudine versus individual components: a community-based retrospective medicaid claims analysis.

    PubMed

    Legorreta, A; Yu, A; Chernicoff, H; Gilmore, A; Jordan, J; Rosenzweig, J C

    2005-11-01

    Adherence to a fixed dose combination of dual nucleoside antiretroviral therapy was compared between human immunodeficiency virus (HIV)-infected patients newly started on a fixed dosed combination of lamivudine (3TC) 150 mg/zidovudine (ZDV) 300 mg versus its components taken as separate pills. Medicaid pharmacy claims data were used for analyses. To examine the association between treatment group and medication adherence, three types of multivariate regressions were employed. In addition, all regressions were conducted for the whole population using data from 1995 to 2001 as well as a subpopulation, which excluded data prior to September 1997. Model covariates included patient characteristics, healthcare utilization, and non-study antiretroviral therapy use. The likelihood of > or =95% adherence among patients on combination therapy was three times greater than patients taking 3TC and ZDV in separate pills. Also, combination therapy patients had on average 1.4 fewer adherence failures per year of follow-up and nearly double the time to adherence failure compared to the separate pills group. Consistency among study results suggests that fixed dose combination therapies such as lamivudine (3TC) 150 mg/ zidovudine (ZDV) 300 mg should be considered when prescribing HIV treatment that includes an appropriate dual nucleoside.

  4. Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study

    PubMed Central

    Leung, Nancy

    2010-01-01

    Background/Aims Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. Methods In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. Results Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log10 copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. Conclusions A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B. PMID:20924215

  5. Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study.

    PubMed

    Lau, George K K; Leung, Nancy

    2010-09-01

    Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B.

  6. Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations.

    PubMed

    Moonsamy, Suri; Bhakat, Soumendranath; Walker, Ross C; Soliman, Mahmoud E S

    2016-03-01

    Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.

  7. Abacavir/Dolutegravir/Lamivudine (Triumeq)–Induced Liver Toxicity in a Human Immunodeficiency Virus–Infected Patient

    PubMed Central

    Jain, Rupali; Roxby, Alison C.

    2017-01-01

    Abstract Drug-induced liver injury related to Triumeq (abacavir/lamivudine/dolutegravir) has not been reported in clinical trials. We report a case of hepatotoxicity related to Triumeq exposure in a human immunodeficiency virus–infected patient. Clinicians should remain aware of the risk for acute and late-onset hepatitis with these agents. Close monitoring is recommended. PMID:28748198

  8. Abacavir/Dolutegravir/Lamivudine (Triumeq)-Induced Liver Toxicity in a Human Immunodeficiency Virus-Infected Patient.

    PubMed

    Christensen, Erin S; Jain, Rupali; Roxby, Alison C

    2017-01-01

    Drug-induced liver injury related to Triumeq (abacavir/lamivudine/dolutegravir) has not been reported in clinical trials. We report a case of hepatotoxicity related to Triumeq exposure in a human immunodeficiency virus-infected patient. Clinicians should remain aware of the risk for acute and late-onset hepatitis with these agents. Close monitoring is recommended.

  9. Dynamic changes of HBV DNA in serum and peripheral blood mononuclear cells of chronic hepatitis patients after lamivudine treatment

    PubMed Central

    Ke, Chang-Zheng; Chen, Yue; Gong, Zuo-Jiong; Meng, Zhong-Ji; Liu, Li; Ren, Ze-Jiu; Zhou, Zuo-Hua

    2006-01-01

    AIM: To study the dynamic changes of hepatits B virus (HBV) DNA in serum and peripheral blood mononuclear cells (PBMCs) of patients after lamivudine therapy. METHODS: A total of 72 patients with chronic HBV infection were included in this study. All patients were confirmed to have the following conditions: above 16 years of age, elevated serum alanine amonotransferase (ALT), positive hepatitis B e antigen (HBeAg), positive HBV DNA in serum and PBMCs, negative antibodies against HAV, HCV, HDV, HEV. Other possible causes of chronic liver damages, such as drugs, alcohol and autoimmune diseases were excluded. Seventy-two cases were randomly divided into lamivudine treatment group (n = 42) and control group (n = 30). HBV DNA was detected both in serum and in PBMCs by fluorescence quantitative polymerase chain reaction (PCR), during and after lamivudine treatment. RESULTS: In the treatment group, HBV DNA became negative both in serum and in PBMC, of 38 and 25 out of 42 cases respectively during the 48 wk of lamivudine treatment, the negative rate was 90.5% and 59.5% respectively. In the control group, the negative rate was 23.3% and 16.7% respectively. It was statistically significant at 12, 24 and 48 wk as compared with the control group (P < 0.005). The average conversion period of HBV DNA was 6 wk (2-8 wk) in serum and 16 wk (8-24 wk) in PBMC. CONCLUSION: Lamivudine has remarkable inhibitory effects on HBV replication both in serum and in PBMCs. The inhibitory effect on HBV DNA in PBMCs is weaker than that in serum. PMID:16810760

  10. A Chewable Pediatric Fixed-dose Combination Tablet of Stavudine, Lamivudine, and Nevirapine

    PubMed Central

    Vanprapar, Nirun; Cressey, Tim R.; Chokephaibulkit, Kulkanya; Muresan, Petronella; Plipat, Nottasorn; Sirisanthana, Virat; Prasitsuebsai, Wasana; Hongsiriwan, Suchat; Chotpitayasunondh, Tawee; Eksaengsri, Achara; Toye, MariPat; Smith, Mary Elizabeth; McIntosh, Kenneth; Capparelli, Edmund; Yogev, Ram

    2010-01-01

    Background Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunode-ficiency virus-infected Thai children. Methods The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children ≥6 to ≤30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis. Results Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 μg · hr/mL (1.42–1.67) for stavudine, 6.39 (5.82–7.00) for lamivudine, and 74.06 (65.62–83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92–1.02), 1.41 (1.30–1.53), and 1.08 (1.04–1.13), respectively. No serious drug-related toxicity was reported. Conclusions The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy. PMID

  11. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

    PubMed

    Walmsley, Sharon L; Antela, Antonio; Clumeck, Nathan; Duiculescu, Dan; Eberhard, Andrea; Gutiérrez, Felix; Hocqueloux, Laurent; Maggiolo, Franco; Sandkovsky, Uriel; Granier, Catherine; Pappa, Keith; Wynne, Brian; Min, Sherene; Nichols, Garrett

    2013-11-07

    Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No

  12. In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir

    PubMed Central

    Colledge, Danni; Civitico, Gilda; Locarnini, Stephen; Shaw, Tim

    2000-01-01

    Penciclovir {9-[2-hydroxy-1-(hydroxymethyl)-ethoxymethyl]guanine [PCV]}, lamivudine ([−]-β-l-2′,3′-dideoxy-3′-thiacytidine [3TC]), and adefovir (9-[2-phosphonylmethoxyethyl]-adenine [PMEA]) are potent inhibitors of hepatitis B virus (HBV) replication. Lamivudine has recently received approval for clinical use against chronic human HBV infection, and both PCV and PMEA have undergone clinical trials against HBV in their respective prodrug forms {famciclovir and adefovir dipivoxil [bis-(POM)-PMEA]}. Since multidrug combinations are likely to be used to control HBV infection, investigation of potential interactions between PCV, 3TC, and PMEA is important. Primary duck hepatocyte cultures which were either acutely or congenitally infected with the duck hepatitis B virus (DHBV) were used to investigate in vitro interactions between PCV, 3TC, and PMEA. Here we show that the anti-DHBV effects of all the combinations containing PCV, 3TC, and PMEA are greater than that of each of the individual components and that their combined activities are approximately additive or synergistic. These results may underestimate the potential in vivo usefulness of PMEA-containing combinations, since there is evidence that PMEA has immunomodulatory activity and, at least in the duck model of chronic HBV infection, is capable of inhibiting DHBV replication in cells other than hepatocytes, the latter being unaffected by treatment with either PCV or 3TC. Further investigation of the antiviral activities of these drug combinations is therefore required, particularly since each of the component drugs is already in clinical use. PMID:10681317

  13. A comparison of lamivudine vs entecavir for prophylaxis of hepatitis B virus reactivation in allogeneic hematopoietic stem cell transplantation recipients: a single-institutional experience.

    PubMed

    Shang, J; Wang, H; Sun, J; Fan, Z; Huang, F; Zhang, Y; Jiang, Q; Dai, M; Xu, N; Lin, R; Liu, Q

    2016-04-01

    The aim of this study was to compare the efficacy of lamivudine vs entecavir in the prevention of hepatitis B virus (HBV) reactivation in HBV surface Ag (HBsAg)-positive patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 216 consecutive patients were enrolled and retrospectively reviewed. Of these patients, 119 received lamivudine and 97 received entecavir. The median treatment duration to complete virological response in patients with baseline HBV-DNA levels >10(5) copies/mL was 2.0 months in the entecavir group, significantly shorter than that of the lamivudine group. After a median follow-up of 24 months post transplantation, the cumulative incidence rates of HBV reactivation at 6, 12 and 24 months following transplantation were 3.0%, 7.0% and 24.0% in the lamivudine group, and 0%, 0% and 2.0% in the entecavir group, respectively. In addition, entecavir treatment was associated with lower cumulative incidence rates of severe hepatitis caused by HBV reactivation. Mutations leading to drug resistance were detected in 25 patients in the lamivudine group and in only one patient in the entecavir group. Our data indicate that compared with lamivudine, entecavir has more potent antiviral efficacy and may be a better choice for prophylaxis of HBV reactivation in HBsAg-positive allo-HSCT recipients.

  14. Comparison of the clinical outcomes between antiviral-naïve patients treated with entecavir and lamivudine-resistant patients receiving adefovir add-on lamivudine combination treatment

    PubMed Central

    Kim, Hong Joo; Park, Soo Kyung; Yang, Hyo Joon; Jung, Yoon Suk; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik; Choi, Kyu Yong

    2016-01-01

    Background/Aims To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. Methods This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. Results During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). Conclusion The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression. PMID:27729626

  15. Effect of starch 1500 as a binder and disintegrant in lamivudine tablets prepared by high shear wet granulation.

    PubMed

    Rahman, Bytul M; Ibne-Wahed, Mir Imam; Khondkar, Proma; Ahmed, Maruf; Islam, Robiul; Barman, Ranjan K; Islam, M Anwarul

    2008-10-01

    High shear wet granulation is a preferred manufacturing method of tablets. It allowed for rapid production of compressible granulations. The resultant granulation characteristics depend on a combination of formulation properties and processing parameters. Fully pregelatinized starches are currently being used as binders in wet granulated formulations. But due to the gelatinization, much of the disintegration properties are lost. Partially pregelatinized starches (starch 1,500) have a mixture of properties of both native and fully gelatinized starches; made them useful as both a binder and a disintegrant in wet granulated formulations. Starch 1,500 performed as an excellent binder producing a granulation that was compressible and produced lamivudine tablets of improved hardness and friability compared with those prepared with povidone. The formulation of lamivudine tablets with starch 1,500 exceeded the disintegration and dissolution performance of the povidone formulation that utilized a super disintegrant. High shear wet granulation is also well suited for the use of partially pregelatinized starches.

  16. Prevention of Hepatitis B Virus Reactivation With Lamivudine in a Patient With Advanced Renal Cell Carcinoma Treated With Everolimus.

    PubMed

    D'Aniello, Carmine; Maruzzo, Marco; Basso, Umberto

    2016-01-01

    Anticancer agents may trigger reactivation of hepatitis B virus infection ensuing in asymptomatic to severe liver damage. Preemptive administration of antiviral agents such as lamivudine to patients receiving cytotoxic chemotherapy has been shown to inhibit viral replication and prevent such events. No data are available so far concerning the coadministration of antiviral agents and everolimus, an oral mammalian target of rapamycin inhibitor recently approved for the treatment of advanced renal cell carcinoma. We present in this study the first case to our knowledge of a hepatitis B surface antigen-positive patient with metastatic renal cell carcinoma who has been successfully treated with prophylactic lamivudine and everolimus. Long-term depletion of viral replication was obtained along with stabilization of lung and bone metastases. Hepatitis B surface antigen positivity may be found in up to 10% of cancer patients but should not be considered a contraindication to treatment with everolimus.

  17. Predicting response to peginterferon α‐2a, lamivudine and the two combined for HBeAg‐negative chronic hepatitis B

    PubMed Central

    Bonino, F; Marcellin, P; Lau, G K K; Hadziyannis, S; Jin, R; Piratvisuth, T; Germanidis, G; Yurdaydin, C; Diago, M; Gurel, S; Lai, M‐Y; Brunetto, M R; Farci, P; Popescu, M; McCloud, P

    2007-01-01

    Objective In a trial of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B, 24 week post‐treatment biochemical and virological response rates with peginterferon α‐2a with or without lamivudine were significantly higher than with lamivudine alone. The effect of pre‐treatment factors on post‐treatment responses was investigated. Methods Multivariate analyses were performed using available data from 518 patients treated with peginterferon α‐2a with or without lamivudine, or with lamivudine alone. A post‐treatment response was defined as alanine aminotransferase (ALT) normalisation and hepatitis B virus (HBV) DNA level of <20 000 copies/ml. Results In logistic regression analyses across all treatment arms, peginterferon α‐2a (with or without lamivudine) therapy, younger age, female gender, high baseline ALT, low baseline HBV DNA and HBV genotype were identified as significant predictors of combined response at 24 weeks post‐treatment. In the peginterferon α‐2a and lamivudine monotherapy arms, patients with genotypes B or C had a higher chance of response than genotype D infected patients (p<0.001), the latter responding better to the combination than to peginterferon α‐2a monotherapy (p = 0.015). At 1 year post‐treatment, response rates by intention‐to‐treat analysis were 19.2% for the peginterferon α‐2a, 19.0% for the combination, and 10.0% for the lamivudine groups, with genotypes B or C associated with a sustained combined response to peginterferon α‐2a with or without lamivudine therapy. Conclusions Baseline ALT and HBV DNA levels, patient age, gender, and infecting HBV genotype significantly influenced combined response at 24 weeks post‐treatment, in patients treated with peginterferon α‐2a and/or lamivudine. At 1 year post‐treatment HBV genotype was significantly predictive of efficacy for patients treated with peginterferon α‐2a with or without lamivudine. PMID:17127704

  18. A model-based approach for the evaluation of once daily dosing of lamivudine in HIV-infected children

    PubMed Central

    Piana, Chiara; Zhao, Wei; Adkison, Kimberly; Burger, David; Jacqz-Aigrain, Evelyne; Danhof, Meindert; Della Pasqua, Oscar

    2014-01-01

    Aim Little attention has been paid to the effects of compliance and prescription practice on treatment outcome in HIV-infected children. In this context, an evaluation of the role of covariates on pharmacokinetics is required to establish the impact of differences in dosing regimens. Here we investigate whether a once daily dosing regimen of lamivudine provides comparable exposure to the currently approved paediatric regimen. Methods A hypothetical group of 180 patients between 3 months and 12 years old was used to evaluate the impact of body weight on systemic exposure to lamivudine. Simulation scenarios were evaluated using AUC and Cmax as parameters of interest. The analysis was performed using a population pharmacokinetic model previously implemented in nonmem v.6.2. Results The simulations show that once daily dosing of lamivudine yields comparable exposure to historical values observed in children and adults, both for liquid and solid dosage forms. Simulated steady-state AUC(0–24 h) and Cmax values after once daily doses ranged respectively from 9.95 mg l−1 h and 1.9 mg l−1 for children lighter than 14 kg to 13.75 mg l−1 h and 3.0 mg l−1 for children heavier than 30 kg. These values are comparable or higher than historical values observed after once daily dosing in children and adults. Conclusions Our findings illustrate how dosing regimens can be evaluated taking into account the effects of developmental growth on drug disposition. Most importantly, they suggest that the reduction in dosing frequency to once daily leads to comparable lamivudine exposure, as observed after administration of a twice daily dosing regimen. PMID:24118047

  19. Serum hyaluronan and laminin level in children with chronic hepatitis B during long-term lamivudine treatment.

    PubMed

    Lebensztejn, Dariusz Marek; Skiba, Elzbieta; Sobaniec-Lotowska, Maria Elzbieta; Kaczmarski, Maciej

    2007-01-01

    The aim was to assess the effect of long-term lamivudine treatment on liver fibrosis by direct assessment of histological scores and by indirect assessment of serum biomarkers in children with chronic hepatitis B (chB). The observation was carried out on 31 children with biopsy proven chB who were nonresponders to previous IFNalpha therapy. The serum concentration of hyaluronan and laminin were measured before and up to 24 months of therapy. ROC analysis was used to calculate the power of the assays to detect advanced liver fibrosis (score > 2 according to Batts & Ludwig). Serum hyaluronan and laminin level were significantly higher in children with chB compared to controls. There was a significant correlation between serum hyaluronan level and the stage of liver fibrosis. The ability of serum hyaluronan to differentiate children with advanced fibrosis from those with mild fibrosis was significant (AUC = 0.7767). Laminin did not allow a useful prediction. Two-year lamivudine treatment did not improve histological fibrosis but it caused significant decrease of serum hyaluronan level. Hyaluronan is a better fibrosis marker than laminin to diagnose children with advanced liver fibrosis. The significant decrease of hyaluronan level during therapy suggests antifibrotic effect of lamivudine in children with chB.

  20. De novo combination therapy adefovir plus lamivudine as a treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B before pregnancy.

    PubMed

    Ma, Li-Na; Ding, Xiang-Chun; Liu, Xiao-Yan; Xu, Chun-Qiong; Liu, Shuai-Wei; Yan, Xie

    2014-03-01

    Substantial progress has been achieved in antiviral therapy for chronic hepatitis B; however, options for women of child-bearing age with HBeAg-positive chronic hepatitis B remain a challenge. In this study, we sought to determine whether de novo combination therapy of Adefovir plus Lamivudine was a super treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B prior to conception. A total of 122 women patients of child-bearing age with HBeAg-positive chronic hepatitis B were randomly assigned to receive (i) 10 mg Adefovir plus 100 mg Lamivudine (64 patients) or (ii) 10 mg Adefovir monotherapy (58 patients), administrated orally once daily for 96 weeks. The therapeutic efficacy within each group was compared at weeks 48 and 96. The results showed that de novo combination therapy of Adefovir plus Lamivudine significantly reduced HBV-DNA detectability, and enhanced ALT normalization and HBeAg seroconversion in women of child-bearing age with HBeAg-positive chronic hepatitis B. No virological breakthrough and genotypic resistance were observed in the combination therapy group. Additionally, the combination therapy with Adefovir plus Lamivudine was well tolerated. This study suggests that de novo combination therapy of Adefovir plus Lamivudine offers a therapeutic advantage for women of child-bearing age with HBeAg-positive chronic hepatitis B when taken before conception.

  1. A micellar liquid chromatography method for the quantification of abacavir, lamivudine and raltegravir in plasma.

    PubMed

    Peris-Vicente, Juan; Villareal-Traver, Mónica; Casas-Breva, Inmaculada; Carda-Broch, Samuel; Esteve-Romero, Josep

    2014-09-01

    An analytical methodology based on micellar liquid chromatography has been developed to quantify abacavir, lamivudine and raltegravir in plasma. These three antiretroviral drugs are prescribed as a set in highly active antiretroviral therapy to acquired immunodeficiency syndrome patients. The experimental procedure consists in the dilution of the sample in micellar media, followed by filtration and, without cleanup step. The analytes were resolved in less than 30min using a mobile phase of 0.05M sodium dodecyl sulphate at pH 7, running at 1mLmin(-1) under isocratic mode at room temperature through a C18 column (125×4.6mm, 5μm particle size). The UV detection wavelength was set at 260nm. The method was successfully validated following the requirements of ICH guidelines in terms of: linear range (0.25-2.5μgmL(-1)), linearity (r(2)>0.990), intra- and interday precision (<6.8%) and accuracy (92.3-104.2%) and robustness (<7.1%). To the extent of our knowledge, this is the first published method to quantify these three drugs in plasma. Several blood samples from AIDS patients taking this HAART set provided by a local hospital were analyzed with satisfactory results.

  2. Quantitative determination and sampling of lamivudine and zidovudine residues for cleaning validation in a production area.

    PubMed

    Santoro, Maria Inês Rocha Miritello; Fazio, Tatiana Tatit; Singh, Anil Kumar; Kedor-Hackmann, Erica Rosa Maria

    2007-01-01

    Lamivudine (3TC) and zidovudine (AZT) are systemic antiviral substances extensively used in human immunodeficiency virus (HIV) infected patients. Nowadays, 3TC, AZT, and several other pharmacologically potent pharmaceuticals are manufactured in the same production area. To assure quality of drug products and patient safety, properly validated cleaning methodology is necessary. A carefully designed cleaning validation and its evaluation can ensure that residues of 3TC and AZT will not carry over and cross contaminate the subsequent product. The aim of this study was to validate a simple analytical method for verification of residual 3TC and AZT in equipment used in the production area and to confirm the efficiency of the cleaning procedure. The liquid chromatography method was validated using a Nova-Pak C18 column (3.9 x 150 mm, 4 microm particle size) and methanol-water (20 + 80, v/v) as the mobile phase at a flow rate of 1.0 mL/min. Ultraviolet detection was made at 266 nm. The calibration curve was linear over a concentration range of 2.0-22.0 microg/mL with a correlation coefficient of 0.9998. The detection and quantitation limits were 0.36 and 1.21 microg/mL, respectively. The intra-day and interday precision expressed as relative standard deviation were below 2.0%. The mean recovery of the method was 99.19%. The mean extraction recovery from manufacturing equipment was 83.5%.

  3. Simultaneous determination of zidovudine and lamivudine in human serum using HPLC with tandem mass spectrometry.

    PubMed

    Kenney, K B; Wring, S A; Carr, R M; Wells, G N; Dunn, J A

    2000-07-01

    A method employing high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS) has been developed and validated for the simultaneous determination of clinically relevant levels of zidovudine (AZT) and lamivudine (3TC) in human serum. The method incorporates a fully automated ultrafiltration sample preparation step that replaces the solid-phase extraction step typically used for HPLC with UV detection. The calibration range of the dual-analyte LC-MS/MS method is 2.5-2,500 and 2.5-5,000 ng ml-1 for AZT and 3TC, respectively, using 0.25 ml of human serum. The lower limit of quantification was 2.5 ng ml-1 for each analyte, with a chromatographic run time of approximately 6 min. Overall accuracy, expressed as bias, and inter- and intra-assay precision are < +/- 7 and < 10% for AZT, and < +/- 5 and < 12.1% for 3TC over the full concentration ranges. A cross-validation study demonstrated that the LC-MS/MS method afforded equivalent results to established methods consisting of a radioimmuno-assay for AZT and an HPLC-UV method for 3TC. Moreover, the LC-MS/MS was more sensitive, allowed markedly higher-throughput, and required smaller sample volumes (for 3TC only). The validated method has been used to support post-marketing clinical studies for Combivir a combination tablet containing AZT and 3TC.

  4. Mutagenic and recombinagenic effects of lamivudine and stavudine antiretrovirals in somatic cells of Drosophila melanogaster.

    PubMed

    Franchi, Leonardo Pereira; Pentiado, Nádia Helena Garofo Rodrigues; Silva, Renata do Nascimento; Guimarães, Nilza Nascimento; Jesuino, Rosália Santos Amorim; de Andrade, Heloísa Helena Rodrigues; Lehmann, Maurício; Cunha, Kênya Silva

    2009-03-01

    Lamivudine (3TC) and stavudine (d4T) are nucleoside analogue reverse transcriptase inhibitors employed in antiretroviral therapies. The mutational and recombinational potential as well as the total genetic toxicity was determined for both compounds at concentrations allowing at least 30% survival using the standard version of wing SMART assay. The standardized clone induction frequency per mg/ml for mwh/flr(3) genotype were approximately 2 and approximately 33 mutant clones/10(5) cells/(mg/ml) for d4T and 3TC, respectively. Comparing these results with those obtained in the mwh/TM3 genotype, it was possible to quantify the recombinagenic action of each drug. Approximately 86% of the mutant clones induced by 3TC and approximately 76% of the d4T induced clones were related to their mitotic recombination action. Our results indicate that both 3TC and d4T have high recombinagenic potential, and suggest that exposure to the drugs could cause genomic instability and loss of heterozygosity. This may be due to the fact that these genetic alterations play a primary role in carcinogenesis, and are also involved in secondary and subsequent steps of carcinogenesis by which recessive oncogenic mutations are revealed.

  5. Formulation development and evaluation of lamivudine controlled release tablets using cross-linked sago starch.

    PubMed

    Singh, Akhilesh Vikram; Nath, Lila Kanta

    2013-02-01

    Modified starches based polymeric substances find utmost applicability in pharmaceutical formulation development. Cross-linked starches showed very promising results in drug delivery application. The present investigation concerns with the development of controlled release tablets of lamivudine using cross-linked sago starch. The cross-linked derivative was synthesized with phosphorous oxychloride and native sago starch in basic pH medium. The cross-linked sago starch was tested for acute toxicity and drug-excipient compatibility study. The formulated tablets were evaluated for various physical characteristics, in vitro dissolution release study and in vivo pharmacokinetic study in rabbit model. In vitro release study showed that the optimized formulation exhibited highest correlation (R) in case of zero order kinetic model and the release mechanism followed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T(max), C(max), AUC, V(d), T(1/2), and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir®. The cross-linked starch showed promising results in terms of controlling the release behavior of the active drug from the matrix. The hydrophilic matrix synthesized by cross-linking could be used with a variety of active pharmaceutical ingredients for making their controlled/sustained release formulations.

  6. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial.

    PubMed

    Walmsley, Sharon; Baumgarten, Axel; Berenguer, Juan; Felizarta, Franco; Florence, Eric; Khuong-Josses, Marie-Aude; Kilby, J Michael; Lutz, Thomas; Podzamczer, Daniel; Portilla, Joaquin; Roth, Norman; Wong, Deborah; Granier, Catherine; Wynne, Brian; Pappa, Keith

    2015-12-15

    The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.

  7. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial

    PubMed Central

    Walmsley, Sharon; Baumgarten, Axel; Berenguer, Juan; Felizarta, Franco; Florence, Eric; Khuong-Josses, Marie-Aude; Kilby, J. Michael; Lutz, Thomas; Podzamczer, Daniel; Portilla, Joaquin; Roth, Norman; Granier, Catherine; Wynne, Brian; Pappa, Keith

    2015-01-01

    Abstract: The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 13 (3%); efavirenz/tenofovir/emtricitabine arm, 48 (11%)] through W144. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144. PMID:26262777

  8. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study.

    PubMed

    Else, Laura J; Jackson, Akil; Puls, Rebekah; Hill, Andrew; Fahey, Paul; Lin, Enmoore; Amara, Alieu; Siccardi, Marco; Watson, Victoria; Tjia, John; Emery, Sean; Khoo, Saye; Back, David J; Boffito, Marta

    2012-03-01

    There is interest in evaluating the efficacy of lower doses of certain antiretrovirals for clinical care. We determined here the bioequivalence of plasma lamivudine (3TC) and intracellular 3TC-triphosphate (3TC-TP) concentrations after the administration of two different doses. ENCORE 2 was a randomized crossover study. Subjects received 3TC at 300 and 150 mg once daily for 10 days (arm 1; n = 13) or vice versa (arm 2; n = 11), separated by a 10-day washout. Pharmacokinetic (PK) profiles (0 to 24 h) were assessed on days 10 and 30. Plasma 3TC and 3TC-TP levels in peripheral blood mononuclear cells were quantified by high-performance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters (the area under the concentration-time curve from 0 to 24 h [AUC(0-24)], the trough concentration of drug in plasma at 24 h [C(24)], and the maximum concentration of drug in plasma [C(max)]) were evaluated by determining the geometric mean ratios (GMRs) adjusted for study arm, period, and intra-individual variation. Regimens were considered bioequivalent if the 90% confidence interval (90% CI) fell within the range of 0.8 to 1.25. A total of 24 subjects completed the study. The GM (90% CI) 3TC AUC(0-24)), expressed as ng·h/ml, for the 300- and 150-mg doses were 8,354 (7,609 to 9,172) and 4,773 (4,408 to 5,169), respectively. Bioequivalence in 3TC PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.57 (0.55 to 0.60), 0.63 (0.59 to 0.67), and 0.56 (0.53 to 0.60), respectively. The GM (90% CI) 3TC-TP AUC(0-24) values (pmol·h/10(6) cells) for the 300- and 150-mg doses were 59.5 (51.8 to 68.3) and 44.0 (38.0 to 51.0), respectively. Bioequivalence in 3TC-TP PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.73 (0.64 to 0.83), 0.82 (0.68 to 0.99), and 0.70 (0.61 to 0.82), respectively. We found that 3TC at 150 mg is

  9. Prophylactic lamivudine to improve the outcome of HBsAg-positive lymphoma patients during chemotherapy: a systematic review and meta-analysis.

    PubMed

    Li, Hong; Zhang, Hong-Min; Chen, Li-Fen; Chen, Ya-Qin; Chen, Ling; Ren, Hong; Hu, Huai-Dong

    2015-02-01

    Hepatitis B viral (HBV) reactivation in lymphoma patients undergoing chemotherapy is associated with significant morbidity and mortality. Increasingly, lamivudine is being used to prevent hepatitis B reactivation. To assess the effects of prophylactic lamivudine on reactivation and mortality following chemotherapy in lymphoma patients who are hepatitis B surface antigen (HBsAg)-positive, we searched Medline/PubMed, Ovid MEDLINE, EMBASE, Web of Knowledge and the Cochrane Library for studies through November 2013. Statistical analysis was performed using REVMAN. Fourteen studies consisting of 636 patients were included in the analysis. The rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis due to HBV reactivation in patients with lamivudine prophylaxis was significantly lower than those with no prophylaxis. Risk ratios [RRs] were 0.25 (95% confidence intervals [CI] 0.13-0.51; P=0.0001), 0.40 (95% CI 0.26-0.63; P<0.0001), and 0.21 (95% CI 0.09-0.51; P=0.0005) respectively. In addition, patients given prophylactic lamivudine had significant reductions in overall mortality and mortality attributable to HBV reactivation compared with control group. Risk ratios [RRs] were 0.45 (95% CI 0.29-0.70; P=0.0004) and 0.41 (95% CI 0.20-0.84; P=0.01) respectively. Chemotherapy disruption was not significantly different between the two groups. Risk ratios [RRs] were 0.34 (95% CI 0.09-1.26; P=0.11). Prophylactic therapy with lamivudine for HBsAg-positive lymphoma patients who are undergoing chemotherapy may reduce the risk for HBV reactivation, hepatitis due to HBV reactivation, overall mortality and mortality attributable to HBV reactivation. Additionally, patients with preventive lamivudine had a trend towards the decreased incidence of chemotherapy disruption.

  10. Formulation development and optimization of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg FDC tablets by D-optimal mixture design.

    PubMed

    Tibalinda, Prosper; Sempombe, Joseph; Shedafa, Raphael; Masota, Nelson; Pius, Dickson; Temu, Mary; Kaale, Eliangiringa

    2016-12-01

    The usage of fixed dose combination (FDC) tablets of Lamivudine and Tenofovir Disoproxil Fumarate (TDF) is increasing due to increased incidences of HIV/Hepatitis B and HIV/TB co-infections. This is likely to increase the financial crisis due to limited resources for funding procurement of ready-made products from the pharmaceuticals manufacturing leading countries. Therefore, production of local oral tablets containing Lamivudine and TDF FDC is inevitable. Lamivudine 300 mg/TDF 300 mg tablets were developed and optimized by D-optimal mixture design and produced by direct compression technique. Twenty trial formulations with independent variables, including PVP-CL 1-12.00%, PVP-K30 1-10.00%, starch-1500 2.5-12.5% and Avicel-PH102 2-19.25% were prepared by direct compression technique. The formulations were assessed on assay, dissolution, friability, weight variation and disintegration time. It was found that assay ranged from 98.13-101.95% for Lamivudine, 98.25-102.84 for TDF, both were within the in-house assay specification of 95 to 105%. Dissolution at single point was above 80% for Lamivudine 93.96-100.55% and 95.85-103.15% for TDF, disintegration time was between 1.92-66.33 min and friability 0.06-12.56%. Out of twenty formulation trials, eight formulations had all parameters in proven acceptable range. On optimization, one formulation with independent variables, PVP-CL 5.67%, PVP-K30 1.00%, Starch-1500 5.76% was selected. The optimized formulation was comparable to the reference product on the market with similarity factor (f2) and difference factor (f1) within the acceptable range for both Lamivudine and TDF.

  11. Effect of lamivudine treatment in patients with decompensated cirrhosis due to anti-HBe positive/HBeAg-negative chronic hepatitis B.

    PubMed

    Nikolaidis, Nikolaos; Vassiliadis, Themistoklis; Giouleme, Olga; Tziomalos, Konstantinos; Grammatikos, Nikolaos; Patsiaoura, Kalliopi; Orfanou-Koumerkeridou, Eleni; Balaska, Aikaterini; Eugenidis, Nikolaos

    2005-06-01

    Lamivudine has been shown to improve liver function and reduce the need for liver transplantation (LT) in patients with decompensated HBeAg-positive cirrhosis. Nevertheless, there is only limited experience with lamivudine in patients with anti-HBe-positive/HBeAg-negative cirrhosis. The primary aim of this study was to determine whether lamivudine treatment improves liver function and subsequently pre-LT survival or delays or obviates the need for LT in patients with anti-HBe-positive/HBeAg-negative cirrhosis. Between July 1998 and June 2003, 20 consecutive patients awaiting LT were enrolled in the study. All patients showed active viral replication and were treated with lamivudine 100 mg daily. Significant clinical improvement, defined as a decrease in the Child-Pugh-Turcotte score by >or=2 points, was observed in 11 (55%) patients. The median change in the Child-Pugh-Turcotte score was -2 (range -5 to +2). The median time required to achieve a 2-point or greater reduction in Child-Pugh-Turcotte score was 6 months (range 3-12 months). In nine patients (45%), the Child-Pugh-Turcotte score decreased to lamivudine with reappearance of HBV DNA after 48 months of treatment. In conclusion, our results provide further evidence to the notion that lamivudine is beneficial in patients with decompensated anti-HBe-positive/HBeAg-negative cirrhosis caused by actively replicating chronic hepatitis B.

  12. Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study.

    PubMed

    Yang, Wan-Lin; Kouyos, Roger D; Scherrer, Alexandra U; Böni, Jürg; Shah, Cyril; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Hirzel, Cédric; Battegay, Manuel; Cavassini, Matthias; Bernasconi, Enos; Vernazza, Pietro; Held, Leonhard; Ledergerber, Bruno; Günthard, Huldrych F

    2015-12-01

    The most recommended NRTI combinations as first-line antiretroviral treatment for HIV-1 infection in resource-rich settings are tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine. Efficacy studies of these combinations also considering pill numbers, dosing frequencies and ethnicities are rare. We included patients starting first-line combination ART (cART) with or switching from first-line cART without treatment failure to tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine plus efavirenz or nevirapine. Cox proportional hazards regression was used to investigate the effect of the different NRTI combinations on two primary outcomes: virological failure (VF) and emergence of NRTI resistance. Additionally, we performed a pill burden analysis and adjusted the model for pill number and dosing frequency. Failure events per treated patient for the four NRTI combinations were as follows: 19/1858 (tenofovir/emtricitabine), 9/387 (abacavir/lamivudine), 11/344 (tenofovir/lamivudine) and 45/1244 (zidovudine/lamivudine). Compared with tenofovir/emtricitabine, abacavir/lamivudine had an adjusted HR for having VF of 2.01 (95% CI 0.86-4.55), tenofovir/lamivudine 2.89 (1.22-6.88) and zidovudine/lamivudine 2.28 (1.01-5.14), whereas for the emergence of NRTI resistance abacavir/lamivudine had an HR of 1.17 (0.11-12.2), tenofovir/lamivudine 11.3 (2.34-55.3) and zidovudine/lamivudine 4.02 (0.78-20.7). Differences among regimens disappeared when models were additionally adjusted for pill burden. However, non-white patients compared with white patients and higher pill number per day were associated with increased risks of VF and emergence of NRTI resistance: HR of non-white ethnicity for VF was 2.85 (1.64-4.96) and for NRTI resistance 3.54 (1.20-10.4); HR of pill burden for VF was 1.41 (1.01-1.96) and for NRTI resistance 1.72 (0.97-3.02). Although VF and emergence of resistance was very low in the

  13. [Effect of Lamivudine on chronic hepatitis B patients with chemotherapy or immunosuppressive agents therapy and research the drug resistance].

    PubMed

    Lu, Li-Xia; Wang, Ying; Lu, Xiao-Jun; Li, Da-Jiang; Xu, Kong-Wen; Tang, Hong; Liu, Li; Liu, Cong; Wang, Li-Chun

    2011-09-01

    To study the effect of Lamivudine on chronic hepatitis B patients with chemotherapy or immunosuppressive agents therapy, and research the drug resistance. Thirty-one cases of chronic hepatitis B patients who needed chemotherapy or immunosuppressive agents therapy were enrolled and divided into two group, HBeAg-positive group (n = 20) and HBeAg-negative group (n = 11), then given Lamivudine for preventive treatment. Virus response, biochemical response and serum response were evaluated as effective index, and analyzed the difference between the two groups for statistical significance. Meanwhile, drug resistance rate, impact factor of resistance and security were analyzed. At the end of 48 weeks' treatment, the rate of HBV DNA under the detection limit was 41.94%, and the decline of HBV DNA compared with baseline was 2.35 lg. The normalization rate of ALT, the negative rate of HbeAg and the seroconversion rate of HBeAg/HBeAb were 92.31%, 25% and 20% respectively. HBeAg-positive group and HBeAg-negative group patients in the complete virus response, the decline of HBV DNA compared with baseline and the resistance rate had no statistics significance (P > 0.05). At the same time, virology breakthrough occurred in four patients, and resistance mutation was detected in three cases among them. The resistance rate was 9.68%. The type of genotype mutation were all rtM204I. Multi-factor regression analysis showed that the baseline factors including age, gender, HBeAg status, baseline HBV DNA level and baseline ALT had no significant compact on drug resistance. Serious adverse reactions were not found in all patients. For chronic hepatitis B patients who needed chemotherapy or immunosuppressive agents treatment, Lamivudine for preventive antiviral therapy is a good option with good antiviral effect and safety. It is necessary to pay attention to the occurrence of drug resistance.

  14. Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study.

    PubMed

    Abhyankar, Dhiraj; Shedage, Ashish; Gole, Milind; Raut, Preeti

    2016-06-17

    The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on Cmax, AUC0-t, and AUC0-inf for tenofovir and lamivudine and on Cmax and AUC0-72 for efavirenz were within the acceptance criteria (80-125%). For tenofovir disoproxil fumarate, the Tmax, Kel, and t1/2 values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the Tmax, Kel, and t1/2 values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the Tmax values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators' formulations, and both treatments were well tolerated.

  15. Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine.

    PubMed

    Gutiérrez, Sonia; Guillemi, Silvia; Jahnke, Natalie; Montessori, Valentina; Harrigan, P Richard; Montaner, Julio S G

    2008-02-01

    We summarize the clinical history and laboratory results following the introduction of tenofovir among 6 patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who presented with severe liver disease while receiving lamivudine-based highly active antiretroviral therapy. In all cases, the introduction of tenofovir led to a sustained undetectable HBV and HIV loads, with marked clinical and laboratory improvement in liver function. We provide supporting evidence for the role of tenofovir in the management of advanced HBV infection in HIV-positive patients after the development of lamivudine resistance.

  16. Early virological response of zidovudine/lamivudine/abacavir for patients co-infected with HIV and tuberculosis in Uganda

    PubMed Central

    Srikantiah, Padmini; Walusimbi, Maria N.; Kayanja, H. Kose; Mayanja-Kizza, Harriet; Mugerwa, Roy D.; Lin, Royce; Charlebois, Edwin D.; Boom, W. Henry; Whalen, Christopher C.; Havlir, Diane V.

    2015-01-01

    Triple nucleoside reverse transcriptase inhibitors are recommended as an alternative regimen for HIV-infected patients undergoing tuberculosis treatment in resource-limited settings. Few data exist on the efficacy of such regimens in tuberculosis patients. In 34 tuberculosis/HIV-co-infected patients treated with zidovudine/lamivudine/abacavir, 76% achieved HIV RNA less than 50 copies/ml at 24 weeks. No cases of hypersensitivity or immune reconstitution syndrome were observed. These data support the continuing evaluation of nucleoside-based antiretroviral regimens as an alternative treatment for this population. PMID:17721107

  17. The NRTIs Lamivudine, Stavudine and Zidovudine Have Reduced HIV-1 Inhibitory Activity in Astrocytes

    PubMed Central

    Gray, Lachlan R.; Tachedjian, Gilda; Ellett, Anne M.; Roche, Michael J.; Cheng, Wan-Jung; Guillemin, Gilles J.; Brew, Bruce J.; Turville, Stuart G.; Wesselingh, Steve L.; Gorry, Paul R.; Churchill, Melissa J.

    2013-01-01

    HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens. PMID:23614033

  18. Preparation and characterization of isoniazid and lamivudine co-loaded polymeric microspheres.

    PubMed

    Pandey, Gitu; Yadav, Sarita Kumari; Mishra, Brahmeshwar

    2016-12-01

    Context The rate of co-infection of HIV/Tuberculosis is increasing alarmingly. This calls for a drug delivery approach targeting both diseases. Objective The study aims to investigate co-loading of isoniazid, an antitubercular drug and lamivudine an antiretroviral drug, into polymeric microspheres for simultaneous treatment of both diseases. Materials and methods Microspheres were prepared by o/o emulsion solvent evaporation method by employing ethylcellulose and eudragit RS 100 as polymers. The prepared formulation was suitably characterized for FTIR, DSC, percent yield, loose surface crystals, entrapment efficiency, and in vitro studies. The surface morphology of microspheres was observed using digital microscope and scanning electron microscope. Cell viability study was done on Caco-2 cells. Results and discussion FTIR and DSC studies demonstrated compatibility and stability of excipients. Microscopy studies revealed that particles were spherical in shape and distributed over a range of 120-270 μm. Percent yield, LSC and %EE have shown promising results. In vitro release showed biphasic release pattern with sustained release up to 12 h. Mechanism of drug release followed Higuchi Kinetics and non-fickian release behaviour. The formulation containing drug/polymer ratio 1:2 and EU/EC of 1:1 showed optimum response in context to achievement of controlled release. The cell viability studies showed that the prepared system had no toxic effect on intestinal epithelial Caco-2 cells. Conclusion Polymeric microspheres were prepared and suitably characterized for simultaneous delivery of two drugs. This matrix system could be used for better therapeutic outcome in this deadly co-infection.

  19. Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

    PubMed Central

    Palacios, Rosario; Santos, Jesús; Camino, Xavier; Arazo, Piedad; Torres Perea, Rafael; Echevarrfa, Santiago; Ribera, Esteban; Sánchez de la Rosa, Rainel; Moreno Guillen, Santiago

    2005-01-01

    Background: The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain. Objective: The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study. Methods: Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003. Results: A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART

  20. Sustained clinical improvement of a patient with decompensated hepatitis B virus-related cirrhosis after treatment with lamivudine monotherapy.

    PubMed

    Nagasaki, Futoshi; Ueno, Yoshiyuki; Yamamoto, Takeshi; Nakagomi, Yu; Kido, Osamu; Kakazu, Eiji; Matsuda, Yasunori; Kogure, Takayuki; Yamagiwa, Yoko; Kikuchi, Kumiko; Fukushima, Koji; Kanno, Noriatsu; Niitsuma, Hirofumi; Shimosegawa, Tooru

    2006-09-01

    Hepatitis B virus (HBV) infection, which causes liver cirrhosis and hepatocellular carcinoma, remains a major health problem in Asian countries. Recent development of vaccine for prevention is reported to be successful in reducing the size of chronically infected carriers, although the standard medical therapies have not been established up to now. In this report, we encountered a patient with decompensated HBV-related cirrhosis who exhibited the dramatic improvements after antiviral therapy. The patient was a 50-year-old woman. Previous conventional medical treatments were not effective for this patient, thus this patient had been referred to our hospital. However, the administration of lamivudine, a reverse transcriptase inhibitor, for 23 months dramatically improved her liver severity. During this period, no drug resistant mutant HBV emerged, and the serum HBV-DNA level was continuously suppressed. These virological responses were also maintained even after the antiviral therapy was discontinued. Moreover, both hepatitis B surface antigen and e antigen were observed to have disappeared in this patient. The administration of lamivudine to patients with HBV-related cirrhosis, like our present case, should be considered as an initial medical therapeutic option, especially in countries where liver transplantation is not reliably available.

  1. A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

    PubMed

    Martínez, Esteban; Arranz, José A; Podzamczer, Daniel; Loncá, Montserrat; Sanz, José; Barragán, Patricia; Ribera, Esteban; Knobel, Hernando; Roca, Victor; Gutiérrez, Félix; Blanco, José L; Mallolas, Josep; Llibre, Josep M; Clotet, Bonaventura; Dalmau, David; Segura, Ferran; Arribas, José R; Cosín, Jaime; Barrufet, Pilar; Casas, Esperanza; Ferrer, Elena; Curran, Adrià; González, Alicia; Pich, Judit; Cruceta, Ana; Arnaiz, Joan A; Miró, José M; Gatell, José M

    2009-07-01

    Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure ["switching = failure" intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval -2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

  2. Influence of TCM therapy for supplementing Pi and nourishing Shen on dendritic cell function in patients with chronic hepatitis B treated by lamivudine.

    PubMed

    Zhang, Yong-Hua; Liu, Yi-Hui

    2009-02-01

    To observe the influence of traditional Chinese medicine (TCM) therapy for supplementing Pi () and nourishing Shen (, SPNS) on dendritic cell function in patients with chronic hepatitis B (CHB) treated by lamivudine. Sixty CHB patients with positive HBeAg were equally randomized by digital table into two groups: the observation group and the control group. Patients in the control group were treated with lamivudine only, while patients in the observation group were treated with lamivudine combined with SPNS fomula, for 12 weeks. The phenotype and function of dendritic cell, as well as its secretion factor interleukin 12 (IL-12) in all patients were determined after termination of therapy and the impacts on alanine transaminase (ALT) and HBVDNA were observed. The phenotypes of dendritic cells such as CD1a, CD80, CD86, human leukocyte antigen (HLA-DR) and intercellular adhesion molecule-1, as well as the levels of stimulation index (SI) and IL-12 were higher in the observation group than those in the control group (P<0.05 or P<0.01). Meanwhile, signififi cant difference between the two groups was also shown in the normalizing rates of ALT and HBV-DNA (P<0.05). TCM therapy for SPNS can signifificantly improve the function of dendritic cells in patients with CHB treated by lamivudine and enhance the early stage response of patients to the treatment.

  3. Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand.

    PubMed

    2017-04-01

    Zidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network. Fourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12-24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described. Of 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged ≥10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade ≥3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were ≤2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)). Scored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening

  4. Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients.

    PubMed

    Maggiolo, Franco; Gulminetti, Roberto; Pagnucco, Layla; Digaetano, Margherita; Benatti, Simone; Valenti, Daniela; Callegaro, Annapaola; Ripamonti, Diego; Mussini, Cristina

    2017-03-16

    combination with lamivudine shows promising results to be confirmed in larger controlled trials.

  5. Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression

    PubMed Central

    Llibre, Josep M.; Cozzi-Lepri, Alessandro; Pedersen, Court; Ristola, Matti; Losso, Marcelo; Mocroft, Amanda; Mitsura, Viktar; Falconer, Karolin; Maltez, Fernando; Beniowski, Marek; Vullo, Vincenzo; Hassoun, Gamal; Kuzovatova, Elena; Szlavik, János; Kuznetsova, Anastasiia; Stellbrink, Hans-Jürgen; Duvivier, Claudine; Edwards, Simon; Laut, Kamilla; Paredes, Roger

    2016-01-01

    Abstract Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant. We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR <50 copies/mL) and a snapshot analysis at 48, 96, and 144 weeks. Virological failure (VF) was defined as confirmed pVL >50 copies/mL. We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50 copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42–0.93] per 100 cells higher), time with pVL ≤50 copies/mL (HR 0.87 [95% CI: 0.79–0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28–6.04]). Resistance selection at failure was uncommon. A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure. PMID:27749561

  6. Histological outcome for chronic hepatitis B patients treated with entecavir vs lamivudine-based therapy

    PubMed Central

    Wang, Jia-Li; Du, Xin-Fang; Chen, Shao-Long; Yu, Yi-Qi; Wang, Jing; Hu, Xi-Qi; Shao, Ling-Yun; Chen, Jia-Zhen; Weng, Xin-Hua; Zhang, Wen-Hong

    2015-01-01

    AIM: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy. METHODS: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People’s Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ2 test or Fisher’s exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test. RESULTS: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The

  7. Evolutionary trends of resistance mutational patterns of HBV reverse transcriptase over years (2002-2012) of different treatment regimens: The legacy of lamivudine/adefovir combination treatment.

    PubMed

    Vincenti, Donatella; Piselli, Pierluca; Solmone, Mariacarmela; D'Offizi, Gianpiero; Capobianchi, Maria R; Menzo, Stefano

    2017-03-16

    Antiviral therapy has revolutionized treatment of chronic HBV infections. First generation compounds, lamivudine and adefovir, displayed a high rate of treatment failures, and have been replaced by more potent compounds with high genetic barrier to resistance. However, the evolution of the virus towards resistance due the use of first generation compounds may still provide useful information for a better management of current antivirals. A single center sequence database including 705 HBV reverse transcriptase sequences from patients failing antiviral treatments (2002-2012) has been statistically analyzed to highlight viral evolution in relationship to the use of antiviral compounds and to their associations/sequencing in those years. The influence of viral genotypes and polymorphisms on resistance-related mutational patterns was also investigated. This study documents how, after the first years of antiviral therapy, the use of adefovir as an add-on strategy allowed a consistent reduction treatment failures. It also documents the effects of the initial misuse of entecavir in lamivudine experienced patients. In the latest years, the correct use of entecavir and the introduction of tenofovir allowed further curbing of resistance-related treatment failures, which virtually disappeared. Furthermore, the study allows a better understanding of how viral genotype (A vs D) conditions specific mutational pathways to resistance against lamivudine and entecavir, and demonstrates that the use of adefovir in lamivudine experienced patients is associated to peculiar mutational patterns, in particular A181V + F/Y221L. Despite some concern may arise for patients previously treated with lamivudine/adefovir, in sequence or combination, where the virus may have developed a lower genetic barrier against resistance to tenofovir, the outlook of antiviral treatment of HBV infection should be quite optimistic.

  8. Addition of 7 Days of Zidovudine plus Lamivudine to Peripartum Single-Dose Nevirapine Effectively Reduces Nevirapine Resistance Postpartum in HIV-Infected Mothers in Malawi

    PubMed Central

    Farr, Sherry L.; Nelson, Julie A.E.; Ng’ombe, Thokozani J.; Kourtis, Athena P.; Chasela, Charles; Johnson, Jeffrey A.; Kashuba, Angela D.M.; Tegha, Gerald L.; Wiener, Jeffrey; Eron, Joseph J.; Banda, Harriet N.; Mpaso, Mwanangwa; Lipscomb, Jonathan; Matiki, Chrissie; Fiscus, Susan A.; Jamieson, Denise J.; van der Horst, Charles

    2010-01-01

    Background We assessed whether 7 days of zidovudine+lamivudine postpartum with single-dose nevirapine at labor decreases nevirapine resistance in HIV-infected women in Malawi. Methods HIV-infected pregnant women receiving intrapartum single-dose nevirapine and 7 days of zidovudine+lamivudine (n=132), and women receiving intrapartum single-dose nevirapine alone (n=66) were followed from an antenatal visit through 6 weeks postpartum. Plasma specimens at 2 and 6 weeks postpartum were tested for genotypic resistance to nevirapine by population sequencing and sensitive real-time PCR. Poisson regression was used to determine predictors of postpartum nevirapine resistance. Results Median HIV RNA was similar at entry (4.27 log vs. 4.35 log, p=0.87), differed at 2 weeks postpartum (2.67 log vs. 3.58 log, p<0.0001), but not at 6 weeks postpartum (4.49 log vs. 4.40 log, p=0.79), between single-dose nevirapine/zidovudine+lamivudine and single-dose nevirapine groups, respectively. Nevirapine resistance, measured by population sequencing and sensitive real-time PCR, was significantly less common in those receiving single-dose nevirapine/zidovudine+lamivudine compared to single-dose nevirapine, respectively, at 2 weeks (10% (4/40) vs. 74% (31/42), p<0.0001) and 6 weeks postpartum [10% (11/115) vs. 64% (41/64), p<0.0001; adjusted relative risk=0.18, 95% confidence interval (0.10–0.34)]. Conclusions The significant decrease in nevirapine resistance conferred by one week of zidovudine+lamivudine should help policymakers optimize peripartum HIV prophylaxis recommendations. PMID:20672451

  9. Monitoring of HBeAg levels may help to predict the outcomes of lamivudine therapy for HBeAg positive chronic hepatitis B.

    PubMed

    Park, N H; Shin, J W; Park, J H; Bang, S-J; Kim, D-H; Joo, K R; Kim, D H

    2005-03-01

    The aim of this study was to determine whether the changing patterns of quantitative hepatitis B e antigen (HBeAg) levels by serial monitoring could predict HBeAg seroconversion and viral breakthrough during lamivudine therapy. We retrospectively analysed 340 HBeAg positive naive chronic hepatitis B patients treated with lamivudine. The mean duration of lamivudine therapy was 18.7 (range 6-56) months. The changing patterns and reduction rates of pretreatment HBeAg levels by serial monitoring were categorized into three groups: Decrescendo group (n = 195), Decrescendo-crescendo group (n = 65) and no changing or fluctuating group (n = 80). Of 109 patients who had achieved HBeAg seroconversion, 105 (96.3%) were included in the decrescendo group. The decrescendo group, pretreatment quantitative HBeAg levels, alanine aminotransferase levels, and the duration of lamivudine therapy were independent predictive factors for HBeAg seroconversion. Of 82 patients who had viral breakthrough, 53 (64.6%) were in the decrescendo-crescendo group and 21 (25.6%) were in the no changing or fluctuating group. The only predictive factor for viral breakthrough was the changing patterns of quantitative HBeAg levels, especially, the decrescendo-crescendo group and the no changing or fluctuating group. The mean time of turning points in the decrescendo-crescendo group was 7.1 months earlier than the mean time of viral breakthrough (9.0 months vs 16.5 months). Therefore, the changing patterns of quantitative HBeAg levels by serial monitoring during lamivudine therapy may allow not only the prediction of treatment responses, but also an early recognition of a viral breakthrough.

  10. Adefovir dipivoxil therapy in liver transplant recipients for recurrence of hepatitis B virus infection despite lamivudine plus hepatitis B immunoglobulin prophylaxis.

    PubMed

    Akyildiz, Murat; Karasu, Zeki; Zeytunlu, Murat; Aydin, Unal; Ozacar, Tijen; Kilic, Murat

    2007-12-01

    Treatment of post-transplantation recurrence of hepatitis B virus (HBV) infection despite prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine combination therapy is not easy. Because HBV reinfection has a severe course and could result in graft failure in liver transplant recipients, prompt medication is essential. Herein is reported the authors' experience with adefovir dipivoxil (AD) therapy in 11 liver transplant recipients who had HBV reinfection despite the administration of lamivudine and HBIG. Two-hundred and nine patients underwent liver transplantation (100 deceased donor liver transplantations [DDLT], 109 living donor liver transplantation [LDLT]) due to chronic hepatitis B infection between April 1997 and May 2005 in Ege University Medical School, Liver Transplantation Unit. Patients had prophylaxis with lamivudine and low-dose HBIG combination after liver transplantation. Treatment of recurrence consisted of AD 10 mg once a day and lamivudine 300 mg/daily and HBIG was discontinued in those patients. In total there were 11 HBV recurrences: five occurred in DDLT recipients and six in LDLT recipients, at a median follow up of 18 months (range, 6-48 months). In one of 11 patients, pretransplant HBV-DNA and HBeAg were positive. Three patients had a severe course and one patient had fibrosing cholestatic hepatitis. After AD treatment, HBV-DNA level decreased in all patients and became negative in seven patients. Two patients died due to hepatocellular carcinoma recurrence after 12 and 14 months of follow up. Serum creatinine level increased mildly in one patient and no other side-effect was observed, and all patients continued therapy. Adefovir dipivoxil is a safe, effective treatment option for post-transplant HBV recurrence even among patients with fibrosing cholestatic hepatitis caused by lamivudine-resistant HBV.

  11. Addition of 7 days of zidovudine plus lamivudine to peripartum single-dose nevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi.

    PubMed

    Farr, Sherry L; Nelson, Julie A E; Ng'ombe, Thokozani J; Kourtis, Athena P; Chasela, Charles; Johnson, Jeffrey A; Kashuba, Angela D M; Tegha, Gerald L; Wiener, Jeffrey; Eron, Joseph J; Banda, Harriet N; Mpaso, Mwanangwa; Lipscomb, Jonathan; Matiki, Chrissie; Fiscus, Susan A; Jamieson, Denise J; van der Horst, Charles

    2010-08-01

    We assessed whether 7 days of zidovudine + lamivudine postpartum with single-dose nevirapine at labor decreases nevirapine resistance in HIV-infected women in Malawi. HIV-infected pregnant women receiving intrapartum single-dose nevirapine and 7 days of zidovudine + lamivudine (n = 132) and women receiving intrapartum single-dose nevirapine alone (n = 66) were followed from an antenatal visit through 6 weeks postpartum. Plasma specimens at 2 and 6 weeks postpartum were tested for genotypic resistance to nevirapine by population sequencing and sensitive real-time polymerase chain reaction. Poisson regression was used to determine predictors of postpartum nevirapine resistance. Median HIV RNA was similar at entry (4.27 log vs. 4.35 log, P = 0.87), differed at 2 weeks postpartum (2.67 log vs. 3.58 log, P < 0.0001) but not at 6 weeks postpartum (4.49 log vs. 4.40 log, P = 0.79), between single-dose nevirapine/zidovudine + lamivudine and single-dose nevirapine groups, respectively. Nevirapine resistance, measured by population sequencing and sensitive real-time polymerase chain reaction, was significantly less common in those receiving single-dose nevirapine/zidovudine + lamivudine compared with single-dose nevirapine, respectively, at 2 weeks [10% (4 of 40) vs. 74% (31 of 42), P < 0.0001] and 6 weeks postpartum [10% (11 of 115) vs. 64% (41 of 64), P < 0.0001; adjusted relative risk = 0.18, 95% confidence interval (0.10 to 0.34)]. The significant decrease in nevirapine resistance conferred by 1 week of zidovudine + lamivudine should help policymakers optimize peripartum HIV prophylaxis recommendations.

  12. Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis

    PubMed Central

    Duque Molina, Marcela María; García García, Héctor Iván

    2017-01-01

    Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.

  13. Comparative Application of PLS and PCR Methods to Simultaneous Quantitative Estimation and Simultaneous Dissolution Test of Zidovudine - Lamivudine Tablets.

    PubMed

    Üstündağ, Özgür; Dinç, Erdal; Özdemir, Nurten; Tilkan, M Günseli

    2015-01-01

    In the development strategies of new drug products and generic drug products, the simultaneous in-vitro dissolution behavior of oral dosage formulations is the most important indication for the quantitative estimation of efficiency and biopharmaceutical characteristics of drug substances. This is to force the related field's scientists to improve very powerful analytical methods to get more reliable, precise and accurate results in the quantitative analysis and dissolution testing of drug formulations. In this context, two new chemometric tools, partial least squares (PLS) and principal component regression (PCR) were improved for the simultaneous quantitative estimation and dissolution testing of zidovudine (ZID) and lamivudine (LAM) in a tablet dosage form. The results obtained in this study strongly encourage us to use them for the quality control, the routine analysis and the dissolution test of the marketing tablets containing ZID and LAM drugs.

  14. Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells.

    PubMed

    Dumond, Julie B; Yang, Kuo H; Kendrick, Racheal; Reddy, Y Sunila; Kashuba, Angela D M; Troiani, Luigi; Bridges, Arlene S; Fiscus, Susan A; Forrest, Alan; Cohen, Myron S

    2015-10-01

    The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.

  15. Validation of a sensitive LC/MS/MS method for the determination of zidovudine and lamivudine in human plasma

    PubMed Central

    Rower, Joseph E.; Klein, Brandon; Bushman, Lane R.; Anderson, Peter L.

    2011-01-01

    A sensitive LC/MS/MS assay for determining zidovudine (ZDV) and lamivudine (3TC) in human plasma was validated to support antiretroviral pharmacology research programs. After addition of stable labeled isotopic zidovudine (ZDV-IS) and lamivudine (3TC-IS) as internal standard, a solid phase extraction was performed with an Oasis HLB 1cc cartridge, with recoveries of 92.3% for ZDV and 93.9% for 3TC. A Phenomonex Synergi Hydro-RP (2.0 × 150 mm) reversed phase analytical column was utilized for chromatographic separation. Mobile phase consisted of an aqueous solution of 15% acetonitrile and 0.1% acetic acid. Detection was accomplished by ESI/MS/MS in the positive ion mode, monitoring 268/127 and 271/130, and 230/112 and 233/115 transitions, for ZDV and ZDV-IS and 3TC and 3TC-IS, respectively. The method was linear from 1 to 3000 ng/mL with a minimum quantifiable limit of 1 ng/mL when 100 μL of plasma were analyzed. Validations results demonstrated high accuracy (≤ 8.3% deviation) and high precision (≤ 10% CV) for the quality control samples. The method was also shown to be specific and reproducible. The value of the high sensitivity was demonstrated by quantitation of approximately 100 existing samples that had ZDV below the limit of quantitation using a previously validated, less sensitive HPLC-UV method utilized in the laboratory. PMID:21465499

  16. Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells

    PubMed Central

    Yang, Kuo H.; Kendrick, Racheal; Reddy, Y. Sunila; Kashuba, Angela D. M.; Troiani, Luigi; Bridges, Arlene S.; Fiscus, Susan A.; Forrest, Alan; Cohen, Myron S.

    2015-01-01

    The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure. PMID:26239974

  17. Meta-analysis of the short-term effects of lamivudine treatment for severe chronic hepatitis B

    PubMed Central

    2013-01-01

    Purpose To evaluate the short-term effect of lamivudine (LMV) treatment for severe chronic hepatitis B. Method Patient data related to the safety and efficacy of using lamivudine (LMV) to treat hepatitis B virus (HBV)-induced liver failure or severe hepatitis were acquired from previous literature. These studies were retrieved from PubMed, Ovid, SpringerLink, Biosis Previews, Academic Search Premier, ProQuest Medical Library, Cochrane Library, China National Knowledge Infrastructure Full-text Database, VIP Chinese Scientific Journal Database, and Chinese Biomedicine. Relative risk and weighted mean difference were used to measure the effects. The major predictors observed included total bilirubin (TBIL), prothrombin activity (PTA), survival rate, and HBV-DNA negative change rate. Groups were further divided according to the clinical course and disease staging. Results A total of 242 studies were retrieved from the databases. At weeks 4, 8, and 12 of the treatment course, the survival rates and PTA of the test group were distinctively higher than those of the control group. However, TBIL concentrations in the test group were lower than the control group. The HBV-DNA negative change rate was distinctively higher throughout the 12 weeks of LMV treatment. For patients who started LMV treatment in the middle stage, the mortality rate of the test group was lower. For patients who started LMV treatment during the advanced stage, no significant difference was observed between the test and control groups. Conclusion LMV decreased HBV-DNA levels in the serum, improved liver function in patients, and enhanced survival rate during the early and medium stages of severe chronic hepatitis B. PMID:23627972

  18. Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

    PubMed

    Khatri, Amit; Trinh, Roger; Zhao, Weihan; Podsadecki, Thomas; Menon, Rajeev

    2016-10-01

    The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally

  19. Development of a microdialysis system to monitor lamivudine in blood and liver for the pharmacokinetic application in herbal drug interaction and the gene expression in rats.

    PubMed

    Lu, Chia-Ming; Hou, Mei-Ling; Lin, Lie-Chwen; Tsai, Tung-Hu

    2014-08-05

    The aim of study is to develop a novel multiple microdialysis technique coupled to a validated chromatographic system for the measurement of protein-unbound form lamivudine and investigation of its herb-drug interaction in rat blood and liver. Furthermore, gene expression changes of drug metabolizing enzymes in rat were evaluated by microarray analysis after being treated with a traditional Chinese herbal formulation, Long-Dan-Xie-Gan-Tang (LDXGT). The analyte was separated by a reverse-phase C18 column using the mobile phase comprising methanol and 10mM KH2PO4 (15:85, v/v, adjusted to pH 6.0 with NaOH) with the flow rate of 0.8mL/min, and the UV wavelength was set at 270nm. The processes of method validation followed Food and Drug Administration (FDA) guidelines. The pharmacokinetic data demonstrated that the area under the concentration-time curve (AUC) of the lamivudine alone and the LDXGT pretreated group were 532±37.6 and 550±44.2minμg/mL in rat blood after lamivudine administration (10mg/kg, i.v.) and 682±196 and 642±153minμg/mL in rat liver, respectively. The herb-drug pharmacokinetic interaction showed that with either lamivudine alone or in combination with pretreated with LDXGT, the pharmacokinetic parameters were not significantly changed except the apparent volume of distribution (Vd) at a high dose of lamivudine (30mg/kg). In addition, microarray analysis showed that among 70 altered genes (selection criteria: |Fold change|≧2 and p<0.05), only 11 genes were involved in drug metabolism and indicated that a relatively small portion of drug metabolizing genes in liver were altered at the genome level after the therapeutic dose of LDXGT treatment. In conclusion, these studies provide constructive information to interpret the herb-drug interactions between lamivudine and a popular Chinese herbal formulation.

  20. Prophylactic Lamivudine to Improve the Outcome of Breast Cancer Patients With HBsAg Positive During Chemotherapy: A Meta-Analysis.

    PubMed

    Zheng, Yihu; Zhang, Shengchu; Tan Grahn, Hooi Min; Ye, Chao; Gong, Zheng; Zhang, Qiyu

    2013-04-01

    Raising the chemotherapy-induced HBV reactivation is parallel to the increment of chemotherapy treatments in breast cancer patients. This meta-analysis aims to evaluate the efficacy of prophylactic use of lamivudine in breast cancer patients with HBsAg positive during chemotherapy. MEDLINE, Pubmed, Ovid and Embase were used to search for clinical studies comparing with or without prophylactic use of lamivudine for HBV reactivation in breast cancer patients receiving chemotherapy. Outcomes of interest were the rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis attributable to HBV reactivation, severity of hepatitis and severity of hepatitis attributable to HBV reactivation, the rate of chemotherapy disruption, and the rate of chemotherapy disruption attributable to HBV reactivation, overall mortality, and mortality attributable to HBV reactivation. Four studies with 285 patients were included in this meta-analysis. The rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis related to HBV reactivation were reduced by use of prophylactic lamivudine compared to control group. Pooled Odds Ratios (ORs) were 0.09 (95% confidence intervals [CI] 0.03-0.26; P < 0.0001), 0.23 (95% CI 0.06-0.92; P = 0.04), and 0.10 (95% CI 0.03-0.32; P < 0.0001) respectively. There was a reduction in chemotherapy disruption related to HBV reactivation by use of prophylactic lamivudine (pooled OR = 0.11; 95% CI 0.02-0.58; P = 0.01). Chemotherapy disruption, overall mortality, and mortality attributable to HBV reactivation were not significantly different between two groups. Pooled ORs were 0.42 (95% CI 0.11-1.58; P = 0.20), 0.37 (95% CI 0.07-2.04; P = 0.25), and 0.25 (95% CI 0.01-6.82; P = 0.41) respectively. Lamivudine was well-tolerated, and no additional toxicity was observed. Use of prophylactic lamivudine may have positive effect on the outcome of breast cancer patients with HBsAg positive during chemotherapy.

  1. Effect of six antiretroviral drugs (delavirdine, stavudine, lamivudine, nelfinavir, amprenavir and lopinavir/ritonavir in association) on albino pregnant rats (Rattus norvegicus Albinus, Rodentia, Mammalia): biological assay.

    PubMed

    Nakamura, M U; Araujo Júnior, E; Simões, J M; Oliveria, R M Filho; Kulay, L Júnior

    2014-08-01

    To compare the chronic effects of antiretrovirals (lamivudine, stavudine, delavirdine, nelfinavir, amprenavir and an association of lopinavir/ritonavir) on albino pregnant rats. Review. Department of Obstetrics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil. This was a comparative retrospective study formed by 18 groups of 10 pregnant rats each, which were nearly three months of age and weighed 200 g. All of them were medicated every day using a stomach probe, while the control group was given 1 mL of distilled water. The study groups received lamivudine (at 5, 15 and 45 mg/kg/day); stavudine (at 1, 3 and 9 mg/kg/day); nelfinavir (at 40, 120 and 360 mg/kg/day); amprenavir (at 46, 138 and 414 mg/kg/day); lopinavir/ritonavir (at 12.8/3.2, 38.4/9.6 and 115/28.8 mg/kg/day) and delavirdine (at 20 and 60 mg/kg/day). These represented 1, 3 and 9 times the human therapeutic dose, except for the last drug, for which the 9-times dose was not used. Maternal, litter and placental weights, implantation and reabsorption numbers, major external fetal malformations and fetal and maternal deaths were evaluated. The Kruskal-Wallis test was used to compare quantitative variables and the chi-square test was used to compare qualitative variables. At all three doses, stavudine increased the maternal weight (p=0.001), while lamivudine at 3- and 9-times doses reduced it (p<0.001). Amprenavir at all of the doses, and lopinavir/ritonavir at 3- and 9-times doses, caused higher rates of maternal death (p<0.001). Regarding the fetuses, none of the antiretroviral drugs studied were harmful with regard to implantation, reabsorption, teratogenity and mortality (p>0.05). Stavudine at all doses reduced the litter weights (p<0.001); however, lamivudine at the usual and 3-times doses, delavirdine at 3-times dose, and amprenavir at 3-times dose increased the litter weight (p<0.001). In the maternal compartment, we observed lethal toxicity in the pregnant rats that received

  2. Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients.

    PubMed

    Yuan, Yong; Iloeje, Uchenna H; Hay, Joel; Saab, Sammy

    2008-01-01

    As new treatment options for chronic hepatitis B virus (HBV) become available, evaluations of cost-effectiveness become important. Entecavir is a deoxyguanine nucleoside analogue approved by the U.S. Food and Drug Administration in March 2005 for HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine aminotransferase or aspartate aminotransferase) or histologically active disease. Entecavir has demonstrated greater suppression of viral replication compared with lamivudine, but also has a relatively higher drug acquisition cost in the United States. To estimate the long-term health and economic impact of treating HBV with entecavir versus lamivudine in patients who are positive for hepatitis B e antigen (HBeAg) based on the efficacy and safety results of the Phase 3, double-blind, randomized controlled trial, Benefits of Entecavir for Hepatitis B Liver Disease (BEHoLD). A decision tree model was developed to evaluate the cost-effectiveness of entecavir compared with lamuvidine in suppressing HBV DNA to an undetectable level. Risks for compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) were derived from the published Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV, 2006) study, a longitudinal (mean follow-up: 11.4 years) cohort study of community residents who were seropositive for the hepatitis B surface antigen; 85% of REVEAL-HBV participants were HBeAg-negative. To estimate future risks of CC, DC, and HCC, the REVEAL-HBV study's multivariate-adjusted relative risks of CC, DC, and HCC for 5 HBV DNA (viral load level) categories were applied to posttreatment HBV DNA levels obtained from the BEHoLD trial of 709 HBeAg-positive HBV patients treated with entecavir (n = 354) or lamivudine (n = 355). Entecavir and lamivudine were assigned annual costs of $7,365 and $2

  3. HIV/AIDS treatment and physicochemical quality control of medicines: evaluation of non-generic lamivudine + zidovudine tablets manufactured in Brazil.

    PubMed

    Beck, Ruy Carlos Ruver; Athayde, Margareth Linde; Cardoso, Simone Gonçalves

    2007-12-01

    In this work it was evaluated the physicochemical quality of lamivudine + zidovudine tablets, whose association belongs to the list of drugs distributed by the Brazil's National Program on Sexually Transmitted Diseases and AIDS. Four non-generic products (lamivudine + zidovudine tablets) were analyzed. They were obtained from different Brazilian manufacturers, besides a reference product. The quality was evaluated by physicochemical tests described in the official codes. A validated reversed-phase high performance liquid chromatography (HPLC) method was used for the assay of the active substances. All samples were in accordance to the requisites in relation to their physicochemical characteristics. Dissolution studies showed similar drug percentual dissolved among all samples. The results reflect the interest of the national pharmaceutical industry to ensure the delivery of safer and cheaper drugs to the Brazilian people, with particular importance in the National Program on Sexually Transmitted Diseases and AIDS.

  4. Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

    PubMed Central

    Shafer, Robert W.; Smeaton, Laura M.; Robbins, Gregory K.; De Gruttola, Victor; Snyder, Sally W.; D’Aquila, Richard T.; Johnson, Victoria A.; Morse, Gene D.; Nokta, Mostafa A.; Martinez, Ana I.; Gripshover, Barbara M.; Kaul, Pamposh; Haubrich, Richard; Swingle, Mary; McCarty, S. Debra; Vella, Stefano; Hirsch, Martin S.; Merigan, Thomas C.

    2016-01-01

    BACKGROUND It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of

  5. Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

    PubMed Central

    Shafer, Robert W.; Smeaton, Laura M.; Robbins, Gregory K.; De Gruttola, Victor; Snyder, Sally W.; D’Aquila, Richard T.; Johnson, Victoria A.; Morse, Gene D.; Nokta, Mostafa A.; Martinez, Ana I.; Gripshover, Barbara M.; Kaul, Pamposh; Haubrich, Richard; Swingle, Mary; McCarty, S. Debra; Vella, Stefano; Hirsch, Martin S.; Merigan, Thomas C.

    2016-01-01

    BACKGROUND It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of

  6. Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity

    PubMed Central

    Singhroy, Diane N.

    2015-01-01

    We investigated the effect of combining the dolutegravir-specific R263K integrase resistance substitution with either M184I or M184V, two reverse transcriptase drug resistance substitutions that are frequently detected in individuals failing therapeutic regimens containing either lamivudine or emtricitabine. The presence of R263K and M184I/V in a single virus resulted in substantial further decreases in the viral replicative capacity compared to that in the presence of single substitutions alone. PMID:25666155

  7. Evaluation of chronic hepatitis B virus (HBV) infection in coinfected patients receiving lamivudine as a component of anti-human immunodeficiency virus regimens.

    PubMed

    Hoff, J; Bani-Sadr, F; Gassin, M; Raffi, F

    2001-03-15

    The effect of lamivudine on chronic coinfection with hepatitis B virus (HBV) in human immunodeficiency virus (HIV)--infected patients was studied prospectively. Nineteen patients with HIV infection, who were receiving an anti-HIV regimen containing lamivudine (150 mg twice daily), and who had replicative chronic HBV infection, were followed for a median of 14 months. Twelve patients' regimens contained protease inhibitors. Serum HBV DNA became undetectable, by means of molecular hybridization, in 14. Seroconversion of hepatitis B e antigen to antibody occurred in 6 of 17 patients, and seroconversion of hepatitis B surface antigen to antibody occurred in 1 of 19. The median serum alanine aminotransferase concentration had decreased by the time of the final evaluation. The median CD4 cell count increased and plasma HIV RNA was undetectable in 10 of 19 patients. Five patients had recurrence of detectable serum HBV DNA despite good compliance with treatment, and 2 mutations related to the resistance of HBV were detected. These patients had a significantly longer duration of treatment (21 versus 13 months; P<.05). In conclusion, resistant strains of HBV emerge at high detectable levels while patients receive anti-HIV regimens containing lamivudine.

  8. Combination dolutegravir-abacavir-lamivudine in the management of HIV/AIDS: clinical utility and patient considerations.

    PubMed

    Cruciani, Mario; Malena, Marina

    2015-01-01

    experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference.

  9. Combination dolutegravir–abacavir–lamivudine in the management of HIV/AIDS: clinical utility and patient considerations

    PubMed Central

    Cruciani, Mario; Malena, Marina

    2015-01-01

    experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference. PMID:25733823

  10. Hepatitis B Virus (HBV) Load Response to 2 Antiviral Regimens, Tenofovir/Lamivudine and Lamivudine, in HIV/ HBV-Coinfected Pregnant Women in Guangxi, China: The Tenofovir in Pregnancy (TiP) Study.

    PubMed

    Wang, Liming; Wiener, Jeffrey; Bulterys, Marc; Wei, Xiaoyu; Chen, Lili; Liu, Wei; Liang, Shujia; Shepard, Colin; Wang, Linhong; Wang, Ailing; Zhang, Fujie; Kourtis, Athena P

    2016-12-01

     There is limited information on antiviral therapy for hepatitis B virus (HBV) infection among pregnant women coinfected with human immunodeficiency virus (HIV) and HBV.  A phase 2 randomized, controlled trial of a regimen containing tenofovir (TDF)/lamivudine (3TC) and a regimen containing 3TC in HIV/HBV-coinfected pregnant women in China. The HBV virological response was compared in study arms.  The median decline in the HBV DNA level was 2.60 log10 copies/mL in the TDF/3TC arm and 2.24 log10 copies/mL in the 3TC arm (P = .41). All women achieved HBV DNA levels of <6 log10 copies/mL at delivery.  Initiation of either regimen led to achievement of HBV DNA levels below the threshold associated with perinatal HBV transmission.  NCT01125696. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  11. Cost-effectiveness analysis of lamivudine, telbivudine, and entecavir in treatment of chronic hepatitis B with adefovir dipivoxil resistance.

    PubMed

    Wang, Guiliang; Liu, Yan; Qiu, Ping; Zhou, Shu-Feng; Xu, Linfang; Wen, Ping; Wen, Jianbo; Xiao, Xianzhong

    2015-01-01

    The purpose of this study was to analyze the cost-effectiveness of lamivudine (LMV), telbivudine (LdT), and entecavir (ETV) in treatment of chronic hepatitis B with adefovir dipivoxil (ADV) resistance. Two hundred and fifty-two patients were recruited and screened for resistance to ADV and randomly assigned into three groups: LMV + ADV, LdT + ADV, and ETV + ADV. The ratio of biochemical response, virological response, seroconversion of hepatitis Be antigen (HBeAg)/hepatitis Be antibody (HBeAb), viral breakthrough, and the cost and effectiveness of treatments were analyzed. A comparison of the results of the ratio of biochemical response, virological response and seroconversion of HBeAg/HBeAb, showed no statistical difference between the three groups, with the economic cost of LMV + ADV the lowest, LdT + ADV the middle, and ETV + ADV the highest. The side effects of the three plans are all rare and tolerable. LMV + ADV is the optimal rescue strategy, and LdT + ADV the alternative selection in the economically less developed regions, while ETV + ADV was used in the economically developed regions.

  12. Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends.

    PubMed

    Singh, Bhupinder; Garg, Babita; Chaturvedi, Subhash Chand; Arora, Sharry; Mandsaurwale, Rachana; Kapil, Rishi; Singh, Baljinder

    2012-05-01

    The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating-bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in-vitro and in-vivo evaluation in animals and humans. Effervescent floating-bioadhesive hydrophilic matrices were prepared and evaluated for in-vitro drug release, floatation and ex-vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. In-vivo gamma scintigraphic studies were performed in human volunteers using (99m) Tc to evaluate formulation retention in the gastric milieu. The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug-release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in-vitro dissolution media for simulating the in-vivo conditions. In-vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  13. Morphine Increases Lamivudine- and Nevirapine-Induced Human Immunodeficiency Virus-1 Drug-Resistant Mutations In Vitro.

    PubMed

    Liang, Bingyu; Jiang, Junjun; Pan, Peijiang; Chen, Rongfeng; Zhuang, Daomin; Zhao, Fangning; Chen, Hui; Huang, Jiegang; Su, Qijian; Cao, Cunwei; Li, Jingyun; Liang, Hao; Ye, Li

    2017-04-01

    Epidemiological studies have demonstrated that the human immunodeficiency virus (HIV)-1 drug-resistant rate among injecting drug users is higher than that in other HIV-1-positive populations, which is generally believed to be largely due to clinical nonadherence. Little is known, however, about whether heroin abuse has a direct impact on the generation of HIV-1 drug-resistant mutations. In this study, we investigated the impacts of morphine, the active metabolite of heroin, on HIV-1 infection/replication and HIV-1 drug-resistant mutations through an in vitro HIV-1-CD4(+) T cell system under selective pressure from two typical antiviral drugs, Lamivudine and Nevirapine. We found that morphine treatment of MT4 cells (a CD4(+) T cell line) significantly increased HIV-1 III B (a T-tropic viral strain) infection and replication in MT4 cells, and the effect of morphine on HIV-1 was mediated through an opioid receptor. More importantly, our results showed that morphine treatment not only induced more drug-resistant mutations under selective pressure from antiretroviral drugs but also shortened the mutations' generation time, compared with the control groups that were treated with antiretroviral drugs alone. Although the in vivo relevance remains to be determined, these findings provide direct in vitro evidence to support the possibility that heroin abuse itself can act as an independent factor contributing to the generation of HIV-1 drug resistance during clinical antiretroviral therapy. Therapeutic guidelines should consider this issue for heroin users with HIV infection.

  14. [Evaluation of tolerance of zidovudine-lamivudine-nevirapine combination in HIV 1 patients in Fann Teaching Hospital in Dakar].

    PubMed

    Fortes Déguénonvo, L; Diop, S A; Leye, M M M; Seydi, M; Dieng, A B; Bentaleb, H; Diouf, A; Lakhe, N A; Ka, D; Cisse, V M P; Dia Badiane, N M; Manga, M N; Ndour, C T; Soumaré, M; Diop, B M; Sow, P S

    2013-10-01

    We conducted a study to evaluate the tolerance of the zidovudine (AZT), lamivudine (3TC) and nevirapine (NVP) combination regimen in HIV-1 patients by a descriptive analytical retrospective study of all HIV-1 patients receiving AZT-3TC-NVP combination between 2008 and 2011. Seventy patients were included. Two thirds of the patients presented at least one side effect (44 cases). The digestive disorders (15 cases) and neuropsychiatric (14 cases) were the most frequent. Epigastralgia (20%), headaches (20%) and arthralgias (13%) were main side effects. A maculo-papular exanthema was noted in three cases. During the follow-up, five patients presented with anemia. No patient presented hepatic cytolysis due to NVP. All the patients followed for more than six months presented a side effect against 29.7% when the duration of treatment was equal to or less than 6 months (p=10(-5)). Most of the side effects due to the association AZT/3TC/NVP are minor. The evaluation of the clinical and biological tolerance must be maintained during all the follow-up.

  15. Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-Naive (TN) patients in France.

    PubMed

    Pialoux, Gilles; Marcelin, Anne-Geneviève; Cawston, Hélène; Guilmet, Caroline; Finkielsztejn, Laurent; Laurisse, Audrey; Aubin, Céline

    2017-07-31

    To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine). Efficacy and safety data were derived from phase III studies and network meta-analysis. Treatment algorithms were based on French guidelines and experts opinion. Costs included routine HIV and opportunistic infection care, and death. The model showed the fixed-dose combination DTG/ABC/3TC was more effective than all other recommended regimens: patients stayed longer on first-line, and lived longer and healthier. With the exception of EFV, DTG/ABC/3TC was more efficacious and less costly compared to all strategies. The cost per QALY gained (ICER) for DTG compared to EFV was €6,939. DTG/ABC/3TC was more efficacious and less costly compared to INIs and PIs in all deterministic sensitivity analyses. DTG/ABC/3TC was cost-effective in the management of HIV TN patients in France. These results are mainly explained by its lower price compared to other INIs and PIs, DTG's superior efficacy and high barrier to resistance.

  16. Clinical course of chronic hepatitis B patients receiving nucleos(t)ide analogues after virological breakthrough during monotherapy with lamivudine.

    PubMed

    De Francesco, Maria Antonia; Gargiulo, Franco; Spinetti, Angiola; Zaltron, Serena; Giagulli, Cinzia; Caccuri, Francesca; Castelli, Francesco; Caruso, Arnaldo

    2015-01-01

    Little is known about the optimal management of patients with chronic hepatitis B (CHB) who develop drug resistance. The aim of this study was to investigate the effectiveness of different drug regimens in chronically HBV-infected patients. HBV viral load was determined using a bDNA assay and the substitutions in HBV-DNA were studied by polymerase sequencing test. The study involved 38 patients who experienced a therapeutic failure to lamivudine (LAM). The sequential treatments used were: LAM + adefovir (ADV), LAM + tenofovir (TDF), entecavir (ETV) monotherapy, ADV monotherapy and TDF monotherapy. Similar activity against HBV replication was observed with all drug regimens. Of the patients treated with LAM, 44% developed resistance mutations. The rt M204I mutation was observed more frequently. Sequential ADV add-on LAM and TDF therapy induced the appearance of resistance in 3/18 (16.6%) and in 1/8 (5.5%) treated patients, respectively. Genotype D was the most prevalent (78.9%), followed by genotype A (13%), genotype E (5.2%) and genotype C (2.6%). Our study showed that baseline serum HBV DNA is an important predictor of virologic response and that virologic breakthrough is significantly associated with the insurgence of genotypic resistance.

  17. Multiple Lipid Nanoparticles (MLN), a New Generation of Lipid Nanoparticles for Drug Delivery Systems: Lamivudine-MLN Experimental Design.

    PubMed

    Cavalcanti, Suellen M T; Nunes, Cláudia; Lima, Sofia A C; Soares-Sobrinho, José L; Reis, Salette

    2017-06-01

    An optimized methodology for the development of a new generation of lipid nanoparticles, the multiple lipid nanoparticles (MLN) is described. MLN have characteristics between nanostructured lipid carriers (NLC) and multiple emulsions (W/O/W), but without the outer aqueous phase. The production is based on a hot homogenization method combined with high shear and ultrasonication. The antiretroviral agent lamivudine (3TC), was loaded in the MLN. For comparison purposes, NLC-3TC formulation was also developed and physico-chemically characterized by the same parameters as MLN-3TC. The development and optimization of MLN and NLC formulations were supported by a Quality by Design (QbD) approach. The MLN-3TC formulation exhibited a size of about 450 nm, polydispersity <0.3 and negative zeta potential > -20 mV. Furthermore, the morphology assessed by TEM showed a structure with multiples aqueous vacuoles. MLN-3TC was physically stable for at least 45 days, had low cytotoxicity and drug release studies showed a sustained and controlled release of 3TC under gastric and plasma-simulated conditions (at pH 7.4 for about 45 h). The optimized formulations present suitable profiles for oral administration. Overall, the results reveal that MLN present higher loading capacity and storage stability than NLC.

  18. RP-HPLC method for simultaneous estimation of tenofovir disoproxil fumarate, lamivudine, and efavirenz in combined tablet dosage form

    PubMed Central

    Bhavsar, Dhara S.; Patel, Bhavini N.; Patel, Chhaganbhai N.

    2012-01-01

    Background: A simple, precise, accurate, and rapid reverse phase-high performance liquid chromatography (RP-HPLC) method with UV-Visible detector has been developed and subsequently validated for the simultaneous determination of tenofovir disoproxil fumarate (TDF), lamivudine (LAMI), and efavirenz (EFV) in their combined tablet dosage form. Materials and Methods: The separation was based on the use of a Kromasil C18 analytical column (150 × 4.6 mm, i.d., 5 μm). The mobile phase consisted of a mixture of 70 volumes of methanol and 30 volumes of 10 mM phosphate buffer (pH 5.0). The separation was carried out at 40°C temperature with a flow rate of 1 ml/min. Results: Quantitation was achieved with UV detection at 254 nm, with linear calibration curves at concentration ranges of 1–6 μg/ml for TDF and LAMI and 2–12 μg/ml for EFV. The recoveries obtained were 99.46–101.36% for LAMI, 99.57–101.42% for TDF, and 99.96–100.87 for EFV. Conclusion: The method was validated according to International conference of harmonisation guidelines in terms of accuracy, precision, specificity, robustness, limits of detection and quantitation, and other aspects of analytical validation. PMID:23781482

  19. Efficacy of lamivudine or entecavir against virological rebound after achieving HBV DNA negativity in chronic hepatitis B patients.

    PubMed

    Miyauchi, Tomoo; Kanda, Tatsuo; Shinozaki, Masami; Kamezaki, Hidehiro; Wu, Shuang; Nakamoto, Shingo; Kato, Kazuki; Arai, Makoto; Mikami, Shigeru; Sugiura, Nobuyuki; Kimura, Michio; Goto, Nobuaki; Imazeki, Fumio; Yokosuka, Osamu

    2013-01-01

    Nucleos(t)ide analogues (NAs) lead to viral suppression and undetectable hepatitis B virus (HBV) DNA in some individuals infected with HBV, but the rate of virological rebound has been unknown in such patients. We examined the prevalence of virological rebound of HBV DNA among NA-treated patients with undetectable HBV DNA. We retrospectively analyzed 303 consecutive patients [158 entecavir (ETV)- and 145 lamivudine (LAM)-treated] who achieved HBV DNA negativity, defined as HBV DNA < 3.7 log IU/mL for at least 3 months. They were followed up and their features, including their rates of viral breakthrough, were determined. Viral rebound after HBV DNA negativity was not observed in the ETV-group. Viral rebound after HBV DNA negativity occurred in 38.7% of 62 HBe antigen-positive patients in the LAM-group. On multivariate analysis, age was an independent factor for viral breakthrough among these patients (P = 0.035). Viral rebound after HBV DNA negativity occurred in 29.1% of 79 HBe antigen-negative patients in the LAM-group. Differently from LAM, ETV could inhibit HBV replication once HBV DNA negativity was achieved. In contrast, LAM could not inhibit HBV replication even if HBV negativity was achieved in the early phase. Attention should be paid to these features in clinical practice.

  20. Hepatitis B virus reactivation in hepatitis B surface antigen seropositive patients with metastatic non-small cell lung cancer receiving cytotoxic chemotherapy: the efficacy of preemptive lamivudine and identification of risk factors.

    PubMed

    Lin, Gui-Nan; Peng, Jie-Wen; Xiao, Jian-jun; Liu, Dong-Ying; Xia, Zhong-Jun

    2014-08-01

    Little is known about the likelihood and degree of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) seropositive patients with disseminated non-small cell lung cancer (NSCLC) receiving chemotherapy. Between January 2003 and December 2013, all HBsAg seropositive patients with metastatic NSCLC receiving cytotoxic chemotherapy were retrospectively evaluated. The morbidity and mortality of HBV reactivation, risk factors associated with reactivation, as well as the efficacy of preemptive lamivudine were investigated. Of 258 patients who were eligible for the present study, 176 were treated without antiviral prophylaxis and 82 received preemptive lamivudine. Patients without lamivudine prophylaxis had a significantly higher prevalence of HBV reactivation (19.3 vs 6.1 %, p = 0.006) and severe hepatitis attributable to reactivation (11.8 vs 3.7 %, p = 0.034) than those with preemptive lamivudine. However, no significant difference in mortality due to reactivation was noted between patients with or without prophylactic lamivudine (0 vs 2.3 %, p = 0.310). Furthermore, patients who developed HBV reactivation were indentified to have a higher rate of HBeAg seropositivity (74.4 vs 43.4 %, p < 0.001), serum HBV-DNA level of 10(4) copies/ml or greater (76.9 vs 47.9 %, p = 0.001), coexisting liver metastasis (50.0 vs 40.6 %, p = 0.033) and treatment with more than 4 cycles of chemotherapy (56.4 vs 39.3 %, p = 0.046) than those who did not experienced reactivation. The current study has demonstrated that preemptive lamivudine significantly reduced the prevalence of HBV reactivation in HBsAg seropositive patients with metastatic NSCLC receiving systemic chemotherapy.

  1. Simultaneous determination of lamivudine, lopinavir, ritonavir, and zidovudine concentration in plasma of HIV-infected patients by HPLC-MS/MS.

    PubMed

    Notari, Stefania; Sergi, Manuel; Montesano, Camilla; Ivanovic, Jelena; Narciso, Pasquale; Pucillo, Leopoldo P; Ascenzi, Paolo

    2012-05-01

    The nucleoside reverse transcriptase inhibitors lamivudine and zidovudine and the protease inhibitors lopinavir and ritonavir are currently used in anti-human immunodeficiency virus (HIV) therapy. Here, a high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method, using a hybrid quadrupole time-of-flight mass analyzer, is reported for the simultaneous quantification of lamivudine, lopinavir, ritonavir, and zidovudine in plasma of HIV-infected patients. The volume of plasma sample was 600 μL. Plasma samples were extracted by solid-phase using 1 cc Oasis HLB Cartridge (divinylbenzene and N-vinylpyrrolidone) and evaporated in a water bath under nitrogen stream. The extracted samples were reconstituted with 100-μL methanol. Five microliters of the reconstituted samples were injected into a HPLC-MS/MS apparatus, and the analytes were eluted on a Vydac column (250 × 1.0 mm i.d.) filled with 3-μm C(18) particles. The mobile phase was delivered at 70 μL/min with a linear gradient elution, both acetonitrile and ultrapure water solvents contained 0.2% formic acid. The calibration curves were linear from 0.47 to 20 ng/mL. The absolute recovery ranged between 91 and 107%. The minimal concentration of lamivudine, lopinavir, ritonavir, and zidovudine detectable by HPLC-MS/MS is 0.47, 0.28, 0.30, and 0.66 ng/mL, respectively. The great advantage of the new HPLC-MS/MS method here reported is the possibility to achieve a very high specificity toward the selected anti-HIV drugs, despite the simple and rapid sample preparation. Moreover, this method is easily extendible to the analysis of co-administrated drugs. Copyright © 2012 Wiley Periodicals, Inc.

  2. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation

    PubMed Central

    Paredes, Roger; Tzou, Philip L.; van Zyl, Gert; Barrow, Geoff; Camacho, Ricardo; Carmona, Sergio; Grant, Philip M.; Gupta, Ravindra K.; Hamers, Raph L.; Harrigan, P. Richard; Jordan, Michael R.; Kantor, Rami; Katzenstein, David A.; Kuritzkes, Daniel R.; Maldarelli, Frank; Otelea, Dan; Wallis, Carole L.; Schapiro, Jonathan M.

    2017-01-01

    Introduction HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. Methods An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). Results There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with “/r” indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in

  3. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation.

    PubMed

    Paredes, Roger; Tzou, Philip L; van Zyl, Gert; Barrow, Geoff; Camacho, Ricardo; Carmona, Sergio; Grant, Philip M; Gupta, Ravindra K; Hamers, Raph L; Harrigan, P Richard; Jordan, Michael R; Kantor, Rami; Katzenstein, David A; Kuritzkes, Daniel R; Maldarelli, Frank; Otelea, Dan; Wallis, Carole L; Schapiro, Jonathan M; Shafer, Robert W

    2017-01-01

    HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the

  4. Prevalence of drug resistance mutations in HAART patients infected with HIV-1 CRF06_cpx in Estonia.

    PubMed

    Avi, Radko; Pauskar, Merit; Karki, Tõnis; Kallas, Eveli; Jõgeda, Ene-Ly; Margus, Tõnu; Huik, Kristi; Lutsar, Irja

    2016-03-01

    HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents.

  5. Lamivudine Concentration in Hair and Prediction of Virologic Failure and Drug Resistance among HIV Patients Receiving Free ART in China

    PubMed Central

    Wang, Zhe; Wu, Jianjun; Zhang, Jiafeng; Ruan, Yuhua; Hsi, Jenny; Liao, Lingjie; Shao, Yiming; Xing, Hui

    2016-01-01

    Background The assessment of adherence to antiretroviral therapy (ART) is important in order to predict treatment outcomes. Lamivudine (3TC) is one of the most widely used NRTIs in China, but its concentrations in hair and association with virologic failure and drug resistance have not been studied. Methods We conducted a cross-sectional survey to investigate 3TC concentrations in hair as a predictor of virologic failure and drug resistance among HIV patients receiving free ART. We also compared the capacity of hair 3TC concentrations with self-reported adherence in predicting virologic responses. Hair 3TC concentrations were detected through the LC-MS/MS system. Results In patients without HIV drug resistance (HIVDR), with a threshold hair 3TC concentration of 260 ng/g, the sensitivity and specificity in predicting virologic suppression were 76.9% and 89.9%, respectively. Some factors, including CD4+ cell counts, initial treatment regimens with 3TC, and current regimens with second-line drugs, influenced the association between hair 3TC concentrations and virologic suppression. In patients who experienced virologic failure with HIVDR, with a threshold of 180 ng/g, the sensitivity and specificity were 70.0% and 74.4%, respectively. Hair 3TC concentrations had higher sensitivity and specificity in predicting virologic failure and drug resistance than self-reported adherence. Conclusions The hair 3TC concentration was a stronger indicator than self-reported adherence in predicting virologic failure and drug resistance in HIV patients receiving free ART. PMID:27119346

  6. Preformulation studies of novel 5'-O-carbonates of lamivudine with biological activity: solubility and stability assays.

    PubMed

    Gualdesi, María S; Ravetti, Soledad; Raviolo, Mónica A; Briñón, Margarita C

    2014-09-01

    As a part of preformulation studies, the aim of this work was to examine the solubility and stability of a series of 5'-O-carbonates of lamivudine with proven antihuman immunodeficiency virus activity. Solubility studies were carried out using pure solvents (water, ethanol and polyethylene glycol 400 [PEG 400]), as well as cosolvents in binary mixture systems (water-ethanol and water-PEG 400). These ionizable compounds showed that their aqueous solubility is decreasing as the carbon length of the substituent moiety increases, but being enhanced as the pH was reduced from 7.4 to 1.2. Thus, 3TC-Metha an active compound of the series, with an intrinsic solubility at 25 °C of 17 mg/mL, was about 70 times more soluble than 3TC-Octa (0.24 mg/mL), and at pHs of 1.2, 5.8 and 7.4 had intrinsic solubilities of 36.48, 19.20 and 15.40 mg/mL, respectively. In addition, the solubility was enhanced significantly by using ethanol and PEG 400 as cosolvents. A stability study was conducted in buffer solutions at pH 1.2, 5.8, 7.4 and 13.0 and in human plasma at 37 °C. Stability-indicating high-performance liquid chromatography procedure was found to be selective, sensitive and accurate for these compounds and good recovery, linearity and precision were also observed.

  7. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.

    PubMed

    Wood, Robin; Phanuphak, Praphan; Cahn, Pedro; Pokrovskiy, Vadim; Rozenbaum, Willy; Pantaleo, Giuseppe; Sension, Michael; Murphy, Robert; Mancini, Marco; Kelleher, Thomas; Giordano, Michael

    2004-06-01

    The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.

  8. Effect of HIV-1 infection and sex on the cellular pharmacology of the antiretroviral drugs zidovudine and lamivudine.

    PubMed

    Rower, Joseph E; Meditz, Amie; Gardner, Edward M; Lichtenstein, Kenneth; Predhomme, Julie; Bushman, Lane R; Klein, Brandon; Zheng, Jia-Hua; Mawhinney, Samantha; Anderson, Peter L

    2012-06-01

    The cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC) in vivo is not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (C(ss)) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higher C(ss) estimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P > 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [-19%, 38%]; P = 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [-9%, 20%] and -5% [-26%, 12%] for HIV serostatus and race, respectively; P > 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacology in vivo and provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.

  9. Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations.

    PubMed

    Bouazza, Naïm; Foissac, Frantz; Fauchet, Floris; Burger, David; Kiechel, Jean-René; Treluyer, Jean-Marc; Capparelli, Edmund V; Lallemant, Marc; Urien, Saïk

    2015-01-01

    Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC. Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively. Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria. This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.

  10. Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine

    PubMed Central

    Smith, Kimberly Y.; Tierney, Camlin; Mollan, Katie; Venuto, Charles S.; Budhathoki, Chakra; Ma, Qing; Morse, Gene D.; Sax, Paul; Katzenstein, David; Godfrey, Catherine; Fischl, Margaret; Daar, Eric S.; Collier, Ann C.; Bolivar, Hector H.; Navarro, Sandra; Koletar, Susan L.; Gochnour, Diane; Seefried, Edward; Hoffman, Julie; Feinberg, Judith; Saemann, Michelle; Patterson, Kristine; Pittard, Donna; Currin, David; Upton, Kerry; Saag, Michael; Ray, Graham; Johnson, Steven; Santos, Bartolo; Funk, Connie A.; Morgan, Michael; Jackson, Brenda; Tebas, Pablo; Thomas, Aleshia; Kim, Ge-Youl; Klebert, Michael K.; Santana, Jorge L.; Marrero, Santiago; Norris, Jane; Valle, Sandra; Cox, Gary Matthew; Silberman, Martha; Shaik, Sadia; Lopez, Ruben; Vasquez, Margie; Daskalakis, Demetre; Megill, Christina; Shore, Jessica; Taiwo, Babafemi; Goldman, Mitchell; Boston, Molly; Lennox, Jeffrey; del Rio, Carlos; Lane, Timothy W.; Epperson, Kim; Luetkemeyer, Annie; Payne, Mary; Gripshover, Barbara; Antosh, Dawn; Reid, Jane; Adams, Mary; Storey, Sheryl S.; Dunaway, Shelia B.; Gallant, Joel; Wiggins, Ilene; Smith, Kimberly Y.; Swiatek, Joan A.; Timpone, Joseph; Kumar, Princy; Moe, Ardis; Palmer, Maria; Gothing, Jon; Delaney, Joanne; Whitely, Kim; Anderson, Ann Marie; Hammer, Scott M.; Yin, Michael T.; Jain, Mamta; Petersen, Tianna; Corales, Roberto; Hurley, Christine; Henry, Keith; Bordenave, Bette; Youmans, Amanda; Albrecht, Mary; Pollard, Richard B.; Olusanya, Abimbola; Skolnik, Paul R.; Adams, Betsy; Tashima, Karen T.; Patterson, Helen; Ukwu, Michelle; Rogers, Lauren; Balfour, Henry H.; Fox, Kathy A.; Swindells, Susan; Van Meter, Frances; Robbins, Gregory; Burgett-Yandow, Nicole; Davis, Charles E.; Boyce, Colleen; O'Brien, William A.; Casey, Gerianne; Morse, Gene D.; Hsaio, Chiu-Bin; Meier, Jeffrey L.; Stapleton, Jack T.; Mildvan, Donna; Revuelta, Manuel; Currin, David; El Sadr, Wafaa; Loquere, Avelino; El-Daher, Nyef; Johnson, Tina; Gross, Robert; Maffei, Kathyrn; Hughes, Valery; Sturge, Glenn; McMahon, Deborah; Rutecki, Barbara; Wulfsohn, Michael; Cheng, Andrew; Dix, Lynn; Liao, Qiming

    2014-01-01

    Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. Clinical Trials Registration NCT00118898. PMID:24253247

  11. Nanoencapsulation of water-soluble drug, lamivudine, using a double emulsion spray-drying technique for improving HIV treatment

    NASA Astrophysics Data System (ADS)

    Tshweu, Lesego; Katata, Lebogang; Kalombo, Lonji; Swai, Hulda

    2013-11-01

    Current treatments available for human immunodeficiency virus, namely antiretrovirals, do not completely eradicate the virus from the body, leading to life-time commitment. Many antiretrovirals suffer drawbacks from toxicity and unpleasant side effects, causing patience non-compliance. To minimize challenges associated with the antiretrovirals, biodegradable nanoparticles used as drug delivery systems hold tremendous potential to enhance patience compliance. The main objective of this work was to load lamivudine (LAM) into poly(epsilon-caprolactone) (PCL) nanoparticles. LAM is a hydrophilic drug with low plasma half-life of 5-7 h and several unpleasant side effects. LAM was nanoencapsulated into PCL polymer via the double emulsion spray-drying method. Formulation parameters such as the effect of solvent, excipient and drug concentration were optimized for the synthesis of the nanoparticles. Spherical nanoparticles with an average size of 215 ± 3 nm and polydispersity index (PDI) of 0.227 ± 0.01 were obtained, when ethyl acetate and lactose were used in the preparation. However, dichloromethane presented sizes larger than 454 ± 11 nm with PDI of more than 0.4 ± 0.05, irrespective of whether lactose or trehalose was used in the preparation. Some of the nanoparticles prepared with trehalose resulted in crystal formation. UV spectroscopy showed encapsulation efficiency ranging from 68 ± 4 to 78 ± 4 % for LAM depending on the starting drug concentration. Fourier transform infrared spectroscopy and X-ray diffraction confirmed the possibility of preparing amorphous PCL nanoparticles containing LAM. Drug release extended for 4 days in pH 1.3, pH 4.5 and pH 6.8. These results indicated that LAM-loaded PCL nanoparticles show promise for controlled delivery.

  12. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine.

    PubMed

    Smith, Kimberly Y; Tierney, Camlin; Mollan, Katie; Venuto, Charles S; Budhathoki, Chakra; Ma, Qing; Morse, Gene D; Sax, Paul; Katzenstein, David; Godfrey, Catherine; Fischl, Margaret; Daar, Eric S; Collier, Ann C

    2014-02-01

    We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1-infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. NCT00118898.

  13. High frequency of lamivudine resistance mutations in Brazilian patients co-infected with HIV and hepatitis B.

    PubMed

    Mendes-Correa, M C; Pinho, J R R; Locarnini, S; Yuen, L; Sitnik, R; Santana, R A F; Gomes-Gouvêa, M S; Leite, O M; Martins, L G; Silva, M H; Gianini, R J; Uip, D E

    2010-09-01

    This study analyzed the genotype distribution and frequency of lamivudine (LAM) and tenofovir (TDF) resistance mutations in a group of patients co-infected with HIV and hepatitis B virus (HBV). A cross-sectional study of 847 patients with HIV was conducted. Patients provided blood samples for HBsAg detection. The load of HBV was determined using an "in-house" real-time polymerase chain reaction. HBV genotypes/subgenotypes, antiviral resistance, basal core promoter (BCP), and precore mutations were detected by DNA sequencing. Twenty-eight patients with co-infection were identified. The distribution of HBV genotypes among these patients was A (n = 9; 50%), D (n = 4; 22.2%), G (n = 3; 16.7%), and F (n = 2; 11.1%). Eighteen patients were treated with LAM and six patients were treated with LAM plus TDF. The length of exposure to LAM and TDF varied from 4 to 216 months. LAM resistance substitutions (rtL180M + rtM204V) were detected in 10 (50%) of the 20 patients with viremia. This pattern and an accompanying rtV173L mutation was found in four patients. Three patients with the triple polymerase substitution pattern (rtV173L + rtL180M + rtM204V) had associated changes in the envelope gene (sE164D + sI195M). Mutations in the BCP region (A1762T, G1764A) and in the precore region (G1896A, G1899A) were also found. No putative TDF resistance substitution was detected. The data suggest that prolonged LAM use is associated with the emergence of particular changes in the HBV genome, including substitutions that may elicit a vaccine escape phenotype. No putative TDF resistance change was detected after prolonged use of TDF.

  14. Simultaneous determination of HIV-protease inhibitors lamivudine and zidovudine in pharmaceutical formulations by micellar electrokinetic chromatography.

    PubMed

    Sekar, R; Azhaguvel, S

    2005-09-15

    A micellar electrokinetic chromatographic (MEKC) method for the simultaneous separation and determination of lamivudine (LMV) and zidovudine (ZDV) in pharmaceutical formulation has been developed. Factors that affect the separation, such as buffer pH, surfactant concentration (sodium dodecyl sulfate, SDS), organic solvents and applied voltage were optimized. Buffer consisting of 12.5 mM sodium tetraborate decahydrate and 15 mM boric acid adjusted at pH 10.8, containing 90 mM SDS and 5% (v/v) acetonitrile (ACN) was found to be suitable for the separation of the drugs. p-Aminobenzoic acid (PABA) was used as internal standard (I.S.). Detection of analytes and I.S. was performed at a wavelength of 210 nm. It was observed that both the drugs and I.S. were migrated within 20 min at the applied voltage of +10 kV. Validation of the method was performed in terms of linearity, accuracy, precision, limit of detection (LOD) and quantification (LOQ). An excellent linearity was obtained in the concentration range 10-80 microg/ml for LMV and 10-100 microg/ml for ZDV. The detection limits for LMV and ZDV were found to be 2.5 and 2.0 microg/ml, respectively. The optimized method was applied to the simultaneous determination of LMV and ZDV in pharmaceutical formulation and human plasma (spiked) samples. Recovery of both the drugs in tablet dosage form and spiked drugs in plasma were > or =99.72% (relative standard deviation (R.S.D.)< or =1.84%) and > or =80.4% (R.S.D.< or =5.4%), respectively. In the electropherogram no interfering peaks were observed in the region of analytes and I.S. due to inactive ingredients in the tablets and matrices in plasma.

  15. Cost impact of prospective HLA-B*5701-screening prior to abacavir/lamivudine fixed dose combination use in Germany.

    PubMed

    Wolf, Eva; Blankenburg, M; Bogner, J R; Becker, W; Gorriahn, D; Mueller, M C; Jaeger, H; Welte, R; Baudewig, M; Walli, R; Stoll, M

    2010-04-08

    Avoiding abacavir in HIV-infected patients tested positive for HLA-B*5701 reduces the risk of abacavir hypersensitivity reaction (ABC-HSR). Our aim was to assess the costs of clinically suspected HSR and to estimate potential cost savings of implementing prospective HLA-B*5701-screening for HIV-infected patients initiating abacavir/lamivudine fixed-dose combination (ABC/3TC FDC) compared to initiating respective treatment without screening. Employing a decision tree model the expected HSR-related costs of screening vs. no screening were estimated from the societal and healthcare payer perspective (reference year 2007). A retrospective standardized assessment of all clinically suspected ABC-HSR cases without screening at 5 German HIV-centres was performed to measure resource consumption. In- and outpatient care, discarded ABC/3TC FDC and concomitant medication were considered. Direct resource utilization was valued using German fees (EBM, G-DRGs). Indirect costs were measured with the human capital approach. Estimates for the HLA-B*5701-prevalence, HSR-incidence, and hospitalization rate were based on clinical trials and cohorts and it was assumed that screening reduces the incidence of clinically suspected ABC-HSR from 10% to 0.5%. Thirty-two ABC-HSR cases were identified from 1998 to 2007. Mean direct and total costs per clinically suspected HSR case were Euro 1,362 and Euro 2,235, respectively. Hospital costs contributed 63.3% to direct costs. Potential cost savings when implementing genetic screening were estimated at Euro 44 and Euro 127 per screened patient, from a healthcare payer or societal perspective. HLA-B*5701 screening prior to ABC/3TC FDC initiation prevents significant HSR-related costs per screened patient and is likely to lead to overall net savings.

  16. Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China.

    PubMed

    Wu, Bin; Shen, Jinfang; Cheng, Huafeng

    2012-11-08

    Several rescue therapies have been used in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB); however, the economic outcome of these therapies is unclear. The object of the current analysis was to evaluate the lifetime cost-effectiveness of rescue therapies among patients with LAM-resistant CHB. A Markov model was developed to simulate the clinical course of patients with LAM-resistant CHB. From the perspective of Chinese health care, a lifetime cost-utility analysis was performedfor 4 rescue strategies: adefovir (ADV), entecavir (ETV) or tenofovir (TDF) monotherapy and combination therapy using LAM and ADV. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model, and the beginning health state was LAM-resistant CHB without other complications. The transition probabilities, efficacy and resistance data for each rescue therapy as well as the costs and utility data were estimated from the literature. The discount rate (3%) utilized for costs and benefits. Sensitivity analyses were used to explore the impact of uncertainty on the results. In LAM-resistant HBeAg-positive and HBeAg-negative CHB cohorts, TDF monotherapy and combination therapy were on the efficiency frontier for both positive and negative populations. Compared with no treatment, the use of combination therapy cost an additional $6,531.7 to gain 1 additional quality-adjusted life year (QALY) for HBeAg-positive patients and $4,571.7 to gain 1 additional QALY for HBeAg-negative patients. TDF monotherapy for HBeAg-positive patients, shows greater increase in QALYs but higher incremental cost-effectiveness ratio (ICER) in comparison with combination therapy. In probabilistic sensitivity analyses, combination therapy was the preferred option for health care systems with limited health resources, such as Chinese health care system. In Chinese patients with LAM-resistant CHB, combination therapy is a more cost-effective option than the

  17. Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression: A prospective cohort study.

    PubMed

    Llibre, Josep M; Cozzi-Lepri, Alessandro; Pedersen, Court; Ristola, Matti; Losso, Marcelo; Mocroft, Amanda; Mitsura, Viktar; Falconer, Karolin; Maltez, Fernando; Beniowski, Marek; Vullo, Vincenzo; Hassoun, Gamal; Kuzovatova, Elena; Szlavik, János; Kuznetsova, Anastasiia; Stellbrink, Hans-Jürgen; Duvivier, Claudine; Edwards, Simon; Laut, Kamilla; Paredes, Roger

    2016-10-01

    Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR <50 copies/mL) and a snapshot analysis at 48, 96, and 144 weeks. Virological failure (VF) was defined as confirmed pVL >50 copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50 copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL ≤50 copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.

  18. Switching from zidovudine/lamivudine to tenofovir/emtricitabine improves fat distribution as measured by fat mass ratio.

    PubMed

    Martínez, E; Ribera, E; Clotet, B; Estrada, V; Sanz, J; Berenguer, J; Rubio, R; Pulido, F; Larrousse, M; Curran, A; Negredo, E; Arterburn, S; Ferrer, P; Álvarez, M L

    2015-07-01

    Fat mass ratio (FMR) has been suggested as an objective indicator of abnormal body fat distribution in HIV infection. Although it could provide more comprehensive information on body fat changes than limb fat mass, FMR has scarcely been used in clinical trials examining body fat distribution in HIV-infected patients. A subanalysis of a controlled, randomized clinical trial in virologically suppressed HIV-1-infected men switching from zidovudine (ZDV)/lamivudine (3TC) to emtricitabine (FTC)/tenofovir (TDF) versus continuing on ZDV/3TC was carried out. FMR was assessed by dual X-ray absorptiometry (DEXA) for a period of 72 weeks. Lipoatrophy was defined as FMR ≥ 1.5. Multivariate linear regression models for the change in FMR from baseline were fitted. Sixty-five men were randomized and treated (28 in the FTC/TDF arm and 37 in the ZDV/3TC arm), and 57 completed the study (25 and 32 in each arm, respectively). In the FTC/TDF arm, adjusted mean FMR decreased by 0.52 at week 72 (P = 0.014), and in the ZDV/3TC arm it increased by 0.13 (P = 0.491; P between arms = 0.023). Among subjects with lipoatrophy (baseline FMR ≥ 1.5), adjusted FMR decreased by 0.76 (P = 0.003) in the FTC/TDF arm and increased by 0.21 (P = 0.411; P between arms = 0.009) in the ZDV/3TC arm. Baseline FMR and treatment group were significant predictors (P < 0.05) of post-baseline changes in FMR. Switching from ZDV/3TC to FTC/TDF led to an improvement in FMR, compared with progressive worsening of FMR in subjects receiving ZDV/3TC, showing that fat mass not only increased but was also distributed in a healthier way after the switch. © 2014 British HIV Association.

  19. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine.

    PubMed

    Squires, Kathleen E; Young, Benjamin; DeJesus, Edwin; Bellos, Nicholaos; Murphy, Daniel; Ward, Douglas; Zhao, Henry H; Ross, Lisa L; Shaefer, Mark S

    2012-01-01

    The open-label study ARIES (ClinicalTrials.gov NCT00440947) utilized a ritonavir (/r)-boosted protease inhibitor treatment simplification strategy. Antiretroviral-naïve subjects received abacavir/lamivudine (ABC/3TC) + atazanavir/ ritonavir (ATV/r) from baseline through randomization at week 36, then maintained or discontinued ritonavir for an additional 108 weeks. Non-inferiority of the unboosted regimen was demonstrated at week 84. In this optional extension phase, virologic suppression and adverse events were assessed through week 144. Patients were randomized at week 36 if they had confirmed HIV RNA <50 copies/mL by week 30 and no previous virologic failure (VF; defined as failure to achieve HIV RNA <400 copies/mL or confirmed rebound after achieving HIV RNA ≥400 copies/mL). Three hundred sixty-nine subjects who completed 84 weeks in ARIES participated in the extension phase and maintained their randomized regimen for an additional 60 weeks post randomization. At week 144, 146/189 (77%) versus 132/180 (73%) subjects in the unboosted ATV and ATV/r groups, respectively, maintained HIV RNA <50 copies/mL. Post randomization (weeks 36-144), treatment-related grade 2-4 adverse events were more common in the ATV/r-treated (23%) compared to the ATV-treated (13%) group; the most frequently reported was increased serum bilirubin (6% of ATV-treated subjects vs 14 % of ATV/r-treated subjects). During the extension phase, 3% (11/369) of subjects met protocol-defined VF (5 ATV-treated and 6 ATV/ r-treated subjects); one ATV/r-treated subject had treatment-emergent major viral resistance-associated mutations. The median change in fasting triglycerides from baseline to week 144 was significantly different (P=.001) in the ATV-treated (-8.5 mg/dL) compared to the ATV/r-treated (28.5 mg/dL) groups. These long-term study results demonstrate that ATV in combination with ABC/3TC is a potent, well-tolerated regimen in patients who have achieved initial suppression on a ritonavir

  20. Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice

    PubMed Central

    Zhang, Hua; Pan, Calvin Q; Pang, Qiumei; Tian, Ruihua; Yan, Miaoe; Liu, Xin

    2014-01-01

    Little observational data exist describing telbivudine (LdT) or lamivudine (LAM) use in late pregnancy for preventing hepatitis B mother-to-child transmission (MTCT) in real-world settings. During the period of January 2009 to March 2011, we enrolled hepatitis B e antigen–positive mothers with HBV DNA >6 log10 copies/mL in China. At gestation week 28, the mothers received LdT or LAM until postpartum week 4 or no treatment (NTx). The study endpoints were the safety of LdT/LAM use and MTCT rates. Of the 700 mothers enrolled, 648 (LdT/LAM/NTx = 252/51/345) completed the 52-week study with 661 infants (LdT/LAM/NTx = 257/52/352). On treatment, viral rebound occurred in 1.6% of mothers, all resulting from medication noncompliance. There was no genotypic mutation detected. At delivery, significantly lower HBV DNA levels were noted in mothers who received LdT or LAM versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers (P < 0.001). At birth, hepatitis B surface antigen (HBsAg) was detected in 20% and 24% of newborns in the treated and NTx groups, respectively. At week 52, an intention-to-treat analysis indicated 2.2% (95% confidence [CI]: 0.6-3.8) of HBsAg+ infants from the treated group versus 7.6% (95% CI: 4.9-10.3) in the NTx group (P = 0.001) and no difference of HBsAg+ rate between infants in the LdT and LAM groups (1.9% vs. 3.7%; P = 0.758). On-treatment analysis indicated 0% of HBsAg+ infants in the treated group versus 2.84% in the NTx group (P = 0.002). There were no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates between infants from the treated and untreated groups. Conclusions: LdT and LAM use in late pregnancy for highly viremic mothers was equally effective in reducing MTCT. The treatment was well tolerated with no safety concerns identified. PMID:25187919

  1. The clinical implication of single nucleotide polymorphisms in deoxycytidine kinase in chronic hepatitis B patients treated with lamivudine.

    PubMed

    Lee, Hyun Woong; Lee, Sung Hee; Lee, Min Goo; Ahn, Sang Hoon; Chang, Hye Young; Han, Kwang-Hyub

    2016-05-01

    Deoxycytidine kinase (dCK) is a critical enzyme involved in intracellular phosphorylation of lamivudine (LAM) to its active triphosphates. We conducted this study to determine dCK polymorphisms in Koreans and to evaluate whether the discovered single nucleotide polymorphisms (SNPs) were associated with treatment outcomes in chronic hepatitis B (CHB) patients treated with LAM. The full-length dCK gene was sequenced from 24 healthy volunteers and 24 patients with CHB. One hundred twenty-seven patients with CHB who were followed-up for at least 24 months after LAM treatment were enrolled. Virological response as determined by undetectable HBV DNA was defined as a good drug response. Primary non-response at 6 months and virological breakthrough within 12 months were defined as a poor drug response. Six novel dCK SNPs were found (-2052C/A, IVS3 - 46G/del, IVS4 + 40G/T, IVS5 + 39T/C, IVS5 - 72A/T, and 966-975T10/T11). In particular, two promoter SNPs, namely -360C/G and -201C/T, were in full linkage disequilibrium. These two SNPs had a higher allele frequency than previously reported in Caucasian, Japanese, and Chinese (26% vs. 2%, 13.1%, and 15.6%, respectively). There was no significant difference between treatment response groups in terms of the distributions of SNP genotypes or allele frequencies. However, there was significant difference in the allele frequency of -360G/-201T between HBeAg seroclearance group and HBeAg non-seroclearance group (P = 0.045). In conclusion, six novel dCK SNPs were discovered. Two promoter SNPs, namely -360C/G and -201C/T, were more frequent in Koreans than other populations. In particular, HBeAg-positive patients with the -360G/-201T haplotype may help HBeAg seroclearance in response to LAM therapy. © 2015 Wiley Periodicals, Inc.

  2. Telbivudine versus lamivudine and entecavir for treatment-naïve decompensated hepatitis B virus-related cirrhosis.

    PubMed

    Yue-Meng, Wan; Li, Yu-Hua; Wu, Hua-Mei; Yang, Jing; Xu, Ying; Yang, Li-Hong; Yang, Jin-Hui

    2016-04-19

    The long-term effects of telbivudine (TBV) on decompensated hepatitis B virus (HBV)-related cirrhosis were still not established. This study aimed to investigate the efficacy and safety of TBV in such cohort of patients as compared to lamivudine (LAM) and entecavir (ETV). We retrospectively evaluated 130 treatment-naïve patients with HBV-related decompensated cirrhosis who started treatment with TBV (n = 31), LAM (n = 45) or ETV (n = 54). After 24 months of treatment, cumulative virological response (VR) rates (HBV DNA <500 copies/mL) were 83.7, 65.3 and 89.1 % in TBV, LAM and ETV groups, respectively (p = 0.009). Reduction in HBV DNA levels in TBV was -3.66 ± 0.56, significantly higher than LAM (-3.34 ± 0.59; p < 0.05) and lower than ETV group (-3.98 ± 0.52; p < 0.05). The rates of HBeAg loss or seroconversion and normalization of alanine aminotransferase (ALT) were similar among the groups. Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease score in TBV were significantly improved compared to at baseline without difference among the groups. TBV resulted in similar cumulative rates of survival and incidence of hepatocellular carcinoma (HCC) to LAM and ETV. Frequencies of complications from cirrhosis, including variceal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis, were comparable among the groups. Four patients (16.7 %) in TBV displayed virological breakthrough, lower than LAM and higher than ETV (p = 0.004). Cox regression analysis showed that baseline HBV DNA (hazard ratio 0.743; 95 % confidence interval 0.582-949, p = 0.017) was an independent predictor for VR at 24 months. Long-term therapy with TBV was effective and safe in HBV-related decompensated cirrhosis.

  3. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir.

    PubMed

    McComsey, Grace A; Kitch, Douglas; Daar, Eric S; Tierney, Camlin; Jahed, Nasreen C; Melbourne, Kathleen; Ha, Belinda; Brown, Todd T; Bloom, Anthony; Fedarko, Neal; Sax, Paul E

    2012-07-17

    The effect of specific antiretrovirals on inflammation is unclear. A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r. Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Δ = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89). Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

  4. Comparison of abacavir/lamivudine and tenofovir/emtricitabine among treatment-naive HIV-infected patients initiating therapy.

    PubMed

    Tan, Darrell H S; Chan, Keith; Raboud, Janet; Cooper, Curtis; Montaner, Julio S G; Walmsley, Sharon; Hogg, Robert S; Klein, Marina B; Machouf, Nima; Rourke, Sean B; Tsoukas, Chris; Loutfy, Mona R

    2011-09-01

    Controversy about the relative performance of abacavir (ABC)/lamivudine (3TC) and tenofovir (TDF)/emtricitabine (FTC) in initial combination antiretroviral therapy (cART) exists. We compared the times to regimen failure (composite of virologic failure or switching/stopping nucleosides for any reason) according to nucleoside backbone in treatment-naive patients starting cART in a retrospective observational cohort study. Additional endpoints included virologic failure, switching/stopping nucleosides for nonvirologic reasons, and virologic suppression. Treatment-naive noninjection drug user individuals in the Canadian Observational Cohort initiating ABC/3TC-containing or TDF/FTC-containing cART with efavirenz, nevirapine, lopinavir/ritonavir, or atazanavir/ritonavir with ≥6 months follow-up were included. Multivariable proportional hazards regression models accounting for competing risks were used to model outcomes. One thousand seven hundred sixty-four individuals (588 ABC/3TC, 1176 TDF/FTC) were included. Median (interquartile range) follow-up times were 34 (23-50) and 20 (13-30) months, respectively. Time to regimen failure was similar for ABC/3TC versus TDF/FTC [adjusted hazard ratio, (aHR) = 0.96, 95% CI = 0.80 to 1.17] after adjusting for baseline viral load (VL), sex, province, third antiretroviral agent, year of cART initiation, HLA-B*5701 test availability, and rate of VL testing. No differences were observed in time to virologic failure (aHR = 0.84, 95% CI = 0.58 to 1.20), switching/stopping nucleosides for nonvirologic reasons (aHR = 1.02, 95% CI = 0.81 to 1.28), or virologic suppression (aHR = 0.96, 95% CI = 0.83 to 1.10). There was no statistical interaction between backbone and baseline VL for any outcome. Results were similar when stratified by baseline VL ≤ 100,000 or > 100,000 copies per milliliter. In our naive noninjection drug user HIV-infected patients starting cART, there was no difference in time to regimen failure, virologic failure

  5. Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China

    PubMed Central

    2012-01-01

    Background Several rescue therapies have been used in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB); however, the economic outcome of these therapies is unclear. The object of the current analysis was to evaluate the lifetime cost-effectiveness of rescue therapies among patients with LAM-resistant CHB. Methods A Markov model was developed to simulate the clinical course of patients with LAM-resistant CHB. From the perspective of Chinese health care, a lifetime cost-utility analysis was performedfor 4 rescue strategies: adefovir (ADV), entecavir (ETV) or tenofovir (TDF) monotherapy and combination therapy using LAM and ADV. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model, and the beginning health state was LAM-resistant CHB without other complications. The transition probabilities, efficacy and resistance data for each rescue therapy as well as the costs and utility data were estimated from the literature. The discount rate (3%) utilized for costs and benefits. Sensitivity analyses were used to explore the impact of uncertainty on the results. Results In LAM-resistant HBeAg-positive and HBeAg-negative CHB cohorts, TDF monotherapy and combination therapy were on the efficiency frontier for both positive and negative populations. Compared with no treatment, the use of combination therapy cost an additional $6,531.7 to gain 1 additional quality-adjusted life year (QALY) for HBeAg-positive patients and $4,571.7 to gain 1 additional QALY for HBeAg-negative patients. TDF monotherapy for HBeAg-positive patients, shows greater increase in QALYs but higher incremental cost-effectiveness ratio (ICER) in comparison with combination therapy. In probabilistic sensitivity analyses, combination therapy was the preferred option for health care systems with limited health resources, such as Chinese health care system. Conclusion In Chinese patients with LAM-resistant CHB, combination therapy is a more

  6. Pharmacokinetics of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children.

    PubMed

    Corbett, Amanda H; Hosseinipour, Mina C; Nyirenda, Jean; Kanyama, Cecelia; Rezk, Naser L; Mkupani, Pax; Sichali, Dorothy; Tien, Hsiao; Kashuba, Angela Dm; Mwansambo, Charles; Weigel, Ralf; Kazembe, Peter

    2010-01-01

    The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL). This was a prospective randomized three-way crossover study. Patients (8-<12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment. A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0-6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three-quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP. Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28-<32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg.

  7. Development of peptide nucleic acid mediated polymerase chain reaction clamping (PMPC)--direct sequencing method for detecting lamivudine-resistant hepatitis B virus (HBV) variants with high sensitivity and specificity.

    PubMed

    Ogata, Norio; Ichida, Takafumi; Aoyagi, Yutaka; Kitajima, Isao

    2003-04-01

    Reduced sensitivity of HBV to lamivudine, which causes a viral breakthrough during treatment, is attributed to mutations within the tyrosine-methionine-aspartate(YMDD) locus in the reverse transcriptase(rt) domain of HBV polymerase, mainly a methionine(rtM204) substitution. The sensitive detection of such mutations before or early in treatment could assist in optimizing antiviral treatment. For this purpose, we developed peptide nucleic acid(PNA) mediated polymerase chain reaction(PCR) clamping(PMPC) with a PNA probe targeting the YMDD locus. We first tested this method for its sensitivity and specificity in detecting a mutant on HBV DNA standards consisting of serial copy number ratios of a known lamivudine-resistant, mutant clone with rtM204I(ATT) to a wild-type clone with rtM204(ATG). The sensitivity was 0.1 to 0.01% in the coexistence of wild-type clones and the specificity was guaranteed by direct sequencing of the products. We next applied this method to HBV DNA specimens extracted from serum from 4 chronic hepatitis B patients treated with lamivudine. Two of these exhibited a break-through of the HBV mutant with rtM204I(ATT), while the other 2 did not. Before treatment, all 4 patients showed HBV with rtM204I encoded by ATA. During treatment, HBV with the rtM204I(ATT) emerged in the 2 breakthrough patients more than 3 months before the breakthrough, whereas this and other known lamivudine-resistant viruses did not appear in the 2 non-breakthrough patients. Thus, our PMPC-direct sequencing method is highly sensitive and reliable for the early identification of lamivudine-resistant HBV that causes a viral breakthrough.

  8. Randomized Controlled Study Investigating Viral Suppression and Serological Response following Pre-S1/Pre-S2/S Vaccine Therapy Combined with Lamivudine Treatment in HBeAg-Positive Patients with Chronic Hepatitis B▿

    PubMed Central

    Hoa, Pham Thi Le; Huy, Nguyen Tien; Thu, Le The; Nga, Cao Ngoc; Nakao, Kazuhiko; Eguchi, Katsumi; Chi, Nguyen Huu; Hoang, Bui Huu; Hirayama, Kenji

    2009-01-01

    The aim of the current study was to evaluate viral suppression following combined treatment with an S/pre-S1/pre-S2 vaccine and lamivudine in patients with chronic hepatitis B. We established a randomized, controlled clinical trial to compare the responses of three different treatment groups: those receiving vaccine monotherapy, lamivudine monotherapy, or combination treatment. Viral response was evaluated via hepatitis B virus (HBV) DNA suppression using different levels of classification. Seroconversion was evaluated via HBeAg loss, HBeAg seroconversion, HBsAg loss, and anti-HBs response. We found that the group receiving combination treatment demonstrated a significant increase in viral suppression over that for the lamivudine or vaccine monotherapy group, although the HBeAg seroconversion rate was not different. This enhanced suppression effect in the combination group was reversed after the discontinuation of vaccine treatment, suggesting that booster doses are required for a sustained viral response. Anti-HBs was detected in 55/120 vaccine recipients, but only 3 patients demonstrated HBsAg loss, indicating that the vaccine-induced anti-HBs was unable to completely neutralize HBsAg in the serum. At the study end point, anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs nonresponders. Our results suggest that combined treatment with the vaccine and lamivudine was significantly more effective than lamivudine monotherapy in the short term and was especially successful in producing viral suppression and an enhanced anti-HBs antibody response. PMID:19770281

  9. Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174

    PubMed Central

    2012-01-01

    Background Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. Methods The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms. HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants. The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and

  10. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial.

    PubMed

    Arribas, José R; Girard, Pierre-Marie; Landman, Roland; Pich, Judit; Mallolas, Josep; Martínez-Rebollar, María; Zamora, Francisco X; Estrada, Vicente; Crespo, Manuel; Podzamczer, Daniel; Portilla, Joaquín; Dronda, Fernando; Iribarren, José A; Domingo, Pere; Pulido, Federico; Montero, Marta; Knobel, Hernando; Cabié, André; Weiss, Laurence; Gatell, José M

    2015-07-01

    Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in

  11. Bayesian network analyses of resistance pathways against efavirenz and nevirapine.

    PubMed

    Deforche, Koen; Camacho, Ricardo J; Grossman, Zehave; Soares, Marcelo A; Van Laethem, Kristel; Katzenstein, David A; Harrigan, P Richard; Kantor, Rami; Shafer, Robert; Vandamme, Anne-Mieke

    2008-10-18

    To clarify the role of novel mutations selected by treatment with efavirenz or nevirapine, and investigate the influence of HIV-1 subtype on nonnucleoside reverse transcriptase inhibitor (nNRTI) resistance pathways. By finding direct dependencies between treatment-selected mutations, the involvement of these mutations as minor or major resistance mutations against efavirenz, nevirapine, or coadministrated nucleoside analogue reverse transcriptase inhibitors (NRTIs) is hypothesized. In addition, direct dependencies were investigated between treatment-selected mutations and polymorphisms, some of which are linked with subtype, and between NRTI and nNRTI resistance pathways. Sequences from a large collaborative database of various subtypes were jointly analyzed to detect mutations selected by treatment. Using Bayesian network learning, direct dependencies were investigated between treatment-selected mutations, NRTI and nNRTI treatment history, and known NRTI resistance mutations. Several novel minor resistance mutations were found: 28K and 196R (for resistance against efavirenz), 101H and 138Q (nevirapine), and 31L (lamivudine). Robust interactions between NRTI mutations (65R, 74V, 75I/M, and 184V) and nNRTI resistance mutations (100I, 181C, 190E and 230L) may affect resistance development to particular treatment combinations. For example, an interaction between 65R and 181C predicts that the nevirapine and tenofovir and lamivudine/emtricitabine combination should be more prone to failure than efavirenz and tenofovir and lamivudine/emtricitabine. Bayesian networks were helpful in untangling the selection of mutations by NRTI versus nNRTI treatment, and in discovering interactions between resistance mutations within and between these two classes of inhibitors.

  12. Late hepatitis B virus reactivation after lamivudine prophylaxis interruption in an anti-HBs-positive and anti-HBc-negative patient treated with rituximab-containing therapy.

    PubMed

    Ceccarelli, Laura; Salpini, Romina; Sarmati, Loredana; Svicher, Valentina; Bertoli, Ada; Sordillo, Pasquale; Ricciardi, Alessandra; Perno, Carlo Federico; Andreoni, Massimo; Sarrecchia, Cesare

    2012-08-01

    We describe a case of an anti-HBs-positive patient who experienced hepatitis B reactivation 18 months after the discontinuation of rituximab and after 12 months of lamivudine prophylaxis. The patient carried a hepatitis B genotype D virus harbouring a single immune escape mutation, sT118K. No consensus guidelines regarding the optimal length of treatment or the best elective drug have been defined for antiviral prophylaxis for HBsAg-negative, anti-HBc- and/or anti-HBs-positive patients undergoing immunosuppressive treatment. Screening based on HBV serological markers and HBV DNA testing is a critical issue to recognise hepatitis B reactivation as early as possible. Furthermore, it is of outstanding importance to identify alternative markers (e.g. cccDNA, HBV core related antigen, etc.), that could be predictive of HBV reactivation.

  13. [Investigation of oxidative stress and antioxidant defense in patients with hepatitis B virus infection and the effect of interferon-alpha plus lamivudine combination therapy on oxidative stress].

    PubMed

    Acar, Ali; Görenek, Levent; Aydin, Ahmet; Eyigün, Can Polat; Eken, Ayşe; Sayal, Ahmet; Pahsa, Alaaddin

    2009-07-01

    The aim of our study is to determine the role of oxidative stress on hepatic damage in patients with acute and chronic hepatitis B virus (HBV) infection and the efficacy of antioxidant-enzyme system against oxidative stress. Furthermore, the effect of interferon-alpha (IFN-alpha) plus lamivudine therapy on oxidative stress was also investigated. Nineteen patients with acute hepatitis B virus (AHBV) infection, 17 patients with chronic hepatitis B virus (CHBV) infection, 24 inactive HBsAg carriers and 21 healthy controls were included in the study. In control and patient groups, serum alanine-aminotransferase (ALT) and aspartate aminotransferase (AST) levels, erythrocyte malondialdehyde (MDA) levels, erythrocyte superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px) activities were measured. In CHBV group, after IFN-alpha plus lamivudine therapy for 6 months, these parameters were measured again. In all patient groups erythrocyte MDA levels were detected higher than control group (p < 0.05). Activity of CuZn-SOD was found to be the highest in AHBV (p < 0.05), and the lowest before the treatment in CHBV group (p < 0.05) compared with other groups. Activity of GSH-Px was found to be the highest in AHBV compared with inactive HBsAg carriers (p < 0.05) and CHBV group before treatment (p < 0.05). Activity of GSH-Px was found to be the lowest in CHBV group before treatment compared with other groups (p < 0.05). In CHBV group there was a significant decrease of MDA levels after treatment (p < 0.05) while there was a significant increase in activity of CuZn-SOD and GSH-Px compared with pretreatment levels (p < 0.05). A significant positive correlation was determined between MDA values and serum ALT levels, before and after the treatment (p < 0.05). Detection of the increase of MDA levels which is a product of lipid peroxidation in all patient groups, indicates that the oxidative stress is increased in HBV infection. Correlation between the levels of erythrocyte

  14. Clinical experience with dolutegravir/abacavir/lamivudine in HIV-HCV co-infected patients treated with a sofosbuvir-based regimen-safety and efficacy.

    PubMed

    Johnson, Tamara M; Sison, Raymund; Fallon, James P; Shukla, Prerak P; Bhattarai, Sristi; Galang, Herbert; Habeeb, Richard; Slim, Jihad

    2016-11-01

    There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination. Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy. Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21-59.78 years). The mean age was 59 years (95% CI: 58.21-59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6-100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events. Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

  15. Efficacy and safety of lamivudine or tenofovir plus intramuscular hepatitis B immunoglobulin in prevention of hepatitis B virus reinfection after liver transplant.

    PubMed

    Nassiri-Toosi, Mohssen; Kasraianfard, Amir; Ahmadinejad, Zahra; Dashti, Habibollah; Moini, Majıd; Najafi, Atabak; Salimi, Javad; Jafarian, Ali

    2015-04-01

    Hepatitis B immunoglobulin prophylaxis in combination with antiviral drugs is recommended for prevention of hepatitis B virus reinfection after liver transplant. However, there is no consensus on a standard prophylactic method, and controversy exists over the duration, dose, and route of administration. We conducted a prospective study to evaluate the safety and effectiveness of intramuscular hepatitis B immunoglobulin in combination with lamivudine and/or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year for prevention of hepatitis B virus reinfection. Patients with hepatitis Brelated liver cirrhosis who had undergone primary liver transplants were enrolled. The prophylactic protocol involved intraoperative intramuscular hepatitis B immunoglobulin at 10 000 IU, tapering to 5000 IU daily for the first 6 days, weekly for a month, every 2 weeks for the next month, and monthly for a year after liver transplant, in combination with antiviral drugs. From January 2002 until March 2014, two hundred sixty-eight liver transplants were performed. Forty-four patients (16.4%) who underwent liver transplants due to hepatitis B-related liver failure were enrolled. Five patients had hepatocellular carcinoma; 20 had both hepatitis D and hepatitis B virus infection. The median age was 47 years (range, 26-59 y) with a median model for end stage liver disease score of 20. Thirty-three patients were men (76%). Sixty-one percent of patients were negative for hepatitis B virus DNA at the time of transplant. The median follow-up was 13.6 months (range, 0-142 mo). Only 1 patient (2.3%) experienced hepatitis B virus reinfection (at 44.7 months posttransplant), which was successfully treated with tenofovir. Five patients died (11.4%) during the follow-up from nonhepatitis B causes. Intramuscular hepatitis B immunoglobulin in combination with lamivudine or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year posttransplant may provide safe and cost

  16. An indirect comparison of efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir and dolutegravir + abacavir/lamivudine

    PubMed Central

    Rogatto, Felipe; Bouee, Stephane; Jeanbat, Vivianne; Piontkowsky, David; Aragao, Filipa; Bosse, Matthew

    2014-01-01

    Background Integrase strand transfer inhibitors (INSTI) are the standard of care for naïve HIV-infected individuals due to their favourable efficacy and safety profile. The newest INSTIs, elvitegravir and dolutegravir, have not been evaluated in a head to head study; however, both have been compared to efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) in phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF) was compared to EFV/FTC/TDF for 144 weeks in Gilead Study 102 (GS-102), while dolutegravir (DTG) with the abacavir/lamivudine fixed-dose combination (ABC/3TC) was compared to EFV/FTC/TDF for 96 weeks in the SINGLE study. The objective of this analysis is to perform an indirect comparison at 48 and 96 weeks of E/C/F/TDF to DTG+ABC/3TC by using the two trials evaluating each of these regimens compared to EFV/FTC/TDF. Methods An indirect comparison was performed by using Bucher's methodology to calculate risk differences based on the two phase III clinical trials described above. Results At week 48 (snapshot analysis), 88% of the patients on E/C/F/TDF and DTG+ABC/3TC had HIV RNA <50 c/mL, while 84% and 81% of patients on EFV/FTC/TDF were suppressed in GS-102 and SINGLE, respectively. At week 96, 84% of patients receiving E/C/F/TDF compared with 80% of patients receiving DTG+ABC/3TC remained suppressed, while 82% and 72% on EFV/FTC/TDF maintained HIV RNA <50 c/mL in GS-102 and SINGLE. At week 144 80% of patients on E/C/F/TDF remained suppressed (vs. 75% of the patients on EFV/FTC/TDF). Results of indirect comparison showed a risk difference of HIV RNA <50 copies per mL between E/C/F/TDF compared with DTG+ABC/3TC of −4% (CI 95%=−11 to 3) for the ITT 48 weeks (p=0.3) and −5% (95% CI=−13 to 3) for the ITT 96 weeks (p=0.2). In regards to safety, there was no significant difference between E/C/F/TDF and DTG+ABC/3TC for any adverse event (AE) (p=0.3), serious AEs (0.13), drug related AEs (0.7), or drug-related serious AEs (0

  17. Therapeutic efficacy of sequential and simultaneous treatments with interferon-alpha and lamivudine in children with chronic hepatitis B.

    PubMed

    Akman, Sezin Asik; Okcu, Sabriye Cokceken; Halicioğlu, Oya; Sutcuoglu, Sumer; Anil, Murat; Kizilgunesler, Asli; Bakiler, Ali Rahmi

    2007-12-01

    Interferon (IFN)-alpha and lamivudine (LAM), a nucleoside analog, are frequently used drugs for the treatment of chronic hepatitis B (CHB), and their combined therapy has been shown to be effective. The purpose of the present study was to examine the therapeutic efficacy of sequential and simultaneous combination therapies of IFN-alpha and LAM in children with CHB. A total of 45 children with CHB, whose antibody status was positive for hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and HBV-DNA at least for 6 months; who had alanine aminotransferase (ALT) levels 1.5-fold higher than normal and hepatic activity index scores higher than 6, were allocated to two groups. The first group included 24 children who were given standard dose IFN-alpha (5 MU/m(2) s.c., thrice weekly) for 6 months, followed by LAM (4 mg/kg per day per oral, maximum 100 mg/day) for an additional 6 months (sequential therapy group). The second group included 21 children who were given IFN-alpha and LAM therapy simultaneously for 6 months and who continued with LAM alone for another 6 months (simultaneous therapy group). Partial response was defined as normalization of ALT and eradication of HBV-DNA. Complete response was defined as normalization of ALT, eradication of HBV-DNA and e seroconversion. Non-responders were defined as having positive HBV-DNA and abnormal ALT levels. Sustained response was defined as absence of HBsAg and presence of hepatitis B surface antibody (anti-HBs). The mean age of the sequential therapy group was 12.7 +/- 4.1 years, and 16 (66.7%) of the patients were male. The mean age of the simultaneous therapy group was 14.8 +/- 4.6 years, and 15 (71.4%) were male. In the first group, 13 patients (54.2%) were non-responders; partial response was observed in five patients (20.8%), and complete response was seen in six patients (25%). Despite the occurrence of e seroconversion, normalization of ALT was not achieved in one case. In the second group

  18. Lamivudine and Zidovudine

    MedlinePlus

    ... and zidovudine does not cure HIV, it may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) ... sex and making other life-style changes may decrease the risk of transmitting (spreading) the HIV virus ...

  19. Abacavir, Dolutegravir, and Lamivudine

    MedlinePlus

    ... or irregular heartbeat; trouble breathing; dark yellow or brown urine; light-colored bowel movements; yellowing of the ... what herbal products you are taking, especially St. John's wort. You should not take St. John's wort ...

  20. Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

    PubMed Central

    Westley, Benjamin; DeLong, Allison; Tray, Chhraing; Sophearin, Dim; Nerrienet, Eric; Schreier, Leeann; Kantor, Rami

    2013-01-01

    Abstract Antiretroviral therapy in resource-limited settings is monitored clinically and immunologically according to WHO guidelines. Frequent misclassification of virologic failure is reported, mostly in adults, leading to early therapy switch or late failure diagnosis. Pediatric treatment monitoring and resistance data upon first-line failure are limited, particularly when the 2010-WHO pediatric guidelines are used without routine viral load monitoring. We previously reported high treatment failure misclassification rates by pediatric 2010 guidelines in Cambodian children on first-line therapy. Here we determine the extent and patterns of resistance, with yearly viral load and 6-monthly CD4. Drug resistance mutations were determined using the IAS-USA 2011 list. Predicted resistance interpretation was determined with Stanford Database tools. Fifty-one children with available genotypes met inclusion criteria. All but one (subtype B) were CRF01_AE. The most common regimen was stavudine, lamivudine, and nevirapine (96%), taken for a median of 2.2 years. Resistance was seen in 98%; 96% to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs); 51% with ≥4 mutations. The most common NRTI mutations were 184V/I and 67N and the most common NNRTI mutations were 181C/Y/I/V and 190A/S. A total of 22% had multiresistant mutations and 18% had predicted high-level resistance to subsequent therapy options didanosine, abacavir, etravirine, and tenofovir. In 98% of Cambodian children misclassified as nonfailing first-line therapy by 2010 guidelines, 51% had extensive drug resistance to current and 18% to subsequent antiretroviral therapy. Affordable routine viral load monitoring allowing for early and more accurate treatment failure diagnosis is desperately needed in resource-limited settings. PMID:23506238

  1. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease.

    PubMed

    Eun, Jong Ryul; Lee, Heon Ju; Kim, Tae Nyeun; Lee, Kyeung Soo

    2010-07-01

    To assess the risk for the development of hepatocellular carcinoma (HCC) according to the underlying liver status and on-treatment viral response during long-term lamivudine therapy in patients with hepatitis B virus-related liver disease. Between March 1997 and February 2005, a total of 872 patients were treated with lamivudine for more than one year. Between 1983 and 1998, a total of 699 patients were enrolled as historical controls. For patients with compensated cirrhosis, HCC occurred in 4.9% (5/103) of cases with sustained viral suppression (persistently <141,500 copies/ml), 11.8% (20/170) in cases with viral breakthrough, and 19.4% (7/36) in cases with a suboptimal response (persistently 141,500 copies/ml): the mean follow-up was 5.1+/-2.7, 5.4+/-2.3, and 3.7+/-1.8 years, respectively. For the control group, HCC developed in 25.0% (37/148) of the cases during a mean follow-up of 6.1+/-4.3 years. Thus, the annual incidence of HCC was 0.95%, 2.18%, 5.26%, and 4.10% in patients with sustained viral suppression, viral breakthrough, suboptimal response, and the control group, respectively. The cumulative incidence of HCC in patients with sustained viral suppression was significantly lower than in patients with a suboptimal response and the controls (p=0.002 and p=0.005, respectively). In patients without cirrhosis and with decompensated cirrhosis, the preventive effects of lamivudine on the development of HCC were not observed (p=0.446 and p=0.123, respectively). Lamivudine therapy reduced the incidence of HCC in patients with compensated cirrhosis when the viral suppression was sustained. Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  2. Pegylated Interferon Alfa-2b Monotherapy and Pegylated Interferon Alfa-2b plus Lamivudine Combination Therapy for Patients with Hepatitis B Virus E Antigen-Negative Chronic Hepatitis B▿

    PubMed Central

    Kaymakoglu, Sabahattin; Oguz, Dilek; Gur, Gurden; Gurel, Selim; Tankurt, Ethem; Ersöz, Galip; Ozenirler, Seren; Kalayci, Cem; Poturoglu, Sule; Cakaloglu, Yılmaz; Okten, Atilla

    2007-01-01

    Forty-eight hepatitis B virus (HBV) E antigen-negative chronic hepatitis B patients received pegylated interferon alfa-2b either alone or with lamivudine for 48 weeks and were followed for an additional 24 weeks. At the end of follow-up, virological response rates (HBV DNA levels of <400 copies/ml) were similar in the monotherapy (24%) and combination therapy (26%) groups. PMID:17517832

  3. Spectra resolution for simultaneous spectrophotometric determination of lamivudine and zidovudine components in pharmaceutical formulation of human immunodeficiency virus drug based on using continuous wavelet transform and derivative transform techniques.

    PubMed

    Sohrabi, Mahmoud Reza; Tayefeh Zarkesh, Mahshid

    2014-05-01

    In the present paper, two spectrophotometric methods based on signal processing are proposed for the simultaneous determination of two components of an anti-HIV drug called lamivudine (LMV) and zidovudine (ZDV). The proposed methods are applied to synthetic binary mixtures and commercial pharmaceutical tablets without the need for any chemical separation procedures. The developed methods are based on the application of Continuous Wavelet Transform (CWT) and Derivative Spectrophotometry (DS) combined with the zero cross point technique. The Daubechies (db5) wavelet family (242 nm) and Dmey wavelet family (236 nm) were found to give the best results under optimum conditions for simultaneous analysis of lamivudine and zidovudine, respectively. In addition, the first derivative absorption spectra were selected for the determination of lamivudine and zidovudine at 266 nm and 248 nm, respectively. Assaying various synthetic mixtures of the components validated the presented methods. Mean recovery values were found to be between 100.31% and 100.2% for CWT and 99.42% and 97.37% for DS, respectively for determination of LMV and ZDV. The results obtained from analyzing the real samples by the proposed methods were compared to the HPLC reference method. One-way ANOVA test at 95% confidence level was applied to the results. The statistical data from comparing the proposed methods with the reference method showed no significant differences.

  4. Virologic failure in first-line human immunodeficiency virus therapy with a CCR5 entry inhibitor, aplaviroc, plus a fixed-dose combination of lamivudine-zidovudine: nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism.

    PubMed

    Demarest, James F; Amrine-Madsen, Heather; Irlbeck, David M; Kitrinos, Kathryn M

    2009-03-01

    The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naïve human immunodeficiency virus type 1-infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure maintained CCR5 tropism, while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.

  5. Conjugates of phosphorylated zalcitabine and lamivudine with SiO2 nanoparticles: Synthesis by CuAAC click chemistry and preliminary assessment of anti-HIV and antiproliferative activity.

    PubMed

    Vasilyeva, Svetlana V; Shtil, Alexander A; Petrova, Albina S; Balakhnin, Sergei M; Achigecheva, Polina Y; Stetsenko, Dmitry A; Silnikov, Vladimir N

    2017-03-01

    Conjugates of phosphorylated dideoxynucleoside antiviral drugs dideoxycytidine (zalcitabine) and lamivudine with SiO2 nanoparticles were obtained via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry between a nucleoside triphosphate containing an alkynyl group at the γ-phosphate or azidothymidine triphosphate and SiO2 nanoparticles containing alkyl azide or alkynyl groups, respectively. 4-(Prop-2-yn-1-yloxy)butylamino group has been attached to the γ-phosphate group of dideoxycytidine (zalcitabine) and lamivudine 5'-triphosphates via the phosphoramidate linkage. New compounds were shown to be potent killers of human colon carcinoma cells. Anti-HIV activity of the conjugates was demonstrated as well. The conjugates of phosphorylated lamivudine and dideoxycytidine (zalcitabine) showed higher potency than the parent nucleosides. The conjugate of phosphorylated azidothymidine was less active against HIV-1 than the parent nucleoside probably because of the replacement of its 3'-azido group by 1,2,3-triazole ring. These results show an opportunity for using SiO2 nanoparticles as a transport for delivering phosphorylated nucleosides to cells in order to increase their efficiency as antiviral and anticancer drugs.

  6. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study).

    PubMed

    Di Giambenedetto, Simona; Fabbiani, Massimiliano; Colafigli, Manuela; Ciccarelli, Nicoletta; Farina, Salvatore; Sidella, Letizia; D'Avino, Alessandro; Mondi, Annalisa; Cingolani, Antonella; Tamburrini, Enrica; Murri, Rita; Navarra, Pierluigi; Cauda, Roberto; De Luca, Andrea

    2013-06-01

    To explore 48 week safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression on a stable atazanavir/ritonavir-based standard triple regimen. This was a single-arm pilot study, enrolling 40 patients on atazanavir/ritonavir + two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), without previous treatment failure, with HIV-RNA <50 copies/mL for >3 months and CD4 >200 cells/mm(3). At baseline, patients were switched to 300/100 mg of atazanavir/ritonavir + 300 mg of lamivudine once daily. Laboratory parameters, atazanavir plasma levels, self-reported adherence, quality of life, neurocognitive performance, bone composition and body fat distribution were monitored. Virological failure was defined as HIV-RNA >50 copies/mL on two consecutive determinations or a single level >1000 copies/mL. After 48 weeks, 4/40 (10%) regimen discontinuations occurred: 1 death (brain haemorrhage), 1 study withdrawal (inadequate atazanavir plasma levels), 1 re-induction with two NRTIs due to pregnancy and 1 virological failure without development of resistance. Seven moderate to severe adverse events were recorded (including four renal colics, possibly treatment-related) in six patients. At week 48, increases in total (mean change +17 mg/dL, P = 0.001), high-density lipoprotein (+6 mg/dL, P < 0.001) and low-density lipoprotein (+8 mg/dL, P = 0.052) cholesterol were observed. The glomerular filtration rate improved (+7 mL/min/1.73 m(2), P < 0.001), as did scores exploring self-reported physical and mental health (+11, P = 0.009 and +13, P < 0.001 on a 0-100 scale), neuropsychological performance (-1 pathological task, P = 0.002) and total bone mineral density (+0.03 g/cm(2), P = 0.026). There were no significant changes in CD4 cell count, bilirubin, atazanavir plasma levels, adherence and body fat distribution over time. Simplification to atazanavir/ritonavir + lamivudine

  7. Cost-utility analysis of the fixed-dose combination of dolutegravir/abacavir/lamivudine as initial treatment of HIV+ patients in Spain.

    PubMed

    Moreno Guillen, Santiago; Losa García, Juan Emilio; Berenguer Berenguer, Juan; Martínez Sesmero, José Manuel; Cenoz Gomis, Santiago; Graefenhain, Ruth; Lopez Sanchez-Cambronero, David; Parrondo Garcia, Francisco Javier

    2017-09-01

    Fixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients. The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System. The ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and the fixed- dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or raltegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in € (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness. Treatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44€/QALY), and vs. RAL + FTC/TDF or

  8. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

    PubMed

    Gallant, Joel; Lazzarin, Adriano; Mills, Anthony; Orkin, Chloe; Podzamczer, Daniel; Tebas, Pablo; Girard, Pierre-Marie; Brar, Indira; Daar, Eric S; Wohl, David; Rockstroh, Jürgen; Wei, Xuelian; Custodio, Joseph; White, Kirsten; Martin, Hal; Cheng, Andrew; Quirk, Erin

    2017-08-31

    Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50-199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non

  9. Efficacy and Safety of Tenofovir and Lamivudine in Combination with Efavirenz in Patients Co-infected with Human Immunodeficiency Virus and Hepatitis B Virus in China

    PubMed Central

    Wu, Ya-Song; Zhang, Wei-Wei; Ling, Xue-Mei; Yang, Lian; Huang, Shao-Biao; Wang, Xi-Cheng; Wu, Hao; Cai, Wei-Ping; Wang, Min; Wang, Hui; Liu, Yan-Fen; He, Hao-Lan; Wei, Fei-Li; Wu, Zun-You; Zhang, Fu-Jie

    2016-01-01

    Background: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China. Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV. Methods: One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen of TDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed. Results: Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%). Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min−1·1.73 m−2) to week 12 (104 ml·min−1·1.73 m−2) but was almost back to baseline at week 48 (111 ml·min−1·1.73 m−2). Conclusion: This combination ART regimen is safe and effective for patients with HIV/HBV co-infection. Trial Registration: ClinicalTrials.gov, NCT01751555; https://clinicaltrials.gov/ct2/show/NCT01751555. PMID:26831232

  10. Low Third-Trimester Serum Levels of Lamivudine/Zidovudine and Lopinavir/Ritonavir in an HIV-Infected Pregnant Woman with Gastric Bypass.

    PubMed

    Michalik, David E; Jackson-Alvarez, Janielle T; Flores, Roxana; Tolentino-Baldridge, Christina; Batra, Jagmohan S

    2015-01-01

    Pharmacokinetics of lamivudine (3TC)/zidovudine (ZDV) and lopinavir/ritonavir (LPV/r) are described in a gravid 27-year-old HIV-infected woman with gastric bypass. Blood levels were obtained for these medications at time points 0 (predose) and 1, 2, 4, 6, 8, and 12 hours postdose. For these times, the levels (µg/mL) of 3TC were 0.0801, 0.69, 0.339, 0.237, 0.202, 0.108, and 0.0461; the levels of ZDV were 0.0153, 0.433, 0.0717, 0.0481, 0.0107, 0.0214, and 0.00864; the levels of lopinavir (LPV) were 2.45, 2.64, 1.95, 2.78, 3.83, 3.20, and 1.92; and the levels of ritonavir (RTV) were 0.09, 0.10, 0.07, 0.11, 0.15, 0.15, and 0.06. These data suggest that gastric bypass affected these antiretroviral drug levels. A functional, intact small bowel is responsible for absorption of these medications.

  11. Raltegravir and Abacavir/Lamivudine in Japanese Treatment-Naïve and Treatment-Experienced Patients with HIV Infection: a 48-Week Retrospective Pilot Analysis.

    PubMed

    Suzuki, Akihito; Uehara, Yuki; Saita, Mizue; Inui, Akihiro; Isonuma, Hiroshi; Naito, Toshio

    2016-01-01

    Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection.

  12. Plasma nevirapine levels and 24-week efficacy of a fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) among Thai HIV-infected patients.

    PubMed

    Manosuthi, Weerawat; Kiertiburanakul, Sasisopin; Chaovavanich, Achara; Sungkanuparph, Somnuek

    2007-02-01

    A fixed-dose combination of stavudine, lamivudine, and nevirapine (GPO-VIR) is the most affordable antiretroviral therapy (ART) regimen in Thailand. The data of nevirapine (NVP) level and efficacy of this fixed-dose combination is limited. Patients who were initiated GPO-VIR in 2004 were enrolled NVP levels at 12 weeks were determined. Patients were followed for 24 weeks. Fifty-nine patients with a mean age of 36.4 years and 54% male were enrolled. Mean body weight was 54.7 kgs. Median baseline CD4 and HIV-RNA were 29 cells/mm3 and 270,000 (5.4 log10) copies/mL, respectively. Mean plasma NVP levels at 12 weeks was 6.4 mg/L. By linear regression, female gender (p = 0.042), and higher weight (p = 0.020) were associated with lower NVP levels. At 24 weeks, 78% achieved undetectable HIV-RNA and median CD4 was 156 cells/mm3. NVP levels and 24-week efficacy of GPO-VIR are favorable. According to the affordable cost, GPO-VIR should be an appropriate initial regimen for naïve HIV-infected patients in resource-limited settings.

  13. Efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-vir) in advanced HIV infection.

    PubMed

    Getahun, Aneley; Tansuphasawadikul, Somsit; Desakorn, Varunee; Dhitavat, Jittima; Pitisuttithum, Punnee

    2006-09-01

    To assess the efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine; GPO-vir in advanced HIV infection. Open-label combined prospective and retrospective study involving 102 HIV infected patients with baseline CD4 cell count < 100 cells/mm3. All patients received GPO-vir for 48 weeks. The CD4 cell count and plasma viral load (pVL) was measured at 48 weeks. The median baseline CD4 cell count and pVL were 13 cells/mm3 and 363,500 copies/ml, respectively. At 48 weeks, the median CD4 cell count increased to 191 cells/mm3 and 63.7% in intention-to treat and 82.3% in on-treatment analysis had pVL < 50 copies/ml. There was no significant difference in pVL between patients with baseline pVL > 100,000 or < or = 100,000 copies/ml (p = 0.312). The incidence of hepatotoxicity, rash and peripheral neuropathy was 4.9%, 14.7% and 6.9%, respectively. GPO-vir was well tolerated and effective in increasing CD4 cell count and suppressing plasma viremia in advanced HIV infection during the 48 weeks follow-up period.

  14. A randomized two-way crossover bioequivalence study in healthy adult volunteers of paediatric zidovudine/lamivudine/nevirapine fast-disintegrating fixed-dose combination tablet.

    PubMed

    Joshi, Anjali; Gbadero, Daniel; Esseku, Fredrick; Adesanya, Olufikayo J; Adeyeye, Moji C

    2017-04-01

    The bioequivalence study was conducted to compare the developed paediatric fixed-dose combination (FDC) zidovudine/lamivudine/nevirapine (60/30/50 mg) tablet - the test formulation - with the combined mixture of single-entity innovator products (reference product). A single-dose open-label randomized two-way crossover study was conducted in healthy adult African volunteers after an informed consent was obtained. The 24 volunteers, divided into two groups, were administered the products after an overnight fast on two treatment days with 14 days of washout period. Blood samples were collected for 96 h and analysed using a validated RP-HPLC-UV assay method. Pharmacokinetic (PK) parameters (non-compartmental model) were assessed with WinNonlin(®) software. Analysis of variance (ANOVA) and FDA bioequivalence statistical criterion of 90% CI or 80% to 125% range (set at P < 0.05) of least square geometric means (LSGM) ratios of test: reference product for Cmax , AUC0-t , and AUC0-∞ were determined. ANOVA indicated that the period, sequence and formulation had no significant effect on the PK parameters (P > 0.05). The 90% CIs for all the drugs were within the 80% to 125% range. The developed FDC tablet is bioequivalent to the reference product. © 2016 Royal Pharmaceutical Society.

  15. Cost/efficacy analysis of preferred Spanish AIDS study group regimens and the dual therapy with lopinavir/ritonavir plus lamivudine for initial ART in HIV infected adults.

    PubMed

    Gatell Artigas, Josep María; Arribas López, José Ramón; Lázaro Y de Mercado, Pablo; Blasco Bravo, Antonio Javier

    2016-01-01

    The National AIDS Plan and the Spanish AIDS study group (GESIDA) proposes "preferred regimens" (PR) of antiretroviral treatment (ART) as initial therapy in HIV-infected patients. In 2013, the recommended regimens were all triple therapy regimens. The Gardel Study assessed the efficacy of a dual therapy (DT) combination of lopinavir/ritonavir (LPV/r) plus lamivudine (3TC). Our objective is to evaluate the GESIDA PR and the DT regimen LPV/r+3TC cost/efficacy ratios. Decision tree models were built. probability of having viral load <50 copies/mL at week 48. ART regime cost: costs of ART, adverse effects, and drug resistance tests during the first 48 weeks. Cost/efficacy ratios varied between 5,817 and 13,930 euros per responder at 48 weeks, for the DT of LPV/r+3TC and tenofovir DF/emtricitabine+raltegravir, respectively. Taking into account the official Spanish prices of ART, the most efficient regimen was DT of LPV/r+3TC, followed by the triple therapy with non-nucleoside containing regimens. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  16. Molecular analysis of hepatitis B virus (HBV) in an HIV co-infected patient with reactivation of occult HBV infection following discontinuation of lamivudine-including antiretroviral therapy

    PubMed Central

    2011-01-01

    Background Occult hepatitis B virus (HBV) infection (OBI) is characterized by HBV DNA persistence even though the pattern of serological markers indicates an otherwise resolved HBV infection. Although OBI is usually clinically silent, immunocompromised patients may experience reactivation of the liver disease. Case presentation We report the case of an individual with human immunodeficiency virus (HIV) infection and anti-HBV core antibody positivity, who experienced severe HBV reactivation after discontinuation of lamivudine-including antiretroviral therapy (ART). HBV sequencing analysis showed a hepatitis B surface antigen escape mutant whose presence in an earlier sample excluded reinfection. Molecular sequencing showed some differences between two isolates collected at a 9-year interval, indicating HBV evolution. Resumption of ART containing an emtricitabine/tenofovir combination allowed control of plasma HBV DNA, which fell to undetectable levels. Conclusion This case stresses the ability of HBV to evolve continuously, even during occult infection, and the effectiveness of ART in controlling OBI reactivation in HIV-infected individuals. PMID:22054111

  17. An integrated molecular dynamics, principal component analysis and residue interaction network approach reveals the impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine.

    PubMed

    Bhakat, Soumendranath; Martin, Alberto J M; Soliman, Mahmoud E S

    2014-08-01

    The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development. Amongst those mutations, M184V was found to cause a complete loss of ligand fitness. In this study, we report the first account of the molecular impact of M184V mutation on HIV RT resistance to 3TC (lamivudine) using an integrated computational approach. This involved molecular dynamics simulation, binding free energy analysis, principle component analysis (PCA) and residue interaction networks (RINs). Results clearly confirmed that M184V mutation leads to steric conflict between 3TC and the beta branched side chain of valine, decreases the ligand (3TC) binding affinity by ∼7 kcal mol(-1) when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network. The comprehensive molecular insight gained from this study should be of great importance in understanding drug resistance against HIV RT as well as assisting in the design of novel reverse transcriptase inhibitors with high ligand efficacy on resistant strains.

  18. Long-Term Outcome of Sequential Therapy with Lamivudine Followed by Interferon-β in Nucleoside-Naive, Hepatitis B e-Antigen-Positive Patients with Chronic Hepatitis B Virus Genotype C Infection.

    PubMed

    Enomoto, Masaru; Nishiguchi, Shuhei; Tamori, Akihiro; Kozuka, Ritsuzo; Hayashi, Takehiro; Kohmoto, Madoka Toyama; Jomura, Hisato; Morikawa, Hiroyasu; Murakami, Yoshiki; Shiomi, Susumu; Kawada, Norifumi

    2015-08-01

    It is unclear whether the combination of a nucleos(t)ide analog and interferon (IFN) is superior to monotherapy for treating chronic hepatitis B. In this study, we report the long-term outcomes of sequential therapy using lamivudine followed by IFN-β. This study included 24 hepatitis B e-antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) genotype C infection who were treated with lamivudine alone for 16-32 weeks, then with both IFN-β and lamivudine for 4 weeks, and finally with IFN-β alone for 20 weeks. All patients were followed up for 7.1±2.8 years post-treatment. The rate of response, defined as transaminase normalization, HBeAg loss, and HBV DNA <10(4) copies/mL, was 5/24 (21%) at 24 weeks post-treatment. The patients with short-term responses were younger than those with no response (P=0.039). More short-term responders had undetectable HBV DNA at the start of IFN-β compared with the nonresponders (P=0.0059). Subsequently, 4 of the 5 short-term responders remained free of the need for further drug treatment for 4.2±3.5 years post-treatment; more short-term responders remained drug free than did nonresponders (P=0.035). In conclusion, the rate of response to sequential therapy was limited in HBeAg-positive patients with chronic HBV genotype C infection at 24 weeks post-treatment. In the majority of the short-term responders, however, the response was sustainable in the long term.

  19. Prediction value of model for end-stage liver disease scoring system on prognosis in patients with acute-on-chronic hepatitis B liver failure after plasma exchange and lamivudine treatment.

    PubMed

    Yu, Jian-Wu; Sun, Li-Jie; Zhao, Yong-Hua; Li, Shu-Chen

    2008-08-01

    We used the model for end-stage liver disease (MELD) scoring system to predict the 3-month prognosis of patients with acute-on-chronic liver failure (ACLF) after plasma exchange (PE) and lamivudine treatment, and studied the predictive factors on the prognosis of patients. A total of 280 patients treated with lamivudine were randomly divided into PE and control groups. The relationship between mortality and influential factors of patients was studied by univariate and multivariate analysis. The mortality (49.4%) of patients in the PE group with a MELD score from 30 to 40 was lower than that (86.1%) of the control group (chi(2) = 24.546, P < 0.01). The total bilirubin (TBIL) rebound rate of the dead group was significantly higher than that of the survival group (P < 0.01). Univariate analysis showed that mortality was significantly related to age (P = 0.003), treatment method (P = 0.000), TBIL (P = 0.010), MELD score (P = 0.001), international normalised ratio (P = 0.014), pretreatment HBV-DNA load (P = 0.000), decline of hepatitis B virus (HBV)-DNA load during therapy (P = 0.013), encephalopathy (P = 0.019), and hepatorenal syndrome (P = 0.026). In multivariate analysis, MELD scores of 30-40, treatment method (P = 0.003), pretreatment HBV-DNA load (P = 0.009), decline of HBV-DNA load during therapy (P = 0.016), and encephalopathy (P = 0.015) were independent predictors of mortality; for MELD scores above 40, only the MELD score (P = 0.012) was an independent predictive. PE significantly decreased the mortality of patients with a MELD score of 30-40. For ACLF patients with a MELD score of 30-40, a low viral load pretreatment and quick decline of HBV-DNA load are good predictors for the survival with PE and lamivudine treatment.

  20. HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy

    PubMed Central

    Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti

    2017-01-01

    The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance. PMID:28303969

  1. Low-level persistence of drug resistance mutations in hepatitis B virus-infected subjects with a past history of Lamivudine treatment.

    PubMed

    Margeridon-Thermet, Severine; Svarovskaia, Evguenia S; Babrzadeh, Farbod; Martin, Ross; Liu, Tommy F; Pacold, Mary; Reuman, Elizabeth C; Holmes, Susan P; Borroto-Esoda, Katyna; Shafer, Robert W

    2013-01-01

    We sought to determine the prevalence of hepatitis B virus (HBV) lamivudine (LAM)-resistant minority variants in subjects who once received LAM but had discontinued it prior to virus sampling. We performed direct PCR Sanger sequencing and ultradeep pyrosequencing (UDPS) of HBV reverse transcriptase (RT) of plasma viruses from 45 LAM-naive subjects and 46 LAM-experienced subjects who had discontinued LAM a median of 24 months earlier. UDPS was performed to a depth of ∼3,000 reads per nucleotide. Minority variants were defined as differences from the Sanger sequence present in ≥0.5% of UDPS reads in a sample. Sanger sequencing identified ≥1 LAM resistance mutations (rtL80I/V, rtM204I, and rtA181T) in samples from 5 (11%) of 46 LAM-experienced and none of 45 LAM-naive subjects (0%; P = 0.06). UDPS detected ≥1 LAM resistance mutations (rtL80I/V, rtV173L, rtL180M, rtA181T, and rtM204I/V) in 10 (22%) of the 46 LAM-experienced subjects, including 5 in whom LAM resistance mutations were not identified by Sanger sequencing. Overall, LAM resistance mutations were more likely to be present in LAM-experienced (10/46, 22%) than LAM-naive subjects (0/45, 0%; P = 0.001). The median time since LAM discontinuation was 12.8 months in the 10 subjects with a LAM resistance mutation compared to 30.5 months in the 36 LAM-experienced subjects without a LAM resistance mutation (P < 0.001). The likelihood of detecting a LAM resistance mutation was significantly increased using UDPS compared to Sanger sequencing and was inversely associated with the time since LAM discontinuation.

  2. HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy.

    PubMed

    Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti

    2017-03-17

    The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance.

  3. The efficacy and adverse effects of GPO-VIR (stavudine+lamivudine+nevirapine) in treatment-naïve adult HIV patients.

    PubMed

    Tin, Ei Ei; Bowonwatanuwong, Chureeratana; Desakorn, Varunee; Wilairatana, Polrat; Krudsood, Srivicha; Pitisuttithum, Punnee

    2005-03-01

    A descriptive, combined retrospective and prospective study was conducted at the Anonymous Clinic, Chon Buri Hospital, Chon Buri Province, Thailand from November 10, 2003 to January 4, 2004. A total of 83 adult HIV-treatment-naïve patients undergoing treatment with GPO-VIR (stavudine, lamivudine, and nevirapine) for at least one year were studied. The objectives of the study were to assess the efficacy of GPO-VIR by evaluating body weight changes, CD4 T-cell count changes, the occurrence of opportunistic infections, and long-term side effects, such as lipodystrophy, during treatment. Of 83 studied patients, approximately half (52.3%) of them had a body weight increase > 10% of pre-treatment body weight after 12 months treatment. After taking GPO-VIR, CD4 T-cell counts increased rapidly, by a median of 78 x 10(6) cells/l during the first three months. 39.5% of the patients attained median CD4 counts > 200 x 10(6) cells/I, and 11.6% achieved > 500 x 10(6) cells/l after 2 years of treatment. The occurrence of opportunistic infections was significantly lower after treatment with GPO-VIR (p = 0.001). Subjective assessment of lipodystrophy by physicians and patients showed that 16.8% had symptoms of lipodystrophy within 2 years of GPO-VIR treatment. There was a significant association between older age group (40-49 years) and occurrence of lipodystrophy (p = 0.043). GPO-VIR is an inexpensive and effective antiretroviral drug regimen for initiating treatment of naïve patients, but careful assessment for lipodystrophy is necessary, especially after one year of treatment.

  4. Efficacy of a generic fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) in Thai HIV-infected patients.

    PubMed

    Kiertiburanakul, Sasisopin; Khongnorasat, Sirinat; Rattanasiri, Sasivimol; Sungkanuparph, Somnuek

    2007-02-01

    GPO-VIR, fixed-dose combination of stavudine 30/40 mg, lamivudine 150 mg, and nevirapine 200 mg are widely used in Thailand. Determine the efficacy and tolerability of GPO-VIR in naive HIV-infected patients. Primary outcome was the time of initiation to achieve the goal of therapy, which was HIV RNA < 50 copies/mL or 50% increased of CD4 cell count. Ninety patients were eligible for the present study. Mean +/- SD age was 35 +/- 7 years and 51% were male. Median baseline CD4 and HIV RNA were 52 cells/ mm3 and 280,000 (5.4 log10) copies/mL, respectively. Sixty-two (69%) patients had previous opportunistic infections. In a median follow-up period of 15 weeks, 49 (54%) patients achieved the goal of therapy. The probability of goal achievement showed that 12-, 24-, 36- and 48- weeks success rates were 8.5% [95% confidence interval (CI): 3.9-18.0%], 62.7% (95% CI: 50.8-74.6%), 80.0% (95% CI: 67.3-90.1%), and 93.3% (95% CI: 76.3-99.4%), respectively. The median success time to achieve the goal was 21 weeks. Eleven (12%) patients needed to discontinue GPO-VIR because of adverse drugs reaction. GPO-VIR may be one of the antiretroviral regimens for HIV-infected patients in Thailand and other resource-limited countries. Its efficacy is good in patients with advanced HIV infection.

  5. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study.

    PubMed

    Trottier, Benoît; Lake, Jordan E; Logue, Ken; Brinson, Cynthia; Santiago, Lizette; Brennan, Clare; Koteff, Justin A; Wynne, Brian; Hopking, Judy; Granier, Catherine; Aboud, Michael

    2017-04-12

    Simplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). The STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24. Of 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART. Data demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.

  6. Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks

    PubMed Central

    Tebas, Pablo; Kumar, Princy; Hicks, Charles; Granier, Catherine; Wynne, Brian; Min, Sherene; Pappa, Keith

    2015-01-01

    Objective: Antiretroviral therapy initiation has been linked to bone mineral density and bone biomarker changes. We assessed long-term bone turnover biomarker effects over 144 weeks in patients initiating dolutegravir (DTG) + abacavir/lamivudine (ABC/3TC) versus efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Methods: Patients randomized in SINGLE received DTG (50 mg once daily) + ABC/3TC or fixed-dose combination EFV/FTC/TDF. We evaluated vitamin D serum levels and bone turnover markers (BTMs), including type 1 collagen cross-linked C-telopeptide (CTx), osteocalcin, bone-specific alkaline phosphatase (BSAP), and procollagen type 1 N-terminal propeptide (P1NP), at baseline and weeks 48, 96, and 144. Results: Among the 833 enrolled patients (68% white, 85% men), baseline median age was 35 years (range 18–85), median CD4+ was 338 cells/μl, and median BMI was 24 kg/m2. Fifty-three percent of patients smoked, and 6% reported baseline vitamin D use, with no meaningful differences between groups. Relative to baseline, CTx, osteocalcin, BSAP, and P1NP increased; vitamin D decreased in both groups at weeks 48, 96, and 144. Changes from baseline typically peaked at weeks 48 or 96 and for the four analytes, excluding vitamin D, with the EFV/FTC/TDF group having significantly greater changes from baseline at all time points. Conclusion: DTG + ABC/3TC in antiretroviral therapy-naive patients resulted in significantly lower increases in BTMs (CTx, osteocalcin, BSAP, P1NP) compared with EFV/FTC/TDF over 144 weeks. The observed changes are consistent with results from other smaller, randomized trials. These differences in BTMs likely correlate with changes in bone mineral density over time. PMID:26355674

  7. Phase IIb trial of in vivo electroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy

    PubMed Central

    Yang, Fu-Qiang; Rao, Gui-Rong; Wang, Gui-Qiang; Li, Yue-Qi; Xie, Yao; Zhang, Zhan-Qing; Deng, Cun-Liang; Mao, Qing; Li, Jun; Zhao, Wei; Wang, Mao-Rong; Han, Tao; Chen, Shi-Jun; Pan, Chen; Tan, De-Ming; Shang, Jia; Zhang, Ming-Xiang; Zhang, Yue-Xin; Yang, Ji-Ming; Chen, Guang-Ming

    2017-01-01

    AIM To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B. METHODS Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT). RESULTS In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations. CONCLUSION The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy. PMID:28127204

  8. Lamivudine switch therapy in chronic hepatitis B patients achieving undetectable hepatitis B virus DNA after 3 years of entecavir therapy: A prospective, open-label, multicenter study.

    PubMed

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

    2016-11-01

    The subsequent maintenance therapy in chronic hepatitis B (CHB) patients after long-term viral replication suppression is still uncertain. We aim to evaluate the efficacy of lamivudine (LAM) maintenance therapy in CHB patients achieving undetectable hepatitis B virus (HBV) DNA after 3 years of entecavir (ETV) therapy. Consecutive CHB patients who received at least 3 years of ETV and achieved HBV DNA negativity were allocated either LAM switch therapy or stopped ETV therapy in a prospective, open-label study. Another group of sex- and age-matched patients with continuous ETV therapy for at least 4 years served as historical control group. The primary outcome measurement of the study was relapse of HBV DNA (defined as serum HBV DNA level ≥ 2000 IU/mL). A total of 74 patients, including 42 of LAM switch and 32 of the nonswitch group, were enrolled. There were no significant differences in demographics, except a higher proportion of patients with positive hepatitis B envelope antigen in the nonswitch group at the initiation of ETV therapy. The LAM switch group had significantly lower 1-year relapse rate of HBV within 1 year compared to the nonswitch group (14.3% vs. 75%, p<0.001). However, none of the 48 historical control patients developed relapse of HBV, which was significantly lower than the rate in LAM switch group (p < 0.001). LAM switch was the only factor associated with HBV DNA relapse. In conclusion, continuous long-term potent nucleot(s)ide analogue therapy is mandatory for prevention of viral relapse in CHB patients.

  9. Hepatitis B Virus Genotype Distribution and Its Lamivudine-Resistant Mutants in HIV-Coinfected Patients with Chronic and Occult Hepatitis B

    PubMed Central

    Quarleri, J.; Moretti, F.; Bouzas, M.B.; Laufer, N.; Carrillo, M. Gómez; Giuliano, S. Fernández; Pérez, H.; Cahn, P.; Salomon, H.

    2010-01-01

    Hepatitis B virus (HBV) genotypes were examined in HIV-infected patients with chronic and occult HBV infection. From a total population of 593 HIV-infected patients, 22 individuals (prevalence 3.7%) were found to be HBsAg while 72 (12.1%) were found to be anti-HBc alone. From them, 20 and 4 were HBV DNA positive, respectively. These last four patients are therefore considered to be HBV infected in an occult form. The genotypes could be determined in all 24 HBV-infected patients. HBV-A was the most common (20/24; 83.3%), followed by HBV-D (2/24; 8.3%) and HBV-F (1/24; 4.2%). The remaining sample exhibited mixed infection involving genotypes A and D as pure ones, thus also forming part of three intergenotypic recombinant forms exhibiting different mosaic S gene patterns. The sexual route of transmission was predominant among HBV genotype A-infected patients. Among the 24 HBV DNA-positive patients, point mutations related to lamivudine resistance were found in four strains. These viral strains showed a methionine-to-valine substitution at codon 204 (rtM204V) in association with an upstream B-domain change at rtL180M. Additionally, two of them exhibited the additional rtV173L mutation. The value of HBV molecular monitoring including both HBV viral genomic characterization and genotypic resistance profile in HIV-HBV-coinfected individuals is discussed. PMID:17506609

  10. Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations.

    PubMed

    Ayres, A; Yuen, L; Jackson, K M; Manoharan, S; Glass, A; Maley, M; Yoo, W; Hong, S P; Kim, S-O; Luciani, F; Bowden, D S; Bayliss, J; Levy, M T; Locarnini, S A

    2014-11-01

    This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>10⁷ IU/mL). Twenty-one women received LMV (treated group) for an average of 53 days (range 22-88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment (EOT) HBV DNA in four (18%) LMV-treated women remained at >10(7) IU/mL (± 0.5 log IU/mL), no mother-to-baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra-deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63-5.92%) at EOT, but one LMV-treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug-resistant viral variants emerged.

  11. Cost-effectiveness comparison of lamivudine plus adefovir combination treatment and nucleos(t)ide analog monotherapies in Chinese chronic hepatitis B patients.

    PubMed

    Zhang, Chi; Ke, Weixia; Liu, Li; Gao, Yanhui; Yao, Zhenjiang; Ye, Xiaohua; Zhou, Shudong; Yang, Yi

    2016-01-01

    Lamivudine (LAM) plus adefovir (ADV) combination therapy is clinically efficacious for treating chronic hepatitis B (CHB) patients in China, but no pharmacoeconomic evaluations of this strategy are available. The aim of this study was to examine the cost-effectiveness of LAM plus ADV combination treatment compared with five other nucleos(t)ide analog monotherapies (LAM, ADV, telbivudine [TBV], entecavir [ETV], and tenofovir [TDF]). To simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for different therapy options, a Markov model that included five initial monotherapies and LAM plus ADV combination as an initial treatment was developed. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: direct use of ETV + ADV) were considered separately for treating patients refractory to initial therapy. One-way and probabilistic sensitivity analyses were used to explore model uncertainties. In base-case analysis, ETV had the lowest lifetime cost and served as the reference therapy. Compared to the reference, LAM, ADV, and TBV had higher costs and lower efficacy, and were completely dominated by ETV. LAM plus ADV combination therapy or TDF was more efficacious than ETV, but also more expensive. Although the incremental cost-effectiveness ratios of combination therapy or TDF were both higher than the willingness-to-pay threshold of $20,466/QALY gained for the reference treatment, in an alternative scenario analysis LAM plus ADV combination therapy would be the preferable treatment option. ETV and LAM plus ADV combination therapy are both cost-effective strategies for treating Chinese CHB patients.

  12. Cost-effectiveness comparison of lamivudine plus adefovir combination treatment and nucleos(t)ide analog monotherapies in Chinese chronic hepatitis B patients

    PubMed Central

    Zhang, Chi; Ke, Weixia; Liu, Li; Gao, Yanhui; Yao, Zhenjiang; Ye, Xiaohua; Zhou, Shudong; Yang, Yi

    2016-01-01

    Background/aim Lamivudine (LAM) plus adefovir (ADV) combination therapy is clinically efficacious for treating chronic hepatitis B (CHB) patients in China, but no pharmacoeconomic evaluations of this strategy are available. The aim of this study was to examine the cost-effectiveness of LAM plus ADV combination treatment compared with five other nucleos(t)ide analog monotherapies (LAM, ADV, telbivudine [TBV], entecavir [ETV], and tenofovir [TDF]). Methods To simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for different therapy options, a Markov model that included five initial monotherapies and LAM plus ADV combination as an initial treatment was developed. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: direct use of ETV + ADV) were considered separately for treating patients refractory to initial therapy. One-way and probabilistic sensitivity analyses were used to explore model uncertainties. Results In base-case analysis, ETV had the lowest lifetime cost and served as the reference therapy. Compared to the reference, LAM, ADV, and TBV had higher costs and lower efficacy, and were completely dominated by ETV. LAM plus ADV combination therapy or TDF was more efficacious than ETV, but also more expensive. Although the incremental cost-effectiveness ratios of combination therapy or TDF were both higher than the willingness-to-pay threshold of $20,466/QALY gained for the reference treatment, in an alternative scenario analysis LAM plus ADV combination therapy would be the preferable treatment option. Conclusion ETV and LAM plus ADV combination therapy are both cost-effective strategies for treating Chinese CHB patients. PMID:27041994

  13. Long-term efficacy and toxicity of abacavir/lamivudine/nevirapine compared to the most prescribed ARV regimens before 2013 in a French Nationwide Cohort Study.

    PubMed

    de Boissieu, Paul; Dramé, Moustapha; Raffi, François; Cabie, André; Poizot-Martin, Isabelle; Cotte, Laurent; Garraffo, Rodolphe; Delobel, Pierre; Huleux, Thomas; Rey, David; Bani-Sadr, Firouzé

    2016-09-01

    Data on the long-term efficacy and safety of abacavir/lamivudine (ABC/3TC) and nevirapine (NVP) are scarce. This combination has the advantage of simplifying treatment and improving long-term tolerance. The aim of this study was to compare the rate of any discontinuation of antiretroviral (ARV) regimen because of virologic failure (VF), and/or adverse drug reaction (ADR) among patients receiving stable ARV regimens for at least 6 months.ABC/3TC/NVP was compared to ABC/3TC with either ritonavir-boosted darunavir (DRV/r) or ritonavir-boosted atazanavir (ATV/r), unboosted ATV, or tenofovir/emtricitabine (TDF/FTC) with either one of the following: ATV/r, unboosted ATV, DRV/r, efavirenz (EFV), or NVP, in the French prospective multicenter Dat'AIDS cohort.The study enrolled 16,511 patients treated with following ARV regimens: ABC/3TC/NVP (n = 1089), TDF/FTC/NVP (n = 1542), ABC/3TC/DRV/r (n = 1065), ABC/3TC/ATV/r (n = 1847), ABC/3TC/ATV (n = 563), TDF/FTC/ATV/r (n = 3519), TDF/FTC/DRV/r (n = 2767), TDF/FTC/ATV (n = 419), and TDF/FTC/EFV (n = 3700). Mean follow-up was 36 ± 24 months. Patients treated with ABC/3TC/NVP received this regimen as a switch regimen in 97% of cases. By multivariable analysis, the risk of treatment discontinuation due to VF was similar between ABC/3TC/NVP and other ARV regimens, except for TDF/FTC/ATV and ABC/3TC/ATV, which were associated with a higher risk of treatment interruption due to VF (hazard ratio [HR] 1.99; 95% confidence interval [CI] 1.29-3.06 and HR 2.19; 95% CI 1.51-3.18, respectively). Treatment discontinuation due to ADR was lowest with the ABC/3TC/NVP regimen. Other ARV regimens were associated with a 1.80- to 3.19-fold increase in the risk of treatment discontinuation due to ADR (P < 0.0001 for all comparisons).ABC/3TC/NVP as a simplification regimen is a long-term effective regimen with lower discontinuation due to long-term toxicity compared with other standard ARV regimens.

  14. YMDD Motif Mutation Profile Among Patients Receiving Liver Transplant Due to Hepatitis B Virus Infection With Long Term Lamivudine/Immunoglobulin Therapy

    PubMed Central

    Rahimi, Rahim; Hosseini, Seyed Younes; Fattahi, Mohammad Reza; Sepehrimanesh, Masood; Safarpour, Alireza; Malekhosseini, Seyed Ali; Nejabat, Maryam; Khodadad, Mahboobeh; Ardebili, Maryam

    2015-01-01

    Background: Recurrence of Hepatitis B Virus infection in patients undergoing liver transplanted (LT) is a serious and often fatal problem. Lamivudine (LAM) and Hepatitis B Immunoglobulin (HBIG) are widely used to manage hepatitis B recurrence after liver transplantation. However, the outcomes in patients are less elucidated. Objectives: The current study aimed to evaluate the YMDD motif mutations profile among the patients undergoing LT infected with HBV and treated with LAM/HBIG at least for one year. Patients and Methods: Thirty patients with liver transplantation due to HBV were enrolled, while DNA level remained under detection limit of 50 IU/mL before transplantation and abnormal higher levels of liver enzymes after LT. The HBV genome detection was performed by two different Polymerase Chain Reaction methods following viral quantification by commercial Real-Time PCR. HbsAg detection, besides liver function tests were conducted as complementary assays. To assess nucleotide analogue mutations, the major part of polymerase gene (aa 80 - 240) was amplified by Nested-PCR, introduced to sequencing and subjected to phylogenetic analysis. Results: Totally, according to the laboratory criteria there were 13 cases with detectable HBV genome, while the mean liver enzyme levels were higher in recurrent patients and HBsAg was detected only in four out of the 13 cases. Phylogenetic analysis demonstrated that all isolated genomes belonged to genotype D. Critical M204I mutation, as a proof for resistance to LAM, was detected among 46% of the subjects and natural entecavir resistance (S202I) was also distinguished in one subject. Viral quantification showed higher titer in LAM resistant group in comparison to the group with undetectable drug resistance mutant (P > 0.05). Conclusions: Although the patients carrying M204I mutation were more likely to show lack of responses to LAM therapy, LAM replacing by other nucleoside/tide analogs plus HBIG maybe still effective in

  15. Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children

    PubMed Central

    Chokephaibulkit, Kulkanya; Cressey, Tim R; Capparelli, Edmund; Sirisanthana, Virat; Muresan, Petronella; Hongsiriwon, Suchat; Ngampiyaskul, Chaiwat; Limwongse, Chanin; Wittawatmongko, Orasri; Aurpibul, Linda; Kabat, Bill; Toye, MariPat; Smith, Mary Elizabeth; Eksaengsri, Achara; McIntosh, Kenneth; Yogev, Ram

    2012-01-01

    Background Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. Methods In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6–30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 (CYP)2B6 polymorphism analysis. Results With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49–1.68), 7.78 (7.38–8.19) and 68.88 (62.13–76.36) μg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet (P<0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 μg•h/ml, respectively (P=0.04). Conclusions Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children. PMID:22155910

  16. Rapid Detection of Hepatitis B Virus Variants Associated with Lamivudine and Adefovir Resistance by Multiplex Ligation-Dependent Probe Amplification Combined with Real-Time PCR

    PubMed Central

    Jia, Shuangrong; Wang, Feng; Li, Fake; Chang, Kai; Yang, Shaojun; Zhang, Kejun; Jiang, Wenbin; Shang, Ya

    2014-01-01

    Drug-resistant mutations of hepatitis B virus (HBV) are the major obstacles to successful therapy for chronic hepatitis B infection. Although there are many methods for detecting the antiviral drug-resistant mutations of HBV, their applications are restricted because of their shortcomings, such as low sensitivity, the time required, and the high cost. For this study, a multiplex ligation-dependent probe real-time PCR (MLP-RT-PCR) method was developed to simultaneously detect lamivudine (LAM)- and adefovir (ADV)-resistant HBV mutants (those with the mutations rtM204V/I, rtA181V/T, and rtN236T). The new method combined the high-throughput nature of multiplex ligation-dependent probe amplification (MLPA) with the rapid and sensitive detection of real-time PCR. In this report, MLP-RT-PCR was evaluated by detecting drug-resistant mutants in 116 patients with chronic hepatitis B infection. By MLP-RT-PCR analysis, LAM-resistant mutations were detected in 41 patients (35.3%), ADV-resistant mutations were detected in 17 patients (14.7%), and LAM- and-ADV-resistant mutations were detected in 5 patients (4.3%). Based on the results of MLP-RT-PCR, the mutations rtM204V, rtM204I, rtA181T, rtA181V, and rtN236T were 95.7% (111/116 patients), 98.3% (114/116 patients), 99.1% (115/116 patients), 98.3% (114/116 patients), and 99.1% (115/116 patients) concordant, respectively, with those of direct sequencing. The MLP-RT-PCR assay was more sensitive than direct sequencing for detecting mutations with low frequencies. Four samples containing the low-frequency (<10%) mutants were identified by MLP-RT-PCR and further confirmed by clonal sequencing. MLP-RT-PCR is a rapid and sensitive method that enables the detection of multidrug-resistant HBV mutations in clinical practice. PMID:24478474

  17. An Indirect Comparison of Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate and Abacavir/Lamivudine + Dolutegravir in Initial Therapy

    PubMed Central

    M. Llibre, Josep; Raffi, François; Moyle, Graeme; Behrens, Georg; Bouee, Stephane; Reilly, Geraldine; Borg, Peter; Piontkowsky, David; Rogatto, Felipe

    2016-01-01

    Objectives The objective of this analysis is to perform an indirect comparison of elvitegravir, cobicistat, emtricitabine and tenofovir DF (E/C/F/TDF) to abacavir/lamivudine and dolutegravir (ABC/3TC + DTG) by using 2 trials evaluating each of these regimens in comparison to efavirenz, emtricitabine and tenofovir DF (EFV/FTC/TDF). Methods An indirect comparison was performed by using a generalization of Bucher's methodology to calculate risk differences. Two phase III clinical trials (GS-US-236-0102 and SINGLE—described above) were used. Results Results of the indirect comparison showed no statistically significant risk difference of the efficacy endpoint of achieving HIV RNA < 50 copies/mL between E/C/F/TDF and ABC/3TC + DTG for the ITT population at weeks 48, 96 and 144: respectively -3.7% (CI95% = [-10.8%; 3.4%]), -5.2% (CI95% = [-13.2%; 2.8%]) and -3.1% (CI95% = [-12.0%; 5.7%]). There was no statistically significant differences in the risk difference for serious adverse events (5.7% (CI95% = [-2.2%; 12.3%])), drug related adverse event (2.7% (CI95% = [-7.0%;12.4%])), drug related serious adverse event (0.8% (CI95% = [-1.6%;3.2%])) and death (0.5% (CI95% = [-0.8%;1.8%])), respectively, between E/C/F/TDF and ABC/3TC + DTG. A significant difference was found for discontinuation due to adverse events with a higher rate for E/C/F/TDF (difference = 8.6% (CI95% = [3.3%; 13.9%])). There was also no statistically significant risk difference of the viral resistance of 1.2% (CI95% = [-1.2; 3.7]) between E/C/F/TDF and ABC/3TC + DTG at week 48, 1.7% at week 96 (CI95% = [-1.1; 4.5]) and 2.2% (CI95% = [-1.0; 5.4]) at week 144. PMID:27196332

  18. The Cost-effectiveness and Budget Impact of 2-Drug Dolutegravir-Lamivudine Regimens for the Treatment of HIV Infection in the United States

    PubMed Central

    Girouard, Michael P.; Sax, Paul E.; Parker, Robert A.; Taiwo, Babafemi; Freedberg, Kenneth A.; Gulick, Roy M.; Weinstein, Milton C.; Paltiel, A. David; Walensky, Rochelle P.

    2016-01-01

    Background. Recommended human immunodeficiency virus (HIV) treatment regimens in the United States contain 3 antiretroviral agents, costing >$30 000/person/year. Pilot studies are evaluating the efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG + 3TC regimens in the United States. Methods. Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)–naive patients under 4 strategies: (1) no ART (for modeling comparison); (2) 2-drug: initial regimen of DTG + 3TC; (3) induction-maintenance: 48-week induction regimen of 3 drugs (DTG/abacavir [ABC]/3TC), followed by DTG + 3TC maintenance if virologically suppressed; and (4) standard of care: 3-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included 48-week virologic suppression (88%–93%), subsequent virologic failure (0.1%–0.6%/month), and Medicaid-discounted ART costs ($15 200–$39 600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was <$100 000/quality-adjusted life-year (QALY). Results. The 3 ART strategies had the same 5-year survival rates (90%). The ICER was $22 500/QALY for induction-maintenance and >$500 000/QALY for standard of care. Two-drug was the preferred strategy only when DTG + 3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or 2-drug for ART-naive patients, cost savings totaled $550 million and $800 million, respectively, within 5 years; savings reached >$3 billion if 25% of currently suppressed patients were switched to DTG + 3TC maintenance. Conclusions. Should DTG + 3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save >$500 million in ART costs in the United States over 5 years. PMID:26658053

  19. Clinical significance of hepatitis B e antigen level easurement during long-term lamivudine therapy in chronic hepatitis B patients with e antigen positive

    PubMed Central

    Shin, Jung Woo; Park, Neung Hwa; Jung, Seok Won; Kim, Byung Chul; Kwon, Sung Ho; Park, Jae Serk; Jeong, In Du; Bang, Sung-Jo; Kim, Do Ha

    2006-01-01

    AIM: To determine the changes of quantitative hepatitis B e antigen (HBeAg) that predicts early detection of non-response or breakthrough to long-term lamivudine (LAM) therapy. METHODS: Among HBeAg positive chronic hepatitis B patients who failed to achieve HBeAg seroconversion within 12 mo, we retrospectively analyzed 220 patients who had received LAM more than 24 mo. RESULTS: The mean duration of LAM therapy was 36 (range, 24-72) mo. HBeAg seroconversion after the first 12 mo of LAM therapy was achieved in 53 (24.1%) patients. Viral breakthrough was observed in 105 (47.7%) patients. To find out whether the changing patterns of HBeAg levels can predict the outcome of LAM therapy, we analyzed the reduction rates of HBeAg levels during LAM therapy. Using the decrease more than 90% of pretreatment HBeAg levels, the sensitivity and specificity of response were 96.2% and 70.1%, respectively. Patients were divided into 3 groups according to the reduction patterns of the decrease of quantitative HBeAg: decrescendo, decrescendo-crescendo, no change or fluctuating groups. The optimal time to predict non-response or breakthrough was the first 9 mo of therapy. At 9 mo of therapy, 49 (92.5%) of 53 patients who had achieved HBeAg seroconversion were included in the decrescendo group. On the contrary, in the no change or fluctuating group, only four (7.5%) had achieved HBeAg seroconversion. Among patients who did not show the continuous decrease of HBeAg levels at 9 mo, 95.2% (negative predictive value) failed to achieve HBeAg seroconversion. CONCLUSION: Almost all patients who failed to show a continuous decrease of HBeAg levels at 9 mo of LAM therapy were non-response or breakthrough. Therefore, monitoring changes of HBeAg levels during LAM therapy in HBeAg positive chronic hepatitis B may be valuable for identifying patients who are at high risk of non-response or breakthrough. PMID:17075986

  20. Adefovir dipivoxil is less expensive than lamivudine and associated with similar prognosis in patients with hepatitis B virus-related hepatocellular carcinoma after radical resection

    PubMed Central

    Zhong, Jian-Hong; Ke, Yang; Zhu, Shao-Liang; Wang, Lin; Luo, Cheng-Piao; Gong, Wen-Feng; You, Xue-Mei; Ma, Liang; Xiang, Bang-De; Li, Le-Qun

    2016-01-01

    Aim Lamivudine (LAM) and adefovir dipivoxil (ADV) are widely used in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but few studies have directly compared their therapeutic efficacy and treatment cost. This study aims to compare LAM with ADV head-to-head in these patients. Methods We retrospectively analyzed 201 patients with HBV-related HCC who underwent radical resection and subsequently received LAM (n=155) or ADV (n=46). The two groups were compared in terms of HBV-DNA levels, liver function, antiviral resistance, recurrence-free, and overall survival, as well as antiviral medication costs. Results Despite significant improvement in HBV-DNA and alanine aminotransferase level in the LAM group after 1 year of antiviral therapy, these parameters did not differ significantly between the two groups over the following 2 years. Incidence of antiviral resistance after 1, 2, and 3 years of antiviral treatment was significantly higher in the LAM group (19.5%, 45.7%, and 56.4%) than in the ADV group (0%, 3.3%, and 14.5%; P<0.001). Overall survival at 1, 2, and 3 years after resection was similar for the LAM group (84.5%, 69.3%, and 64.6%) and the ADV group (84.1%, 77.8%, and 63.4%; P=0.905). Recurrence-free survival at the three follow-up points was also similar for the LAM group (71.7%, 58.3%, and 43.9%) and the ADV group (81.1%, 66.1%, and 53.0%; P=0.452). Cox regression analysis confirmed that both nucleos(t)ide analogues were associated with similar overall and recurrence-free survival. However, the average medication costs after 1, 2, and 3 years of antiviral treatment were significantly higher in the LAM group (€3.0, €4.8, and €5.6 per person per day) than in the ADV group (€2.2, €2.4, and €3.1 per person per day; all P<0.05). Conclusion ADV and LAM are associated with similar survival benefit in patients with HBV-related HCC after radical resection, but ADV is more cost-effective. PMID:27877054

  1. Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy▿

    PubMed Central

    Delaugerre, Constance; Flandre, Philippe; Chaix, Marie Laure; Ghosn, Jade; Raffi, François; Dellamonica, Pierre; Jaeger, H.; Shürmann, D.; Cohen-Codar, Isabelle; Ngo Van, Philippe; Norton, Michael; Taburet, Anne-Marie; Delfraissy, Jean-François; Rouzioux, Christine

    2009-01-01

    The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society—USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The

  2. Pharmacokinetics and Safety of Nelfinavir When Used in Combination with Zidovudine and Lamivudine in HIV-Infected Pregnant Women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353

    PubMed Central

    Bryson, Y.J.; Mirochnick, M.; Stek, A.; Mofenson, L.M.; Connor, J.; Capparelli, E.; Watts, D.H.; Huang, S.; Hughes, M.D.; Kaiser, K.; Purdue, L.; Asfaw, Y.; Keller, M.; Smith, E.

    2014-01-01

    Background Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. Method HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0–24 > 30 μg · h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. Results Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 μg/mL vs. 5.01 μg/mL, p < .05) and AUC0–24 (56.6 vs. 86.8 μg · h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. Conclusion NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and

  3. Abacavir/Lamivudine plus Rilpivirine Is an Effective and Safe Strategy for HIV-1 Suppressed Patients: 48 Week Results of the SIMRIKI Retrospective Study

    PubMed Central

    Troya, Jesús; Ryan, Pablo; Ribera, Esteban; Podzamczer, Daniel; Hontañón, Victor; Terrón, Jose Alberto; Boix, Vicente; Moreno, Santiago; Barrufet, Pilar; Castaño, Manuel; Carrero, Ana; Galindo, María José; Suárez-Lozano, Ignacio; Knobel, Hernando; Raffo, Miguel; Solís, Javier; Yllescas, María; Esteban, Herminia

    2016-01-01

    Objectives Based on data from clinical practice, we evaluated the effectiveness and safety of switching to abacavir/lamivudine plus rilpivirine (ABC/3TC+RPV) treatment in virologically suppressed HIV-1-infected patients. Methods We performed a multicenter, non-controlled, retrospective study of HIV-1-infected patients who switched treatment to ABC/3TC+RPV. Patients had an HIV-RNA <50 copies/mL for at least 24 weeks prior to changing treatments. The primary objective was HIV-1 RNA <50 copies/mL at week 48. Effectiveness was analyzed by intention-to-treat (ITT), missing = failure and on-treatment (OT) analyses. The secondary objectives analyzed were adverse effects changes in renal, hepatic or lipid profiles, changes in CD4+ cell count and treatment discontinuations. Results Of the 205 patients included, 75.6% were men and the median age was 49. At baseline, before switching to ABC/3TC+RPV, median time since HIV diagnosis was 13.1 years, median time with undetectable HIV-1 RNA was 6.2 years and median time of previous antiretroviral regimen was 3.1 years (48.3% patients were taking efavirenz and ABC/3TC was the most frequent backbone coformulation in 69.7% of patients). The main reasons for switching were drug toxicity/poor tolerability (60.5%) and simplification (20%). At week 48, the primary objective was achieved by 187 out of 205 (91.2%) patients by ITT analysis, and 187 out of 192 (97.4%) patients by OT analysis. The CD4+ lymphocyte count and CD4+ percentage increased significantly from baseline to week 48 by a median of 48 cells/μL (−50 to 189) and 1.2% (−1.3% to 4.1%), respectively, P<0.001. Thirty-eight adverse events (AE) were detected in 32 patients. Of these, 25 had no clear association with treatment. Three patients interrupted therapy due to AE. We observed a decrease in all lipid parameters, P<0.001, and a slight improvement in the glomerular filtration rate, P<0.01. Therapy was considered to have failed in 18 patients owing to virological failure

  4. Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

    PubMed

    Bryson, Y J; Mirochnick, M; Stek, A; Mofenson, L M; Connor, J; Capparelli, E; Watts, D H; Huang, S; Hughes, M D; Kaiser, K; Purdue, L; Asfaw, Y; Keller, M; Smith, E

    2008-01-01

    Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that

  5. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s.

    PubMed

    McComsey, Grace A; Kitch, Douglas; Sax, Paul E; Tebas, Pablo; Tierney, Camlin; Jahed, Nasreen C; Myers, Laurie; Melbourne, Kathleen; Ha, Belinda; Daar, Eric S

    2011-07-15

    We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥ 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test. A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. ABC-3TC- and TDF-FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. NCT00118898.

  6. Emergence of HBV resistance to lamivudine (3TC) in HIV/HBV co-infected patients in The Gambia, West Africa

    PubMed Central

    2011-01-01

    Background Lamivudine (3TC) is a potent inhibitor of both Hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) replication and is part of first-line highly active antiretroviral therapy (HAART) in the Gambia. Unfortunately, the effectiveness of 3TC against HBV is limited by the emergence of resistant strains. Aim The aim of this retrospective study was to characterise 3TC-resistant mutations in HBV from co-infected patients receiving HAART, by generating HBV polymerase sequence data and viral loads from HBV genotype E infected patients, both at initiation and during a course of 3TC therapy. Method Samples from 21 HBV chronic carriers co-infected with HIV-1 (n = 18), HIV-2 (n = 2) and HIV-dual (n = 1) receiving HAART for a period of 6-52 months were analysed for the emergence of 3TC-resistance mutations. Findings Sixteen out of 21 HBV/HIV co-infected patients responded well to HAART treatment maintaining suppression of HBV viraemia to low (≤ 104 copies/mL) (n = 5) or undetectable levels (< 260 copies/ml) (n = 11). Out of the 5 non-responders, 3 had developed 3TC-resistant HBV strains showing mutations in the YMDD motif at position 204 of the RT domain of the HBV polymerase. One patient showed the M204V+ L180M+ V173L+ triple mutation associated with a vaccine escape phenotype, which could be of public health concern in a country with a national HBV vaccination programme. All except one patient was infected with HBV genotype E. Conclusions Our findings confirm the risk of 3TC mutations in HAART patients following monotherapy. This is a novel study on 3TC resistance in HBV genotype E patients and encourage the use of tenofovir (in association with 3TC), which has not shown unequivocally documented HBV resistance to date, as part of first-line therapy in HIV/HBV co-infected patients in West Africa. HBV- hepatitis B infection; HIV- human immunodeficiency virus; HAART- antiretroviral therapy. PMID:22195774

  7. A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand.

    PubMed

    Vanprapar, Nirun; Cressey, Tim R; Chokephaibulkit, Kulkanya; Muresan, Petronella; Plipat, Nottasorn; Sirisanthana, Virat; Prasitsuebsai, Wasana; Hongsiriwan, Suchat; Chotpitayasunondh, Tawee; Eksaengsri, Achara; Toye, MariPat; Smith, Mary Elizabeth; McIntosh, Kenneth; Capparelli, Edmund; Yogev, Ram

    2010-10-01

    Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunodeficiency virus-infected Thai children. The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children ≥6 to ≤30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis. Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 μg·hr/mL (1.42-1.67) for stavudine, 6.39 (5.82-7.00) for lamivudine, and 74.06 (65.62-83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92-1.02), 1.41 (1.30-1.53), and 1.08 (1.04-1.13), respectively. No serious drug-related toxicity was reported. The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy.

  8. Effectiveness and safety of generic version of abacavir/lamivudine and efavirenz in treatment naïve HIV-infected patients: a nonrandomized, open-label, phase IV study in Cali-Colombia, 2011-2012.

    PubMed

    Galindo, Jaime; Amariles, Pedro; Mueses-Marín, Héctor F; Hincapié, Jaime A; González-Avendaño, Sebastián; Galindo-Orrego, Ximena

    2016-10-03

    Generic drug policies are often associated with concerns about the quality and effectiveness of these products. Phase IV clinical trials may be a suitable design to assess the effectiveness and safety of generic drugs. The objective of this study was to describe the effectiveness and the safety of the generic abacavir/lamivudine and efavirenz in treatment-naïve HIV-infected patients. A monocentric, nonrandomized, open-label, phase IV study in treatment naïve HIV-infected patients 18 years or older with indication to receive abacavir/lamivudine and efavirenz were recruited from a program that provides comprehensive outpatient consultation and continuing care. The primary end-point was to achieve viral load <40 copies/mL at 12 months after baseline to assess effectiveness. Secondary end-point of the study were 1) to asses increasing in T-CD4 lymphocytes levels as accompaniment to asses effectiveness, and 2) to assess both gastrointestinal, skin, and central nervous system symptoms, and lipid profile, cardiovascular risk, renal, and hepatic function as safety profile. Data were determined at baseline, 3, 6, and 12 months. Close clinical monitoring and pharmaceutical care were used for data collection. Wilcoxon matched-pairs signed-rank test was used to compare proportions or medians. Sixty patients were invited to participate in the study; 42 were enrolled and 33 completed the follow-up. Of the nine patients excluded from the study, only one was withdrawn due to adverse events. At 12 months, 31 of 42 patients (73.8 % in intention-to-treat analysis) achieved a viral load of HIV1 RNA <40 copies/mL. There was a significant increase (172 cells/mm(3)) in the median for CD4 T lymphocyte count. The adverse events were mild and met the safety profile for this antiretroviral regimen, mainly of central nervous system symptoms, skin rash, lipid abnormalities, and an increase of 2 % in the median of the percentage of cardiovascular risk. The clinical outcomes of generic

  9. COMPARISON OF THAI GOVERNMENT MANUFACTURED TENOFOVIR (TENOFOVIR GPO300) WITH PRIVATELY MANUFACTURED TENOFOVIR (VIREAD) USED ALONG WITH LAMIVUDINE AND EFAVIRENZ TO TREAT THAI HIV PATIENTS.

    PubMed

    Manosuthi, Weerawat; Thongyen, Supeda; Nilkamhang, Samruay; Manosuthi, Sukanya; Sungkanuparph, Somnuek

    2015-01-01

    The Thai Government Pharmaceutical Organization (GPO) has produced a nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (Tenofovir GPO300). No clinical trial to date has compared plasma tenofovir concentrations, renal function, and treatment responses in HIV-infected patients who received Teno- fovir GPO300 versus Viread (original tenofovir) as part of an antiretroviral regimen. We studied 129 antiretroviral treatment (ART)-naive HIV-1 infected patients who received an antiretroviral regimen of lamivudine, efavirenz and Tenofovir GPO300 (n = 65) or Viread (n = 64). We examined plasma tenofovir concentrations (12 hours after dosing), serum creatinine, estimated glomerular filtration rate (eGFR) using the Modification in Diet in Renal Disease (MDRD) study formula, fractional excretion of phosphate (FEphos), CD4 and plasma HIV-1 RNA levels at 12 weeks, and CD4 and plasma HIV-1 RNA levels at 24 weeks after initiating the drugs. At baseline, the mean ± SD subject body weight was 54 ± 10 kilograms and the mean ± SD subject age was 37 ± 8 years. At baseline, the median (IQR) CD4 count was 44 (18-120) cells/ mm3 and the median (IQR) HIV-1 RNA level was 5.8 log copies/ml. At baseline, the mean ± SD eGFR was 134.8 ± 43.6 ml/min/1.73 m2. The baseline values for the two groups were not significantly different from each other (p > 0.05). At 12 weeks, the mean ± SD plasma tenofovir concentration was 106.9 ± 41.5 ng/ml among the patients who received Tenofovir GPO300 and 100.7 ± 49.4 ng/ml among those who received Viread (p = 0.437). At week 12, there were no differences between those who rceived Tenofovir GPO300 and Vilead in mean serum creatinine (0.78 vs 0.81 mg/dl, p = 0.283), mean eGFR (117.9 vs 109.1 ml/min/1.73 m2, p = 0.089), decline in eGFR from baseline (-21.8 vs -20.6 ml/min/1.73 m2, p = 0.860) or mean FEphos (11.4 vs 11.2, p = 0.923). The median CD4 cell counts and number of patients with undetectable plasma HIV-1 RNA at week 24 were

  10. Long term effectiveness of once-daily unboosted atazanavir plus abacavir/lamivudine as a switch strategy in subjects with virological suppression.

    PubMed

    Llibre, Josep M; Cozzi-Lepri, Alessandro; La Rosa, Jorge Antonio Valencia; Pedersen, Court; Ristola, Matti; Losso, Marcelo; Mocroft, Amanda; Mitsura, Victor M; Ormaasen, Vidar; Maltez, Fernando; Beniowski, Marek; Paredes, Roger

    2014-01-01

    Use of unboosted atazanavir (ATV400) is approved in the US but not in Europe (1). Due to pharmacokinetic interactions it should not be used with tenofovir but can be used with abacavir/lamivudine (ABC/3TC) (1, 2) (3). Effectiveness data of ATV400+ABC/3TC as a switch strategy in clinical routine however are scant. We evaluated treatment outcomes of ATV400+ABC/3TC in pre-treated subjects in the EuroSIDA cohort with undetectable HIV-1 RNA, and previous ABC experience or assumed previous HLA B57*01 testing. We performed a time to loss of virologic response (TLOVR below 50 c/mL) and a snapshot analysis at 48, 96 and 144 weeks. Virological failure (VF) was defined as a confirmed plasma HIV-1 RNA >50 c/mL. We included 258 subjects: 176 (68%) male, median age 46 (IQR 41, 53) y, 225 (87.2%) white, hepatitis virus co-infection 36%, median baseline CD4 at switch 540 cells (360, 700), time with VL≤ 50 c/mL 45 (24, 69) months. The median calendar year of switching was 2008 (2006, 2010). The 3rd drug in previous regimen was ATV/r in 70 (27.1%), other PI/r in 25 (9.7%), and other 163 (63.2%); 85 (32.9%) had previously failed with a PI. The virological response at 48/96/144 weeks was, respectively, 89.5 [95% CI 85.1, 92.9]/88 [83.4, 91.7]/86.3% [81.6, 90.4] (TLOVR, composite endpoint failure or stop for any reason) and the risk of VF was 8.3/7.6/7.6%. In the snapshot analysis HIV-RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count (RH 0.60 [0.39, 0.93] per 100 cells higher), time with VL≤50 c/mL (RH 0.89 [0.81, 0.98] per 6 months longer) and previous failure with a PI (3.04 [1.36, 6.80]). There was no association with gender, age, hepatitis virus co-infection, CD4 count at time of switching or third drug

  11. Optimized combination therapies with adefovir dipivoxil (ADV) and lamivudine, telbivudine, or entecavir may be effective for chronic hepatitis B patients with a suboptimal response to ADV monotherapy

    PubMed Central

    Li, Xiangyong; Jie, Yusheng; You, Xu; Shi, Hong; Zhang, Min; Wu, Yuankai; Lin, Guoli; Li, Xinhua; Gao, Zhiliang; Chong, Yutian

    2015-01-01

    Objective: To identify high risk factors in chronic hepatitis B (CHB) patients for suboptimal response to adefovir dipivoxil (ADV) monotherapy, and to assess the efficacy of optimized therapy combining ADV with lamivudine (LAM), telbivudine (LdT), or entecavir (ETV) in patients with a suboptimal response to ADV alone. Methods: Suboptimal response to ADV monotherapy was defined as having a decline in serum hepatitis B virus (HBV) DNA level of more than 1 log compared to baseline, but with viremia still detectable (HBV DNA ≥ 100 IU/mL), after 48 weeks of therapy. All patients who received ADV monotherapy in our clinic were analyzed retrospectively. Both univariate and multivariate logistic regression models were applied for risk factor analysis. Patients who showed suboptimal response completed at least 12 months of optimized combination therapy consisting of ADV plus LAM, ADV plus LdT, ADV plus ETV, or continuous ADV monotherapy. The primary outcome measurement was complete viral suppression, indicated by a reduction of HBV DNA to undetectable levels (CVS, with HBV DNA < 100 IU/mL). Secondary outcome measures were HBeAg seroconversion for HBeAg-positive patients, HBsAg loss, alanine aminotransferase (ALT) normalization and virological breakthrough rates. Results: Of 521 patients who received ADV monotherapy, 170 showed a suboptimal response. These were grouped for continued therapy as follows: 34 in group A (continuous ADV monotherapy), 55 in group B (ADV plus LAM), 38 in group C (ADV plus LdT), and 43 in group D (ADV plus ETV). Using a logistic model, five conditions were identified as high risk factors for suboptimal response: presence of the tyrosine-methionine-aspartate-aspartate (YMDD) HBV DNA polymerase mutation; being HBeAg positive; having a high baseline level of HBV DNA; having a primary virological non-response to ADV; and [initial virological response] to ADV. After 48 weeks of ADV monotherapy, there were no withdrawn patients who had experienced side

  12. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed.

    PubMed

    Ristig, Maria B; Crippin, Jeffrey; Aberg, Judith A; Powderly, William G; Lisker-Melman, Mauricio; Kessels, Lisa; Tebas, Pablo

    2002-12-15

    A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.

  13. Evaluation of the Lipid Concentrations after Switching from Antiretroviral Drug Tenofovir Disoproxil Fumarate/Emtricitabine to Abacavir Sulfate/Lamivudine in Virologically-suppressed Human Immunodeficiency Virus-infected Patients.

    PubMed

    Arae, Hirotaka; Tateyama, Masao; Nakamura, Hideta; Tasato, Daisuke; Kami, Kaoru; Miyagi, Kyoko; Maeda, Saori; Uehara, Hitoshi; Moromi, Makiko; Nakamura, Katsunori; Fujita, Jiro

    Objective Recently, tenofovir disoproxil fumatate (TDF)-related side effects, such as renal nephrotoxicity and reduction of bone mineral density, have been reported. Consequently, increased switching from fixed-dose tablet TDF and emtricitabine (TDF/FTC) to abacavir and lamivudine (ABC/3TC) has occurred. Interestingly, while TDF has a lipid-lowering property, one of the ABC-related side effects is hyperlipidemia. Therefore, such switching could cause lipid elevation. To evaluate the change in lipid levels associated with switching from TDF/FTC to ABC/3TC in virologically-suppressed human immunodeficiency virus (HIV)-infected patients. Methods This is a retrospective, single-center study. We included the HIV-infected patients whose therapy included a drug switch from TDF/FTC to ABC/3TC between September 2009 and December 2012 at Ryukyu University Hospital. The exclusion criteria were HIV-RNA >40 copies/mL on the switching day, and a documented therapy change to a lipid-lowering agent or any other antiretroviral agents within 3 months before or after switching. We compared the low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels before switching to three months after. Results A total of 18 patients met the inclusion criteria. The LDL, HDL, and TC levels significantly increased three months following the switch (p<0.05), with median (interquartile range) values of 17 (7, 32), 6 (2, 13), and 27 (10, 45) mg/dL, respectively. The TG values did not markedly change. Conclusion Switching from TDF/FTC to ABC/3TC resulted in significantly increased LDL, HDL, and TC levels.

  14. Efficacy and safety of entecavir versus lamivudine over 5 years of treatment: A randomized controlled trial in Korean patients with hepatitis B e antigen-negative chronic hepatitis B.

    PubMed

    Lee, Kwan Sik; Kweon, Young-Oh; Um, Soon-Ho; Kim, Byung-Ho; Lim, Young Suk; Paik, Seung Woon; Heo, Jeong; Lee, Heon-Ju; Kim, Dong Joon; Kim, Tae Hun; Lee, Young-Sok; Byun, Kwan Soo; Kim, Daeghon; Lee, Myung Seok; Yu, Kyungha; Suh, Dong Jin

    2017-09-26

    Long-term data on antiviral therapy in Korean patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are limited. This study evaluated the efficacy and safety of entecavir (ETV) and lamivudine (LAM) over 240 weeks. Treatment-naive patients with HBeAg-negative CHB were randomized to receive ETV 0.5 mg/day or LAM 100 mg/day during the 96 week double-blind phase, followed by open-label treatment through week 240. The primary endpoint was the proportion of patients with virologic response (VR; hepatitis B virus [HBV] DNA<300 copies/mL) at week 24. Secondary objectives included alanine aminotransferase (ALT) normalization and emergence of ETV resistance (week 96), VR and log reduction in HBV DNA levels (week 240), and safety evaluation. In total, 120 patients (>16 years old) were included (ETV, n=56; LAM, n=64). Baseline characteristics were comparable between the two groups. A significantly higher proportion of ETV-treated patients achieved VR compared to LAM at week 24 (92.9% vs. 67.2%, P=0.0006), week 96 (94.6% vs. 48.4%, P<0.0001), and week 240 (95.0% vs. 47.6%, P<0.0001). At week 96, ALT normalization was observed in 87.5% and 51.6% of ETV and LAM patients, respectively (P<0.0001). Virologic breakthrough occurred in one patient (1.8%) receiving ETV and 26 patients (42.6%) receiving LAM (P<0.0001) up to week 96. Emergence of resistance to ETV was not detected. The incidence of serious adverse events was low and unrelated to the study medications. Long-term ETV treatment was superior to LAM, with a significantly higher proportion of patients achieving VR. Both treatments were well tolerated.

  15. Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor.

    PubMed

    Cerva, C; Colagrossi, L; Maffongelli, G; Salpini, R; Di Carlo, D; Malagnino, V; Battisti, A; Ricciardi, A; Pollicita, M; Bianchi, A; Picardi, A; Cudillo, L; Cerretti, R; De Angelis, G; Cantonetti, M; Andreoni, M; Perno, C F; Arcese, W; Svicher, V; Sarmati, L

    2016-11-01

    The overall rate of hepatitis B virus (HBV) reactivation was evaluated in a population of 373 haematological stem cell transplant (HSCT) patients treated with lamivudine (LMV) if they were anti-HBc-positive/HBV-DNA-negative recipients or if they were HBV-negative recipients with an anti-HBc-positive donor. The incidence of HBV reactivation was calculated in two groups of autologous (auto) or allogeneic (allo) HSCT patients who were stratified according to their HBV serostatus. The former group included 57 cases: 10 auto-HSCT and 27 allo-HSCT anti-HBc-positive recipients, two auto-HSCT and three allo-HSCT inactive carriers, and 15 allo-HSCT recipients with an anti-HBc-positive donor. Forty-seven (82.4%) patients in this group received LMV prophylaxis (the median (interquartile range, IQR) of LMV treatment was 30 (20-38) months). The second group consisted of 320 anti-HBc-negative auto-HSCT and allo-HSCT recipients with anti-HBc-negative donors. None of these patients received any prophylaxis. Two patients in the first group and two in the second group experienced reactivation of HBV infection, with an incidence of 3.5% (95% CI 0.4-12.1%) and 0.6% (95% CI 0.1-2.2%), respectively. Only one out of four reactivated patients was LMV-treated. The cumulative probability of HBV reactivation at 6 years from HSCT was 15.8% (95% CI 15.2-16.4%). Three of four viral isolates obtained from the HBV-reactivated patients harboured mutations in the immune-active HBsAg-region. In a HSCT population carefully evaluated for HBV prophylaxis, a risk of HBV reactivation persisted in the group of patients who were not LMV-treated. Only one LMV-treated patient experienced reactivation of HBV with a resistant HBV isolate.

  16. Amino acid similarities and divergences in the small surface proteins of genotype C hepatitis B viruses between nucleos(t)ide analogue-naïve and lamivudine-treated patients with chronic hepatitis B.

    PubMed

    Ding, Hai; Liu, Baoming; Zhao, Chengyu; Yang, Jingxian; Yan, Chunhui; Yan, Ling; Zhuang, Hui; Li, Tong

    2014-02-01

    Entire C-genotype small hepatitis B surface (SHBs) sequences were isolated from 139 nucleos(t)ide analogues (NA)-naïve and 74 lamivudine (LMV)-treated chronic hepatitis B (CHB) patients. The conservation and variability of total 226 amino acids (AAs) within the sequences were determined individually, revealing significant higher mutant isolate rate and mutation frequency in LMV-treated cohort than those in the NA-naïve one (P=0.009 and 0.0001, respectively). Three absolutely conserved fragments (s16-s19, s176-s181 and s185-s188) and seven moderately conserved regions (a few AA sites acquiring increased variability after LMV-treatment) were identified. The significant mutation rate increase after LMV-treatment occurred primarily in major hydrophilic region (except 'a' determinant) and transmembrane domain 3/4, but not in other upstream functional regions of SHBs. With little influence on immune escape-associated mutation frequencies within 'a' determinant, LMV-monotherapy significantly induced classical LMVr-associated mirror changes sE164D/rtV173L, sI195M/rtM204V and sW196L/S/rtM204I, as well as non-classical ones sG44E/rtS53N, sT47K/A/rtH55R/Q and sW182stop/rtV191I outside 'a' determinant. Interestingly, another newly-identified truncation mutation sC69stop/rtS78T decreased from 7.91% (11/139) in NA-naïve cohort to 2.70% (2/74) in LMV-treated one. Altogether, the altered AA conservation and diversity in SHBs sequences after LMV-treatment in genotype-C HBV infection might shed new insights into how LMV-therapy affects the SHBs variant evolution and its antigenicity.

  17. Effectiveness of fixed-dose combination stavudine, lamivudine and nevirapine (GPO-VIR) for treatment of naïve HIV patients in Thailand: a 3-year follow-up.

    PubMed

    Desakorn, Varunee; Karmacharya, Biraj Man; Thanachartwet, Vipa; Kyaw, Nyan Lin; Tansuphaswadikul, Somsit; Sahassananda, Duangjai; Dhitavat, Jittima; Maek-a-nantawat, Wirach; Pitisuttithum, Punnee

    2011-11-01

    Generic fixed dose combination stavudine (d4T), lamivudine (3TC) and nevirapine (NVP), named GPO-VIR is recommended in the HIV treatment guidelines for Thailand. The long term effectiveness and adverse effects of this drug combination for the treatment of HIV were evaluated in an ambispective study at Bamrasnaradura Infectious Diseases Institute, Nonthaburi Province, Thailand from March 2002 to January 2006. A total of 152 adult treatment naive HIV patients who had received at least 12 months of GPO-VIR were enrolled. The median (IQR) CD4 cell count increased from 23 (8-94) cells/microl at baseline to 126 (38-180), 136 (98-189), 199 (141-255) and 334 (243-414) cells/microl at 3, 6, 12 and 24 months (p < 0.001), respectively. The median (IQR) percentage of body weights increased from baseline by 3.0% (0.3-6.3), 6.2% (2.2-9.3), 7.3% (3.9-10.9) and 8.1% (3.4-11.9) at 3, 6, 12 and 24 months, respectively and then remained at a plateau until the end of the 3-year study. The occurrence of new opportunistic infections decreased significantly (p < 0.001) with GPO-VIR treatment. Drug resistance occurred in 5 cases (3.3%) with a median (IQR) time of 18.0 (16.5-32.5) months to occurrence. Adverse effects included hypercholesterolemia (43.2%), lipodystrophy (35.5%), hypertriglyceridemia (25%), hypertension (13.1%), peripheral neuropathy (11.9%), hyperlactatemia (2.6%) and lactic acidosis (1.3%). Thirty-six patients (27%) switched from GPO-VIR to other anti-retroviral drugs regimens due to lipodystrophy. This study showed GPO-VIR had clinical and immunological benefits, but one-third of patients had adverse effects.

  18. A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial

    PubMed Central

    Ulbricht, K.U; Behrens, G.M; Stoll, M; Salzberger, B; Jessen, H; Jessen, A.B; Kuhlmann, B; Heiken, H; Trein, A; Schmidt, R.E

    2011-01-01

    Objective: The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen. Design: Multicenter, randomized, open-label, phase III clinical trial. Subjects: Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48. Results: In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48. Conclusions: ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication. PMID:21643422

  19. Evidence of susceptibility to lamivudine-based HAART and genetic stability of hepatitis B virus (HBV) in HIV co-infected patients: A South African longitudinal HBV whole genome study.

    PubMed

    Amponsah-Dacosta, Edina; Rakgole, J Nare; Gededzha, Maemu P; Lukhwareni, Azwidowi; Blackard, Jason T; Selabe, Selokela G; Mphahlele, M Jeffrey

    2016-09-01

    Reports on the concomitant impact of HIV co-infection and long term highly active anti-retroviral therapy (HAART) on the genetic stability and molecular evolution of HBV are limited in sub-Saharan Africa. This retrospective study investigated the molecular evolution of chronic HBV in HIV co-infected patients on lamivudine (3TC)-based HAART over a 5year period. Four HIV co-infected patients, consecutively recruited and followed-up, were screened for hepatitis B serological markers, and their viral loads determined. The HBV genome was amplified from longitudinal samples and characterized by Bayesian inference, mutational analysis, and identification of immune selection pressure. All patients exhibited persistent chronic HBV infection at baseline, as well as over the course of follow-up despite exposure to 3TC-based HAART. The polymerase gene in all isolates was relatively variable prior to HAART initiation at baseline and during the course of follow-up, although primary drug resistance mutations were not detected. All but one patient were infected with HBV subgenotype A1. The divergence rates between baseline and the last follow-up sequences ranged from 0 to 2.0×10(-3) substitutions per site per year (s/s/y). Positive selection pressure was evident within the surface and core genes. Despite persistent HBV infection in the HIV co-infected patients exposed to long term 3TC-based HAART, the molecular evolution of HBV over a 5year period was unremarkable. In addition, HBV exhibited minimal genetic variability overtime. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Evaluation of the Lipid Concentrations after Switching from Antiretroviral Drug Tenofovir Disoproxil Fumarate/Emtricitabine to Abacavir Sulfate/Lamivudine in Virologically-suppressed Human Immunodeficiency Virus-infected Patients

    PubMed Central

    Arae, Hirotaka; Tateyama, Masao; Nakamura, Hideta; Tasato, Daisuke; Kami, Kaoru; Miyagi, Kyoko; Maeda, Saori; Uehara, Hitoshi; Moromi, Makiko; Nakamura, Katsunori; Fujita, Jiro

    2016-01-01

    Objective Recently, tenofovir disoproxil fumatate (TDF)-related side effects, such as renal nephrotoxicity and reduction of bone mineral density, have been reported. Consequently, increased switching from fixed-dose tablet TDF and emtricitabine (TDF/FTC) to abacavir and lamivudine (ABC/3TC) has occurred. Interestingly, while TDF has a lipid-lowering property, one of the ABC-related side effects is hyperlipidemia. Therefore, such switching could cause lipid elevation. To evaluate the change in lipid levels associated with switching from TDF/FTC to ABC/3TC in virologically-suppressed human immunodeficiency virus (HIV)-infected patients. Methods This is a retrospective, single-center study. We included the HIV-infected patients whose therapy included a drug switch from TDF/FTC to ABC/3TC between September 2009 and December 2012 at Ryukyu University Hospital. The exclusion criteria were HIV-RNA >40 copies/mL on the switching day, and a documented therapy change to a lipid-lowering agent or any other antiretroviral agents within 3 months before or after switching. We compared the low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels before switching to three months after. Results A total of 18 patients met the inclusion criteria. The LDL, HDL, and TC levels significantly increased three months following the switch (p<0.05), with median (interquartile range) values of 17 (7, 32), 6 (2, 13), and 27 (10, 45) mg/dL, respectively. The TG values did not markedly change. Conclusion Switching from TDF/FTC to ABC/3TC resulted in significantly increased LDL, HDL, and TC levels. PMID:27904105

  1. A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV-infected patients with limited antiretroviral experience. Amprenavir PROAB2002 Study Team.

    PubMed

    Haubrich, R; Thompson, M; Schooley, R; Lang, W; Stein, A; Sereni, D; van der Ende, M E; Antunes, F; Richman, D; Pagano, G; Kahl, L; Fetter, A; Brown, D J; Clumeck, N

    1999-12-03

    To determine the safety and efficacy of amprenavir (APV) in combination with lamivudine (3TC) and zidovudine (ZDV). Multicenter, randomized, partially blinded trial. Nine study sites in the United States and Europe. A group of 84 HIV-infected subjects with no prior 3TC or protease inhibitor therapy experience, CD4 cell count > or = 150 x 10(6) cells/l, and plasma HIV RNA > 10000 copies/ml. 3TC/ZDV with one of three doses of APV (900, 1050, or 1200 mg) versus 3TC/ZDV with 1050 mg placebo. All medications were dosed twice daily. The 1050 mg placebo and the APV 1050 mg dose were administered blinded. After 12 weeks, APV 1050 mg was substituted for 1050 mg placebo in the control group and the blind was maintained. Reduction in plasma HIV RNA from baseline; proportion of subjects with plasma HIV RNA < 400 copies/ml; and an increase in CD4 cell count from baseline. During the initial 12-week study period, APV/3TC/ZDV-treated subjects had greater viral suppression than the group receiving two nucleosides. By 48 weeks, 89% of subjects in the group taking the highest APV dose (1200 mg) had plasma HIV RNA < 400 copies/ml while 42% of the 900 mg group and 60% of the 3TC/ZDV group (1050 mg APV added at week 12) had plasma HIV RNA < 400 copies/ml using an as-treated analysis. By 60 weeks, 86% of subjects in the APV 1200 mg group had plasma HIV RNA < 400 copies/ml in the as-treated analysis, while 25% (900 mg), 43% (1050 mg), and 20% (1200 mg) of subjects had viral load <400 copies/ml in a strict intent-to-treat analysis owing to treatment discontinuations. Median CD4 cell count increases at week 60 were highest for the three treatment groups who received APV throughout the study, by intent-to-treat and as-treated analyses. The most common adverse events considered to be possibly drug related were nausea, rash, oral paresthesia, diarrhea, and fatigue. Treatment with APV, dosed at 1200 mg twice daily in combination with 3TC/ZDV, resulted in sustained viral suppression. This

  2. Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates.

    PubMed

    Gane, Edward J; Patterson, Scott; Strasser, Simone I; McCaughan, Geoffrey W; Angus, Peter W

    2013-03-01

    Without effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. Combination prophylaxis with hepatitis B immune globulin (HBIG) and lamivudine (LAM) reduces long-term recurrence rates below 10%; however, HBIG is costly and inconvenient to administer. We, therefore, conducted a multicenter, prospective study of outcomes with an HBIG-sparing regimen of LAM plus adefovir dipivoxil (ADV) initiated at the time of listing for liver transplantation and continued after transplantation. Twenty-six patients were recruited into this study at the time of listing for transplantation, and 20 subsequently underwent transplantation. Twelve of the 26 patients had LAM exposure before the study baseline, but none had LAM resistance. The median HBV viral load before the institution of antiviral therapy was approximately 4.0 log(10) IU/mL (range=2.3-7.5 log(10) IU/mL). To the 20 patients who underwent transplantation, 800 IU of intramuscular HBIG was given immediately after transplantation and daily for 7 days only (total HBIG dose=6400 IU). All transplant patients remained alive without HBV recurrence (they were negative for hepatitis B surface antigen, and HBV DNA was undetectable) after a median follow-up of 57 months after transplantation (range=27-83 months). The median serum creatinine level in these patients rose from 81 to 119 μmol/L over the course of the study. No patient required dose reduction or cessation. After the completion of this prospective study, the regimen was modified so that no perioperative HBIG was administered if the pretransplant serum HBV DNA level was suppressed below 3 log(10) IU/mL. Another 28 patients with HBV-related liver disease underwent transplantation (18 without HBIG). All remained alive and well without HBV recurrence after a median follow-up of 22 months after transplantation (range=10-58 months). In conclusion, a combination of

  3. Lamivudine monotherapy-based cART is efficacious for HBV treatment in HIV/HBV co-infection when baseline HBV DNA<20,000IU/ml

    PubMed Central

    LI, Yijia; XIE, Jing; HAN, Yang; WANG, Huanling; ZHU, Ting; WANG, Nidan; LV, Wei; GUO, Fuping; QIU, Zhifeng; LI, Yanling; DU, Shanshan; SONG, Xiaojing; THIO, Chloe L; LI, Taisheng

    2016-01-01

    Background Although combination antiretroviral therapy (cART) including tenofovir (TDF)+lamivudine (3TC) or emtricitabine (FTC) is recommended for treatment of HIV/HBV co-infected patients, TDF is unavailable in some resource-limited areas. Some data suggest that 3TC monotherapy-based cART may be effective in patients with low pre-treatment HBV DNA. Methods Prospective study of 151 Chinese HIV/HBV co-infected subjects of whom 60 received 3TC-based cART and 91 received TDF+3TC-based cART. Factors associated with HBV DNA suppression at 24 and 48 weeks, including anti-HBV drugs, baseline HBV DNA, and baseline CD4 cell count, were evaluated overall and stratified by baseline HBV DNA using Poisson regression with a robust error variance. Results Baseline HBV DNA≥20,000 IU/ml was present in 48.3% and 44.0% of subjects in the 3TC and TDF groups, respectively (P=0.60). After 48 weeks of treatment, HBV DNA suppression rates were similar between these two groups (96.8% vs. 98.0% for 3TC and TDF+3TC, P>0.999) in subjects with baseline HBV DNA<20,000 IU/ml; while in those with baseline HBV DNA ≥20,000 IU/ml, TDF+3TC was associated with higher suppression rates (34.5% vs. 72.5% in 3TC and TDF+3TC groups, respectively, P=0.002). In stratified multivariate regression, TDF use (RR 1.98, P=0.010) and baseline HBV DNA (per 1 log increase in IU/ml, RR 0.74, P<0.001) were associated with HBV DNA suppression only when baseline HBV DNA≥20,000IU/ml. Conclusion This study suggests that 3TC monotherapy-based cART is efficacious for HBV treatment through 48 weeks in HIV/HBV co-infection when baseline HBV DNA<20,000IU/ml. Studies with long-term follow-up are warranted to determine if this finding persists. PMID:26745828

  4. Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES.

    PubMed

    Young, Benjamin; Squires, Kathleen E; Ross, Lisa L; Santiago, Lizette; Sloan, Louis M; Zhao, Henry H; Wine, Brian C; Pakes, Gary E; Margolis, David A; Shaefer, Mark S

    2013-02-01

    Propensity for developing coronary heart disease (CHD) is linked with Framingham-defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category of <6% or ≥6%, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were assessed at baseline, week 84, and week 144. Biomarkers were stratified by FRS category. When ritonavir-boosted/nonboosted treatment groups were combined, median hsCRP did not change significantly between baseline (1.6 mg/liter) and week 144 (1.4 mg/liter) in subjects with FRS <6% (p=0.535) or with FRS ≥6% (1.9 mg/liter vs. 2.0 mg/liter, respectively; p=0.102). Median IL-6 was similar for subjects with FRS <6% (p=0.267) at baseline (1.6 pg/ml) and week 144 (1.4 pg/ml) and for FRS ≥6% (2.0 pg/ml vs. 2.2 pg/ml, respectively; p=0.099). Median Lp-PLA(2) decreased significantly (p<0.001) between baseline (197 nmol/min/ml) and week 144 (168 nmol/min/ml) in subjects with FRS <6% and with FRS ≥6% (238 nmol/min/ml vs. 175 nmol/min/ml, respectively; p<0.001). In conclusion, in antiretroviral-naive subjects treated with abacavir-based therapy for 144 weeks, median inflammatory biomarker levels for hsCRP and IL-6 generally remained stable with no significant difference between baseline and week 144 for subjects with either FRS <6% or FRS ≥6%. Lp-PLA(2) median values declined significantly over 144 weeks for subjects in either FRS stratum.

  5. Budget impact analysis of the simplification to atazanavir + ritonavir + lamivudine dual therapy of HIV-positive patients receiving atazanavir-based triple therapies in Italy starting from data of the Atlas-M trial

    PubMed Central

    Restelli, Umberto; Fabbiani, Massimiliano; Di Giambenedetto, Simona; Nappi, Carmela; Croce, Davide

    2017-01-01

    Background This analysis aimed at evaluating the impact of a therapeutic strategy of treatment simplification of atazanavir (ATV)+ ritonavir (r) + lamivudine (3TC) in virologically suppressed patients receiving ATV+r+2 nucleoside reverse transcriptase inhibitors (NRTIs) on the budget of the Italian National Health Service (NHS). Methods A budget impact model with a 5-year time horizon was developed based on the clinical data of Atlas-M trial at 48 weeks (in terms of percentage of patients experiencing virologic failure and adverse events), from the Italian NHS perspective. A scenario in which the simplification strategy was not considered was compared with three scenarios in which, among a target population of 1,892 patients, different simplification strategies were taken into consideration in terms of percentage of patients simplified on a yearly basis among those eligible for simplification. The costs considered were direct medical costs related to antiretroviral drugs, adverse events management, and monitoring activities. Results The percentage of patients of the target population receiving ATV+r+3TC varies among the scenarios and is between 18.7% and 46.9% in year 1, increasing up to 56.3% and 84.4% in year 5. The antiretroviral treatment simplification strategy considered would lead to lower costs for the Italian NHS in a 5-year time horizon between −28.7 million € and −16.0 million €, with a reduction of costs between −22.1% (−3.6 million €) and −8.8% (−1.4 million €) in year 1 and up to −39.9% (−6.9 million €) and −26.6% (−4.6 million €) in year 5. Conclusion The therapy simplification for patients receiving ATV+r+2 NRTIs to ATV+r+3TC at a national level would lead to a reduction of direct medical costs over a 5-year period for the Italian NHS. PMID:28280375

  6. The intracellular activation of lamivudine (3TC) and determination of 2′-deoxycytidine-5′-triphosphate (dCTP) pools in the presence and absence of various drugs in HepG2 cells

    PubMed Central

    Kewn, Stephen; Hoggard, Patrick G; Sales, Sean D; Johnson, Mark A; Back, David J

    2000-01-01

    Aims Lamivudine (3TC, 2′-deoxy-3′-thiacytidine) requires intracellular metabolism to its active 5′-triphosphate, 3TC-5′-triphosphate (3TCTP), to inhibit the replication of hepatitis B virus (HBV). We have investigated the activation of 3TC, in the presence and absence of a range of compounds, in HepG2 cells. The intracellular levels of the endogenous competitor of 3TCTP, 2′-deoxycytidine-5′-triphosphate (dCTP), were also determined and 3TCTP/dCTP ratios calculated. Methods The effects of a number of compounds on 3TC (3H; 1 μM) phosphorylation were investigated by radiometric h.p.l.c. dCTP levels were determined using a template primer extension assay. 3TCTP/dCTP ratios were calculated from these results. Results The phosphorylation of 3TC was significantly increased in the presence of either hydroxyurea (HU), methotrexate (MTX), or fludarabine (FLU). For example, at 100 μm HU, control 3TCTP levels were increased to 361% of control, whereas at 100 μm FLU, control 3TCTP levels were increased to 155%. dCTP pools were significantly reduced in the presence of HU and FLU, at 100 μm concentrations only. However, for all the above three compounds investigated, the ratio of 3TCTP/dCTP was favourably enhanced (e.g. at 1 μm MTX, 255% of control). Neither ganciclovir (GCV), lobucavir (LCV), penciclovir (PCV), adefovir dipivoxil (ADV), nor foscarnet (FOS) had any significant effects on 3TC phosphorylation or dCTP pools. Conclusions These results suggest that the activity of 3TC may be potentiated when combined with one of the modulators studied. The lack of an interaction between 3TC and the other anti-HBV agents is reassuring. These in vitro studies can be used as an initial screen to examine potential interactions at the phosphorylation level. PMID:11136299

  7. Efficacy and resistance in de novo combination lamivudine and adefovir dipivoxil therapy versus entecavir monotherapy for the treatment-naive patients with chronic hepatitis B: a meta-analysis

    PubMed Central

    2014-01-01

    Background Currently, there is no consensus on the efficacy and resistance of de novo combination therapy versus monotherapy for treatment naive patients of chronic hepatitis B (CHB). Objectives The aim of this study was to evaluate the effectiveness and resistance of de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) compared with entecavir (ETV) monotherapy for nucleos(t)ide–naive patients with CHB. Study design Publications on the effectiveness and resistance of LAM plus ADV versus ETV monotherapy for nucleos(t)ide-naive patients with CHB were identified by a search of PubMed, Embase, the Cochrane Library, Web of science, OVID, and CBM (Chinese Biological Medical Literature) until May 1, 2013. Biochemical response, hepatitis B e antigen seroconversion, and viroligic response were extracted and combined to obtain an integrated result. Viral resistance and safety were reviewed. Results Five eligible studies (328 patients in total) were included in the analysis. LAM plus ADV combination therapy produced more rapid HBV DNA reduction rate at 12 weeks than that of ETV monotherapy. At 48 weeks, the combination group had superior viroligic response rates compared with ETV group (90.0% vs. 78.9%, P=0.01). The difference in the ALT normalization and HBeAg seroconversion rates was not found. At week 96, LAM + ADV was more effective than ETV in ALT normalization [RR = 1. 11, 95% CI (1.02, 1.21), P =0.01] and HBeAg seroconversion [RR = 2.00, 95% CI (1.26, 3.18, P=0.003)], and no significant difference was found in the virologic response (P =0.23). No viral resistance occurred in combination therapy and six patients in ETV group were experienced with viral breakthrough. Both groups were well tolerated. Conclusion The de novo LAM plus ADV combination therapy for treatment-naïve patients with CHB was greater than ETV monotherapy in both biochemical response and HBeAg seroconversion rate up to 96 weeks. The rate of emergence of viral

  8. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202.

    PubMed

    McComsey, Grace A; Daar, Eric S; O'Riordan, MaryAnn; Collier, Ann C; Kosmiski, Lisa; Santana, Jorge L; Fichtenbaum, Carl J; Fink, Heidi; Sax, Paul E; Libutti, Daniel E; Gerschenson, Mariana

    2013-02-15

    The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear. A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests. Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03). ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels. NCT00118898.

  9. [The efficacy and safety of a therapy regimen including raltegravir and a fixed dose combination of lamivudine and abacavir in previously rifabutin-treated patients with tuberculosis and HIV infection].

    PubMed

    Kravchenko, A V; Zimina, V N; Popova, A A; Deulina, M O; Kanestri, V G; Ivanova, E S; Yakovlev, A A; Pokrovsky, V V

    2014-01-01

    To evaluate the efficiency and safety of using raltegravir (RAL) twice daily in conjunction with a once-daily fixed dose combination of abacavir (ABC)/lamivudine (3TC) in patients with HIV infection and active tuberculosis who have not previously received antiretroviral therapy (ART) and have taken rifabutin as antituberculosis therapy (ATT). The efficiency of ART was evaluated in 28 patients from a change in HIV RNA levels and from an increase in CD4+ lymphocyte counts during 48-week treatment that had been completed by 15 (53.6%) patients. The main reason for therapy discontinuation was that the patients returned to the use psychoactive agents. After 24 and 48 weeks of ART, the level of HIV RNA reached the undetectable values (less than 50 copies/ml) in 81.25 and 75% of the patients, respectively (according to an analysis including the patients who had completed the study in conformity with the requirements of the protocol). In only 2 patients, the virological therapy proved to be ineffective, which was likely to be associated with noncompliance with drug therapy. Following 24- and 48-week therapy, the increase in median CD4+ lymphocyte counts was 70 and 208.5 per μl, respectively. The concurrent use of ART and ATT caused positive changes in the lung skiagraphic pattern in 92.9% of the patients and complete resolution of lung tissue infiltration in 71.4%. Mixed infection ended in a fatal outcome caused by a progressive tuberculous process in 3 (10.7%) patients, in 2 of them within the first 8 weeks of treatment. The concomitant use of ATT including rifabutin and an ART (RAL + ABC/3TC) regimen was safe since one patient was noted to have a RAL-related adverse event (AE) (an allergic reaction) and caused the patient to discontinue therapy. ATT was not discontinued because of AE in any case. The ART regimen containing RAL and a fixed dose combination of ABC/3TC for adult patients with tuberculosis concurrent with HIV infection who are on combined therapy using

  10. Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naïve HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort.

    PubMed

    Rokx, C; Gras, L; van de Vijver, Damc; Verbon, A; Rijnders, Bja

    2016-09-01

    Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable in recommended tenofovir disoproxil-fumarate (TDF)-containing combination antiretroviral therapies (cARTs). This statement of equivalence has not been systematically studied. We compared the treatment responses to 3TC and FTC combined with TDF in boosted protease inhibitor (PI)-based cART for HIV-1-infected patients. An observational study in the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort was carried out between 2002 and 2013. Virological failure rates, time to HIV RNA suppression < 400 copies/mL, and time to treatment failure were analysed using multivariable logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. A total of 1582 ART-naïve HIV-1-infected patients initiated 3TC or FTC with TDF and ritonavir-boosted darunavir (29.6%), atazanavir (41.5%), lopinavir (27.1%) or another PI (1.8%). Week 48 virological failure rates on 3TC and FTC were comparable (8.9% and 5.6%, respectively; P = 0.208). The multivariable adjusted odds ratio of virological failure when using 3TC instead of FTC with TDF in PI-based cART was 0.75 [95% confidence interval (CI) 0.32-1.79; P = 0.51]. Propensity score-adjusted models showed comparable results. The adjusted hazard ratio (HR) for treatment failure of 3TC compared with FTC was 1.15 (95% CI 0.58-2.27) within 240 weeks after cART initiation. The time to two consecutive HIV RNA measurements < 400 copies/mL within 48 weeks (HR 0.94; 95% CI 0.78-1.16) and the time to treatment failure after suppression < 400 copies/mL (HR 0.94; 95% CI 0.36-2.50) were not significantly influenced by the use of 3TC in TDF/PI-containing cART. The virological responses were not significantly different in treatment-naïve HIV-1-infected patients starting either 3TC/TDF or FTC/TDF and a ritonavir-boosted PI. © 2016 British HIV Association.

  11. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.

    PubMed

    Sabin, Caroline A; Worm, Signe W; Weber, Rainer; Reiss, Peter; El-Sadr, Wafaa; Dabis, Francois; De Wit, Stephane; Law, Matthew; D'Arminio Monforte, Antonella; Friis-Møller, Nina; Kirk, Ole; Pradier, Christian; Weller, Ian; Phillips, Andrew N; Lundgren, Jens D

    2008-04-26

    Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients. We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals. Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir). There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

  12. Safety and efficacy of a simplified fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) for the treatment of advanced HIV-infected patients: a 24-week study.

    PubMed

    Anekthananon, Thanomsak; Ratanasuwan, Winai; Techasathit, Wichai; Sonjai, Areeaue; Suwanagool, Surapol

    2004-07-01

    To determine the efficacy and safety of the fixed-dose combination of stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) in the treatment of antiretroviral naive HIV-infected Thai adults. An open-label, single arm trial was conducted Baseline clinical assessment and blood test was done on 10, antiretroviral naive HIV-infected patients, who then received a fixed dose combination of d4T, 3TC and NVP (GPO- VIR, Thai Government Pharmaceutical Organization, Bangkok, Thailand). Nevirapine was given as 200 mg once daily for the first 2 weeks. The patients were followed up at 2, 4, 8, 12 and 24 weeks. A CD4 cell count and HIV-RNA assay were done at 12 and 24 weeks. One hundred and one patients were enrolled The mean baseline CD4 cell count and mean HIV RNA were 58.7 (57.7) cells/mm3 and 5.3 (0.5) log10, copies/mL respectively. At week 24th, the mean decrease in log HIV RNA was 3.6 (0.7) log10 copies/mL [P < 0.001; 95% confidence interval (CI), 2.70-3.03]. Eighty one (80.2%) patients had HIV RNA < 400 copies/mL by intention-to-treat analysis (ITT) and 97.6% had HIV RNA < 400 copies/mL by on-treatment analysis (OT). Sixteen (84.2%) patients with baseline HIV RNA < or = 100,000 copies/mL and 65 (82.3%) patients with baseline HIV RNA > 100,000 copies/mL had viral load < 400 copies/mL by ITT (P = 0.842; 95% CI, -20.9%-16.2%). Sixteen (94.1%) patients with baseline HIV RNA < or = 100,000 copies/mL and 65 (98.5%) patients with baseline HIV RNA > 100,000 copies/mL had viral load < 400 copies/mL by OT (P = 0.295; 95% CI, -25.5%-3.8%). The mean CD4 cell count at week 24 was 155.1 (89.0) cells/mm3 (range 13-402). The mean increase in CD4 cell count from baseline was 96.5 (63.5) cells/ mm3 (P < 0.001). A total of 12% of the patients receiving d4T + 3TC + NVP developed skin rashes. Grade 3 or 4 hepatotoxicity was recognized in 7% of the patients. Fixed-dose combination of d4T + 3 TC + NVP (GPO- VIR) is safe, well tolerated and effective in increasing CD4 cell counts and suppression

  13. Effectiveness and metabolic complications after 96 weeks of a generic fixed-dose combination of stavudine, lamivudine, and nevirapine among antiretroviral-naive advanced HIV-infected patients in Thailand: A prospective study

    PubMed Central

    Manosuthi, Weerawat; Sungkanuparph, Somnuek; Tansuphaswadikul, Somsit; Prasithsirikul, Wisit; Athichathanabadi, Chatiya; Likanonsakul, Sirirat; Chaovavanich, Achara

    2008-01-01

    Background: Generic fixed-dose combination (FDC) antiretroviral therapy (ART) has been widely used in resource-limited settings. Treatment based on these combinations provide low pill burden and are less expensive. Objective: The aim of this study was to determine the long-term effectiveness and metabolic complications of a generic FDC of stavudine (d4T)/lamivudine (3TC)/ nevirapine (NVP), among ART-naive HIV-infected patients. Methods: A prospective study was conducted among patients who were initiated on d4T/3TC/NVP between November 2004 and March 2005. Plasma HIV-1 RNA, CD4 and alanine transaminase were assessed every 12 weeks. Fasting plasma glucose (FPG) and lipid profile were determined at 96 weeks. Adverse events and genotypic drug resistance were recorded. The primary outcome of interest was the proportion of patients who achieved plasma HIV-1 RNA <50 copies/mL after 96 weeks of ART and analyzed by intent-to-treat (ITT) and on-treatment (OT) populations. Results: There were 140 patients (mean [SD] age, 35.7 [7.6] years; male, 67.9%) enrolled in the study. Median (interquartile range [IQR]) baseline CD4 was 31 (14–79) cells/mm3 and HIV-1 RNA count was 433,500 (169,000–750,000) copies/mL. At week 96, 87 patients (ITT, 62.1%; OT, 87.0%) achieved HIV-1 RNA –50 copies/mL. Median (IQR) CD4 at 96 weeks was 328 (229–450) cells/mm3. The reasons for drug discontinuation were as follows: drug resistance (9.3%), lost to follow-up (9.3%), NVP- related rashes (7.9%), death (5.0%), d4T-related adverse events (3.6%), and transferred to another hospital (2.1%). At 96 weeks, 25 patients (28.7%) had low-density lipoprotein cholesterol (LDL-C) >130 mg/dL, 7 (8.0%) had LDL-C >160 mg/dL, 6 (6.9%) had triglycerides >400 mg/dL, and 2 (2.3%) had FPG >126 mg/dL. Eleven patients (12.6%) had a lactic acid level >2.5 mmol/L. Eight patients (9.2%) needed to take antihypertensive agents. Of 13 patients who developed virologic failure, 76.9% and 61.5% had M184V/I and Y181C

  14. Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection.

    PubMed

    Senanayake, T H; Gorantla, S; Makarov, E; Lu, Y; Warren, G; Vinogradov, S V

    2015-12-07

    Nucleoside reverse transcriptase inhibitors (NRTIs) are an integral part of the current antiretroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5'-succinate derivatives (sNRTI). Biodegradability, small particle size, and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2-10, 2-4, and 1-2 μM drug levels, respectively, for single nanodrugs and dual and triple nanodrug cocktails. Nanogel conjugate of lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Infrequent iv injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

  15. Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human X- and Y-family DNA polymerases.

    PubMed

    Brown, Jessica A; Pack, Lindsey R; Fowler, Jason D; Suo, Zucai

    2011-01-01

    Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established both in vitro and in vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X- and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypass in vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active, 5'-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40- to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5'-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X- and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.

  16. NRTI Sparing Therapy in Virologically Controlled HIV-1 Infected Subjects: Results of a Controlled, Randomized Trial (Probe).

    PubMed

    Maggiolo, Franco; Di Filippo, Elisa; Valenti, Daniela; Ortega, Paula S; Callegaro, Annapaola

    2016-05-01

    Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic backbone, while maintaining the efficacy and convenience of robust combination antiretroviral therapy (cART). We explored the combination of rilpivirine plus boosted darunavir (DRV) as an option when switching from standard cART in patients who are virologically suppressed. In this randomized, open-label, proof-of-concept, noninferiority trial, we recruited patients aged 18 years or older with chronic HIV-1 infection and on a stable, effective (>6 months) protease inhibitor-based cART including a nucleosidic backbone. The primary endpoint was noninferiority of the virological response between treatment groups, according to FDA snapshot approach. Sixty patients were randomly allocated to dual treatment with rilpivirine plus boosted DRV or to continue their ongoing triple treatment. Noninferiority was shown at the prespecified level of -12% both at 24 and 48 weeks. At week 24, 100% of patients in the dual arm presented a blood HIV-RNA level <50 copies per milliliter compared with 90.1% in the triple drug arm (difference 9.9%, 95% CI: -0.7 to 20.7), whereas, at 48 weeks, the same proportions were 96.7% and 93.4%, respectively (difference 3.3%, 95% CI: -7.15 to 13.5). The mean change in CD4 cell count from baseline was 6.0 cells per microliter (SD, 184) for dual treatment and 16.5 cells per microliter (SD, 142) for triple treatment. A relevant decrement in CD838HLADR cells was observed in both arms. The reduction was, however, significantly more pronounced in the dual-therapy arm. At week 48, the CD838HLADR cell count was 3.4% (SD, 2.2) in the dual-therapy arm and 5.2% (SD, 3.1) in the triple arm (P = 0.018). None of the patients developed severe adverse events nor had to stop treatment because of adverse events or presented grade 3-4 laboratory abnormalities. A greater reduction of bone stiffness (-2.25; SD, 7.1) was observed in patients randomized to continue triple therapy compared with patients switched to dual therapy (-0.32; SD, 8.8). Finally, baseline HIV-DNA content directly correlated with pre-cART viral load of patients (P = 0.021), but not with time on cART or time with HIV-RNA below 50 copies per milliliter. Independently of the study arm, patients with a n HIV-RNA level constantly above 3 copies per milliliter or showing viral blips had baseline HIV-DNA levels significantly higher (64,656 copies per 10 cells; SD, 93057) compared with patients who constantly presented a HIV-RNA level below the detection limit of 3 copies per milliliter (14,457 copies per 10 cells; SD, 14098) (P = 0.001). A rilpivirine-boosted plus ritonavir-boosted DRV therapy was not inferior over 48 weeks to a standard boosted protease inhibitor-based triple cART. The dual therapy did not negatively affect lipid profile and renal function and was more friendly on bone metabolism. This approach constitutes an alternative for patients experiencing nucleoside reverse transcriptase inhibitor-related toxicities.

  17. HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

    PubMed Central

    Harrison, Linda; Melvin, Ann; Fiscus, Susan; Saidi, Yacine; Nastouli, Eleni; Harper, Lynda; Compagnucci, Alexandra; Babiker, Abdel; McKinney, Ross; Gibb, Diana; Tudor-Williams, Gareth

    2015-01-01

    Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. Methods PENPACT-1 had a 2x2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART, and switch at a 1000c/ml versus 30000c/ml threshold. Switch-criteria were: not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or CDC-C event. Resistance tests were performed on samples ≥1000c/ml before switch, re-suppression and at 4-year/trial-end. Results Sixty-seven children started PI-based ART and were randomized to switch at 1000c/ml (PI-1000), 64 PIs and 30000c/ml (PI-30000), 67 NNRTIs and 1000c/ml (NNRTI-1000), and 65 NNRTI and 30000c/ml (NNRTI-30000). Ninety-four (36%) children reached the 1000c/ml switch-criteria during 5 years follow-up. In 30000c/ml threshold arms, median time from 1000c/ml to 30000c/ml switch-criteria was 58 (PI) versus 80 (NNRTI) weeks (P=0.81). In NNRTI-30000 more NRTI resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000c/ml (23% NNRTI-1000, 27% NNRTI-30000). Sixty-two children started abacavir+lamivudine, 166 lamivudine+zidovudine or stavudine, and 35 other NRTIs. The abacavir+lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30000, 64% NNRTI-1000 and 100% NNRTI-30000 were <400c/ml 24 weeks later. Conclusion Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet re-suppressed on second-line. An abacavir+lamivudine NRTI combination seemed protective against development of NRTI resistance. PMID:26322666

  18. Involvement of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in the Regulation of Resistance to Nucleoside Inhibitors

    PubMed Central

    Svicher, Valentina; Sing, Tobias; Santoro, Maria Mercedes; Forbici, Federica; Rodríguez-Barrios, Fátima; Bertoli, Ada; Beerenwinkel, Niko; Bellocchi, Maria Concetta; Gago, Federigo; d'Arminio Monforte, Antonella; Antinori, Andrea; Lengauer, Thomas; Ceccherini-Silberstein, Francesca; Perno, Carlo Federico

    2006-01-01

    We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naïve patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L+L210W+T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N+K70R+K219Q+T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to

  19. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial.

    PubMed

    Perez-Molina, José A; Rubio, Rafael; Rivero, Antonio; Pasquau, Juan; Suárez-Lozano, Ignacio; Riera, Melcior; Estébanez, Miriam; Santos, Jesús; Sanz-Moreno, José; Troya, Jesús; Mariño, Ana; Antela, Antonio; Navarro, Jordi; Navarro, José; Esteban, Herminia; Moreno, Santiago

    2015-07-01

    Problems associated with lifelong antiretroviral therapy, such as need for strict adherence, drug-related toxic effects, difficulties with treatment schedules, and cost, mean that simplification strategies should be sought. We aimed to explore the efficacy and safety of dual treatment with atazanavir-ritonavir plus lamivudine as an option to switch to from standard combination antiretroviral therapy in patients with an HIV-1 infection who are virologically suppressed. In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years and older with chronic HIV-1 infection and no previous treatment failure or resistance, and with HIV-1 RNA of less than 50 copies per mL for at least 6 months, negative hepatitis B virus surface antigen, and good general health, from 30 hospitals in Spain. Exclusion criteria were switch in antiretroviral therapy during the previous 4 months, previous virological failure, pregnancy or breastfeeding, Gilbert's syndrome, use of contraindicated drugs, grade 4 laboratory abnormalities, and previous intolerance to any of the study drugs. We randomly assigned patients (1:1; stratified by active hepatitis C virus infection and previous treatment; computer-generated random number sequence) to dual treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus lamivudine (300 mg once daily) or triple treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus two nucleos(t)ide reverse transcriptase inhibitors at the discretion of the investigators. The primary endpoint was virological response, defined as HIV-1 RNA of less than 50 copies per mL at week 48, in the per-protocol population, with a non-inferiority margin of 12%. We included patients who received at least one dose of the study drug in the safety analysis. This study is registered at ClinicalTrials.gov, number NCT01307488. Between Sept 29, 2011, and May 2, 2013, we randomly assigned 286 patients (143 [50

  20. Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study).

    PubMed

    Perez-Molina, J A; Rubio, R; Rivero, A; Pasquau, J; Suárez-Lozano, I; Riera, M; Estébanez, M; Palacios, R; Sanz-Moreno, J; Troya, J; Mariño, A; Antela, A; Navarro, J; Esteban, H; Moreno, S

    2017-01-01

    We evaluated whether maintenance therapy with atazanavir/ritonavir plus lamivudine (ATV/r + 3TC) was non-inferior to ATV/r plus two nucleosides (ATV/r + 2NUCs) at 96 weeks of follow-up. SALT is a multicentre, open-label, non-inferiority clinical trial in HIV-1-infected virologically suppressed patients. Hepatitis B virus surface antigen-negative subjects with no previous treatment failure/resistance mutations and HIV-1-RNA <50 copies/mL for ≥6 months were randomized (1 : 1) to ATV/r + 3TC or ATV/r + 2NUCs. The primary endpoint was HIV-1-RNA <50 copies/mL in the PP population. Non-inferiority was demonstrated if the lower bound of the 95% CI for the difference was not below -12%. Some 286 patients were analysed. At week 96, 74.4% had HIV-1-RNA <50 copies/mL in the ATV/r + 3TC arm versus 73.9% in the ATV/r + 2NUCs arm (95% CI for the difference, -9.9%-11.0%). In both groups, similar values were observed for patients with confirmed virological failure in ATV/r + 3TC versus ATV/r + 2NUCs (9 versus 5), death (1 versus 0), discontinuation due to ART-related toxicity (7 versus 11), withdrawal from the study (7 versus 9) and loss to follow-up (6 versus 6). One patient taking ATV/r + 2NUCs developed resistance mutations (M184V and L63P). Similar values were obtained for change in mean CD4 count [19 versus 18 cells/mm(3) (95% CI for the difference, -49.3-50.7), grade 3-4 adverse events (70.7% versus 70.2%) and changes in the global deficit score, -0.3 (95% CI, -0.5 to -0.1) for ATV/r + 3TC, versus -0.2 (95% CI, -0.4 to -0.1) for ATV/r + 2NUCs]. The long-term results of switching to ATV/r + 3TC show that this strategy is effective, safe and non-inferior to ATV + 2NUCs in virologically suppressed HIV-infected patients. © 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.

  1. Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202

    PubMed Central

    Kitch, Douglas; Daar, Eric S.; Tierney, Camlin; Jahed, Nasreen C.; Tebas, Pablo; Myers, Laurie; Melbourne, Kathleen; Ha, Belinda; Sax, Paul E.

    2011-01-01

    (See the editorial commentary by Yin and Overton, on pages 1705-7.) Background.  Long-term effects of abacavir (ABC)–lamivudine (3TC), compared with tenofovir (TDF)–emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. Methods.  A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests. Results.  Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log10 copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. Conclusions. Compared with ABC-3TC, TDF-FTC–treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898. PMID:21606537

  2. Cost-effectiveness analysis of tenofovir/emtricitabine and abacavir/lamivudine in combination with efavirenz or atazanavir/ritonavir for treatment-naïve adults with HIV-1 infection in the UK, based on the AIDS Clinical Trials Group 5202 clinical trial.

    PubMed

    Wilkins, E; Fisher, M; Brogan, A J; Talbird, S E; La, E M

    2016-08-01

    The aim of the study was to assess the cost-effectiveness of the four regimens studied in the AIDS Clinical Trials Group (ACTG) 5202 clinical trial, tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) in combination with efavirenz (EFV) or atazanavir/ritonavir (ATV/r), for treatment-naïve adults with HIV-1 infection in the UK. A Markov model with six health states based on CD4 cell count ranges was developed to predict long-term costs and health outcomes for individuals on first-line therapy. Head-to-head efficacy data comparing TDF/FTC + EFV, TDF/FTC + ATV/r, ABC/3TC + EFV, and ABC/3TC + ATV/r were obtained from ACTG 5202 for up to 192 weeks. Antiretroviral drug costs were based on current list prices. Other medical costs (2013 UK pounds sterling), utility values, and mortality rates were obtained from published sources. Base-case, sensitivity, and subgroup analyses (by baseline viral load) were conducted. Individuals using TDF/FTC-based regimens were predicted to remain on first-line therapy longer and accrue more quality-adjusted life-years (QALYs) than individuals using ABC/3TC-based regimens. At a willingness-to-pay threshold of £30 000 per QALY gained, TDF/FTC-based regimens were predicted to be cost-effective compared with ABC/3TC-based regimens, with incremental cost-effectiveness ratios of £23 355 for TDF/FTC + EFV vs. ABC/3TC + EFV and £23 785 for TDF/FTC + ATV/r vs. ABC/3TC + ATV/r. Results were generally robust in subgroup, sensitivity, and scenario analyses. In an analysis of the regimens studied in ACTG 5202 for treatment-naïve adults with HIV-1 infection in the UK, TDF/FTC-based regimens yielded more favourable health outcomes and were generally predicted to be cost-effective compared with ABC/3TC-based regimens. These results confirm that TDF/FTC-based regimens are not only clinically effective but also cost-effective. © 2015 British HIV Association.

  3. Toxicology and carcinogenesis studies of mixtures of 3'-azido-3'-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV) (Cas Nos. 30516-87-1, 134678-17-4, 129618-40-2, 159989-65-8) in B6C3F1 Mice (transplacental exposure studies).

    PubMed

    2013-01-01

    Antiretroviral drugs are used to treat patients positive for the human immunovirus HIV-1, and increasingly treatments include a combination of such drugs. The noninfected children of women who are pregnant and receiving such treatment may also be exposed to the drugs by transplacental exposure. We studied the long-term effects of such transplacental exposure in mice by exposing pregnant mice to combinations of four such antiretroviral drugs for seven days and then observing their pups for two years following birth. The four drugs studied were 3′-azido-3′-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV). Four different sets of exposure studies were performed: exposure to AZT; to AZT plus 3TC; to AZT, 3TC, and NVP; or to AZT, 3TC, and NFV. In each of these studies, groups of pregnant females were given one of three concentrations of the drug combinations seven times though a tube directly into their stomachs, and after birth their pups were maintained with no further exposure for two years. The offspring of another group of pregnant females not treated with the drugs served as controls. At the end of the study, tissues from more than 40 sites were examined for every animal. Survival of pups whose mothers were exposed to AZT or AZT plus 3TC was similar to their controls, while the survival rates for offspring of mice exposed to AZT, 3TC, and NVP or AZT, 3TC, and NFP were lower than for controls. In most cases the body weights of pups from mothers exposed were slightly less than those of the controls. There were slight increases in the incidences of thyroid gland tumors and skin tumors in the female pups of mothers exposed to AZT alone and of lung tumors in female pups of mothers exposed to AZT plus 3TC. For offspring of mothers exposed to AZT, 3TC, and NVP there were increased incidences of skin tumors in both male and female pups, and more so in the males. We conclude that exposure to the combination of AZT, 3TC, and NVP

  4. Molecular analysis of mitochondrial compromise in rodent cardiomyocytes exposed long term to nucleoside reverse transcriptase inhibitors (NRTIs).

    PubMed

    Liu, Yongmin; Nguyen, Phuonggiang; Baris, Tara Z; Poirier, Miriam C

    2012-06-01

    Despite the highly effective impact of NRTI therapy in patients infected with the human immunodeficiency virus type 1 (HIV-1), long-term treatment has revealed cardiotoxicity, considered to be due to mitochondrial dysfunction. To evaluate mitochondrial damage, and design therapeutic interventions, we established cultures of rat H9c2 and mouse HL-1 cardiomyocytes and exposed them to the NRTIs zidovudine (AZT), and AZT plus didanosine (ddI). Proliferation assays showed that H9c2 cells grew well in 50 μM AZT and 50 μM AZT/50 μM ddI and that HL-1 cells grew well in 10 μM AZT and 10 μM AZT/10 μM ddI. Both types of cells were exposed to the drugs for 39 passages (P), and mitochondrial integrity in the form of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was examined by Seahorse XF24 analyzer. In NRTI-exposed H9c2 cells at most passages, OCR was reduced, in both the basal and uncoupled states, compared to unexposed controls (P < 0.05). NRTI-exposed HL-1 cells showed a different pattern of mitochondrial compromise, with inhibition of OCR, in basal and uncoupled cells, occurring largely before P14 and after P17 (P < 0.05). The ECAR response in uncoupled cells of both types was unchanged at early passages, but increased after P18 (P < 0.05). Evaluation of mitochondrial biogenesis in H9c2 cells revealed reduction before P29, no change at P29, and reduction at P39 in NRTI-exposed cells, compared to unexposed cells (P < 0.05). Western blotting of transcription factors critical for mitochondrial biogenesis, PGC-1α, Nrf-1 and mtTFA, showed downregulation in NRTI-exposed H9c2 cells compared to unexposed controls. In addition, electron microscopy (EM) revealed increasing mitochondrial morphological damage in H9c2 cells over passages. For both cell types, AZT/ddI was more damaging than AZT alone. These studies demonstrate progressive mitochondrial compromise in cardiomyocytes-exposed long term, and the model will be used to evaluate

  5. Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS.

    PubMed

    Lewis, William; Haase, Chad P; Miller, Yoon K; Ferguson, Brandy; Stuart, Tami; Ludaway, Tomika; McNaught, Jamie; Russ, Rodney; Steltzer, Jeffrey; Santoianni, Robert; Long, Robert; Fiermonte, Giuseppe; Palmieri, Ferdinando

    2005-08-01

    Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2', 3'-didehydro-2', 3'-deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3' azido-3'-deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs.

  6. Real-world persistence with antiretroviral therapy for HIV in the United Kingdom: A multicentre retrospective cohort study.

    PubMed

    Lewis, Joseph M; Smith, Colette; Torkington, Adele; Davies, Craig; Ahmad, Shazaad; Tomkins, Andrew; Shaw, Jonathan; Kingston, Margaret; Muqbill, Ghadeer; Hay, Philip; Mulka, Larissa; Williams, Deborah; Waters, Laura; Brima, Nataliya; Marshall, Neal; Johnson, Margaret; Chaponda, Mas; Nelson, Mark

    2017-04-01

    Persistence with an antiretroviral therapy (ART) regimen for HIV can be defined as the length of time a patient remains on therapy before stopping or switching. We aimed to describe ART persistence in treatment naïve patients starting therapy in the United Kingdom, and to describe differential persistence by treatment regimen. We performed a retrospective cohort study at eight UK centres of ART-naïve adults commencing ART between 2012 and 2015. Aggregate data were extracted from local treatment databases. Time to discontinuation was compared for different third agents and NRTI backbones using incidence rates. 1949 patients contributed data to the analysis. Rate of third agent change was 28 per 100 person-years of follow up [95% CI 26-31] and NRTI backbone change of 15 per 100 person-years of follow up [95% CI 14-17]). Rilpivirine, as co-formulated rilpivirine/tenofovir/emtricitabine had a significantly lower discontinuation rate than all other third agents and, excluding single tablet regimens, co-formulated tenofovir/emtricitabine had a significantly lower discontinuation rate than co-formulated abacavir/lamivudine. The reasons for discontinuation were not well recorded. Treatment discontinuation is not an uncommon event. Rilpivirine had a significantly lower discontinuation rate than other third agents and tenofovir/emtricitabine a lower rate than co-formulated abacavir/lamivudine. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  7. [Resistance profile of rilpivirine].

    PubMed

    Imaz, Arkaitz; García, Federico; di Yacovo, Silvana; Llibre, Josep M

    2013-06-01

    Rilpivirine (RPV) is a new second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for use in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) as initial therapy in treatment-naïve HIV-1-infected patients with a baseline viral load ≤100,000 copies/mL. RPV is a diarylpyrimidine derivative with potent in vitro activity against multiple HIV-1 variants with resistance mutations to first-generation NNRTI such as K103N. In vitro studies and phase III clinical trials have allowed the identification of 16 mutations associated with resistance to RPV K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L. The risk of virologic failure in patients receiving RPV plus 2 NRTI with plasma viral load ≤ 100,000 copies/mL is low, but a high percentage of patients failing RPV develop resistance mutations to both RPV and NRTI. The most common resistance mutation that emerges in this setting is E138K. This mutation is usually associated with M184I due to a double compensatory effect of this combination, which confers resistance to RPV, as well as to lamivudine and emtricitabine. The emergence of RPV resistance confers cross-resistance to all NNRTI and, importantly, high percentages of cross-resistance to etravirine.

  8. Prevalence of HIV-1 drug resistance among patients failing first-line ART in Monrovia, Liberia: a cross-sectional study.

    PubMed

    Loubet, Paul; Charpentier, Charlotte; Visseaux, Benoit; Borbor, Abraham; Nuta, Cecilia; Adu, Eric; Chapplain, Jean-Marc; Baysah, Maima; Tattevin, Pierre; Yazdanpanah, Yazdan; Descamps, Diane

    2015-01-01

    To assess the prevalence of acquired drug resistance in HIV-1-infected patients living in Monrovia, Liberia, who had clinical and/or immunological failure of first-line ART according to WHO criteria. Patients receiving ART for >1 year with clinical and/or immunological failure were included. Sequencing of protease and reverse transcriptase regions was performed using Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) procedures and sequences were interpreted using the ANRS resistance algorithm. Ninety patients were enrolled. They had been receiving ART for a median time of 42 months and half were receiving zidovudine/lamivudine/nevirapine. Seventy-five per cent of patients were infected with CRF02_AG. Twenty-seven per cent of patients displayed a plasma viral load <50 copies/mL. Among the 66 patients with detectable viraemia, the median viral load was 4.7 log10 copies/mL (IQR = 3.0-5.6). The prevalence of NRTI and NNRTI resistance-associated mutations (RAMs) was 63% and 71%, respectively; and the median number of NRTI and NNRTI RAMs was 2 and 3, respectively. Two patients (4%) displayed viruses with PI RAMs. Regarding NRTI drug resistance, 29%, 38%, 63%, 29% and 25% of patients had viruses resistant to zidovudine, stavudine, lamivudine/emtricitabine, abacavir and tenofovir, respectively. Regarding the NNRTI drug class, 56%, 65%, 33% and 42% of patients had viruses resistant to efavirenz, nevirapine, etravirine and rilpivirine, respectively. The high prevalence of acquired drug resistance in patients followed in two centres of the Liberian capital city, documented after a median of 3 years on a first-line ART regimen, jeopardizes the activity of second-line regimens and highlights the need for virological monitoring in these settings. © The Author 2015. 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.

  9. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study.

    PubMed

    Orrell, Catherine; Hagins, Debbie P; Belonosova, Elena; Porteiro, Norma; Walmsley, Sharon; Falcó, Vicenç; Man, Choy Y; Aylott, Alicia; Buchanan, Ann M; Wynne, Brian; Vavro, Cindy; Aboud, Michael; Smith, Kimberly Y

    2017-07-17

    Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive

  10. The history of antiretrovirals: key discoveries over the past 25 years.

    PubMed

    De Clercq, Erik

    2009-09-01

    Within 25 years after zidovudine (3'-azido-2',3'-dideoxythymidine, AZT) was first described as an inhibitor of HIV replication, 25 anti-HIV drugs have been formally approved for clinical use in the treatment of HIV infections: seven nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir [in its oral prodrug form: tenofovir disoproxil fumarate (TDF)]; four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, efavirenz and etravirine; ten protease inhibitors (PIs): saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir; one fusion inhibitor (FI): enfuvirtide; one co-receptor inhibitor (CRI): maraviroc and one integrase inhibitor (INI): raltegravir. These compounds are used in various drug combination (some at fixed dose) regimens so as to achieve the highest possible benefit and tolerability, and to diminish the risk of virus-drug resistance development. (c) 2009 John Wiley & Sons, Ltd.

  11. Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae

    PubMed Central

    Baruffini, Enrico; Ferrari, Jessica; Dallabona, Cristina; Donnini, Claudia; Lodi, Tiziana

    2015-01-01

    Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol γ, the solely mitochondrial replicase in animals and fungi. However, little is known regarding non-pathological polymorphisms found in this gene. Here we studied, in the yeast model Saccharomyces cerevisiae, eight human polymorphisms. We found that most of them are not neutral but enhanced both mtDNA extended mutability and the accumulation of mtDNA point mutations, either alone or in combination with a pathological mutation. In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability. PMID:25462018

  12. Toxicology and Carcinogenesis Studies of Mixtures of 3'-Azido-3'-Deoxythymidine (AZT), Lamivudine (3TC), and Nevirapine (NVP) (CAS Nos. 30516-87-1, 134678-17-4, 129618-40-2) in Genetically Modified C3B6.129F1-Trp53(tm1Brd) N12 Haploinsufficient Mice (in utero and postnatal gavage studies).

    PubMed

    2013-10-01

    3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS). Antiviral therapy is essential for treatment and prevention of AIDS in adults and children infected with human immunodeficiency virus (HIV), and to prevent mother-to-child transmission of HIV during pregnancy and labor. The studies described in this report were designed to determine possible long-term sequelae from AZT treatment, often used in combination with other antiviral drugs, such as lamivudine (3TC) and nevirapine (NVP) in preventing mother-to-child transmission of HIV. Male and female heterozygous F1 p53+/- mice were exposed to AZT, 3TC, NVP, or combinations of the chemicals in utero on gestation days (GD) 12 through 18, then administered the same chemical or combination of chemicals by gavage from postnatal day (PND) 1 through PND 28 and then observed until 45 weeks of age. Vehicle control mice received only an aqueous solution containing 0.2% methylcellulose and 0.1% Tween 80. Mice were dosed twice daily until PND 28. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. The study compared three combination doses of AZT, 3TC and NVP (AZT/3TC/NVP-L, AZT/3TC/NVP-M, and AZT/3TC/NVP-H) with the vehicle controls, and compared the individual components with each other at the highest dose (AZT-H, 3TC-H, NVP-H, AZT/3TC-H and AZT/3TC/NVP-H). Because exposure to AZT/3TC/NVP-M and AZT/3TC/NVP-H reduced pup survival, additional litters were required to provide sufficient pups to load the 45-week study. 45-WEEK STUDY: In general, survival was relatively high once the pup exposure phase had been completed, with at least 75% of the mice surviving to terminal sacrifice in all groups. For males, survival was significantly greater in the AZT/3TC/NVP-L and AZT/3TC/NVP-M groups relative to the vehicle control group. There were no significant differences in survival between high

  13. An association between K65R and HIV-1 subtype C viruses in patients treated with multiple NRTIs.

    PubMed

    Smit, Erasmus; White, Ellen; Clark, Duncan; Churchill, Duncan; Zhang, Hongyi; Collins, Simon; Pillay, Deenan; Sabin, Caroline; Nelson, Mark; Winston, Alan; Jose, Sophie; Tostevin, Anna; Dunn, David T

    2017-07-01

    HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Subtype B patients ( n  =   3410) were mostly MSM (78%) and those with subtype C ( n  =   810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P  <   0.001). Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

  14. Optimizing antiretroviral product selection: a sample approach to improving patient outcomes, saving money, and scaling-up health services in developing countries.

    PubMed

    Amole, Carolyn D; Brisebois, Catherine; Essajee, Shaffiq; Koehler, Erin; Levin, Andrew D; Moore, Meredith C; Brown Ripin, David H; Sickler, Joanna J; Singh, Inder R

    2011-08-01

    Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

  15. Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.

    PubMed

    Balotta, C; Violin, M; Monno, L; Bagnarelli, P; Riva, C; Facchi, G; Berlusconi, A; Lippi, M; Rusconi, S; Clementi, M; Galli, M; Angarano, G; Moroni, M

    2000-07-01

    We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.

  16. Viral Suppression Following Switch to Second-line Antiretroviral Therapy: Associations With Nucleoside Reverse Transcriptase Inhibitor Resistance and Subtherapeutic Drug Concentrations Prior to Switch

    PubMed Central

    Johnston, Victoria; Cohen, Karen; Wiesner, Lubbe; Morris, Lynn; Ledwaba, Johanna; Fielding, Katherine L.; Charalambous, Salome; Churchyard, Gavin; Phillips, Andrew; Grant, Alison D.

    2014-01-01

    Background. High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification. Methods. Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression. Results. One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77–263) and 4.3 log10 copies/mL (IQR, 3.8–4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL. Conclusions. Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure. PMID:23943851

  17. Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study.

    PubMed

    Salomon, H; Wainberg, M A; Brenner, B; Quan, Y; Rouleau, D; Coté, P; LeBlanc, R; Lefebvre, E; Spira, B; Tsoukas, C; Sekaly, R P; Conway, B; Mayers, D; Routy, J P

    2000-01-28

    Prolonged treatment with antiretroviral drugs results in the selection of HIV-1 variants with mutations conferring resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) or to protease inhibitors (PI). There is serious concern about transmission of resistant viruses to newly infected persons. This study monitored the prevalence of resistant viruses in individuals undergoing primary HIV infection. Resistance testing was performed on 81 individuals infected between 1997 and 1999 by injecting drug use (n =21), sexual (n = 56), or unknown (n = 4) transmission. Automated sequencing was used to genotype the reverse transcriptase (RT) and protease regions of virus isolated from patients' plasma. The phenotypic susceptibility of stimulated peripheral blood mononuclear cells to antiretroviral drugs was assayed. Line probe assays detected quasispecies variations in wild-type and mutated RT codons. A high prevalence of PI and RT genotypic variants, associated with high-level resistance to antiretroviral drugs, was observed in individuals newly infected by injecting drug use (PI = 24%, RT = 24%) or sexual transmission (PI = 12%, RT = 22%). The PI mutations, L101, V82A, and L90M, were found in 10.5, 3 and 4% of cases, respectively; whereas for RT, primary mutations at positions T215Y (zidovudine), M184V (lamivudine), T69D/A (zalcitabine), and K103N (multi-NNRTI) were present in 8, 5, 4, and 4% of subjects, respectively. Resistance to NRTI was demonstrated by phenotypic, genotypic, and line probe analyses. Transmission of multidrug (NRTI/NNRTI/PI) resistance in eight subjects (9.9%) was confirmed by showing that source partners possessed viruses of similar genotype. The transmission of drug-resistant HIV is a serious problem that merits further attention by public health officials as well as virologists and clinicians.

  18. High Treatment Success Rates When Switching to Once Daily Nevirapine Containing Antiretroviral Therapy

    PubMed Central

    Benzie, Andrew; Marett, Brett; Mackie, Nicola E; Winston, Alan

    2008-01-01

    Introduction Two recent studies have highlighted low rates of virological response to once daily nevirapine containing combination antiretroviral therapy (CART) in treatment naïve HIV-1 infected subjects. Aim We assessed factors associated with treatment responses in a cohort of HIV-1 infected, therapy naïve individuals, commencing nevirapine CART with two nucleoside reverse transcriptase inhibitors (NRTI) containing either lamivudine or emtricitabine. Results Between January 2002 and 2006, 173 subjects (80 female) met the study inclusion criteria. All subjects initially commenced on twice daily nevirapine with six different NRTI backbones. Mean follow up was 802 days. 49 (28%) subjects switched to once daily nevirapine, 23 (13%) within the first year. After 48 weeks of therapy, HIV RNA was < 50 copies/mL in 154/173 subjects (89%). A trend was observed towards improved virological outcome (HIV RNA < 50 copies/mL) and switching to once daily nevirapine during the first year of therapy (p=0.051). Conclusion Whilst awaiting the results of prospective studies assessing once daily nevirapine, our data describe high treatment success rates and good safety responses when switching to once daily nevirapine. PMID:19274065

  19. Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling.

    PubMed

    Wu, Ting; Zhang, Juan; Geng, Mingxing; Tang, Shao-Jun; Zhang, Wenping; Shu, Jianhong

    2017-06-23

    HAART is very effective in suppressing HIV-1 replication in patients. However, patients staying on long-term HAART still develop various HIV-associated neurological disorders, even when the viral load is low. The underlying pathogenic mechanisms are largely unknown. Emerging evidence implicated that persistent neuroinflammation plays an important role in NeuroAIDS. Although residual virus or viral proteins are commonly thought as the causal factors, we are interested in the alternative possibility that HAART critically contributes to the neuroinflammation in the central nervous system (CNS). To test this hypothesis, we have determined the effect of NRTIs on the expression of proinflammatory cytokines in the various CNS regions. Mice (C57Bl/6) were administered with AZT (Zidovudine 100 mg/kg/day), 3TC (Lamivudine 50 mg/kg/day) or D4T (Stavudine 10 mg/kg/day) for 5 days, and cortices, hippocampi and spinal cords were collected for immunoblotting. Our results showed that NRTI administration up-regulated cytokines, including IL-1β, TNF-α and IL-6 in various CNS regions. In addition, we found that NRTIs also up-regulated Wnt5a protein. Importantly, BOX5 attenuated NRTI-induced cytokine up-regulation. These results together suggest that NRTIs up-regulate proinflammatory cytokines via a Wnt5a signaling-dependent mechanism. Our findings may help understand the potential pathogenic mechanisms of HAART-associated NeuroAIDS and design effective adjuvants.

  20. The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

    PubMed

    Vasan, Ashwin; Hoos, David; Mukherjee, Joia S; Farmer, Paul E; Rosenfield, Allan G; Perriëns, Joseph H

    2006-05-01

    The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world.

  1. The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

    PubMed Central

    Vasan, Ashwin; Hoos, David; Mukherjee, Joia S.; Farmer, Paul E.; Rosenfield, Allan G.; Perriëns, Joseph H.

    2006-01-01

    The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world. PMID:16710550

  2. Determination of the antiretroviral drug nevirapine in diluted alkaline electrolyte by adsorptive stripping voltammetry at the mercury film electrode.

    PubMed

    Castro, Arnaldo Aguiar; Aucélio, Ricardo Queiroz; Rey, Nicolás Adrián; Miguel, Eliane Monsores; Farias, Percio Augusto Mardini

    2011-01-01

    This paper describes a stripping method for the determination of nevirapine at the submicromolar concentration levels. The method is based on controlled adsorptive accumulation of nevirapine at thin-film mercury electrode, followed by a linear cyclic scan voltammetry measurement of the surface species. Optimal experimental conditions include a 2.0 x 10(-3) mol L(-1) NaOH solution (supporting electrolyte), an accumulation potential of -0.20 V, and a scan rate of 100 mV s(-1). The response of nevirapine is linear over the concentration range 0.01-0.14 ppm. For an accumulation time of 6 minutes, the detection limit was found to be 0.87 ppb (3.0 x 10(-9) mol L(-1)). More convenient methods to measure the nevirapine in presence of the efavirenz, acyclovir, didanosine, indinavir, nelfinavir, saquinavir, lamivudine, zidovudine and metals ions were also investigated. The utility of this method is demonstrated by the presence of nevirapine together with ATP or DNA.

  3. Emerging role of riboflavin in the treatment of nucleoside analogue-induced type B lactic acidosis.

    PubMed

    Dalton, S D; Rahimi, A R

    2001-12-01

    Type B lactic acidosis is a rare and often fatal complication seen in patients receiving the nucleotide analogues zidovudine, stavudine, didanosine, and lamivudine. We describe a case of a 51-year-old human immunodeficiency virus (HIV)-positive woman receiving three nucleotide analogues. She presented with nausea, vomiting, abdominal pain, and hepatic steatosis. Signs of mitochondrial toxicity were demonstrated by diffuse myopathy and pancreatitis. Serum riboflavin levels documented a deficiency that was treated with 50 mg of riboflavin daily. Immediately after treatment, serum blood urea nitrogen level, lactic acid levels, and arterial blood pH all returned to normal values. Her signs of mitochondrial toxicity also improved after treatment with riboflavin. Successful reversal of the patient's type B lactic acidosis after riboflavin therapy suggested that riboflavin deficiency plays a direct role in the development of nucleotide analogue-induced lactic acidosis. It is impossible to predict which patients are predisposed to the development of this syndrome. For this reason, it may be important to screen and treat riboflavin deficiency in patients on nucleoside analogues.

  4. The Effect of Individual Antiretroviral Drugs on Body Composition in HIV-Infected Persons Initiating Highly Active Antiretroviral Therapy

    PubMed Central

    Shlay, Judith C.; Sharma, Shweta; MS, Grace Peng; Gibert, Cynthia L.; Grunfeld, Carl

    2009-01-01

    Objectives To examine the long-term effects of individual antiretroviral drugs on body composition among 416 persons initiating antiretroviral therapy (ART). Methods In a substudy of a clinical trial of persons initiating ART, changes in body composition attributable to individual ART were examined. ART assessed were: indinavir, ritonavir, nelfinavir, efavirenz, nevirapine, stavudine (d4T), zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), and abacavir (ABC). Skinfolds and circumferences were measured at baseline and every 4 months. Mid-arm, mid-thigh and waist subcutaneous tissue areas (STAs) and non-subcutaneous tissue areas (NSTAs) were calculated. Rates of change per year of exposure to each individual ART drug were determined using multivariate longitudinal regression. Results D4T and ZDV use were associated with losses in STA and skinfold thickness. 3TC use was associated with gains in all STAs and skinfold thickness, while ABC use was associated with an increase in waist STA. Indinavir was associated with gains in waist STA, while indinavir, efavirenz and nevirapine were associated with increases in upper back skinfolds. D4T use was also associated with increases in all NSTAs; 3TC use was associated with the greatest increase in waist NSTA. Conclusions In this prospective non-randomized evaluation, the NRTIs d4T and ZDV were associated with decreases in STAs, while 3TC use was associated with increased STAs and waist NSTA. PMID:19412117

  5. Determination of the Antiretroviral Drug Acyclovir in Diluted Alkaline Electrolyte by Adsorptive Stripping Voltammetry at the Mercury Film Electrode

    PubMed Central

    Castro, Arnaldo Aguiar; Cordoves, Ana Isa Perez; Farias, Percio Augusto Mardini

    2013-01-01

    This paper describes a stripping method for the determination of acyclovir at the submicromolar concentration level. This method is based on controlled adsorptive accumulation of acyclovir at thin-film mercury electrode, followed by a linear cyclic scan voltammetry measurement of the surface species. Optimal experimental conditions include a NaOH solution of 2.0 × 10−3 mol L−1 (supporting electrolyte), an accumulation potential of −0.40 V, and a scan rate of 100 mV s−1. The response of acyclovir is linear over the concentration range 0.02 to 0.12 ppm. For an accumulation time of 4 minutes, the detection limit was found to be 0.42 ppb (1.0 × 10−9 mol L−1). More convenient methods to measure the acyclovir in presence of the didanosine, efavirenz, nevirapine, nelfinavir, lamivudine, and zidovudine were also investigated. The utility of this method is demonstrated by the presence of acyclovir together with Adenosine triphosphate (ATP) or DNA. PMID:23761958

  6. Discordance between genotypic resistance and pseudovirus phenotypic resistance in AIDS patients after long-term antiretroviral therapy and virological failure.

    PubMed

    Yang, Jing; Geng, Wenqing; Zhang, Min; Han, Xiaoxu; Shang, Hong

    2014-10-01

    Sixteen original recombinant pseudoviruses were generated by cloning the reverse transcriptase and protease genes of human immunodeficiency virus (HIV)-1 from patients into a plasmid vector (pNL4-3-ΔE-EGFP). By site-directed mutagenesis two restriction endonuclease sites, ApaI and AgeI, were inserted into pNL4-3-ΔE-EGFP. Phenotypic susceptibility of recombinant pseudoviruses to five different classes of antiretroviral drugs was determined using a luciferase reporter assay system. The results were subjected to comparative analyses to detect genotype-phenotype associations. Among 16 strains tested, 12 strains had a discordant genotype-phenotype resistance pattern to at least one drug. In five strains resistance to two, in two strains to three, and in one strain resistance to four drugs was detected. HIV resistance genotyping could predict the phenotype for nevirapine and azidothymidine. For lamivudine, 2'-3'-didehydro-2'-3'dideoxythymidine and didanosine, phenotypic resistance testing was necessary. The study showed that in patients who experienced long-term highly active antiretroviral therapy and virological failure, there is some discordance between genotypic and phenotypic HIV drug resistance. To address the issue of limited resources in China, genotypic and phenotypic resistance testing should be done for different drugs in order to guide clinical therapy more effectively.

  7. Backbone switch to abacavir/lamivudine fixed-dose combination: implications for antiretroviral therapy optimization.

    PubMed

    Fantauzzi, Alessandra; Floridia, Marco; Falasca, Francesca; Spanedda, Pierpaolo; Turriziani, Ombretta; Vullo, Vincenzo; Mezzaroma, Ivano

    2015-10-01

    Current guidelines recommend treatment optimization in virologically suppressed patients through switching/ simplification strategies to minimize long-term toxicities and improve adherence. The assessment of inflammation/ coagulation profiles may support therapeutic decisions. We undertook a prospective, non-randomized study to evaluate the efficacy and safety of switching to ABC/3TC from ZDV/3TC or TDF/FTC backbones, in 40 HIV-1 infected patients with HIV-RNA levels <37 copies/mL (>24 months). Main endpoints were viral load levels, CD4+ T cells and toxicities after 48 weeks. Serum inflammation/coagulation markers (ESR, CRP, D-dimer and fibrinogen) and pro-inflammatory cytokines (IL-6, TNF-α, adiponectin, resistin) were evaluated. Baseline characteristics were similar in the two arms, with significantly lower values of e-GFR in patients on TDF/FTC. Markers of inflammation/ coagulation and cytokine profile were also similar, except for higher values of resistin in patients on TDF/ FTC. During follow up, CD4+ T cells increased and viral load remained undetectable in both groups. Patient from ZDV/3TC had significantly greater changes in total cholesterol and serum creatinine. Markers of inflammation/ coagulation remained unchanged. Adiponectin significantly increased in patients from ZDV/3TC. Switching to ABC/3TC was effective and safe. Inflammatory markers remained low in both groups. Some changes in metabolic, kidney and cytokine profiles were apparently specific for baseline cART treatment.

  8. [A clinical study on lamivudine treatment for advanced schistosomisis with chronic B hepatits].

    PubMed

    Li, Yu-chun

    2013-10-01

    to explore the clinical effect of LVD on patients with advanced schistosomiasis with chronic B hepatitis and on the course of disease development. A total of 58 patients with advanced schistosomiasis with chronic B hepatitis were enrolled and randomly divided into the treatment group (30 cases) and the control group (28 cases).patients in the treatment group received routinet colligative treatment and LVD 100 mg daily, while patients in the control group received routinet colligative treatment only.All the patients were followed up for 36 +/- 3 months. The mortality rate was 13.33% vs. 55.56% in the treatment and control (P < 0.01). The patients whose Child-Pugh score decreased by more than 2 were 89.2% vs. 62.3% (P < 0.05). After treatment the serum ALT TBIL levels dropped, the serum albumin level increased and The improvement of liver function in the treatment group was better than that in the control group(P < 0.01). The HBeAg and HBV-DNA negutive rate in the treatment group were higher than those in the control (P < 0.01). The HBV-DNA negative rate in thetreatment group was 93.3% at the end of 12 weekes. The rate of YMDD mutations was 6.7%, 23.3% and 40% in the treatment group at the end of 48 , 96 and 144 weeks. LVD and ADV can inhibit virus replication and the relative stability liver function remained the same in most YMDD mutation patients. LVD can inhibit virus replication rapidly and improveliver function, prevent exacerbation in patients with advanced schistosomiasis with chronic B hepatitis, LVD and ADV can inhibit virus replication and improve liver function in most YMDD mutation patients.

  9. A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects

    PubMed Central

    Pozniak, Anton L; Boffito, Marta; Russell, Deborah; Ridgway, Caroline E; Muirhead, Gary J

    2008-01-01

    Aims Maraviroc (UK-427 857), an antagonist of the CCR5 receptor with potent anti-HIV activity, was recently approved for use in treatment-experienced patients infected with CCR5-tropic HIV-1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV-positive subjects compared with historical controls. Methods In this study, four cohorts of HIV-positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1 – efavirenz + Combivir® (lamivudine/zidovudine); cohort 2 – efavirenz + didanosine + tenofovir; cohort 3 – nevirapine + lamivudine + tenofovir; cohort 4 – Kaletra® (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV-positive subjects receiving maraviroc monotherapy in a Phase IIa study. Results A total of 29 subjects were recruited (eight each in cohorts 1–3, and five in cohort 4). The geometric mean ratios for AUC12 and Cmax for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. Tmax was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h−1 (cohort 1) to 13.2 l h−1 (cohort 4). There were no renal clearance data collected in the comparator study. Conclusions The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead

  10. Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses.

    PubMed

    Hofstra, Laura Marije; Nijhuis, Monique; Mudrikova, Tania; Fun, Axel; Schipper, Pauline; Schneider, Margriet; Wensing, Annemarie

    2014-01-01

    Dolutegravir is a second generation integrase inhibitor with a proposed high genetic barrier to resistance. However, in clinical trials, decreased virological response was seen in a subset of patients with prior exposure to raltegravir and multiple integrase resistance mutations. We describe two cases of HIV subtype B-infected patients starting dolutegravir after previous failure on a raltegravir-containing regimen with extensive resistance. Genotypic analysis was performed using population sequencing and 454 ultradeep sequencing of integrase at time of raltegravir exposure. Both patients were diagnosed in early 1990s and received mono- and dual therapy, followed by several cART-regimens. Due to presence of extensive resistance, the genotypic susceptibility score of these regimens never reached a score >2 and never resulted in sustained virological suppression despite good adherence. Early 2012, the clinical condition of patient 1 worsened during persistent failure of a mega-cART regimen despite excellent drug levels. Six major PI, six minor PI, seven NRTI, six NNRTI and two INI mutations plus DM-virus were detected (Table 1). Ultra-deep sequencing of integrase showed the selection of Q148R, E138K+Q148K, and N155H variants and phenotypic raltegravir resistance was demonstrated. After addition of dolutegravir and enfuvirtide to the failing regimen (zidovudine, lamivudine, tenofovir, etravirine, darunavir/ritonavir, maraviroc), viral load (VL) decreased from 244,000 to <20 cps/mL within five months, CD4-count increased (33 to 272 mm(3)) and the clinical condition improved substantially. In patient 2, similar worsening of the clinical condition was observed late 2012 during persistent failure on mega-cART. Five major PI, six minor PI, nine NRTI, seven NNRTI and one INI mutation plus DM-virus were detected. Ultra-deep sequencing showed selection of N155H, followed by Q95K and V151I variants and phenotypic raltegravir resistance was demonstrated. Dolutegravir was added

  11. 48-Week Efficacy and Safety of Dolutegravir Relative to Commonly Used Third Agents in Treatment-Naive HIV-1–Infected Patients: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Patel, Dipen A.; Snedecor, Sonya J.; Tang, Wing Yu; Sudharshan, Lavanya; Lim, Jessica W.; Cuffe, Robert; Pulgar, Sonia; Gilchrist, Kim A.; Camejo, Rodrigo Refoios; Stephens, Jennifer; Nichols, Garrett

    2014-01-01

    Background A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1–infected patients. Methods A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. Results Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. Conclusion Three clinical

  12. Interindividual Variability in Pharmacokinetics of Generic Nucleoside Reverse Transcriptase Inhibitors in TB/HIV Co-infected Ghanaian Patients: UGT2B7*1C is Associated with Faster Zidovudine Clearance and Glucuronidation

    PubMed Central

    Kwara, Awewura; Lartey, Margaret; Boamah, Isaac; Rezk, Naser L.; Oliver-Commey, Joseph; Kenu, Ernest; Kashuba, Angela D.M.; Court, Michael H.

    2009-01-01

    There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, where they are commonly used. We characterized the pharmacokinetics of lamivudine (n=27), zidovudine (n=16) and stavudine (n=11) in HIV/TB co-infected Ghanaians, and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values [mean±SD (CV%)] were 7.3±2.8 (39%), 31.9±33.6 (106%), and 16.4±5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2±1.9 (46%), 8.1±7.9 (98%), and 1.5±1.0 (65%) hr, respectively. Zidovudine CL/F was 196% higher (P=0.004) in UGT2B7*1c (c.735A>G) carriers versus non-carriers. This was confirmed using human liver bank samples (n=52), which showed 48% higher (P=0.020) zidovudine glucuronidation and 33% higher (P=0.015) UGT2B7 protein in UGT2B7*1c carriers versus non-carriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB co-infected Ghanaians are similar to other populations, while the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance. PMID:19628728

  13. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study.

    PubMed

    Kovari, Helen; Sabin, Caroline A; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; d'Arminio Monforte, Antonella; Smith, Colette; de Wit, Stephane; Kirk, Ole; Lundgren, Jens D; Weber, Rainer

    2016-01-01

    Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results.  Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89-6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11-1.49; >2 years RR = 1.26, 95% CI, 1.13-1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26-1.81; >2 years RR = 1.17, 95% CI, 1.03-1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40-1.72; >2 years RR = 1.18, 95% CI, 1.05-1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29-1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03-1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04-1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04-1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions.  Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.

  14. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

    PubMed Central

    Kovari, Helen; Sabin, Caroline A.; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; d'Arminio Monforte, Antonella; Smith, Colette; de Wit, Stephane; Kirk, Ole; Lundgren, Jens D.; Weber, Rainer

    2016-01-01

    Background. Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results. Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions. Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be

  15. Improved Neuropsychological and Neurological Functioning Across Three Antiretroviral Regimens in Diverse Resource-Limited Settings: AIDS Clinical Trials Group Study A5199, the International Neurological Study

    PubMed Central

    Robertson, K.; Jiang, H.; Kumwenda, J.; Supparatpinyo, K.; Evans, S.; Campbell, T. B.; Price, R.; Tripathy, S.; Kumarasamy, N.; La Rosa, A.; Santos, B.; Silva, M. T.; Montano, S.; Kanyama, C.; Faesen, S.; Murphy, R.; Hall, C.; Marra, C. M.; Marcus, C.; Berzins, B.; Allen, R.; Housseinipour, M.; Amod, F.; Sanne, I.; Hakim, J.; Walawander, A.; Nair, A.

    2012-01-01

    Background. AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. Methods. Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. Results. The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). Conclusions. The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization –recommended first-line antiretroviral regimens in resource-limited settings will improve

  16. Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384

    PubMed Central

    Leger, Paul D.; Johnson, Daniel H.; Robbins, Gregory K.; Shafer, Robert W.; Clifford, David B.; Li, Jun; McLaren, Paul J.; Haas, David W.

    2014-01-01

    Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed peripheral neuropathy. The identification of genetic predictors of increased risk might suggest novel therapeutic targets for such patients. In AIDS Clinical Trials Group protocol 384, antiretroviral-naïve patients were randomized to d4T/didanosine (ddI)- or zidovudine/lamivudine-containing regimens. Data from d4T/ddI recipients were analyzed for genome-wide associations (approximately 1 million genetic loci) with new onset distal sensory peripheral neuropathy. Analyses involved 254 patients (49 % White, 34 % Black, 17 % Hispanic), comprising 90 peripheral neuropathy cases (32 grade 1, 35 grade 2, 23 grade 3) and 164 controls. After correcting for multiple comparisons, no polymorphism was consistently associated with neuropathy among all patients, among White, Black, and Hispanic patients analyzed separately, both in genome-wide analyses (threshold, P<5.0×10−8) and focused on 46 neuropathy-associated genes (threshold, P<3.5×10−5). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P=8.4×10−4), in LITAF among Blacks (rs13333308, P=6.0×10−6), and in NEFL among Hispanics (rs17763685, P=5.6×10−6). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect. PMID:24554482

  17. Development and Evaluation of an Oligonucleotide Ligation Assay for Detection of Drug Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 2 pol Gene▿

    PubMed Central

    Jallow, Sabelle; Kaye, Steve; Schutten, Martin; Brandin, Eleonor; Albert, Jan; McConkey, Samuel J.; Corrah, Tumani; Whittle, Hilton; Vanham, Guido; Rowland-Jones, Sarah; Janssens, Wouter

    2007-01-01

    Human immunodeficiency virus type 2 (HIV-2) is naturally resistant to several antiretroviral drugs, including all of the non-nucleoside reverse transcriptase inhibitors and the entry inhibitor T-20, and may have reduced susceptibility to some protease inhibitors. These resistance properties make treatment of HIV-2 patients difficult, with very limited treatment options. Therefore, early detection of resistance mutations is important for understanding treatment failures and guiding subsequent therapy decisions. With the Global Fund Initiative, a substantial number of HIV-2 patients in West Africa will receive antiretroviral therapy. Therefore, development of cheaper and more sustainable resistance assays, such as the oligonucleotide ligation assay (OLA), is a priority. In this study, we designed oligonucleotide probes to detect the Q151M mutation, associated with phenotypic resistance to zidovudine, didanosine, zalcitabine, and stavudine, and the M184V mutation, associated with phenotypic resistance to lamivudine and emtricitabine, in HIV-2. The assay was successfully developed and evaluated with 122 samples from The Gambia, Guinea Bissau, The Netherlands, and Sweden. The overall sensitivity of the assay was 98.8%, with 99.2% for Q151M and 98.4% for M184V. OLA results were compared with sequencing to give high concordances of 98.4% (Q151M) and 97.5% (M184V). OLA demonstrated a higher sensitivity for detection of minor variants as a mixture of wild-type and mutant viruses in cases when sequencing detected only the major population. In conclusion, we have developed a simple, easy-to-use, and economical assay for genotyping of drug resistance in HIV-2 that is more sustainable for use in resource-poor settings than is consensus sequencing. PMID:17329450

  18. Change in Vitamin D Levels Occurs Early after Antiretroviral Therapy Initiation and Depends on Treatment Regimen in Resource-Limited Settings

    PubMed Central

    Havers, Fiona P.; Detrick, Barbara; Cardoso, Sandra W.; Berendes, Sima; Lama, Javier R.; Sugandhavesa, Patcharaphan; Mwelase, Noluthando H.; Campbell, Thomas B.; Gupta, Amita

    2014-01-01

    Study Background Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations. Methods Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation. Results Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: −7.94 [95% Confidence Interval (CI) −10.42, −5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: −6.66 [95% CI −9.40, −3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: −2.29 [95% CI –4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001). Conclusion Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care. PMID:24752177

  19. Change in vitamin d levels occurs early after antiretroviral therapy initiation and depends on treatment regimen in resource-limited settings.

    PubMed

    Havers, Fiona P; Detrick, Barbara; Cardoso, Sandra W; Berendes, Sima; Lama, Javier R; Sugandhavesa, Patcharaphan; Mwelase, Noluthando H; Campbell, Thomas B; Gupta, Amita

    2014-01-01

    Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations. Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation. Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: -7.94 [95% Confidence Interval (CI) -10.42, -5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: -6.66 [95% CI -9.40, -3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: -2.29 [95% CI -4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001). Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care.

  20. Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors.

    PubMed

    Benhammou, Valérie; Warszawski, Josiane; Bellec, Stéphanie; Doz, François; André, Nicolas; Lacour, Brigitte; Levine, Martine; Bavoux, Françoise; Tubiana, Roland; Mandelbrot, Laurent; Clavel, Jacqueline; Blanche, Stéphane

    2008-10-18

    Long-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules. To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers. Cancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population. Ten cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990-1999 or 2000-2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3-1.5) and 1.0 (0.5-1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0-7.2] P = 0.05 and 2.4 [0.8-5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine-lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5-73.9)]. This study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.

  1. Simultaneous analysis of several antiretroviral nucleosides in rat-plasma by high-performance liquid chromatography with UV using acetic acid/hydroxylamine buffer Test of this new volatile medium-pH for HPLC-ESI-MS/MS.

    PubMed

    Bezy, Vincent; Morin, Philippe; Couerbe, Philippe; Leleu, Ghislaine; Agrofoglio, Luigi

    2005-07-25

    Zalcitabine (ddC), lamivudine (3TC), didanosine (ddI), stavudine (d4T), carbovir (CBV), zidovudine (AZT), tenofovir (PMPA) and its administrated form (tenofovir diisoproxyl fumarate, TDF), are nucleosides currently approved in HIV therapy. To facilitate pharmacokinetics studies, a specific reversed-phase high-performance liquid chromatography (HPLC) method was developed for their analysis in rat plasma. The method involved a quantitative recovery of these drugs from rat plasma by solid-phase extraction on Oasis HLB Waters cartridges followed by optimised HPLC separation on an Atlantis dC18 column with acetic acid-hydroxylamine buffer (ionic strength 5mM, pH 7)-acetonitrile elution gradient. Quantitation was performed by HPLC/UV at 260 nm. Linear calibration curves were obtained within a 30-10,000 ng/mL plasma concentration range. Correlation coefficients (r2) greater than 0.992 were obtained by least-squares regression and limits of quantification were in 30-90 ng/mL concentration range. Quantitative parameters (accuracy, intra-day repeatability and inter-day reproducibility) yielded satisfactory results. Finally, a new buffer, obtained with acetic acid and hydroxylamine, has been tested in HPLC/ESI-MS/MS and appears to be an efficient volatile buffer in the medium 5-7 pH range. Indeed, at pH 7 and low ionic strength (5 mM), its buffer capacity is one hundred times higher to that obtained for the usual acetic acid/ammonia buffer.

  2. National adult antiretroviral therapy guidelines in resource-limited countries: concordance with 2003 WHO guidelines?

    PubMed

    Beck, Eduard J; Vitoria, Marco; Mandalia, Sundhiya; Crowley, Siobhan; Gilks, Charles F; Souteyrand, Yves

    2006-07-13

    To investigate the existence of national adult antiretroviral therapy (ART) guidelines in 43 World Health Organization (WHO) '3 by 5' focus countries and compare their content with the 2003 WHO ART guidelines. Questionnaires covered initiation of ART, selection of first or second-line ART, monitoring treatment response and toxicity and dissemination of national guidelines. Weighted concordance scores were created and country scores correlated with national indicators and WHO recommendations. Thirty-nine (91%) countries returned questionnaires, three of which had no national ART guidelines. Of the 36, 16 (44%) recommended to start ART based on WHO clinical staging criteria and CD4 cell count or T-lymphocyte count, 12 (33%) WHO clinical staging criteria and CD4 cell count, four (11%) only CD4 cell counts. 35 (97%) recommended a standard first-line regimen and 24 (67%) preferred stavudine + lamivudine + nevirapine; 33 (92%) recommended second-line regimens, and 24 (60%) preferred abacavir + didanosine + lopinavir/ritonavir. Thirty-one (94%) recommended CD4 cell count, possibly combined with other indicators, to monitor ART. Concordance scores were higher in countries with lower health expenditure per capita (P = 0.009) and lower GDP per capita (P < 0.03). Median concordance scores for starting ART was 100 [interquartile range (IQR), 67 to 100]; first line therapy, 70 (IQR, 60 to 80); second-line regimens, 45 (IQR, 27 to 55) and for laboratory investigations, 80 (IQR, 80 to 100). Most countries had developed national ART guidelines as part of a comprehensive national HIV program. Concordance with WHO recommendations was strong on starting first-line ART regimens and routine monitoring but lower for second-line recommendations.

  3. Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism.

    PubMed

    Saeedi, Ramesh; Mojebi-Mogharar, Ali; Sandhu, Supna K; Dubland, Joshua A; Ford, Jo-Ann; Yousefi, Masoud; Pudek, Morris; Holmes, Daniel T; Erb, Siegfried R; Peter Kwan, Wing; Kendler, David L; Yoshida, Eric M

    2017-01-01

    Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (&lt;-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

  4. Tempol protects cardiomyocytes from nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity.

    PubMed

    Liu, Yongmin; Shim, Eunwoo; Nguyen, Phuonggiang; Gibbons, Alexander T; Mitchell, James B; Poirier, Miriam C

    2014-05-01

    Nucleoside reverse transcriptase inhibitors (NRTIs), essential components of combinational therapies used for treatment of human immunodeficiency virus-1, damage heart mitochondria. Here, we have shown mitochondrial compromise in H9c2 rat cardiomyocytes exposed for 16 passages (P) to the NRTIs zidovudine (AZT, 50μM) and didanosine (ddI, 50μM), and we have demonstrated protection from mitochondrial compromise in cells treated with 200μM 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (Tempol) or 200μM 1-hydroxy-4-[2-triphenylphosphonio)-acetamido]-2,2,6,6-tetramethylpiperidine (Tempol-H), along with AZT/ddI, for 16P. Exposure to AZT/ddI caused a moderate growth inhibition at P3, P5, P7, and P13, which was not altered by addition of Tempol or Tempol-H. Mitochondrial oxidative phosphorylation capacity was determined as uncoupled oxygen consumption rate (OCR) by Seahorse XF24 Analyzer. At P5, P7, and P13, AZT/ddI-exposed cells showed an OCR reduction of 8.8-57.2% in AZT/ddI-exposed cells, compared with unexposed cells. Addition of Tempol or Tempol-H, along with AZT/ddI, resulted in OCR levels increased by about 300% above the values seen with AZT/ddI alone. The Seahorse data were further supported by electron microscopy (EM) studies in which P16 cells exposed to AZT/ddI/Tempol had less mitochondrial pathology than P16 cells exposed to AZT/ddI. Western blots of P5 cells showed that Tempol and Tempol-H upregulated expression of mitochondrial uncoupling protein-2 (UCP-2). However, Complex I activity that was reduced by AZT/ddI, was not restored in the presence of AZT/ddI/Tempol. Superoxide levels were increased in the presence of AZT/ddI and significantly decreased in cells exposed to AZT/3TC/Tempol at P3, P7, and P10. In conclusion, Tempol protects against NRTI-induced mitochondrial compromise, and UCP-2 plays a role through mild uncoupling.

  5. Tempol Protects Cardiomyocytes from Nucleoside Reverse Transcriptase Inhibitor-Induced Mitochondrial Toxicity

    PubMed Central

    Liu, Yongmin; Shim, Eunwoo; Nguyen, Phuonggiang; Gibbons, Alexander T.; Mitchell, James B.; Poirier, Miriam C.

    2014-01-01

    Nucleoside reverse transcriptase inhibitors (NRTIs), essential components of combinational therapies used for treatment of human immunodeficiency virus-1, damage heart mitochondria. Here, we have shown mitochondrial compromise in H9c2 rat cardiomyocytes exposed for 16 passages (P) to the NRTIs zidovudine (AZT, 50μM) and didanosine (ddI, 50μM), and we have demonstrated protection from mitochondrial compromise in cells treated with 200μM 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (Tempol) or 200μM 1-hydroxy-4-[2-triphenylphosphonio)-acetamido]-2,2,6,6-tetramethylpiperidine (Tempol-H), along with AZT/ddI, for 16P. Exposure to AZT/ddI caused a moderate growth inhibition at P3, P5, P7, and P13, which was not altered by addition of Tempol or Tempol-H. Mitochondrial oxidative phosphorylation capacity was determined as uncoupled oxygen consumption rate (OCR) by Seahorse XF24 Analyzer. At P5, P7, and P13, AZT/ddI-exposed cells showed an OCR reduction of 8.8–57.2% in AZT/ddI-exposed cells, compared with unexposed cells. Addition of Tempol or Tempol-H, along with AZT/ddI, resulted in OCR levels increased by about 300% above the values seen with AZT/ddI alone. The Seahorse data were further supported by electron microscopy (EM) studies in which P16 cells exposed to AZT/ddI/Tempol had less mitochondrial pathology than P16 cells exposed to AZT/ddI. Western blots of P5 cells showed that Tempol and Tempol-H upregulated expression of mitochondrial uncoupling protein-2 (UCP-2). However, Complex I activity that was reduced by AZT/ddI, was not restored in the presence of AZT/ddI/Tempol. Superoxide levels were increased in the presence of AZT/ddI and significantly decreased in cells exposed to AZT/3TC/Tempol at P3, P7, and P10. In conclusion, Tempol protects against NRTI-induced mitochondrial compromise, and UCP-2 plays a role through mild uncoupling. PMID:24591154

  6. Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.

    PubMed

    Hillaireau, Hervé; Dereuddre-Bosquet, Nathalie; Skanji, Rym; Bekkara-Aounallah, Fawzia; Caron, Joachim; Lepêtre, Sinda; Argote, Sébastien; Bauduin, Laurent; Yousfi, Rahima; Rogez-Kreuz, Christine; Desmaële, Didier; Rousseau, Bernard; Gref, Ruxandra; Andrieux, Karine; Clayette, Pascal; Couvreur, Patrick

    2013-07-01

    Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of (3)H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free (3)H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.

  7. An analysis of drug resistance among people living with HIV/AIDS in Shanghai, China

    PubMed Central

    Sun, Meiyan; Sun, Jianjun; Lu, Hongzhou

    2017-01-01

    Background Understanding the mechanisms of drug resistance can facilitate better management of antiretroviral therapy, helping to prevent transmission and decrease the morbidity and mortality of people living with HIV/AIDS. However, there is little data about transmitted drug resistance and acquired drug resistance for HIV/AIDS patients in Shanghai. Methods A retrospective cohort study of HIV-infected patients who visited the Department of Infectious Disease from June 2008 to June 2015 was conducted in Shanghai, China. Logistic regression analysis was performed to analyze risk factors for drug resistance among HIV-infected people with virological failure. The related collected factors included patient age, gender, marital status, infection route, baseline CD4 count, antiretroviral therapy regimens, time between HIV diagnosis and initiating antiretroviral therapy. Factors with p<0.1 in the univariate logistic regression test were analyzed by multivariate logistic regression test. Results There were 575 subjects selected for this study and 369 participated in this research. For the antiretroviral therapy drugs, the rates of transmitted drug resistance and acquired drug resistance were significantly different. The non-nucleoside reverse transcriptase inhibitor (NNRTI) had the highest drug resistance rate (transmitted drug resistance, 10.9%; acquired drug resistance, 53.3%) and protease inhibitors (PIs) had the lowest drug resistance rate (transmitted drug resistance, 1.7%; acquired drug resistance, 2.7%). Logistic regression analysis found no factors that were related to drug resistance except marital status (married status for tenofovir: odds ratio = 6.345, 95% confidence interval = 1.553–25.921, P = 0.010) and the time span between HIV diagnosis and initiating antiretroviral therapy (≤6M for stavudine: odds ratio = 0.271, 95% confidence interval = 0.086–0.850, P = 0.025; ≤6M for didanosine: odds ratio = 0.284, 95% confidence interval = 0.096–0.842, P = 0

  8. Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

    PubMed Central

    Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R.; Taylor, Jonathan; Lemey, Philippe; Varghese, Vici; Hamers, Raph L.; Bertagnolio, Silvia; de Wit, Tobias F. Rinke; Aghokeng, Avelin F.; Albert, Jan; Avi, Radko; Avila-Rios, Santiago; Bessong, Pascal O.; Brooks, James I.; Boucher, Charles A. B.; Brumme, Zabrina L.; Busch, Michael P.; Bussmann, Hermann; Chaix, Marie-Laure; Chin, Bum Sik; D’Aquin, Toni T.; De Gascun, Cillian F.; Derache, Anne; Descamps, Diane; Deshpande, Alaka K.; Djoko, Cyrille F.; Eshleman, Susan H.; Fleury, Herve; Frange, Pierre; Fujisaki, Seiichiro; Harrigan, P. Richard; Hattori, Junko; Holguin, Africa; Hunt, Gillian M.; Ichimura, Hiroshi; Kaleebu, Pontiano; Katzenstein, David; Kiertiburanakul, Sasisopin; Kim, Jerome H.; Kim, Sung Soon; Li, Yanpeng; Lutsar, Irja; Morris, Lynn; Ndembi, Nicaise; NG, Kee Peng; Paranjape, Ramesh S.; Peeters, Martine; Poljak, Mario; Price, Matt A.; Ragonnet-Cronin, Manon L.; Reyes-Terán, Gustavo; Rolland, Morgane; Sirivichayakul, Sunee; Smith, Davey M.; Soares, Marcelo A.; Soriano, Vincent V.; Ssemwanga, Deogratius; Stanojevic, Maja; Stefani, Mariane A.; Sugiura, Wataru; Sungkanuparph, Somnuek; Tanuri, Amilcar; Tee, Kok Keng; Truong, Hong-Ha M.; van de Vijver, David A. M. C.; Vidal, Nicole; Yang, Chunfu; Yang, Rongge; Yebra, Gonzalo; Ioannidis, John P. A.; Vandamme, Anne-Mieke; Shafer, Robert W.

    2015-01-01

    NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen. PMID:25849352

  9. Successful simplification of HAART in patients with acute primary HIV infection.

    PubMed

    Sinicco, A; Bonora, S; Arnaudo, I; Zeme, D A; Audagnotto, S; Raiteri, R; Di Perri, G

    2002-01-01

    Aggressive treatment has been advocated for the management of primary HIV infection (PHI), but the composition and the optimal duration of therapy are still to be determined. In addition, time to undetectable viral load (VL), rate and duration of VL suppression as well as subsequent therapeutic choices remain issues widely debated. We evaluated the rate and duration of VL suppression in 12 consecutive patients with PHI given triple-drug treatment with zidovudine, lamivudine and indinavir (highly active antiretroviral therapy, HAART) at onset of the acute illness and subsequently switched to a simplified 2-NRTI-based regimen once VL suppression was maintained for at least 6 months. Throughout the study, no patient discontinued treatment because of symptoms attributed to the study medications. In the study population, undetectable VL was achieved after a median of 84 days (range: 67-135) on HAART and was maintained for a median of 194 days (range: 179-205) before simplification. After switching to simplified maintenace, undetectable VL was maintained in all patients for at least 6 months. Only one patient experienced virological failure, plasma HIV-RNA remaining suppressed for a median foliow-up of 33 months (15-54) and T-CD4+ being steadily higher than 500/mL in the remaining patients. Our results suggest that simplification of HAART in patients promptly treated during PHI and maintaining undetectable VL for at least 6 months before simplification may be a valid option capable of controlling viral replication and maintaining an optimal immunological profile for a prolonged time.

  10. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials

    PubMed Central

    Raffi, François; Rachlis, Anita; Brinson, Cynthia; Arasteh, Keikawus; Górgolas, Miguel; Brennan, Clare; Pappa, Keith; Almond, Steve; Granier, Catherine; Nichols, W. Garrett; Cuffe, Robert Liam; Jr, Joseph Eron; Walmsley, Sharon

    2015-01-01

    Objectives: Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. Design: Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. Methods: We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. Results: Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4+ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) −1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference −2.5, 95% CI −8.9, 3.8 percentage points, P = 0.42). Conclusions: DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics. PMID:25387312

  11. Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?

    PubMed Central

    The Antiretroviral Cohort Collaboration (ART-CC); Mugavero, Michael J.; May, Margaret; Harris, Ross; Saag, Michael S.; Costagliola, Dominique; Egger, Matthias; Phillips, Andrew; Günthard, Huldrych F.; Dabis, Francois; Hogg, Robert; De Wolf, Frank; Fatkenheuer, Gerd; John Gill, M.; Justice, Amy; D'Arminio Monforte, Antonella; Lampe, Fiona; Miró, Jose M.; Staszewski, Schlomo; Sterne, Jonathan A. C.

    2008-01-01

    Objective To determine if differences in short-term virologic failure among commonly used ART regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART. Design Observational cohort study of patients initiating ART between January 2000 and December 2005. Setting The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. Subjects, participants A total of 13,546 antiretroviral-naïve HIV-positive patients initiating ART with efavirenz (EFV), nevirapine (NVP), lopinavir/ritonavir (LPV/r), nelfinavir (NFV), or abacavir (ABC) as third drugs in combination with a zidovudine and lamivudine NRTI backbone. Main outcome measures Short-term (24-week) virologic failure (>500 copies/mL) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). Results Compared with EFV as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; NVP (adjusted odds ratio=1.87, 95%CI=1.58,2.22), LPV/r (1.32, 95%CI=1.12–1.57), NFV (3.20, 95%CI=2.74,3.74), and ABC (2.13, 95%CI=1.82,2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with NVP (adjusted hazard ratio for composite outcome measure 1.27, 95%CI=1.04,1.56) and ABC (1.22, 95%CI=1.00,1.48). Conclusions Among antiretroviral-naïve patients initiating therapy, between-ART regimen differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication. PMID:19005271

  12. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

    PubMed

    Günthard, Huldrych F; Aberg, Judith A; Eron, Joseph J; Hoy, Jennifer F; Telenti, Amalio; Benson, Constance A; Burger, David M; Cahn, Pedro; Gallant, Joel E; Glesby, Marshall J; Reiss, Peter; Saag, Michael S; Thomas, David L; Jacobsen, Donna M; Volberding, Paul A

    New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in

  13. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials.

    PubMed

    Raffi, François; Rachlis, Anita; Brinson, Cynthia; Arasteh, Keikawus; Górgolas, Miguel; Brennan, Clare; Pappa, Keith; Almond, Steve; Granier, Catherine; Nichols, W Garrett; Cuffe, Robert Liam; Eron, Joseph; Walmsley, Sharon

    2015-01-14

    Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⁺ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) -1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, P = 0.42). DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics.

  14. Nucleoside reverse transcriptase inhibitors (NRTIs)-induced expression profile of mitochondria-related genes in the mouse liver.

    PubMed

    Desai, Varsha G; Lee, Taewon; Delongchamp, Robert R; Leakey, Julian E A; Lewis, Sherry M; Lee, Fei; Moland, Carrie L; Branham, William S; Fuscoe, James C

    2008-03-01

    Mitochondrial dysfunction has been implicated in the adverse effects of nucleoside reverse transcriptase inhibitors (NRTIs) used to treat HIV-1 infections. To gain insight into the mechanism by which NRTIs alter mitochondrial function, the expression level of 542 genes associated with mitochondrial structure and functions was determined in the livers of p53 haplodeficient (+/-) C3B6F1 female mouse pups using mouse mitochondria-specific oligonucleotide microarray. The pups were transplacentally exposed to zidovudine (AZT) at 240 mg/kg bw/day or a combination of AZT and lamivudine (3TC) at 160 and 100mg/kg bw/day, respectively, from gestation day 12 through 18, followed by continuous treatment by oral administration from postnatal day 1-28. In addition, AZT/3TC effect was investigated in wild-type (+/+) C3B6F1 female mice. The genotype did not significantly affect the gene expression profile induced by AZT/3TC treatment. However, the transcriptional level of several genes associated with oxidative phosphorylation, mitochondrial tRNAs, fatty acid oxidation, steroid biosynthesis, and a few transport proteins were significantly altered in pups treated with AZT and AZT/3TC compared to their vehicle counterparts. Interestingly, AZT/3TC altered the expression level of 153 genes with false discovery rate of less than 0.05, in contrast to only 20 genes by AZT alone. These results suggest that NRTI-related effect on expression level of genes associated with mitochondrial functions was much greater in response to AZT/3TC combination treatment than AZT alone.

  15. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial

    PubMed Central

    2013-01-01

    Summary Background No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). Methods In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. This trial is registered, ISRCTN24791884. Findings 1206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and

  16. Expenditures for the care of HIV-infected patients in rural areas in China's antiretroviral therapy programs

    PubMed Central

    2011-01-01

    Background The Chinese government has provided health services to those infected by the human immunodeficiency virus (HIV) under the acquired immunodeficiency syndrome (AIDS) care policy since 2003. Detailed research on the actual expenditures and costs for providing care to patients with AIDS is needed for future financial planning of AIDS health care services and possible reform of HIV/AIDS-related policy. The purpose of the current study was to determine the actual expenditures and factors influencing costs for untreated AIDS patients in a rural area of China after initiating highly active antiretroviral therapy (HAART) under the national Free Care Program (China CARES). Methods A retrospective cohort study was conducted in Yunnan and Shanxi Provinces, where HAART and all medical care are provided free to HIV-positive patients. Health expenditures and costs in the first treatment year were collected from medical records and prescriptions at local hospitals between January and June 2007. Multivariate linear regression was used to determine the factors associated with the actual expenditures in the first antiretroviral (ARV) treatment year. Results Five ARV regimens are commonly used in China CARES: zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP), stavudine (D4T) + 3TC + efavirenz (EFV), D4T + 3TC + NVP, didanosine (DDI) + 3TC + NVP and combivir + EFV. The mean annual expenditure per person for ARV medications was US$2,242 (US$1 = 7 Chinese Yuan (CNY)) among 276 participants. The total costs for treating all adverse drug events (ADEs) and opportunistic infections (OIs) were US$29,703 and US$23,031, respectively. The expenses for treatment of peripheral neuritis and cytomegalovirus (CMV) infections were the highest among those patients with ADEs and OIs, respectively. On the basis of multivariate linear regression, CD4 cell counts (100-199 cells/μL versus <100 cells/μL, P = 0.02; and ≥200 cells/μL versus <100 cells/μL, P < 0.004), residence in Mangshi

  17. The 48-week efficacy of once-daily saquinavir/ritonavir in patients with undetectable viral load after 3 years of antiretroviral therapy.

    PubMed

    Cardiello, P; Srasuebkul, P; Hassink, E; Mahanontharit, A; Samor, T; Ruxrungtham, K; Lange, J; Cooper, D; Phanuphak, P

    2005-03-01

    To evaluate the efficacy and safety of once-daily saquinavir-soft-gel-capsules/ritonavir (SQV-SGC/RTV) 1600 mg/100 mg plus dual nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-infected patients with plasma viral load (pVL) <50 HIV-1 RNA copies/mL following 3 years of antiretroviral therapy. A total of 69 patients with pVL <50 copies/mL after 162 weeks of antiretroviral treatment started SQV-SGC/RTV 1600 mg/100 mg once-daily while continuing dual NRTIs. Previous treatment consisted of 66 weeks of treatment with a half/full dose of zidovudine (ZDV)/zalcitabine (ddC), followed by 2 years of SQV-SGC twice a day (bid) plus ZDV/lamivudine (3TC) or didanosine (ddI)/stavudine (d4T). Efficacy (pVL), safety and immunological changes (CD4 cell counts) were evaluated after 48 weeks in this open-label, single-arm prospective study. SQV-SGC/RTV once-daily was well tolerated. No patient changed regimens or was lost to follow-up. After 48 weeks, 63 of 69 patients (91%) had pVL <50 copies/mL (five of the six remaining patients had pVL <400 copies/mL, and one patient had an unexplained rise to 39 500 copies/mL, which decreased to <50 copies/mL 12 weeks later). Median CD4 count increased from 534 cells/muL at the start of the SQV-SGC/RTV once-daily treatment to 664 cells/muL (P<0.001). Compared to the preceding 48 weeks on bid SQV-SGC, the CD4 cell count improved significantly on once-daily SQV-SGC/RTV (P<0.001). These data support the use of SQV-SGC/RTV 1600 mg/100 mg once-daily with two NRTIs as a convenient, safe and cost-saving regimen to maintain viral suppression and CD4 counts for 48 weeks in this preselected cohort on highly active antiretroviral therapy (HAART) with pVL <50 copies/mL. The CD4 count rise may be a result of continued immune reconstitution in patients with well-controlled infection.

  18. Long-term outcomes of second-line antiretroviral treatment in an adult and adolescent cohort in Myanmar.

    PubMed

    Kyaw, Nang Thu Thu; Kumar, Ajay M V; Oo, Myo Minn; Oo, Htun Nyunt; Kyaw, Khine Wut Yee; Thiha, Soe; Aung, Thet Ko; Win, Than; Mon, Yin Yin; Harries, Anthony D

    2017-01-01

    Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now. To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged ≥ 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015. Retrospective cohort study using routinely collected program data. Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes. Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs available after a careful cost-benefit analysis.

  19. Long-term outcomes of second-line antiretroviral treatment in an adult and adolescent cohort in Myanmar

    PubMed Central

    Kyaw, Nang Thu Thu; Kumar, Ajay M. V.; Oo, Myo Minn; Oo, Htun Nyunt; Kyaw, Khine Wut Yee; Thiha, Soe; Aung, Thet Ko; Win, Than; Mon, Yin Yin; Harries, Anthony D.

    2017-01-01

    ABSTRACT Background: Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now. Objective: To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged ≥ 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015. Design: Retrospective cohort study using routinely collected program data. Results: Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes. Conclusions: Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs

  20. Eruptive cheilitis: a new adverse effect in reactive HIV-positive patients subjected to high activity antiretroviral therapy (HAART). Presentation of six clinical cases.

    PubMed

    Casariego, Z; Pombo, T; Pérez, H; Patterson, P

    2001-01-01

    A variety of exfoliative cheilitis has been observed in reactive HIV-1 patients subjected to high activity antiretroviral therapy (HAART). The lesions exhibit exfoliation, crater formation, fissuring, erosions and/or the formation of papules, vesicles and blisters associated to erythema and edema. The condition is not included in the 1993 EEC Clearinghouse classification (1) of oral lesions associated with HIV infection. In an earlier series of 1899 patients (2), we failed to observe this pathology and have only found one similar case described in the literature to date (3). We present a series of 6 patients with HIV infection and morpho-histological alterations of the labial semimucosa, subjected to HAART. The 6 patients were selected from among 20 HIV-positive individuals treated in our Infectious Diseases Unit with a combination of nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors requiring stomatological care for painful lesions of the lips and oral cavity. The study was conducted over a 6-month period between May and October 1998. An analysis was made of the case histories, CD4-positive cell counts and viral load. The stomatological explorations were completed with biopsies, hematoxylin-eosin staining and immunohistochemical studies involving AE1 and AE3 monoclonal antibodies, vimentin, protein S-100, carcinoembryonic antigen (CEA), laminin, CD8, HLA-DR, BM-1 and CD31 markers. At the time of detection of the oral lesions, the patients had received different combinations of the following antiretroviral treatments: stavudine (D4T), zalcitabine (DDC), didanosine (DDI), zidovudine (AZT), lamivudine (3TC), nelfinavir (NFV), saquinavir (SQV), ritonavir (RTV), hydroxyurea (HU), indinavir (IDN) and efavirenz (EFV). There were four males and two females (age range 31-42 years). The CD4-positive and viral load ranges were 70-330 cells/mm3 and 200-500,200 copies, respectively. Stomatologic manifestations: The oral clinical

  1. Online solid phase extraction and liquid chromatography-mass spectrometric determination of nucleoside drugs in plasma.

    PubMed

    Wang, Man; Ma, Ping; Xi, Xiaonan; Liu, Lei; Wen, Yabin; Liu, Kangning; Sun, Liang; Lu, Yaxin; Yin, Zheng

    2016-12-01

    The bioanalysis and especially the sample preparation of nucleoside drugs in complex media, such as human plasma, has been challenging due to the high polarity and high solubility of these drugs in water. Online solid phase extraction (SPE) offers significant advantages, such as automation and timesaving. Thus, several types of SPE columns have been developed for compounds with different polarities. In this study, SPE was applied to overcome the issue of sample pretreatment of nucleoside drugs in human plasma, with the final aim of establishing a robust analytical platform for drugs with similar structures. A simple, easy-to-use, and efficient method is described for the simultaneous determination of lamivudine, zidovudine, didanosine and emtricitabine in human plasma via online SPE and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Following a simple centrifugation step, a 10μL plasma sample was injected directly onto the HPLC system. The Oasis MCX cartridge was washed, and the analytes were removed by back-flushing directly onto the analytical column. The analytes were quantified using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. Similarly, with the development and application of a Bond Elut phenylboronic acid (PBA) SPE cartridge, a fully automated online SPE-HPLC-MS/MS method was established for the simultaneous determination of ribavirin and taribavirin in human plasma. Linear calibration curves were obtained over the range of 0.5-2000ngmL(-1), and the limit of quantification ranged from 0.5ngmL(-1) to 10ngmL(-1), which is sensitive enough for clinical drug monitoring. The intra- and inter-day precisions were in the range of 0.2-8.9%, and the trueness ranged between 88.9% and 113.1%. Excellent recoveries from plasma were achieved with a range between 86.7% and 105.1%. This procedure is easier to perform and requires less sample handling compared to methods previously described in the

  2. Virologic response and safety of the abacavir/lamivudine fixed-dose formulation as part of highly active antiretroviral therapy: analyses of six clinical studies.

    PubMed

    Ha, Belinda; Liao, Qiming M; Dix, Lynn P; Pappa, Keith A

    2009-01-01

    We analyzed virologic response and safety data from six recent clinical studies conducted in antiretroviral-naïve subjects treated with ABC/3TC or its components to assess the impact of baseline viral load on efficacy and safety endpoints used in the ACTG5202 protocol. Primary endpoints were time to virologic failure (confirmed HIV-1 RNA > or = 1,000 copies/mL at 16-24 weeks or > or = 200 copies/mL at > or = 24 weeks) and time to first grade 3 or 4 adverse event or laboratory abnormality that was at least one grade higher than at baseline. The survival distributions of both endpoints were estimated using the Kaplan-Meier method overall and by baseline viral load (<100,000 vs. 100,000 copies/mL). A weighted mean of the virologic response and 95% confidence intervals (CI) were calculated by inverse-variance weighting for baseline viral load 100,000 copies/mL across studies. For subjects with baseline HIV-1 RNA 100,000 copies/mL, the rate of virologic survival ranged from 87% to 95% by 48 weeks. Few subjects treated with ABC/3TC developed grade 3 or 4 adverse events, laboratory toxicities, or changes in lipid levels. The weighted mean (CI) for the pooled virologic response was 91% (87%-96%). Based on the A5202 endpoints, ABC/3TC-containing regimens in this analysis had a high rate of virologic survival and were generally well tolerated in antiretroviral-naïve subjects regardless of baseline viral load. The pooled virologic response for ABC/3TC in our analysis is higher than the A5202 estimate.

  3. Steady-state nevirapine, lamivudine and stavudine levels in Malawian HIV-infected children on antiretroviral therapy using split Triomune 30 tablets.

    PubMed

    Poerksen, Goenke; Pollock, Louisa; Moons, Peter; Chesshyre, Emily; Burger, David; Khoo, Saye; Molyneux, Elizabeth

    2010-01-01

    Children remain under-represented in national antiretroviral treatment (ART) programmes in settings with limited resources and high HIV prevalence. In Malawi, an increasing number of HIV-infected children have been started on ART with split tablets of an adult fixed-dose combination drug in the past few years. In 2006, the national paediatric ART regime was changed from Triomune 40 (T40) to Triomune 30 (T30). This was a cross-sectional study conducted at the paediatric ART clinic in Blantyre (Malawi) from September 2006 to July 2007. Children taking T30 for > 6 weeks from each dosing weight band (<5, 5-<8, 8-<12, 12-<14, 14-<19, 19-<26, 26-<30 and > or = 30 kg) were recruited. Plasma drug concentration, CD4+ T-cell count and HIV viral load were measured. A total of 74 children were analysed. The median nevirapine (NVP) concentration was 7.35 mg/l. A therapeutic NVP plasma level > 3 mg/l was found in 62 (87.8%) children. A subtherapeutic NVP level (< 3 mg/l) occurred significantly more often in children treated with T30 doses between one-quarter tablet once daily and one-half tablet twice daily (P=0.035). Median prescribed NVP dose was 342 mg/m(2)/day, but 13 (17.6%) children received a dose below the recommended dose of 300 mg/m(2)/day. Compared with a historical control, the median prescribed NVP dose was increased (from 243 to 342 mg/m(2)/day). Our findings indicate that with the Malawian T30-based ART regime, the majority (87.8%) of children in the study group achieved a therapeutic NVP level. However, treatment remains suboptimal especially for young children receiving T30 dosages less than or equal to one-half tablets twice daily and child appropriate formulations are warranted.

  4. Lopinavir and Ritonavir

    MedlinePlus

    ... irregular heartbeat such as amiodarone (Cordarone, Nexterone, Pacerone), lidocaine (Lidoderm; in Xylocaine with Epinephrine), and quinidine (in ... taking didanosine, take it 1 hour before or 2 hours after you take lopinavir and ritonavir solution ...

  5. Recreational Drugs and HIV

    MedlinePlus

    ... when used with didanosine (Videx, fact_sheet 413 ) Cocaine Although interactions between cocaine and ARVs are unlikely to increase cocaine toxicity, the cocaine use may decrease ARV effectiveness ...

  6. Approved Generic Formulations of Antiretroviral Drugs Used in the Treatment of HIV Infection

    MedlinePlus

    ... Name Approval Date Time to Approval* lamivudine and zidovudine tablets USP, 150 mg/300 mg Hetero Labs ... 15-May-2012 84.5 months lamivudine and zidovudine tablets, 150 mg/300 mg Aurobindo Pharma Limited ...

  7. Drug resistance testing through remote genotyping and predicted treatment options in human immunodeficiency virus type 1 infected Tanzanian subjects failing first or second line antiretroviral therapy.

    PubMed

    Svärd, Jenny; Mugusi, Sabina; Mloka, Doreen; Neogi, Ujjwal; Meini, Genny; Mugusi, Ferdinand; Incardona, Francesca; Zazzi, Maurizio; Sönnerborg, Anders

    2017-01-01

    Antiretroviral therapy (ART) has been successfully introduced in low-middle income countries. However an increasing rate of ART failure with resistant virus is reported. We therefore described the pattern of drug resistance mutations at antiretroviral treatment (ART) failure in a real-life Tanzanian setting using the remote genotyping procedure and thereafter predicted future treatment options using rule-based algorithm and the EuResist bioinformatics predictive engine. According to national guidelines, the default first-line regimen is tenofovir + lamivudine + efavirenz, but variations including nevirapine, stavudine or emtricitabine can be considered. If failure on first-line ART occurs, a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and boosted lopinavir or atazanavir is recommended. Plasma was obtained from subjects with first (n = 174) or second-line (n = 99) treatment failure, as defined by clinical or immunological criteria, as well as from a control group of ART naïve subjects (n = 17) in Dar es Salaam, Tanzania. Amplification of the pol region was performed locally and the amplified DNA fragment was sent to Sweden for sequencing (split genotyping procedure). The therapeutic options after failure were assessed by the genotypic sensitivity score and the EuResist predictive engine. Viral load was quantified in a subset of subjects with second-line failure (n = 52). The HIV-1 pol region was successfully amplified from 55/174 (32%) and 28/99 (28%) subjects with first- or second-line failure, respectively, and 14/17 (82%) ART-naïve individuals. HIV-1 pol sequence was obtained in 82 of these 97 cases (84.5%). Undetectable or very low (<2.6 log10 copies/10-3 L) viral load explained 19 out of 25 (76%) amplification failures in subjects at second-line ART failure. At first and second line failure, extensive accumulation of NRTI (88% and 73%, respectively) and NNRTI (93% and 73%, respectively) DRMs but a limited number of PI DRMs (11% at

  8. HIV Drug Resistance in Antiretroviral Treatment-Naïve Individuals in the Largest Public Hospital in Nicaragua, 2011-2015.

    PubMed

    Avila-Ríos, Santiago; García-Morales, Claudia; Matías-Florentino, Margarita; Tapia-Trejo, Daniela; Hernández-Álvarez, Bismarck F; Moreira-López, Sumaya E; Quant-Durán, Carlos J; Porras-Cortés, Guillermo; Reyes-Terán, Gustavo

    2016-01-01

    Increasing HIV pre-treatment drug resistance (PDR) levels have been observed in regions with increasing antiretroviral treatment (ART) coverage. However, data is lacking for several low/middle-income countries. We present the first PDR survey in Nicaragua since ART introduction in the country in 2003. HIV-infected, ART-naïve Nicaraguan individuals were enrolled at Roberto Calderón Hospital, the largest national HIV referral center, from 2011 to 2015. HIV pol sequences were obtained at a WHO-accredited laboratory in Mexico by Sanger and next generation sequencing (NGS). PDR was assessed using the WHO surveillance drug resistance mutation (SDRM) list and the Stanford HIVdb tool. 283 individuals were enrolled in the study. The overall PDR prevalence based on the list of SDRMs was 13.4%. Using the Stanford HIVdb tool, overall PDR reached 19.4%; with both nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI) PDR levels independently reaching moderate levels (6.7% and 11.3% respectively). Protease inhibitor PDR was low (2.8%). Using NGS with 2% threshold to detect SDRMs, PDR increased to 25.3%. K103N and M41L were the most frequent SDRMs and were present mostly in proportions >20% in each individual. A significant temporal increase in NNRTI PDR was observed (p = 0.0422), with no apparent trends for other drug classes. Importantly, PDR to zidovudine + lamivudine + efavirenz and tenofovir + emtricitabine + efavirenz, the most widely used first-line regimens in Nicaragua, reached 14.6% and 10.4% respectively in 2015. Of note, a higher proportion of females was observed among individuals with PDR compared to individuals without PDR (OR 14.2; 95% CI: 7.1-28.4; p<0.0001). Overall PDR in the Nicaraguan cohort was high (19.4%), with a clear increasing temporal trend in NNRTI PDR. Current HIVDR to the most frequently used first-line ART regimens in Nicaragua reached levels >10%. These observations are worrisome and need to be evidenced to strengthen the

  9. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study.

    PubMed

    Clotet, Bonaventura; Feinberg, Judith; van Lunzen, Jan; Khuong-Josses, Marie-Aude; Antinori, Andrea; Dumitru, Irina; Pokrovskiy, Vadim; Fehr, Jan; Ortiz, Roberto; Saag, Michael; Harris, Julia; Brennan, Clare; Fujiwara, Tamio; Min, Sherene

    2014-06-28

    Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100,000 or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929. Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9-13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly

  10. HIV Drug Resistance in Antiretroviral Treatment-Naïve Individuals in the Largest Public Hospital in Nicaragua, 2011-2015

    PubMed Central

    Tapia-Trejo, Daniela; Hernández-Álvarez, Bismarck F.; Moreira-López, Sumaya E.; Quant-Durán, Carlos J.; Porras-Cortés, Guillermo; Reyes-Terán, Gustavo

    2016-01-01

    Background Increasing HIV pre-treatment drug resistance (PDR) levels have been observed in regions with increasing antiretroviral treatment (ART) coverage. However, data is lacking for several low/middle-income countries. We present the first PDR survey in Nicaragua since ART introduction in the country in 2003. Methods HIV-infected, ART-naïve Nicaraguan individuals were enrolled at Roberto Calderón Hospital, the largest national HIV referral center, from 2011 to 2015. HIV pol sequences were obtained at a WHO-accredited laboratory in Mexico by Sanger and next generation sequencing (NGS). PDR was assessed using the WHO surveillance drug resistance mutation (SDRM) list and the Stanford HIVdb tool. Results 283 individuals were enrolled in the study. The overall PDR prevalence based on the list of SDRMs was 13.4%. Using the Stanford HIVdb tool, overall PDR reached 19.4%; with both nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI) PDR levels independently reaching moderate levels (6.7% and 11.3% respectively). Protease inhibitor PDR was low (2.8%). Using NGS with 2% threshold to detect SDRMs, PDR increased to 25.3%. K103N and M41L were the most frequent SDRMs and were present mostly in proportions >20% in each individual. A significant temporal increase in NNRTI PDR was observed (p = 0.0422), with no apparent trends for other drug classes. Importantly, PDR to zidovudine + lamivudine + efavirenz and tenofovir + emtricitabine + efavirenz, the most widely used first-line regimens in Nicaragua, reached 14.6% and 10.4% respectively in 2015. Of note, a higher proportion of females was observed among individuals with PDR compared to individuals without PDR (OR 14.2; 95% CI: 7.1–28.4; p<0.0001). Conclusions Overall PDR in the Nicaraguan cohort was high (19.4%), with a clear increasing temporal trend in NNRTI PDR. Current HIVDR to the most frequently used first-line ART regimens in Nicaragua reached levels >10%. These observations are worrisome

  11. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes

    PubMed Central

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A.; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T.; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M.

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007–2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5–10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  12. SAMHD1 Has Differential Impact on the Efficacies of HIV Nucleoside Reverse Transcriptase Inhibitors

    PubMed Central

    Huber, Andrew D.; Michailidis, Eleftherios; Schultz, Megan L.; Ong, Yee T.; Bloch, Nicolin; Puray-Chavez, Maritza N.; Leslie, Maxwell D.; Ji, Juan; Lucas, Anthony D.; Kirby, Karen A.; Landau, Nathaniel R.

    2014-01-01

    Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI triphosphates (TPs) at significantly lower rates than dNTPs and that SAMHD1 depletion from monocytic cells affects the susceptibility of HIV-1 infections to NRTIs in complex ways that depend not only on the relative changes in dNTP and NRTI-TP concentrations but also on the NRTI activation pathways. PMID:24867973

  13. Hepatotoxicity of nucleoside reverse transcriptase inhibitors.

    PubMed

    Montessori, Valentina; Harris, Marianne; Montaner, Julio S G

    2003-05-01

    Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase gamma, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes.

  14. Mitochondrial DNA mutations in ageing and disease: implications for HIV?

    PubMed

    Payne, Brendan A I; Gardner, Kristian; Chinnery, Patrick F

    2015-01-01

    Mitochondrial DNA (mtDNA) mutations cause neurological and multisystem disease. Somatic (acquired) mtDNA mutations are also associated with degenerative diseases and with normal human ageing. It is well established that certain nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drugs cause inhibition of the mtDNA polymerase, pol γ, leading to a reduction in mtDNA content (depletion). Given this effect of NRTI therapy on mtDNA replication, it is plausible that NRTI treatment may also lead to increased mtDNA mutations. Here we review recent evidence for an effect of HIV infection or NRTI therapy on mtDNA mutations, as well as discussing the methodological challenges in addressing this question. Finally, we discuss the possible implications for HIV-infected persons, with particular reference to ageing.

  15. Different Viral Rebound following Discontinuation of Antiretroviral Therapy in Cases of Infection with Viruses Carrying L74V or Thymidine-Associated Mutations

    PubMed Central

    de Mendoza, Carmen; Paxinos, Ellen; Barreiro, Pablo; Camino, Nuria; Núñez, Marina; Soriano, Vincent

    2004-01-01

    A total of 76 patients discontinued treatment with didanosine plus hydroxyurea after 1 year of maintenance therapy. The greatest human immunodeficiency virus (HIV)-RNA rebounds were seen in 10 patients harboring an L74V mutation, and the presence of viruses with this mutation rapidly waned. In contrast, viral rebounds were significantly less pronounced (P < 0.01) in 12 subjects harboring thymidine-associated mutations; these mutations persisted in all instances. Thus, selection of an L74V mutation during didanosine therapy may compromise HIV replication in vivo. PMID:14766874

  16. Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

    PubMed Central

    Campbell, Thomas B.; Smeaton, Laura M.; Kumarasamy, N.; Flanigan, Timothy; Klingman, Karin L.; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I.; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F.; Uy, Jonathan; Schooley, Robert T.; De Gruttola, Victor; Hakim, James Gita; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan; Safren, Steven; Fiscus, Susan A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne; Celentano, David; Chilongozi, David; Cohen, Myron; Collier, Ann C.; Currier, Judith Silverstein; Cu-Uvin, Susan; Eron, Joseph; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Chiedza; Martinson, Francis; Mayer, Kenneth; Nielsen, Karin; Pendame, Richard B.; Ramratnam, Bharat; Sanne, Ian; Severe, Patrice; Sirisanthana, Thira; Solomon, Suniti; Tabet, Steve; Taha, Taha; van der Horst, Charles; Wanke, Christine; Gormley, Joan; Marcus, Cheryl J.; Putnam, Beverly; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy; Shugarts, David L.; Winters, Mark A.; Descallar, Renard S.; Steele, Joseph; Wulfsohn, Michael; Said, Farideh; Chen, Yue; Martin, John C; Bischofberger, Norbert; Cheng, Andrew; Jaffe, Howard; Sharma, Jabin; Poongulali, S.; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly; Mngqibisa, Rosie; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai P.; Chisada, Anthony; Faesen, Sharla; Chariyalertsak, Suwat; Santos, Breno; Lira, Rita Alves; Joglekar, Anjali A.; Rosa, Alberto La; Infante, Rosa; Jain, Mamta; Petersen, Tianna; Godbole, Sheela; Dhayarkar, Sampada; Feinberg, Judith; Baer, Jenifer; Pollard, Richard B.; Asmuth, David; Gangakhedkar, Raman R; Gaikwad, Asmita; Ray, M. Graham; Basler, Cathi; Para, Michael F.; Watson, Kathy J.; Taiwo, Babafemi; McGregor, Donna; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael K.; Cox, Gary Matthew; Silberman, Martha; Mildvan, Donna; Revuelta, Manuel; Tashima, Karen T.; Patterson, Helen; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S; Lopez, Ruben; Frarey, Laurie; Currin, David; Haas, David H.; Bailey, Vicki L.; Tebas, Pablo; Zifchak, Larisa; Noel-Connor, Jolene; Torres, Madeline; Sha, Beverly E.; Fritsche, Janice M.; Cespedes, Michelle; Forcht, Janet; O'Brien, William A.; Mogridge, Cheryl; Hurley, Christine; Corales, Roberto; Palmer, Maria; Adams, Mary; Luque, Amneris; Lopez-Detres, Luis; Stroberg, Todd

    2012-01-01

    Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected

  17. A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

    PubMed

    Pinheiro, Eloan Dos Santos; Antunes, Octavio Augusto Ceva; Fortunak, Joseph M D

    2008-09-01

    It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely

  18. Recovery of fat following a switch to nucleoside reverse transcriptase inhibitor-sparing therapy in patients with lipoatrophy: results from the 96-week randomized ANRS 108 NoNuke Trial.

    PubMed

    Valantin, M A; Lanoy, E; Bentata, M; Kalmykova, O; Boutekadjirt, A; Allavena, C; Rozenbaum, W; Peytavin, G; Amellal, B; Calvez, V; Costagliola, D; Katlama, C

    2008-10-01

    To evaluate the impact on peripheral fat tissue of a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen in lipoatrophic HIV-1 infected patients. This 96-week prospective, randomized study compared lipoatrophic patients switched to an NRTI-sparing regimen with patients remaining on an NRTI-containing regimen. The primary endpoint was the change in thigh subcutaneous fat tissue volume between baseline and week 48, as assessed by computerized tomography. One hundred patients were included, 50 in each arm. At baseline, patients had been on highly active antiretroviral therapy (HAART) for a median time of 6.6 years (4.9-9.7); 71% of the patients had received thymidine analogues [stavudine (37%), zidovudine (34%)]. The mean change in fat volume between baseline and week 48 significantly favoured the NRTI-sparing arm over the NRTI-maintaining arm in the intent-to-treat analysis, with a last-observation-carried-forward approach [+34 cm(3); 95% confidence interval (CI) 5-63 cm(3); P=0.002]. This was confirmed in the intent-to-treat analysis of available data, with a mean difference of +109 cm(3) (95% CI 34-185 cm(3)) at week 96 (n=53; P=0.001). This corresponded to increases of 12 and 30% in fat volume at weeks 48 and 96, respectively, in the NRTI-sparing arm. Switching from an effective NRTI-containing regimen to an NRTI-sparing regimen preserves immunovirological status and increases subcutaneous fat volume at weeks 48 and 96.

  19. Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors

    PubMed Central

    Gonzales, Matthew J.; Wu, Thomas D.; Taylor, Jonathan; Belitskaya, Ilana; Kantor, Rami; Israelski, Dennis; Chou, Sunwen; Zolopa, Andrew R.; Fessel, W. Jeffrey; Shafer, Robert W.

    2008-01-01

    Objective To characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI. Design A total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published. Methods Chi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results Mutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228. Conclusions Mutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts. PMID:12660525

  20. [Regenerative nodular hyperplasia in HIV].

    PubMed

    González, Ramiro Javier Romo; Chaves, Emiliano; Mullen, Eduardo; Copello, Hercilia

    2011-12-01

    Nodular regenerative hyperplasia of the liver is a rare condition. We describe here the case of a patient with HIV who presented with a clinical syndrome of portal hypertension. After multiple evaluations the diagnosis was recognized by the histology. The findings were attributed to the prolonged use of didanosine.

  1. Metabolism evaluation of biomimetic prodrugs by in vitro models and mass spectrometry.

    PubMed

    Lalanne, Muriel; Khoury, Hania; Deroussent, Alain; Bosquet, Nathalie; Benech, Henri; Clayette, Pascal; Couvreur, Patrick; Vassal, Gilles; Paci, Angelo; Andrieux, Karine

    2009-09-11

    Glycerolipidic prodrug is an interesting concept to enhance lymphatic absorption of polar drugs intended to oral delivery such as didanosine (ddI). In order to improve ddI bioavailability, two didanosine glycerolipidic prodrugs, the phosphorylated (ProddIP) and the non-phosphorylated derivatives (ProddINP) were synthesized to follow triglyceride metabolism. The biomimetism approach of these prodrugs has been studied in vitro at two steps. First, liposomal formulation of each prodrug was incubated with a lipolysis model based on pancreatin and analysed using liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). These experiments evidenced that both didanosine prodrugs were recognized by the lipases; as expected, they were cleaved at both positions sn-1 and sn-3 of glycerol. ProddIP was metabolised twice more rapidly than ProddINP suggesting an implication of some phospholipases in ProddIP degradation. Secondly, the detection of dideoxyadenosine triphosphate (ddA-TP) into HIV-1 infected cells after their incubation with ProddINP loaded liposomes evidenced their ability to release ddI that could penetrate into the cells and be metabolised by intracellular kinases. These results confirmed that the synthesized glycerolipidic prodrugs of didanosine could be investigated for a biomimetic approach with final aiming of increasing the drug oral bioavailability by enhancing intestinal absorption.

  2. Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.

    PubMed

    Xue, Stephen Y; Hebert, Valeria Y; Hayes, Danicia M; Robinson, Corie N; Glover, Mitzi; Dugas, Tammy R

    2013-08-01

    Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18-24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8-10h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction.

  3. [Pilot study of antiretroviral therapy in Djibouti].

    PubMed

    Ahmed, A A; Latoundji, S

    2007-01-01

    A cross-sectional survey was conducted among 112 HIV positive patients who had received antiretroviral therapy for >3 months to assess the efficacy of treatment (viral load <400 copies/mL). The median age at enrolment was 36 years, 90% of patients were at the AIDS stage and median CD4 rate was 118/mm3. Patients received a combined treatment of 2 NRTI +1 NNRTI (51%), 3 NRTI (45%) and 2 NRTI+1 PI (4%). Virological efficacy was seen in 74% of the patients, irrespective of the prescribed protocol and the initial clinical and immunological profile. Mean improvements measured were 20% on the Karnofsky index (KI), 2.1 kg/m2 in body mass index and 82 cells/mm in CD4. The prevalence of side effects was 84%. The predictors for treatment success were quality of care and KI > 70%.

  4. Drug Susceptibility and Resistance Mutations After First-Line Failure in Resource Limited Settings

    PubMed Central

    Wallis, Carole L.; Aga, Evgenia; Ribaudo, Heather; Saravanan, Shanmugam; Norton, Michael; Stevens, Wendy; Kumarasamy, Nagalingeswaran; Bartlett, John; Katzenstein, David

    2014-01-01

    Background. The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania. Methods. CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall–Wallis tests. Results. Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site. Conclusions. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance. PMID:24795328

  5. [Entecavir--close perspective for using it].

    PubMed

    Halota, Waldemar; Pawłowska, Małgorzata

    2006-01-01

    There are 3 drugs registered to treatment of chronic hepatitis B: interferon, lamivudine and adefovir. Many other nucleoside and nucleotide analougs are examined. In experiments on the animals: woodchucks infected with WHBV and ducks infected with DHBV beneficial influence of entecavir on viral DNA and cccDNA supression. In these examination no resistance was present. In clinical studies resistanse to entecavir conserned only patients with resistance to lamivudine. Entecavir is safety and effective in the treatment of chronic hepatits B in patients HBeAg positive and negative and in patients with resistance to lamivudine.

  6. Pharmaceutical approval update.

    PubMed

    Gohil, Kunj

    2014-11-01

    Naltrexone/bupropion (Contrave) for weight management; pembrolizumab (Keytruda) for melanoma; dolutegravir/abacavir/lamivudine (Triumeq) for HIV-1; and immune globulin infusion 10% (human) with recombinant human hyaluronidase (Hyqvia) for primary immunodeficiency.

  7. Approved Antiretroviral Drugs Used for Pediatric Treatment of HIV Infection

    MedlinePlus

    ... 12 yr and ≥ 30 kg: Tablet: 1 tablet (300 mg zidovudine/ 150 mg lamivudine) twice daily Not ... Sciences >12 years and ≥35 kg: 1 tablet (300 mg tenofovir /200 emtricitabine) once daily Not recommended ...

  8. Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors

    PubMed Central

    Warren, G; Makarov, E; Lu, Y; Senanayake, T; Rivera, K; Gorantla, S; Poluektova, LY; Vinogradov, SV

    2015-01-01

    Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity. PMID:25559020

  9. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

    PubMed

    La Rosa, Alberto M; Harrison, Linda J; Taiwo, Babafemi; Wallis, Carole L; Zheng, Lu; Kim, Peter; Kumarasamy, Nagalingeswaran; Hosseinipour, Mina C; Jarocki, Bernadette; Mellors, John W; Collier, Ann C

    2016-06-01

    For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma