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Sample records for nrti didanosine lamivudine

  1. Didanosine, lamivudine-emtricitabine and efavirenz as initial therapy in naive patients.

    PubMed

    Palacios, Rosario; Aguilar, Isabel; Hidalgo, Ana; Santos, Jesús

    2006-12-01

    There are currently several suitable and different antiretroviral regimens to start highly active antiretroviral therapy (HAART), and many clinicians and patients prefer once-daily therapy. The efficacy and potency of efavirenz (EFV) has been established in many clinical trials and cohort studies; its pharmacokinetics, allowing for a convenient once-daily administration, make EFV one of the first agents to be included in once-daily regimens in naive patients. The two nucleoside reverse transcriptase inhibitors (NRTIs) accompanying the third drug have become the central skeleton, or the 'backbone' of the therapeutic scheme. Among the different NRTI pairs, a didanosine-lamivudine (3TC) or emtricitabine backbone for combination antiretroviral therapy may be a good option compared with any current NRTI-combinations due to its security, tolerance and once-daily dose. In this article, we review the advantages and drawbacks of didanosine-XTC-EFV as the initial regimen of HAART in HIV-infected patients. PMID:17181413

  2. Didanosine

    MedlinePlus

    ... Didanosine may also cause serious or life-threatening lactic acidosis (build-up of acid in the blood) that will probably need to be treated in the hospital. The risk that you will develop lactic acidosis is higher if you are a woman, ...

  3. Lamivudine

    MedlinePlus

    ... infection. Lamivudine (Epivir-HBV) is used to treat hepatitis B infection. Lamivudine is in a class of medications ... works by decreasing the amount of HIV and hepatitis B in the blood. Although lamivudine does not cure ...

  4. Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual's NRTI-SN risk.

    PubMed

    Cherry, Catherine L; Rosenow, Ann; Affandi, Jacquita S; McArthur, Justin C; Wesselingh, Steven L; Price, Patricia

    2008-02-01

    Nucleoside analog-associated sensory neuropathy (NRTI-SN) attributed to stavudine, didanosine, or zalcitabine (the dNRTIs) and distal sensory polyneuropathy (DSP) attributed to HIV are clinically indistinguishable. As inflammatory cytokines are involved in DSP, we addressed a role for inflammation in NRTI-SN by determining the alleles of immune-related genes carried by patients with and without NRTI-SN. Demographic details associated with risk of various neuropathies were included in the analysis. Alleles of 14 polymorphisms in 10 genes were determined in Australian HIV patients with definite NRTI-SN (symptom onset <6 months after first dNRTI exposure, n = 16), NRTI-SN-resistant patients (no neuropathy despite >6 months on dNRTIs, n = 20), patients with late onset NRTI-SN (neuropathy onset after >6 months of dNRTIs, n = 19), and HIV-negative controls. Carriage of TNFA-1031*2 was highest in NRTI-SN patients, suggesting potentiation of NRTI-SN. Carriage of IL12B (3' UTR)*2 was higher in NRTI-SN-resistant patients than controls or NRTI-SN patients, suggesting a protective role. BAT1 (intron 10)*2 was more common in NRTI-SN than resistant patients, but neither group differed from controls. This marks the conserved HLA-A1, B8, DR3 haplotype. Of the demographic details considered, increasing height was associated with NRTI-SN risk. A model including cytokine genotype and height predicted NRTI-SN status (p < 0.0001, R(2) = 0.54). Late onset NRTI-SN patients clustered genetically with NRTI-SN-resistant patients, so these patients may be genetically "protected." In addition to patient height, cytokine genotype influenced NRTI-SN risk following dNRTI exposure, suggesting inflammation contributes to NRTI-SN. PMID:18240960

  5. A farewell to didanosine: harm reduction and cost savings by eliminating use of didanosine.

    PubMed

    Dziuban, Eric J; Raizes, Elliot; Koumans, Emilia H

    2015-10-01

    Didanosine (ddI) is a nucleoside reverse transcriptase inhibitor associated with adverse events and public health concerns which have diminished its place in HIV clinical practice, particularly in resource-rich settings. While international guidelines do not contain ddI-containing regimens in preferred first- or second-line antiretroviral therapy (ART), there is no guidance for management of patients currently on ddI. In 2012 at least 20 countries purchased a total of $1-2 million of ddI. Drug purchase data in that year show 3.2-10.3 times higher costs for ddI compared to lamivudine (3TC). Given issues of multiple toxicities, monitoring, drug interactions, inconvenience, and virologic efficacy, as well as cost and formulary concerns, national (including resource-limited setting) ART programmes should consider complete phase-out of ddI. PMID:25281538

  6. Didanosine

    MedlinePlus

    ... will probably need to be treated in the hospital. The risk that you will develop lactic acidosis is higher ... of developing acquired immunodeficiency syndrome (AIDS) and HIV-related ... may decrease the risk of transmitting (spreading) the HIV virus to other ...

  7. 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

  8. 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

  9. 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. PMID:25698454

  10. 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

  11. Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections.

    PubMed Central

    Morse, G D; Fischl, M A; Shelton, M J; Borin, M T; Driver, M R; DeRemer, M; Lee, K; Wajszczuk, C P

    1996-01-01

    Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of < 2, and therefore, normal gastric acidity is most likely necessary for optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 +/- 2.8 to 0.854 +/- 0.33 microM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 +/- 2.2 microM.h (P = 0.004) relative to a value of 11.3 +/- 4.8 microM.h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since

  12. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection.

    PubMed Central

    Morse, G D; Fischl, M A; Shelton, M J; Cox, S R; Driver, M; DeRemer, M; Freimuth, W W

    1997-01-01

    Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [+/- standard deviation] CD4+ cell count, 304 +/- 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (Cmax) was reduced from 7.22 +/- 4.0 to 3.51 +/- 1.9 microM, and the area under the concentration-time curve from 0 h to infinity (AUC0-->infinity) was reduced from 22.5 +/- 14 to 14 +/- 5.7 microM.h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC0-->infinity to the delavirdine AUC0-->infinity, was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a Cmax reduction from 4.65 +/- 2.0 to 3.22 +/- 0.59 microM and an AUC0-->infinity reduction from 7.93 +/- 3.9 to 6.54 +/- 2.3 microM.h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC0-->infinity of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady

  13. [Two novel fixed formulations of nucleoside analogues (tenofovir-emtricitabine, and abacavir-lamivudine). Prospective, open study on clinical practice and therapeutic perspectives, in patients naïve and in subjects pre-treated with antiretrovirals].

    PubMed

    Manfredi, Roberto; Calza, Leonardo

    2008-10-01

    The introduction of novel, fixed nucleoside-nucleotide reverse transcriptase inhibitor (NRTI) combinations (tenofovir-emtricitabine, and abacavir-lamivudine), expanded the spectrum of available formulations and increased patient's adherence. A prospective survey of the open-label use of these two fixed combinations was performed in 158 patients belonging to our single-centre cohort of over 1,000 HIV-infected subjects enrolled in the last 18 months, and followed for at least 12 months. During the last 18 months, 95 consecutive, evaluable patients (60.1%) received for the first time tenofovir-emtricitabine, or abacavir-lamivudine (63 patients, 39.9%), and were followed for at least 12 months. A major role seems to be played by tenofovir-emtricitabine in first-line treatments (preferably among "compact" regimens based on efavirenz), while the proportionally increased abacavir-lamivudine prescription to pre-treated patients is mostly attributable to the different genetic barrier of abacavir (often associated with boosted protease inhibitors, in this last patient group). The present availability to two more fixed NRTI combinations favored by their single pill, once-daily administration encourages randomized, controlled "head to head" studies in both first-line and experienced patients, in order to better exploit and target their therapeutic potential. PMID:19040127

  14. Clinically Relevant Genotype Interpretation of Resistance to Didanosine

    PubMed Central

    Marcelin, Anne-Geneviève; Flandre, Philippe; Pavie, Juliette; Schmidely, Nathalie; Wirden, Marc; Lada, Olivier; Chiche, Dan; Molina, Jean-Michel; Calvez, Vincent

    2005-01-01

    We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as −1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E − K70R − M184V/I; P = 4.5 × 10−9) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 × 10−7). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log10 copies/ml when they were ranked as having a genotypic score II of −2, −1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI. PMID:15855490

  15. Lamivudine

    MedlinePlus

    ... HIV, it may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses such as serious infections or cancer. Taking these medications along with practicing ...

  16. Liposomal formulation of a glycerolipidic prodrug for lymphatic delivery of didanosine via oral route.

    PubMed

    Lalanne, M; Andrieux, K; Paci, A; Besnard, M; Ré, M; Bourgaux, C; Ollivon, M; Desmaele, D; Couvreur, P

    2007-11-01

    Didanosine is a polar drug with poor membrane absorption and high hepatic first pass metabolism. This study aimed at developing a lipidic formulation of a glycerolipidic prodrug of didanosine in order to improve its bioavailability. In the course of a preformulation study, the glycerolipidic prodrug of didanosine was characterized by microscopy, DSC and XRDT. In anhydrous conditions, the prodrug displayed a polymorphic behaviour similar to that of triglycerides. Then, we evaluated three types of lipidic formulations (emulsions, mixed micelles and liposomes) in order to encapsulate the prodrug. Solubilities in water - even in the presence of taurocholate micelles - but also in some oils were very low (max 244 microg/mL) as the prodrug was found to be amphiphilic (log P=2). On the contrary, the prodrug was found to be perfectly incorporated in dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes up to a ratio of 1:5 (mol:mol) prodrug:DPPC as suggested by HPLC-UV and DSC experiments. Moreover, these liposomes could be freeze-dried whereas the chemical integrity of the prodrug was preserved. Then, the freeze-dried liposomal preparation could be formulated as gastro-resistant capsules to prevent didanosine from acidic degradation. Further experiments are on the way to evaluate in vitro the absorption of prodrug incorporated in liposomes by enterocytes. PMID:17616448

  17. 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

  18. Equivalent Steady-State Pharmacokinetics of Lamivudine in Plasma and Lamivudine Triphosphate within Cells following Administration of Lamivudine at 300 Milligrams Once Daily and 150 Milligrams Twice Daily

    PubMed Central

    Yuen, Geoffrey J.; Lou, Yu; Bumgarner, Nancy F.; Bishop, Jim P.; Smith, Glenn A.; Otto, Victoria R.; Hoelscher, David D.

    2004-01-01

    Once-daily administration of 300 mg of lamivudine in combination with other antiretroviral agents has been proposed as a possible way to optimize anti-human immunodeficiency virus (HIV) treatment and to facilitate adherence. A single-center, randomized, two-way, crossover study was conducted in 60 healthy subjects to compare the steady-state pharmacokinetics of lamivudine in plasma and its putative active anabolite, lamivudine 5′-triphosphate (lamivudine-TP), in peripheral blood mononuclear cells (PBMCs) following 7 days of treatment with lamivudine at 300 mg once daily and 7 days of the standard regimen of 150 mg twice daily. Serial blood samples were collected over 24 h for determination of plasma lamivudine concentrations by liquid chromatography-mass spectrometry and intracellular lamivudine-TP concentrations in peripheral blood mononuclear cells by high-performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine-TP concentration-time data. Regimens were considered bioequivalent if 90% confidence intervals (CI) for the ratio (once daily/twice daily) of geometric least-squares (GLS) means for lamivudine and lamivudine-TP pharmacokinetic values fell within the acceptance range of 0.8 to 1.25. Steady-state plasma lamivudine pharmacokinetics following the once- and twice-daily regimens were bioequivalent with respect to the area under the drug concentration-time curve from 0 to 24 h at steady state (AUC24,ss) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97) and average plasma lamivudine concentration over the dosing interval (Cave,ss) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97). Steady-state intracellular lamivudine-TP pharmacokinetics after the once- and twice-daily regimens were bioequivalent with respect to AUC24,ss (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), Cave,ss (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), and maximum lamivudine concentration (Cmax,ss) (GLS mean ratio, 0.93; 90% CI, 0

  19. 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

  20. Scoring Methods for Building Genotypic Scores: An Application to Didanosine Resistance in a Large Derivation Set

    PubMed Central

    Houssaini, Allal; Assoumou, Lambert; Miller, Veronica; Calvez, Vincent; Marcelin, Anne-Geneviève; Flandre, Philippe

    2013-01-01

    Background Several attempts have been made to determine HIV-1 resistance from genotype resistance testing. We compare scoring methods for building weighted genotyping scores and commonly used systems to determine whether the virus of a HIV-infected patient is resistant. Methods and Principal Findings Three statistical methods (linear discriminant analysis, support vector machine and logistic regression) are used to determine the weight of mutations involved in HIV resistance. We compared these weighted scores with known interpretation systems (ANRS, REGA and Stanford HIV-db) to classify patients as resistant or not. Our methodology is illustrated on the Forum for Collaborative HIV Research didanosine database (N = 1453). The database was divided into four samples according to the country of enrolment (France, USA/Canada, Italy and Spain/UK/Switzerland). The total sample and the four country-based samples allow external validation (one sample is used to estimate a score and the other samples are used to validate it). We used the observed precision to compare the performance of newly derived scores with other interpretation systems. Our results show that newly derived scores performed better than or similar to existing interpretation systems, even with external validation sets. No difference was found between the three methods investigated. Our analysis identified four new mutations associated with didanosine resistance: D123S, Q207K, H208Y and K223Q. Conclusions We explored the potential of three statistical methods to construct weighted scores for didanosine resistance. Our proposed scores performed at least as well as already existing interpretation systems and previously unrecognized didanosine-resistance associated mutations were identified. This approach could be used for building scores of genotypic resistance to other antiretroviral drugs. PMID:23555613

  1. Conservation Patterns of HIV-1 RT Connection and RNase H Domains: Identification of New Mutations in NRTI-Treated Patients

    PubMed Central

    Santos, André F. A.; Lengruber, Renan B.; Soares, Esmeralda A.; Jere, Abhay; Sprinz, Eduardo; Martinez, Ana M. B.; Silveira, Jussara; Sion, Fernando S.; Pathak, Vinay K.; Soares, Marcelo A.

    2008-01-01

    Background Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood. Methods and Findings We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naïve and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher's exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI. Conclusions This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions. PMID:18335052

  2. New nucleoside/nucleotide backbone options: a review of recent studies.

    PubMed

    Ruane, Peter J; DeJesus, Edwin

    2004-09-01

    The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) class continues to serve as an important component of the standard of care for HIV infection. Combinations of dual NRTIs/NtRTIs with protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most commonly used regimens in clinical practice. In recent years, clinical outcomes data on previously novel NRTI/NtRTI backbone combinations have provided clinicians with new options to address potency, tolerability, and convenience of antiretroviral therapy. However, the tolerability, drug-drug interactions, and resistance profiles of specific regimens using new NRTI/NtRTI combinations must be weighed against the needs and preferences of individual patients. This review summarizes recent efficacy and safety data on emerging NRTI/NtRTI combination backbones, including tenofovir DF (TDF) with lamivudine (3TC), abacavir with 3TC, didanosine (ddI) with 3TC, ddI with emtricitabine (FTC), and TDF with FTC. PMID:15319666

  3. Effect of time of food administration on the bioavailability of didanosine from a chewable tablet formulation.

    PubMed

    Knupp, C A; Milbrath, R; Barbhaiya, R H

    1993-06-01

    The effect of the time of food administration on the bioavailability of didanosine, administered as a 300-mg dose of a chewable tablet formulation, was evaluated in 10 men seropositive for the human immunodeficiency virus (HIV), but free of any symptoms of acquired immune deficiency syndrome (AIDS). Using an open, randomized, balanced, incomplete block crossover study design, each patient received the dose of didanosine under four of the five following conditions: (1) after an overnight fast, (2) 30 minutes before a meal, (3) 1 hour before a meal, (4) 1 hour after a meal, or (5) 2 hours after a meal. The meal consisted of a standard high-fat, high-calorie breakfast, consumed over a 15-minute period. Serial blood samples and the total urinary output were collected over a 12-hour interval after each dose for analysis using validated high-pressure liquid chromatography (HPLC)/ultraviolet (UV) methods. Concentration data were used to calculate pharmacokinetic parameters using noncompartmental methods. There were no significant differences among the fasting, 30-minute before, and 1-hour before the meal treatments with respect to maximum peak plasma concentration (Cmax), area under the curve (AUC(0-infinity)), or urinary recovery (%UR). Values for Cmax, AUC(0-infinity), and %UR observed for the 1 and 2 hours after the meal treatments were significantly less than those obtained under either fasting conditions or before the meal. There were no significant differences among any of the treatments with respect to time to reach peak concentration (tmax), half-life (t1/2), or renal clearance (CLR).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8366182

  4. Amino acid esters substituted phosphorylated emtricitabine and didanosine derivatives as antiviral and anticancer agents.

    PubMed

    Sekhar, Kuruva Chandra; Janardhan, Avilala; Kumar, Yellapu Nanda; Narasimha, Golla; Raju, Chamarthi Naga; Ghosh, S K

    2014-07-01

    Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 μg/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 μg/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester-substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition. PMID:24789416

  5. Synthesis and Antiviral Activity of Novel Phosphorylated Derivatives of Didanosine Against Newcastle Disease Virus in Chicken.

    PubMed

    Suresh, Karanam Anandan; Kadiam, Venkata Subbaiah C; Basha, Thaslim S K; Chamarti, Naga Raju; Kumar, Suresh M; Wudayagiri, Rajendra; Valluru, Lokanatha

    2016-06-01

    A series of novel phosphorylated derivatives of didanosine were designed and docking studies were performed with a fusion protein of the Newcastle disease virus (NDV), to develop antiviral compounds against NDV. Based on the docking scores and binding affinities, three derivatives were selected. These compounds were synthesized and characterized by IR, (1) H, (13) C, (31) P, and CHN analysis and mass spectra. They were assessed for their in vitro antiviral activity in DF-1 cells; DDI-10 showed better antiviral activity as evidenced by significant reduction in plaque formation and cytopathic effects. DDI-10 was further evaluated in NDV-infected chicken; the survival rates and antioxidant enzyme levels in brain, liver, and lung tissues were estimated. Superoxide dismutase and catalase were significantly raised, and lipid peroxidation and HA titer levels were decreased upon treatment with 1.5 mg/kg body weight of DDI-10 than with 3 mg/kg body weight of DDI. Further histopathological alterations in NDV-infected tissues were restored in chicken treated with DDI-10. Thus, based on the results from in silico, in vitro, and in vivo assays, the novel phosphorylated DDI-10 might be considered as potent antiviral compound for NDV infection in chicken. PMID:27128998

  6. 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.

  7. HBV lamivudine resistance among hepatitis B and HIV coinfected patients starting lamivudine, stavudine and nevirapine in Kenya.

    PubMed

    Kim, H N; Scott, J; Cent, A; Cook, L; Morrow, R A; Richardson, B; Tapia, K; Jerome, K R; Lule, G; John-Stewart, G; Chung, M H

    2011-10-01

    Widespread use of lamivudine in antiretroviral therapy may lead to hepatitis B virus resistance in HIV-HBV coinfected patients from endemic settings where tenofovir is not readily available. We evaluated 389 Kenyan HIV-infected adults before and for 18 months after starting highly active antiretroviral therapy with stavudine, lamivudine and nevirapine. Twenty-seven (6.9%) were HBsAg positive and anti-HBs negative, 24 were HBeAg negative, and 18 had HBV DNA levels ≤ 10,000 IU/mL. Sustained HBV suppression to <100 IU/mL occurred in 89% of 19 evaluable patients. Resistance occurred in only two subjects, both with high baseline HBV DNA levels. Lamivudine resistance can emerge in the setting of incomplete HBV suppression but was infrequently observed among HIV-HBV coinfected patients with low baseline HBV DNA levels. PMID:21914062

  8. Ichthyosiform eruption associated with lamivudine in a patient with chronic hepatitis-B infection.

    PubMed

    Kaptanoglu, A F; Kutluay, L

    2005-10-01

    The side-effects of antiretroviral agents have been widely reported in the literature. Lamivudine is an antiretroviral agent, and skin eruption because of this agent has been rarely reported. Previous reports regarding these few side-effects of lamivudine include angioedema, urticaria, anaflactoid reactions, allergic contact dermatitis and alopecia. There is no report of an ichthyosiform eruption associated with lamivudine. The authors present a case of 43-year-old female patient presenting with an ichthyosiform eruption during lamivudine therapy for chronic hepatitis-B for the first time. PMID:16178993

  9. Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

    PubMed Central

    Bouazza, Naïm; Tréluyer, Jean-Marc; Ghosn, Jade; Hirt, Déborah; Benaboud, Sihem; Foissac, Frantz; Viard, Jean-Paul; Urien, Saik

    2014-01-01

    Aims This study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations. Methods A total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117 kg (median 71 kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft–Gault formula; 177 patients had normal renal function (CLCR > 90 ml min−1), 50 patients had mild renal impairment (CLCR = 60–90 ml min−1), 20 patients had moderate renal impairment (CLCR = 30–60 ml min−1), and five patients had severe renal impairment (CLCR < 30 ml min−1). Results A two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (Vc/F) and peripheral volumes of distribution (Vp/F), intercompartmental clearance (Q/F) and absorption rate constant (Ka) were 29.7 l h−1 (32%), 68.2 l, 114 l, 10.1 l h−1 (85%) and 1 h−1, respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300 mg day−1 in patients with mild renal impairment could overexpose them. A dose of 200 mg day−1 maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures. Conclusions Lamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200 mg day−1 instead of 300 mg day−1. PMID:24750102

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

    PubMed

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

    2016-09-01

    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

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

    PubMed

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

    2007-01-01

    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. PMID:18181532

  12. Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1.

    PubMed

    Danial, Maarten; Andersen, Anna H F; Zuwala, Kaja; Cosson, Steffen; Riber, Camilla Frich; Smith, Anton A A; Tolstrup, Martin; Moad, Graeme; Zelikin, Alexander N; Postma, Almar

    2016-07-01

    In this article a library of polymeric therapeutic agents against the human immunodeficiency virus (HIV) is presented. The library of statistical copolymers of varied molar mass was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The synthesized polymers comprise pendent hydroxyl and sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC) attached via a disulfide self-immolative linker. The glutathione mediated release of 3TC is demonstrated as well as the antiviral efficacy against HIV entry and polymerase activity. Although a high degree of polymer sulfonation is required for effective HIV entry inhibition, polymers with approximately ∼50% sulfonated monomer demonstrated potent kinase independent reverse transcriptase inhibition. In addition, the sulfonated polymers demonstrate activity against DNA-DNA polymerase, which suggests that these polymers may exhibit activity against a broad spectrum of viruses. In summary, the polymers described provide a triple-active arsenal against HIV with extracellular activity via entry inhibition and intracellular activity by kinase-dependent lamivudine-based and kinase-independent sulfonated polymer based inhibition. Since these sulfonated copolymers are easily formulated into gels, we envision them to be particularly suited for topical application to prevent the mucosal transmission of viruses, particularly HIV. PMID:27244595

  13. 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

  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

    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 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s 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. 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. PMID:27025356

  16. Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics.

    PubMed

    Yan, Zhongtian; Sun, Jin; Chang, Yannan; Liu, Yanhua; Fu, Qiang; Xu, Youjun; Sun, Yongbing; Pu, Xiaohui; Zhang, Youxi; Jing, Yongkui; Yin, Shiliang; Zhu, Meng; Wang, Yongjun; He, Zhonggui

    2011-04-01

    Five peptidomimetic prodrugs of didanosine (DDI) were synthesized and designed to improve bioavailability of DDI following oral administration via targeting intestinal oligopeptide transporter (PepT1) and enhancing chemical stability. The permeability of prodrugs was screened in Caco-2 cells grown on permeable supports. 5'-O-L-valyl ester prodrug of DDI (compound 4a) demonstrated the highest membrane permeability and was selected as the optimal target prodrug for further studies. The uptake of glycylsarcosine (Gly-Sar, a typical substrate of PepT1) by Caco-2 cells could be inhibited by compound 4a in a concentration-dependent manner. The Caco-2 cells were treated with 0.2 nM leptin for enhanced PepT1 expression. The uptake of compound 4a was markedly increased in the leptin-treated Caco-2 cells compared with the control Caco-2 cells, both of which were obviously inhibited by 20 mM Gly-Sar. The K(m) and V(max) values of kinetic study of compound 4a transported by PepT1 in Caco-2 cells were 0.91 mM and 11.94 nmol/mg of protein/10 min, respectively. The chemical stability studies were performed in simulated gastric fluid (SGF), phosphate buffers under various pH conditions, rat tissue homogenates and plasma at 37 °C. The concentrations of DDI could not be detected in the two minutes in SGF. But compound 4a could significantly increase DDI acidic stability, and its t(½) was extended to as long as 36 min in SGF. Compound 4a was stable in pH 6.0 phosphate buffer but could be quickly transformed into DDI in plasma and tissue homogenates. The oral absolute bioavailability of DDI was 47.2% and 7.9% after compound 4a and DDI were orally administered to rats at a dose of 15 mg/kg, respectively. The coadministration with antiacid agent could also suggest that compound 4a was more stable under harsh acidic conditions compared with DDI. Compound 4a bioavailability in rats was reduced to 33.9% when orally co-administered with Gly-Sar (100 mg/kg). The In Vivo bioactivation

  17. Virologic response and breakthrough in chronic hepatitis B Egyptian patients receiving lamivudine therapy

    PubMed Central

    Ismail, Sohair; Hafez, Hanan Abdel; Darweesh, Samar K.; Kamal, Kamal Hassan; Esmat, Gamal

    2014-01-01

    Background Lamivudine monotherapy is effective in suppressing hepatitis B virus (HBV) replication to undetectable levels by PCR, in ameliorating liver disease and to some extent in achieving HBsAg seroconversion. This study aimed at assessing the virological and biochemical responses as well as breakthrough in HBeAg-negative chronic HBV (CHB) Egyptian patients receiving lamivudine therapy. Methods This retrospective study included 140 CHB patients with positive serum HBV-DNA by quantitative PCR assays and negative HBeAg who had never received prior anti-viral therapy for HBV. According to duration of lamivudine therapy (100 mg/day) patients were grouped into: group I (n=59) who received lamivudine for 1 year, group II (n=50) who received lamivudine for 2 years, and group III (n=31) who received lamivudine for 3 years. Results In group I, 76.3% patients had virologic response but this was reduced in group II and group III to 72% and 67.7% respectively. None of the patients in group I developed virologic breakthrough, whereas 12% and 25.8% in groups II and III respectively developed breakthrough. In group I, 25% of patients having high pre-treatment viremia showed virologic response compared to 84.6% and 83.3% having mild and moderate viremia respectively (P<0.01). However, in groups II and III, there was no significant relationship between pre-treatment viremia and virologic response. No significant relationship was found between pre-treatment viral load and incidence of breakthrough within each group. Conclusion Lamivudine remains one of the antiviral therapies for HBeAg negative CHB patients. The rates of maintained virologic and biochemical responses to lamivudine decrease in time due to selection of drug-resistant mutants and, hence, breakthrough. PMID:25331321

  18. 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. PMID:26517111

  19. Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir

    PubMed Central

    Mutimer, D; Feraz-Neto, B; Harrison, R; O'Donnell, K; Shaw, J; Cane, P; Pillay, D

    2001-01-01

    BACKGROUND—Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure.
CASE REPORT—A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the devlopment of graft failure.
OUTCOME—A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved.
CONCLUSION—The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.


Keywords: hepatitis B virus; adefovir; liver graft; lamivudine PMID:11709523

  20. 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.

  1. Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients

    PubMed Central

    Yang, Dan-Hong; Xie, Yuan-Jun; Zhao, Nian-Feng; Pan, Hong-Ying; Li, Ming-Wei; Huang, Hai-Jun

    2015-01-01

    AIM: To assess the efficacy of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM)-resistant patients with a suboptimal response to LAM plus adefovir (ADV). METHODS: We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir. Charts were reviewed for LAM-resistant chronic hepatitis B (CHB) patients who visited the Zhejiang Province People’s Hospital and The First Affiliated Hospital, College of Medicine, Zhejiang University, from June 2009 to May 2013. Patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included. Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy (300 mg/d orally; TDF group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally; LAM plus ADV group) and were followed for 48 wk. Serum HBV DNA was determined at baseline and weeks 4, 12, 24, 36, and 48. HBV serological markers and biochemistry were assessed at baseline and weeks 12, 24, and 48. Resistance surveillance and side effects were monitored during therapy. RESULTS: Fifty-nine patient were randomized to switch to TDF (n = 28) or continuation with LAM plus ADV (n = 31). No significant differences were found between the groups at baseline. Prior to TDF therapy, all patients had been exposed to LAM plus ADV for a median of 11 mo (range: 6-24 mo). No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/mL (TDF) vs 5.04 ± 31.16 log10 copies/mL (LAM + ADV), P = 0.639]. There was no significant difference in the rates of achieving complete virological response (CVR) at week 4 between the TDF and LAM + ADV groups (17.86% vs 6.45%, P = 0.24). The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12, 82.14% vs 22.58% at week 24, 89.29% vs 25.81% at week 36, and 96.43% vs 29.03% at week 48, respectively

  2. 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

  3. Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

    PubMed Central

    Park, Chan Ho; Jung, Seok Won; Shin, Jung Woo; Bae, Mi Ae; Lee, Yoon Im; Park, Yong Tae; Chung, Hwa Sik; Park, Neung Hwa

    2016-01-01

    Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary. PMID:27044766

  4. Abacavir/lamivudine versus tenofovir/emtricitabine in virologically suppressed patients switching from ritonavir-boosted protease inhibitors to raltegravir.

    PubMed

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

    2013-02-01

    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

  5. 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. PMID:22452408

  6. 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. PMID:26295538

  7. Analysis of hepatitis B virus quasispecies changes during emergence and reversion of lamivudine resistance in liver transplantation.

    PubMed

    Cane, P A; Mutimer, D; Ratcliffe, D; Cook, P; Beards, G; Elias, E; Pillay, D

    1999-01-01

    This report describes nucleotide sequence analysis of part of the polymerase gene of hepatitis B virus (HBV) during the development of lamivudine-resistant HBV in five patients who received lamivudine treatment in conjunction with liver transplantation. Samples from patients were analysed before, during and after drug treatment in conjunction with serum HBV quantification by PCR. Lamivudine resistance was found to be associated with L526M and M550V changes in two patients and M550I change in three patients. Other changes associated with lamivudine resistance in some patients were V509I, A546V, S565A and A568T. The effects on HBV surface antigen are also described. Some patients were subsequently treated with famciclovir and/or ganciclovir with variable outcomes. In two out of three patients who stopped lamivudine treatment, reversion (partial or complete) to wild-type virus was observed after about 5 months. In contrast, a complex mixture of mutant viruses emerged in a third patient who stopped lamivudine treatment. PMID:10682123

  8. 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

  9. 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. PMID:27220342

  10. 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. PMID:24329913

  11. A viral kinetic study using pegylated interferon alfa-2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative.

    PubMed

    Sypsa, Vassiliki-Anastasia; Mimidis, Konstantinos; Tassopoulos, Nicholas C; Chrysagis, Dimitrios; Vassiliadis, Themistoklis; Moulakakis, Antonios; Raptopoulou, Maria; Haida, Caterina; Hatzakis, Angelos

    2005-07-01

    We studied viral dynamic parameters in 44 chronic hepatitis B/hepatitis B e antigen (HBeAg)(-) patients treated with pegylated interferon alfa-2b (PEG-IFN) 100 or 200 microg weekly or lamivudine 100 mg daily or the combination of PEG-IFN 100 or 200 microg with lamivudine. Patients receiving PEG-IFN monotherapy exhibited viral load oscillations between weekly injections, which were resolved by the addition of lamivudine. The median pharmacological delay was estimated at 4.1, 5.8, and 1.8 hours in PEG-IFN monotherapy, PEG-IFN 100/200 microg + lamivudine, and lamivudine monotherapy, respectively (P = .44). The median half-life of free virus was 12.7 hours (range, 2.4-69.2 hours). The mean antiviral effectiveness of PEG-IFN 100/200 microg monotherapy was lower than that of lamivudine (82.6% vs. 96.4%; P = .005). The mean effectiveness of PEG-IFN 100 microg + lamivudine and PEG-IFN 200 microg + lamivudine was 92.8% and 94.4%, respectively. The half-life of infected cells ranged from 2.7 to 75 days. The median half-life of infected cells in patients receiving the combination regimens of PEG-IFN and lamivudine was similar to that of lamivudine patients (5.0 days vs. 6.0 days, P = .77). In conclusion, the addition of pegylated interferon alfa-2b in lamivudine treatment was found to neither enhance the potency of blocking HBV production nor the decay rates of infected cells. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). PMID:15962284

  12. pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo.

    PubMed Central

    Eron, J J; Chow, Y K; Caliendo, A M; Videler, J; Devore, K M; Cooley, T P; Liebman, H A; Kaplan, J C; Hirsch, M S; D'Aquila, R T

    1993-01-01

    Specific mutations in the human immunodeficiency virus type 1 (HIV-1) pol gene that cause zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI) resistance were studied. The 50% inhibitory concentrations (IC50s) of nucleosides for cloned viruses containing these mutations were compared with the IC50s of the corresponding triphosphate analogs for mutant recombinant-expressed reverse transcriptases (RTs). Changes in ddATP inhibition of RNA-dependent DNA polymerase activity fully accounted for the ddI resistance of the virus caused by a Leu-74-->Val substitution in RT, including an augmentation by the AZT-selected substitutions Thr-215-->Tyr and Lys-219-->Gln in RT. In contrast, the AZT-selected substitutions studied did not cause as great a change in the IC50 of AZT-triphosphate (AZT-TP) for polymerase as they did in the IC50 of AZT for mutant virus. In addition, the mutation at codon 74 suppressed AZT resistance in the virus caused by the mutations at codons 215 and 219 but did not suppress the AZT-TP resistance of enzyme containing these same mutations in RT. The mutation at codon 74 was found in clinical isolates whether or not the patient had received AZT prior to starting ddI therapy. AZT resistance coexisted with ddI resistance following acquisition of Leu-74-->Val in three clinical isolates, indicating that the suppressive effect of Val-74 on the AZT resistance of the virus does not occur in all genetic contexts. When this suppression of AZT resistance was seen in the virus, Val-74 did not appear to cause mutually exclusive changes in AZT-TP and ddATP binding to RT in vitro. The results of the in vitro experiments and characterization of clinical isolates suggest that there are differences in the functional effects of these AZT and ddI resistance mutations. PMID:7689822

  13. 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. PMID:19175878

  14. Covariate effects and population pharmacokinetics 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 Lamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and Cmax). Methods Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building. Results A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h−1 and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg−1 ranged from 4.44 mg l−1 h for children <14 kg to 7.25 mg l−1 h for children >30 kg. Conclusions The use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered. PMID:24118070

  15. Simplification to atazanavir/ritonavir+lamivudine in virologically suppressed HIV-infected patients: 24-weeks interim analysis from ATLAS-M trial

    PubMed Central

    Fabbiani, Massimiliano; Di Giambenedetto, Simona; Quiros-Roldan, Eugenia; Latini, Alessandra; Vullo, Vincenzo; Antinori, Andrea; Castagna, Antonella; Orofino, Giancarlo; Francisci, Daniela; Grilli, Elisabetta; Madeddu, Giordanu; Grima, Pierfrancesco; Rusconi, Stefano; Del Pin, Barbara; Mondi, Annalisa; Borghetti, Alberto; Focà, Emanuele; Colafigli, Manuela; De Luca, Andrea; Cauda, Roberto

    2014-01-01

    Introduction We report interim 24-weeks efficacy data of ATLAS-M trial, a phase IV, multicentre, open-label, randomized study designed to show 48-weeks, non-inferior efficacy (margin of −12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3-drugs ATV/r-based cART. Methods Subjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV-RNA <50copies/mL for >3 months and CD4>200 cells/mm3 for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3-drug regimen (arm two). Primary endpoint: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure (VF=two consecutive HIV-RNA>50 copies/mL or a single value >1000 copies/mL). Enrollment of 266 patients was planned. Results A total of 266 patients (78% males, median age 44 years, median CD4 603 cells/µL, 79% treated with a tenofovir-containing backbone) were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8–97.6) and 85.1% (95% CI 77.6–92.6) in arm one and two, respectively (difference +6.6%, 95% CI −2.9/+16.1). VF was observed in two patients randomized to arm one (one at baseline, before treatment simplification) and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 (mean change +90 vs +10 cells/µL, p=0.007). A greater increase in total cholesterol (+18 vs −2 mg/dL, p<0.001), HDL (+4 vs +0 mg/dL, p=0.001) and LDL (+12 vs +0 mg/dL, p=0.001) was also observed in arm one without differences in other lipid

  16. 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

  17. Nanoreticulations of etherified locust bean polysaccharide for controlled oral delivery of lamivudine.

    PubMed

    Maiti, Sabyasachi; Mondol, Ranjit; Sa, Biswanath

    2014-04-01

    Herein, an aqueous solution of etherified locust bean polysaccharide (ELBP) containing lamivudine was reticulated in presence of trivalent aluminium (Al(3+)) ions to nanoscale level (43.82-197.70 nm) by surfactant assisted homogenization-reticulation technique. The variation in aluminium chloride (AlCl3) strength (1.5-3.5% (w/v)) and drug:ELBP weight ratio (0.11-0.43) affected the properties of the nanoreticulations. Regardless of the variables, a maximum of ∼44% drug entrapment efficiency was noted. In simulated intestinal fluid (phosphate buffer solution, pH 7.4), the drug release rate was inversely proportional to the strength of AlCl3; but followed a proportional relationship with the drug:ELBP ratio. The mechanism of drug release shifted from Fickian diffusion to anomalous transport as the salt strength was increased above 2.5% (w/v). At intermediate drug:ELBP ratio, the drug release rate was regulated by polymer chain relaxation as opposed to simple diffusion mechanism. Fourier transform infrared spectroscopy did not show any evidence of chemical interaction between the drug and ELBP. Thermal analysis and X-ray diffraction studies suggested amorphous dispersion of drug in the nanoreticulations. Thus, the nanoreticulations were expected to absorb via intestine and phagocytosed by the virus-infected hepatic macrophages and hence could be useful for controlled delivery of lamivudine avoiding dose-dependent toxicity of the drug. PMID:24463266

  18. In vitro human immunodeficiency virus type 1 resistance selections with combinations of tenofovir and emtricitabine or abacavir and lamivudine.

    PubMed

    Margot, N A; Waters, J M; Miller, M D

    2006-12-01

    Human immunodeficiency virus type 1 (HIV-1) resistance development was evaluated in vitro by using combinations of the drugs tenofovir and emtricitabine or abacavir and lamivudine, as well as by using the compounds individually. Emtricitabine- and lamivudine-resistant HIV-1 isolates with the M184I or M184V mutation in reverse transcriptase were readily selected in the cultures with emtricitabine alone, lamivudine alone, and the two drug combinations and conferred high-level resistance to emtricitabine and lamivudine. Tenofovir-resistant HIV-1 isolates with the K65R mutation occurred in both the culture with tenofovir alone and the culture with the combination of emtricitabine and tenofovir. The S68N and S68K mutations were also observed in the tenofovir cultures, with no detectable impact on resistance, suggesting a possible compensatory role in viral fitness. At low concentrations of emtricitabine and tenofovir, the M184I mutation appeared first, followed by the K65R mutation, in a subset of viruses. At intermediate concentrations of emtricitabine and tenofovir, viruses harboring the K65R mutation or a novel K65N and K70R double mutation grew before they gave rise to mutants with K65R and M184V/I double mutations at higher emtricitabine concentrations. Abacavir resistance was characterized by the accumulation of the M184V, Y115F, and K65R mutations in the abacavir culture, while the M184V and L74V mutations were selected in combination with lamivudine. In the presence of the abacavir resistance mutations, viral growth was strong even in the presence of high concentrations of abacavir. In contrast, viral growth was markedly impaired in the cultures with high tenofovir concentrations, even in the presence of K65R. In conclusion, these studies show that HIV-1 mutants with a K65R and M184V genotype are generated under maximum selection pressure from the combination of tenofovir and emtricitabine. PMID:16982781

  19. Betaine Inhibits Hepatitis B Virus with an Advantage of Decreasing Resistance to Lamivudine and Interferon α.

    PubMed

    Zhang, Mengmeng; Wu, Xiaoying; Lai, Furao; Zhang, Xiaoyuan; Wu, Hui; Min, Tian

    2016-05-25

    Betaine (BET) is a native compound known for its ability to protect the liver from toxicants. However, few studies have examined the effects of BET on the most common cause of liver disease, hepatitis B virus (HBV). In this study, the anti-HBV activity of BET was assessed in vitro and in vivo using enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and Southern blotting. The resistance of HBV to lamivudine and interferon α is challenging in the clinical treatment of HBV. The effect of BET on resistance was also investigated. The results showed that the secretion of HBsAg (HBV surface antigen), HbeAg (HBV e antigen), and HBV DNA in HepG2.2.15 cells was significantly decreased by BET via suppression of GRP78 expression. In duck HBV (DHBV)-infected ducklings, 1.0 or 2.0 g/kg BET significantly reduced serum DHBV DNA, and DHBV DNA did not rebound after the 5 day withdrawal period. BET suppressed HBV DNA rebound produced by the resistance of HBV to lamivudine and decreased the resistance mutation (rtM204V/I) of HBV DNA. Supplementation of BET may improve the anti-HBV effect of interferon α by increasing the expression of antiviral dsRNA-dependent protein kinase induced by the JAK-STAT (JAK = Janus kinase; STAT = signal transducer and activator of transcription) signaling pathway. These results may provide useful information for the clinical application of BET and solution of HBV drug resistance in anti-HBV therapy. PMID:27144395

  20. 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.

  1. Hepatitis B virus reactivation and efficacy of prophylaxis with lamivudine in patients undergoing allogeneic stem cell transplantation.

    PubMed

    Giaccone, Luisa; Festuccia, Moreno; Marengo, Andrea; Resta, Isabel; Sorasio, Roberto; Pittaluga, Fabrizia; Fiore, Francesca; Boccadoro, Mario; Rizzetto, Mario; Bruno, Benedetto; Marzano, Alfredo

    2010-06-01

    Patients previously infected with hepatitis B virus (HBV) undergoing an allograft and recipients from HBV carrier donors are at risk of posttransplant viral reactivation. The role of prophylaxis with lamivudine remains unclear. One hundred seventeen patients, with a median age of 52 years (20-67 years), with various hematologic malignancies transplanted between 1999 and 2007 entered the study. Eighty-seven recipients negative for HBV surface antigen (HBsAg), antihepatitis B core antigen antibodies (anti-HBc), and HBV-DNA with HBsAg and HBV-DNA negative donors were defined as at low risk of HBV reactivation, whereas all the remaining 30 patients were defined as at high risk. Patients at high risk transplanted in 2005 or after received lamivudine to prevent HBV reactivation as per the Italian guidelines by the Associazione Italiana per lo Studio del Fegato (AISF). Patients at low risk did not experience HBV reactivation/hepatitis. Among the recipients at high risk, 11 of 25 anti-HBc positive, those HBsAg positive (2 of 2) or negative but transplanted from HBsAg positive donors (3 of 3) were treated with lamivudine. None of these developed HBV reactivation/hepatitis after a median follow-up of 40 months (17-55 months). Hepatitis developed in 3 anti-HBc positive untreated patients conditioned with a reduced-intensity regimen. Hepatitis B was not observed in recipients at low risk, transplanted from HBsAg negative/anti-HBc positive or negative donors. Lamivudine was effective in controlling reactivation in: HBsAg positive recipients, in patients transplanted from HBsAg positive donors and in HBsAg negative/antiHBc positive recipients, who showed a significant risk of reactivation if not given prophylaxis (NCT 00876148). PMID:20060484

  2. 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

  3. The Importance of Lamivudine Therapy in Liver Cirrhosis Patients Related HBV with Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy

    PubMed Central

    Momiyama, Koichi; Nagai, Hidenari; Ogino, Yu; Mukouzu, Takanori; Matsui, Daigo; Kogame, Michio; Matsui, Teppei; Wakui, Noritaka; Shinohara, Mie; Igarashi, Yoshinori; Sumino, Yasukiyo

    2015-01-01

    Purpose: We have previously reported that continuous hepatic arterial infusion chemotherapy (HAIC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with liver cirrhosis (LC) related to HCV infection (C-LC) or alcohol abuse (A-LC) than in patients who had LC related to HBV infection (B-LC). The aim of the present study was to retrospectively assess the efficacy of lamivudine therapy for B-LC patients with aHCC undergoing HAIC. Methods: Seventeen adult Japanese B-LC patients with aHCC were treated by HAIC with or without lamivudine (100 mg/day) between 2002 and 2008 at our hospital. Their tumors were inoperable according to computed tomography findings. HAIC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was given via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. Results: Nine of the 17 patients received lamivudine at a dose of 100 mg/day together with HAIC (LAM group), while 8 patients did not receive lamivudine and only had HAIC (non-LAM group). The response rate was 12.5 in the non-LAM group and 0.0% in the LAM group. However, the survival of the LAM group was better than that of the non-LAM group, although there was no significant difference between them. The median survival time of the LAM and non-LAM groups was 310 and 157 days, respectively. HBV-DNA levels were significantly lower after chemotherapy compared with that before chemotherapy in the LAM group. In the non-LAM group, the percentage of Th2 cells before HAIC and after HAIC was significantly higher than in the control group. However, the percentage of Th2 cells in the LAM group after HAIC was not different from that in the control group, although it was significantly higher in the LAM group than in the control group before chemotherapy. Conclusions: These results indicate that lamivudine therapy may prolong the survival of B-LC patients receiving HAIC for aHCC by reducing HBV

  4. 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%. PMID:17580624

  5. 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. PMID:26262777

  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 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

  7. 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. PMID:18181733

  8. Adefovir- or Lamivudine-Induced Renal Tubular Dysfunction after Liver Transplantation.

    PubMed

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2015-09-01

    To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral nucleoside/nucleotide analogs (NUCs); however, proximal renal tubular dysfunction (RTD) that was induced by NUCs in liver recipients was rarely reported. Here, we analyzed RTD and renal impairment (RI) following adefovir (ADV) and lamivudine (LAM) treatment in liver recipients. We retrospectively reviewed medical records of patients treated with HBIG alone (group 1, n = 42) or combined with ADV or LAM (group 2, n = 21) after LT. We compared RTD and RI incidence during the 12 months after LT. An RTD diagnosis required manifestation of at least 3 of the following features: hypophosphatemia, RI, hypouricemia, proteinuria, or glucosuria. No significant differences were observed regarding sex, age, donor type, model of end-stage liver score, and estimated glomerular filtration rate at pre-LT between the 2 groups. Hepatitis B virus recurrence within 12 months was 4.8% in both groups (P = 1.000); however, the RTD incidence was 0% in group 1 and 19.0% in group 2 (P = 0.010). RI occurrence did not differ between the groups. The only risk factor for RI was HBIG administration combined with both LAM and ADV (odds ratio 11.27, 95% confidence interval 1.13-112.07, P = 0.039, vs HBIG alone). RTD occurred more frequently in patients treated with HBIG combined with LAM or ADV compared with HBIG alone. Thus, LAM or ADV therapy can induce RTD after LT, and when administered, liver recipients should be monitored. PMID:26402818

  9. Adefovir- or Lamivudine-Induced Renal Tubular Dysfunction after Liver Transplantation

    PubMed Central

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2015-01-01

    Abstract To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral nucleoside/nucleotide analogs (NUCs); however, proximal renal tubular dysfunction (RTD) that was induced by NUCs in liver recipients was rarely reported. Here, we analyzed RTD and renal impairment (RI) following adefovir (ADV) and lamivudine (LAM) treatment in liver recipients. We retrospectively reviewed medical records of patients treated with HBIG alone (group 1, n = 42) or combined with ADV or LAM (group 2, n = 21) after LT. We compared RTD and RI incidence during the 12 months after LT. An RTD diagnosis required manifestation of at least 3 of the following features: hypophosphatemia, RI, hypouricemia, proteinuria, or glucosuria. No significant differences were observed regarding sex, age, donor type, model of end-stage liver score, and estimated glomerular filtration rate at pre-LT between the 2 groups. Hepatitis B virus recurrence within 12 months was 4.8% in both groups (P = 1.000); however, the RTD incidence was 0% in group 1 and 19.0% in group 2 (P = 0.010). RI occurrence did not differ between the groups. The only risk factor for RI was HBIG administration combined with both LAM and ADV (odds ratio 11.27, 95% confidence interval 1.13–112.07, P = 0.039, vs HBIG alone). RTD occurred more frequently in patients treated with HBIG combined with LAM or ADV compared with HBIG alone. Thus, LAM or ADV therapy can induce RTD after LT, and when administered, liver recipients should be monitored. PMID:26402818

  10. Early virologic response to abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202

    PubMed Central

    Grant, Philip M.; Tierney, Camlin; Budhathoki, Chakra; Daar, Eric S.; Sax, Paul E.; Collier, Ann C.; Fischl, Margaret A.; Zolopa, Andrew R.; Balamane, Maya; Katzenstein, David

    2014-01-01

    Background ACTG A5202 randomized treatment-naive individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high screening viral load (VL) stratum (≥100,000 copies/mL) had increased rates of virologic failure with ABC/3TC. Objective Compare regimen-specific early virologic response. Methods Using Wilcoxon rank-sum tests, we compared regimen-specific VL changes from entry to week 4 in A5202 subjects (n=1813) and from entry to week 1, 2 and 4 in a 179-patient substudy. We evaluated associations between week 4 VL change and time to virologic failure with Cox proportional-hazards models. Results TDF/FTC- and ABC/3TC produced similar Week 4 viral load declines in the entire study population and in the high VL stratum. EFV produced greater VL declines from baseline at week 4 than ATV/r (median −2.1 vs. −1.9 log10 copies/mL; p<0.001). In the substudy of subjects with week 1, 2 and 4 VL data, there was no difference in viral load decline in those randomized to TDF/FTC versus ABC/3TC, but EFV resulted in greater VL decline from entry at each of these timepoints than ATV/r. Smaller Week 4 viral load decline was associated with increased risk of virologic failure. Conclusions Within all treatment arms, a less robust week 4 virologic response was associated with higher risk for subsequent virologic failure. However, between-regimen differences in week 4 VL declines did not parallel the previously reported differences in longer term virologic efficacy in A5202, suggesting that between-regimen differences in responses were not due to intrinsic differences in antiviral activity. PMID:24334181

  11. The use of hot and cold high pressure homogenization to enhance the loading capacity and encapsulation efficiency of nanostructured lipid carriers for the hydrophilic antiretroviral drug, didanosine for potential administration to paediatric patients.

    PubMed

    Kasongo, Kasongo Wa; Müller, Rainer H; Walker, Roderick B

    2012-01-01

    A major obstacle to the application of nanostructured lipid carriers (NLCs) as carriers for hydrophilic drugs is the limited loading capacity (LC) and encapsulation efficiency (EE) of NLCs for these molecules. The purpose of this research was to design and implement a strategy to enhance the LC and EE of NLCs for the hydrophilic drug, didanosine (DDI). DDI was dispersed in Transcutol(®) HP and the particle size of DDI in the liquid lipid was reduced gradually using hot high pressure homogenization (HPH). The product obtained thereafter was added to Precirol(®) ATO 5 and the hot mixture was immediately dried using liquid nitrogen. The dried materials were then ground and passed through a 200 μm sieve and the solid lipid particles were dispersed in a surfactant solution and subsequently used to manufacture DDI-loaded NLCs using cold HPH. The LC and EE of NLCs for DDI manufactured using the new strategy were 3.39 ± 0.63% and 51.58 ± 1.31%, respectively, compared to 0.079 ± 0.001% and 32.45 ± 0.08%, respectively, obtained when DDI-loaded NLCs were produced using conventional hot HPH. The enhanced LC and EE for DDI make NLCs a potential technology for the oral administration of DDI to paediatric patients. PMID:21241166

  12. Generation of a human hepatoma cell line supporting efficient replication of a lamivudine resistant hepatitis B virus.

    PubMed

    Zhang, Yijun; Zhang, Yongmei; Kang, Yaoyue; Wang, Jinyu; Liu, Hongyan; Zhu, Haoxiang; Qin, Yanli; Mao, Richeng; Lin, Xu; Lu, Mengji; Zhang, Jiming

    2014-06-01

    Emergence of lamivudine (LAM) resistance causes treatment failure in patients with chronic hepatitis B and compromise the efficacy of subsequent salvage therapies with other nucleot(s)ide analogs (NAs). Establishment of cell-based assays supporting LAM-resistant hepatitis B virus (HBV) replication will not only provide tools for investigating the replication property, but also screening for antiviral agents efficiently inhibiting the replication of LAM-resistant HBV variants. Accordingly, a human hepatoma (HepG2)-derived cell line was established by stable transfection of a plasmid containing a 1.2 unit length of HBV genome harboring rtL180M and rtM204V mutations that confer LAM resistance. In addition to support efficient viral genome replication, the cell line also produces high levels of HBV virions and subviral particles. As expected, HBV DNA replication in this cell line is completely resistant to lamivudine, but sensitive to adefovir (ADV), entecavir (ETV) and tenofovir (TDF). The cell line is suitable for screening for antiviral agents that inhibit LAM-resistant HBV replication and inhibitors of HBsAg biosynthesis and secretion, which may reduce HBsAg antigenemia and ultimately help to restore host antiviral immune response against HBV and cure chronic HBV infection. PMID:24583110

  13. [Hepatitis B virus reactivation after cessation of prophylactic lamivudine therapy in B-cell lymphoma patients treated with rituximab combined CHOP therapy].

    PubMed

    Mimura, Naoya; Tsujimura, Hideki; Ise, Mikiko; Sakai, Chikara; Kojima, Hiroshige; Fukai, Kenichi; Yokosuka, Osamu; Takagi, Toshiyuki; Kumagai, Kyoya

    2009-12-01

    Here we report three cases of hepatitis B virus (HBV) reactivation after cessation of preemptive lamivudine therapy in B-cell lymphoma patients treated with rituximab plus CHOP (R-CHOP). Two patients received eight cycles of R-CHOP, and one received two cycles of R-CHOP followed by two courses of rituximab. As all the patients were HBV surface antigen (HBsAg) positive, lamivudine was administered simultaneously with R-CHOP to prevent virus reactivation. All the patients developed hepatitis due to HBV reactivation 6, 8 and 13 months after completion of chemotherapy, and 4, 2 and 2 months after cessation of lamivudine, respectively. They were treated with either lamivudine or entecavir and all achieved full recovery. When HBV carriers undergo immunosuppressive anticancer treatment, prophylactic antiviral therapy is well recognized as effective. However, the optimal method of prophylaxis has not yet been established. Since the introduction of rituximab, new problems such as delayed HBV reactivation from HBsAg positive patients and de novo hepatitis B from HBsAg negative patients have emerged. Guidelines for prophylactic antiviral therapy in the era of rituximab need to be established. PMID:20068280

  14. Lamivudine Inhibits the Replication of ALV-J Associated Acutely Transforming Virus and its Helper Virus and Tumor Growth In vitro and In vivo

    PubMed Central

    Wang, Yixin; Xu, Shuzhen; Li, Sifei; Su, Hongqin; Chang, Shuang; Li, Yang; Sun, Xiaolong; Zhao, Peng; Cui, Zhizhong

    2015-01-01

    To study the antiviral effects of lamivudine on avian leukosis virus subgroup J (ALV-J) and its inhibitory effect on the growth of fibrosarcomas caused by acute transforming avian leukosis virus, a series of experiments were performed in chicken embryo fibroblast cultures and 1-day-old chickens inoculated with an acutely transforming viral stock Fu-J (SDAU1005). This stock was prepared from an acutely fibrosarcoma of field cases in chicken farms and contained both the replication-defective virus Fu-J carrying v-fps oncogene and its helper virus ALV-J strain SDAU1005. The results from three different assays in cell cultures demonstrated the significant inhibitory effect of lamivudine on the replication of both SDAU1005 and Fu-J viruses. Furthermore, the effect was dose dependent in the concentration range of 1–4 μg/ml. In chicken experiments, lamivudine could decrease the viral loads of SDAU1005 and Fu-J in the plasma of inoculated chickens, delay the appearance of acute sarcomas, and decrease chicken mortality in the early stage. This model may be used to directly evaluate the inhibitory effects of lamivudine on such tumors and to understand the relationship between the replication-defective virus and its helper virus while also assessing tumor processes. PMID:26648914

  15. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption.

    PubMed

    Yuen, G J; Lou, Y; Thompson, N F; Otto, V R; Allsup, T L; Mahony, W B; Hutman, H W

    2001-03-01

    A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relative to the separate brand-name components administered simultaneously and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 2-day washout period: one A/L/Z combination tablet after an overnight fast, one abacavir 300 mg tablet + one lamivudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after an overnight fast, or one A/L/Z combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for determination of abacavir, lamivudine, and zidovudine serum concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration-time curve (AUC(infinity)) and maximum observed serum concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. GLS ratios and 90% CI for AUC(infinity) and Cmax were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively, for lamivudine; and 0.95 (0.89, 1.02) and 0.96 (0.80, 1.15), respectively, for zidovudine. The extent of absorption of abacavir, lamivudine, and zidovudine from the combination tablet was not altered by administration with meals, indicating that

  16. 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. PMID:26085428

  17. Long-term lamivudine for chronic hepatitis B and cirrhosis: A real-life cohort study

    PubMed Central

    Su, Ming-Hua; Lu, Ai-Lian; Li, Shi-Hua; Zhong, Shao-Hua; Wang, Bao-Jian; Wu, Xiao-Li; Mo, Yan-Yan; Liang, Peng; Liu, Zhi-Hong; Xie, Rong; He, Li-Xia; Fu, Wu-Dao; Jiang, Jian-Ning

    2015-01-01

    AIM: To investigate clinical outcomes of chronic hepatitis B (CHB) and liver cirrhosis (LC) patients under whole-course management with lamivudine (LAM). METHODS: This was a retrospective-prospective cohort study based on two nonrandom cohorts of Chinese patients (LAM group and history control group). Two hundred thirty-eight patients with LAM treatment for at least 12 mo under whole-course management were included in the LAM group. The management measures included regular follow-up and timely adjustment of the therapeutic regimen according to drug-resistance and relapse. Two hundred thirty-eight patients with CHB or LC without any antiviral treatment and with follow-up over 12 mo were included in the history control group. The LAM and control group patients were 1:1 matched by propensity score method to ensure both patients were similar in general datum, sex, age, E antigen, and diagnosis. The incidence rates of endpoint events [LC, hepatocellular carcinoma (HCC), and death] were compared between the LAM and control groups. RESULTS: Hepatitis B virus-DNA < 1000 copies per mL rate and rate of alanine transaminase < 1.3 of the upper normal limit in LAM and control groups were 89.1% vs 18.5% (P < 0.05) and 89.8% vs 31.1% (P < 0.05), respectively. Viral breakthrough occurred in 77 patients (32.4%); the one-, three-, and five-year cumulative rates were 6.8%, 33.1%, and 41.3%, respectively. In total, 44.5% (106/238) of patients had once stopped LAM, and 63 (59.4%) of them developed virologic relapse; the relapse rate of patients with and without reaching Asian Pacific Association for the Study of the Liver endpoint criteria were 52.4% and 69.8%, respectively. Six CHB patients in the LAM group developed LC compared to 47 patients in the control group; the three-, and five-year cumulative rates of CHB at baseline of LAM were lower than those of the control group: 0.7% vs 12.0% and 1.8% vs 23.8% (P < 0.01), respectively. The incidence of HCC in CHB at baseline of LAM was

  18. Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir

    PubMed Central

    Park, Hana; Park, Jun Yong; Kim, Seung Up; Kim, Do Young; Han, Kwang-Hyub; Chon, Chae Yoon; Ahn, Sang Hoon

    2013-01-01

    AIM: To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV. METHODS: This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48. RESULTS: The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m2 in the LdT + ADV group increased from 49.1% (26/53) at

  19. 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

  20. 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

    2014-08-01

    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. PMID:24780924

  1. 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

  2. Combination of the R263K and M184I/V resistance substitutions against dolutegravir and lamivudine decreases HIV replicative capacity.

    PubMed

    Singhroy, Diane N; Wainberg, Mark A; Mesplède, Thibault

    2015-05-01

    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

  3. Characterization of thermal and rheological properties of zidovudine, lamivudine and plasticizer blends with ethyl cellulose to assess their suitability for hot melt extrusion.

    PubMed

    Maru, Shital M; de Matas, Marcel; Kelly, Adrian; Paradkar, Anant

    2011-11-20

    The influence of antiretroviral drugs and plasticizers on the rheological and thermal characteristics of ethyl cellulose formulations intended for hot melt extrusion has been investigated. Antiretroviral drugs used were zidovudine and lamivudine, whilst plasticizers included triethylcitrate (TEC) and polyethylene glycol (PEG-6000). Physical mixtures containing ethyl cellulose with varying concentrations of drugs and plasticizers were characterized using differential scanning calorimetry (DSC) and parallel plate oscillatory rheometry. The viscosity of physical mixtures containing both drugs was lower than observed for pure ethyl cellulose, indicating that the drugs had a plasticizing effect. This was confirmed by lowering of the glass transition temperature (Tg) of ethyl cellulose. At the highest loading of 40% by weight, lamivudine appeared to become saturated within the polymer, causing an increase in viscosity and showing evidence of recrystallization upon cooling. Both TEC and PEG-6000 were found to lower the Tg of ethyl cellulose, although PEG-6000 recrystallized upon cooling which makes it unsuitable for use in the proposed controlled release formulations. Both plasticizers were also shown to reduce the viscosity of ethyl cellulose, more significantly so for TEC. The results indicate that ethyl cellulose formulations containing up to 40% by weight of zidovudine, not more than 30% by weight of lamivudine, with 5-10% by weight of TEC as the plasticizer are suitable for processing by hot melt extrusion. PMID:21925600

  4. [Efficacy and tolerance of tenofovir-lamivudine-efavirenz combination in HIV-1 patients in Fann Teaching Hospital in Dakar].

    PubMed

    Diop, S A; Fortes-Déguénonvo, L; Seydi, M; Dieng, A B; Basse, C D; Manga, N M; Dia, N M; Ndaw, G; Ndour, C T; Soumaré, M; Diop, B M; Sow, P S

    2013-02-01

    We conducted a study to evaluate the efficacy and tolerance of the tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV) combination regimen in HIV-1 patients by a descriptive analytical retrospective study of all HIV-1 patients receiving TDF-3TC-EFV combination between 2007 and 2011. Collected data was analysed using EpiInfo™ version 6.04. One hundred patients were included, with an average follow-up duration of 27 months and 19 days (± 21 months and 14 days).We observed an average increase in body weight of about 8 kg per annum, with an average rise in CD4 count of 100/mm(3) by the end of the second year. A reduction in viral load with 71% of patients in therapeutic success at 24 month of treatment was noted. Ninety-two patients presented with at least one side effect, mostly being Grade 1 or 2 (96.36%). Neurological (24 patients) and digestive (20 patients) complaints comprised the commonest reported side effects. Four patients had adverse effects severe enough to warrant a change in treatment regimen, principally due to renal insufficiency. Thirteen subjects died. Patients receiving TDF-3TC-EVF combination therapy need rigorous surveillance because this combination, although efficient, is not without significant adverse effects. PMID:23247755

  5. Cost-effectiveness of entecavir versus lamivudine for the suppression of viral replication in chronic hepatitis B patients in Brazil.

    PubMed

    Costa, Anna Maria N; L 'italien, Gilbert; Nita, Marcelo Eidi; Araujo, Evaldo Stanislau A

    2008-10-01

    Hepatitis B virus infection is an important public-health issue. Chronic patients have a higher risk of death due to complications, which increases health-care expenses in. Cost-effectiveness analysis of entecavir (ETV) versus lamivudine (LVD) for treatment of chronic hepatitis B, in e antigen (AgHBe)-positive and negative patients, based on two phase 3, controlled and randomized studies. A decision analysis model was developed, using the following endpoints: cost per patient with undetectable viral load and cost per quality life year (QALY) gained. Risks for complications (compensated or decompensated cirrhosis and hepatocellular carcinoma) were based on the cohort study REVEAL, published in 2006. The REVEAL parameters were applied to the results of the viral load levels obtained from the clinical assay data. The complication costs were based on a study of the disease cost conducted in Brazil, in 2005. The cost data were obtained predominantly from Sistema Unico de Saúde [SUS - Brazilian public health system] payment tables and drug price lists. The utility data were obtained from literature and life expectancy information was based on IBGE data. The analysis perspective was that of SUS. A discount rate of 3% per year was used. For the horizon of time of 10 years, the ETV had an incremental cost of approximately two million Brazilian Reais (R$) compared to LVD. Reducing the number of complications, ETV treatment reduced costs by around 3 million, reducing final costs by 1 million, for AgHBe-positive patients. ETV also reduced the incremental cost per QALY gained. ETV was found to be the most cost-effective alternative for AgHBe-positive and negative patients. PMID:19219274

  6. Abacavir/Lamivudine Versus Tenofovir DF/Emtricitabine as Part of Combination Regimens for Initial Treatment of HIV: Final Results

    PubMed Central

    Tierney, Camlin; Collier, Ann C.; Daar, Eric S.; Mollan, Katie; Budhathoki, Chakra; Godfrey, Catherine; Jahed, Nasreen C.; Myers, Laurie; Katzenstein, David; Farajallah, Awny; Rooney, James F.; Ha, Belinda; Woodward, William C.; Feinberg, Judith; Tashima, Karen; Murphy, Robert L.; Fischl, Margaret A.

    2011-01-01

    (See the editorial commentary by Hull and Montaner, on pages 1154–6.) Background. AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥105 copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. Methods. Primary endpoints were times to virologic failure, regimen modification, and safety event. Results. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). Conclusions. In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r. PMID:21917892

  7. 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

  8. 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

  9. A novel LC-MS/MS method for simultaneous quantification of tenofovir and lamivudine in human plasma and its application to a pharmacokinetic study.

    PubMed

    Matta, Murali Krishna; Burugula, Laxminarayana; Pilli, Nageswara Rao; Inamadugu, Jaswanth Kumar; J V L N, Seshagiri Rao

    2012-10-01

    A new, rapid, sensitive and specific LC-MS/MS method has been developed and validated for the simultaneous quantification of tenofovir and lamivudine in human plasma using abacavir as an internal standard. An API-4000 LC-MS/MS with electrospray ionization was operated in multiple-reaction monitoring mode for the analysis. The analytes were extracted from plasma by solid-phase extraction technique using an Oasis HLB cartridge. The reconstituted samples were chromatographed on a Chromolith ROD speed C(18) column using a mixture of 0.1% formic acid in water and acetonitrile (90:10 v/v) at a flow-rate of 1 mL/min. The method was validated as per the FDA guidelines. The calibration curves were found to be linear in the range of 5-600 ng/mL for tenofovir and 25- 4000 ng/mL for lamivudine. The intra- and inter-day precision and accuracy results were well within the acceptable limits. A run time of 2.8 min consumed for each sample made it possible to analyze more samples per day. The proposed assay method was found to be applicable to a pharmacokinetic study in human male volunteers. PMID:22222724

  10. Entecavir Versus Lamivudine Therapy for Patients With Chronic Hepatitis B-Associated Liver Failure: A Meta-Analysis

    PubMed Central

    Zhang, Xiaoguo; An, Yong; Jiang, Xuemei; Xu, Minling; Xu, Linlin; Chen, Shijun; Xi, Yaguang

    2014-01-01

    Background: Nucleoside analogues are recommended as antiviral treatments for patients with hepatitis B virus (HBV)-associated liver failure. Clinical data comparing entecavir (ETV) and lamivudine (LAM) are inconsistent in this setting. Objectives: To compare the efficacy and safety of ETV and LAM in patients with chronic hepatitis B (CHB)-associated liver failure. Patients and Methods: A literature search was performed on articles published until January 2014 on therapy with ETV and LAM for patients with CHB-associated liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was the primary efficacy measure, while total bilirubin (TBIL), prothrombin activity (PTA) changes and HBV DNA negative change rates were secondary efficacy measures. A quantitative meta-analysis was performed to compare the efficacy of the two drugs. Safety of ETV and LAM was observed. Results: Four randomized controlled trials and nine retrospective cohort studies comprising a total of 1549 patients were selected. Overall analysis revealed comparable survival rates between patients received ETV and those received LAM (4 weeks: RR = 1.03, 95%CI [0.89, 1.18], P = 0.73; 8 weeks: RR = 0.98, 95% CI [0.85, 1.14], P = 0.84; 12 weeks: RR = 0.98, 95% CI [0.90, 1.08], P = 0.70; 24 weeks: RR = 1.02, 95% CI [0.94, 1.10], P = 0.66). After 24 weeks of treatment, patients treated with ETV had a significantly lower TBIL levels (MD = -37.34, 95% CI [-63.57, -11.11], P = 0.005), higher PTA levels (MD = 11.10, 95% CI [2.47, 19.73], P = 0.01) and higher HBV DNA negative rates (RR = 2.76, 95% CI [1.69, 4.51], P < 0.0001) than those treated with LAM. In addition, no drug related adverse effects were observed in the two treatment groups. Conclusions: ETV and LAM treatments had similar effects to improve 24 weeks survival rate of patients with CHB-associated liver failure, but ETV was associated with greater clinical improvement. Both drugs were tolerated well during

  11. A Novel Hydrodynamic Injection Mouse Model of HBV Genotype C for the Study of HBV Biology and the Anti-Viral Activity of Lamivudine

    PubMed Central

    Li, Xiumei; Liu, Guangze; Chen, Meijuan; Yang, Yang; Xie, Yong; Kong, Xiangping

    2016-01-01

    Background: Absence of an immunocompetent mouse model of persistent hepatitis B virus (HBV) infection has hindered the research of HBV infection and the development of antiviral medications. Objectives: In the present study, we aimed to develop a novel HBV genotype C mouse model by hydrodynamic injection (HI) and then used it to evaluate the antiviral activity of lamivudine. Materials and Methods: A quantity of 15 μg of HBV plasmid [pcDNA3.1 (+)-HBV1.3C], adeno-associated virus-HBV1.3C (pAAV-HBV1.3C) or pAAV-HBV1.2A) were injected into male C57BL/6 mice, by HI, accounting for a total of 13 mice per group. Then, lamivudine was administered to mice with sustained HBV viremia, for 4 weeks. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry methods were used to detect HBsAg, HBeAg, HBsAb, HBcAg and HBV DNA, in serum or liver of the mice, at indicated time points. Results: In 60% of the mice injected with pcDNA3.1 (+)-HBV1.3C, HBsAg, HBeAg, HBcAg and HBV DNA persisted for > 20 weeks in liver, post-injection, with no HBsAb appearance. Meanwhile, no significant inflammation was observed in these mice. Compared with pAAV-HBV1.2A and pAAV-HBV1.3C, pcDNA3.1 (+)-HBV1.3C administration led to higher and longer HBV viremia. Furthermore, serum HBV DNA was significantly reduced by lamivudine, after 4 weeks administration, and returned to the original level, after ceasing administration for 1 week, in the mice. Conclusions: In conclusion, our observations indicated that pcDNA3.1 (+)-HBV1.3C was superior to AAV/HBV plasmid for establishment of persistent HBV infection by HI, in vivo, and this mouse model could be useful for studies of hepatitis virology and for the development of innovatory treatments for HBV infections. PMID:27195013

  12. 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

  13. 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. PMID:26291050

  14. Lamivudine and Zidovudine

    MedlinePlus

    ... are in a class of medications called nucleoside reverse transcriptase inhibitors (NRTIs). They work by decreasing the ... staying asleep excessive tiredness depression stuffy nose cough hair loss Some side effects can be serious. The following ...

  15. Lamivudine and Zidovudine

    MedlinePlus

    ... Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for ...

  16. A Simplified HAART Regimen with Raltegravir and Lamivudine, and Pharmacokinetic Interactions with a Combined Immunosuppressive Therapy with Tacrolimus and Everolimus in an HIV/HCV/HBV/HDV Patient after Liver Transplantation

    PubMed Central

    Cirioni, O; Weimer, LE; Fragola, V; Giacometti, A; Ancarani, F; Maracci, M; Gabrielli, E; Marchionni, E; Pirillo, MF; Vella, S

    2014-01-01

    ABSTRACT In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions. PMID:25867565

  17. Steady-state pharmacokinetic comparison of generic and branded formulations of stavudine, lamivudine and nevirapine in HIV-infected Ugandan adults

    PubMed Central

    Byakika-Kibwika, Pauline; Lamorde, Mohammed; Kalemeera, Francis; D’Avolio, Antonio; Mauro, Sciandra; Di Perri, Giovanni; Ryan, Mairin; Mayanja-Kizza, Harriet; Khoo, Saye; Back, David; Boffito, Marta; Merry, Concepta

    2013-01-01

    Background We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40® (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded formulations of these drugs in HIV-infected Ugandans. Methods This includes a randomized, open-label, cross-over study of HIV-infected patients stable on therapy for 1 month. Patients were randomized to generic or branded formulation. Plasma pharmacokinetics were assessed after 1 month. The following day, alternate formulation was administered, and 1 month later, drug pharmacokinetics were re-assessed. Plasma pharmacokinetics were determined using HPLC–UV detection. Similarity between steady-state pharmacokinetic parameters was assessed using the US Food and Drug Administration standards for bioequivalency testing. Tolerability was assessed using questionnaires. Results Sixteen (10 females) patients completed the study. Median (IQR) age, weight and CD4 count were 37 (33.7–40) years, 65 (63.4–66) kg and 292 (220.7–344.5) cells/mm3, respectively. All patients received co-trimoxazole. The geometric mean ratio (90% CI) for stavudine, lamivudine and nevirapine was 0.92 (0.78–1.08), 1.11 (0.95–1.30) and 0.84 (0.64–1.11), respectively, for Cmax, and 0.83 (0.70–0.97), 1.06 (0.94–1.20) and 0.88 (0.71–1.10), respectively, for AUC. Stavudine plasma concentrations were significantly lower for the generic formulation. Pharmacokinetic parameter inter-individual variability ranged from 29% to 99%. There were no differences in tolerability for the two formulations. Conclusions Pharmacokinetic profiles of generic and branded drugs were similar. Differences particularly with regard to stavudine were demonstrated. Surveillance of the quality of generic antiretroviral drugs in the target populations is needed. Capacity building for pharmacokinetic research in resource-limited settings is a priority. PMID:18641036

  18. Stability behaviour of antiretroviral drugs and their combinations. 2: Characterization of interaction products of lamivudine and tenofovir disoproxil fumarate by mass and NMR spectrometry.

    PubMed

    Kurmi, Moolchand; Kushwah, Bhoopendra Singh; Sahu, Archana; Narayanam, Mallikarjun; Singh, Saranjit

    2016-06-01

    This study focused on drug-drug interaction behaviour among lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), the two anti-retroviral drugs. Apart from pre-known degradation products of individual drugs, a total of twelve interaction products were detected by high performance liquid chromatography (HPLC) using a C18 column as the stationary phase, and methanol and ammonium formate in gradient mode as the mobile phase. The same HPLC method was employed for liquid chromatography-high resolution mass spectrometry (LC-HRMS) and liquid chromatography-multi stage mass spectrometry (LC-MS(n)). For the characterization of interaction products, stability samples were subjected to LC-HRMS, LC-MS(n) and online hydrogen/deuterium exchange studies. Two isomeric interaction products were isolated and subjected to 1D and 2D nuclear magnetic resonance (NMR) studies. The collated information was utilized for the characterization of all twelve interaction products of the two drugs. Pathway of their formation was also outlined. PMID:27042808

  19. 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

  20. 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

  1. 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. PMID:25971320

  2. Lamivudine or emtricitabine (XTC)/protease inhibitor dual therapy as a harm-reduction strategy in patients with tenofovir-related renal toxicity: a case-control study.

    PubMed

    Rossotti, Roberto; Moioli, Maria Cristina; Chianura, Leonardo; Errante, Isabella; Orcese, Carloandrea; Orso, Maurizio; Schiantarelli, Clara; Schlacht, Irene; Travi, Giovanna; Vigo, Beniamino; Villa, Maria Riccarda; Volonterio, Alberto; Puoti, Massimo

    2012-11-01

    Tenofovir disoproxil fumarate (TDF) is widely used in HIV-infected patients. It is associated with tubular toxicity, but its management is controversial. A possible strategy is to switch to a dual therapy based on lamivudine or emtricitabine (XTC) and protease inhibitors (PIs). A case-control study was designed to evaluate the switch to XTC + PI therapy in patients with TDF-related renal toxicity. A case was defined as a patient who was on TDF/XTC + PI and who switched to XTC + PI. A control was defined as a patient with the same clinical features who remained on TDF/XTC + PI. Twenty-one cases and 21 controls were included. After 48 weeks, no differences in efficacy were observed. No improvement in the glomerular filtration rate as estimated with the Cockroft-Gault formula (eGFR) was seen, but the number of times that patients had values below 60 ml/min was higher with standard TDF/XTC 1 PI treatment than with dual XTC + PI treatment. A switch to dual therapy could be an option for patients at risk of TDF-related renal damage with no relevant risk of virological or immunological failure. PMID:22804338

  3. Long-term exposure of HIV type 1-infected cell cultures to combinations of the novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of nonnucleoside reverse transcriptase inhibitors.

    PubMed

    Balzarini, J; De Clercq, E; Carbonez, A; Burt, V; Kleim, J P

    2000-04-10

    The novel quinoxaline GW420867X has been combined with a variety of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1(IIIB)-infected CEM cell cultures. Whereas the antiviral efficacy of combinations of GW420867X with the NRTIs lamivudine (3TC) and abacavir (ABC) proved additive when administered to HIV-1-infected cells in a short-term (4-day) infection experiment, combination of GW420867X with the NRTIs 3TC and ABC resulted in a marked delay of virus breakthrough compared with the single drugs alone in a long-term (2-month) infection experiment. Delay of virus breakthrough was less pronounced for combinations of GW420867X with the NNRTIs. Combination of GW420867X with the NRTIs and NNRTIs resulted in additive inhibitory effects on recombinant HIV-1 reverse transcriptase as evident from isobolograms. Lamivudine plus GW420867X selected for the 3TC-specific M184I mutation and a number of NNRTI-characteristic mutations (i.e., V106A, V108I, and Y188H). Abacavir plus GW420867X selected only for NNRTI-specific mutations (i.e., K101E, K103R, V106A, and Y181C), including the novel L100V mutation. Combination of GW420867X with five different NNRTIs selected solely for NNRTI-specific mutations, and also for the L100V mutation in the combined presence of efavirenz, nevirapine, or emivirine, respectively. Five single-, two double-, and two triple-mutated HIV-1 strains that emerged from this study were evaluated for their sensitivity/resistance to AZT, lamivudine, and seven different NNRTIs. In all cases, efavirenz, GW420867X, and UC-781 retained pronounced antiviral potency. Our data suggest that combinations of GW420867X with 3TC, ABC, and NNRTIs (e.g., efavirenz) would be worth pursuing as therapeutic modalities against HIV-1 infections. PMID:10777142

  4. 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

  5. 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

  6. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

    PubMed Central

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  7. Antiviral Effects of Lamivudine, Emtricitabine, Adefovir Dipivoxil, and Tenofovir Disoproxil Fumarate Administered Orally Alone and in Combination to Woodchucks with Chronic Woodchuck Hepatitis Virus Infection ▿

    PubMed Central

    Menne, Stephan; Butler, Scott D.; George, Andrea L.; Tochkov, Ilia A.; Zhu, Yuao; Xiong, Shelly; Gerin, John L.; Cote, Paul J.; Tennant, Bud C.

    2008-01-01

    Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log10 and 6.1 log10 genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log10 genome equivalents/ml), ADV alone (4.8 log10 genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log10 genome equivalents/ml), TDF alone (2.9 log10 genome equivalents/ml), 3TC alone (2.7 log10 genome equivalents/ml), and FTC alone (2.0 log10 genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection. PMID:18676881

  8. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions.

    PubMed

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  9. A multiphase model of the dynamics of HBV infection in HBeAg-negative patients during pegylated interferon-alpha2a, lamivudine and combination therapy.

    PubMed

    Colombatto, Piero; Civitano, Luigi; Bizzarri, Ranieri; Oliveri, Filippo; Choudhury, Somesh; Gieschke, Ronald; Bonino, Ferruccio; Brunetto, Maurizia R

    2006-01-01

    Using a multiphase bio-mathematical model, we studied the dynamics of hepatitis B virus (HBV) infection in 72 HBeAg-negative patients who received 48 weeks of either lamivudine (3TC; 25 patients); pegylated interferon-alpha2a (peg-IFN-alpha2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-alpha2a 180 mg weekly plus placebo (24 patients). During the first month of therapy most of the 3TC -/+ peg-IFN-alpha2a treated patients showed a multiphase decay of viral load: during the first two phases, where we hypothesized a direct inhibition of virus production, the mean viral production per infected cell was reduced by 2.22 log10 and 2.36 log10, respectively. At variance, peg-IFN-alpha2a treated patients had a biphasic profile: the first phase HBV DNA decline was slower than that observed in 3TC patients (mean HBV DNA t(1/2) = 1.6 +/- 1.1 days and 9.5 +/- 3.0 h, respectively) and the direct antiviral effect reduced virus production by 1.14 log10. From day 14 onwards (third or second phase according to multi- or biphasic patterns), HBV DNA declined mainly because of the infected hepatocyte clearance that slowed down in approximately 50% of the patients from day 35, possibly because of a negative feedback on the immune system activity. Computing the number of infected cells at the end of therapy we found that peg-IFN-alpha2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log10), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log10, P = 0.039). In conclusion, peg-IFN-alpha2a, in spite of having direct antiviral activity lower than that of 3TC, achieved a comparable reduction of infected hepatocytes, possibly because of a higher infected cell clearance rate. PMID:16640101

  10. 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

  11. 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

  12. CD4(+) T Cell Response to Lamivudine, Stavudine and Nevirapine in Human Immunodeficiency Virus Infected Antiretroviral-Naive Men in Nigeria.

    PubMed

    Sule, Waidi Folorunso; Sani, Enejoh Simon

    2011-12-01

    Increase of (≥) 50 CD4(+) T cells/μl in post-commencement of highly active antiretroviral therapy (HAART) is acceptable as indicator of therapeutic success (TS). We therefore hypothesized that median change in CD4 count of the TS and therapeutic failure (TF) groups were comparable after 3 months; and that no associations existed between HAART outcome and adherence to therapy. One hundred Human immunodeficiency virus (HIV) infected antiretroviral (ARV) naive men on lamivudine + stavudine + nevirapine at Federal Medical Centre (FMC), Lokoja, Kogi State, Nigeria were studied. Data of the men were obtained with interviewer-administered questionnaire forms. Their ethylene diamine tetra acetic acid (EDTA)-treated whole blood samples were analysed with Partec CyFlow(®) Counter for pre-HAART and follow-up CD4 counts. Adherence to the ARV regimen was recorded for each patient as self-reported. We used Mann-Whitney U test, Kruskal-Wallis, Wilcoxon's matched pair and CHI(2) statistical tests for analyses. Overall adherence rate was 95.0%. Though the median follow-up CD4 count was higher (P = 0.001) than the pre-HAART value; only 85% of the men attained TS (increase of ≥50 cells/μl) at follow-up. Median change in CD4 count (+104.0 cells/μl; n = 85) of the TS was higher (P = 0.001) than that (-8.0 cells/μl; n = 15) of TF group; the two groups were however, comparable in age (P = 0.17) and body weight (P = 0.96). Only adherence and pre-HAART CD4 counts were associated (P = 0.001) with HAART outcome; while only age apparently influenced (P = 0.01) adherence rate. Eighty-five percent of the men benefited from the HAART. The success was apparently due to adherence and less than or (≤) 200 pre-HAART CD4 counts; while age ≥40 years appearently reduced adherence level. PMID:23637509

  13. Peripheral and Central Fat Changes in Subjects Randomized to Abacavir-Lamivudine or Tenofovir-Emtricitabine With Atazanavir-Ritonavir or Efavirenz: ACTG Study A5224s

    PubMed Central

    Kitch, Douglas; Sax, Paul E.; Tebas, Pablo; Tierney, Camlin; Jahed, Nasreen C.; Myers, Laurie; Melbourne, Kathleen; Ha, Belinda; Daar, Eric S.

    2011-01-01

    Background. We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. Methods. 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. Results. 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 log10 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 cm2, 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. Conclusions. 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. Clinical Trials Registration

  14. Single-Dose Pharmacokinetics and Safety of Abacavir (1592U89), Zidovudine, and Lamivudine Administered Alone and in Combination in Adults with Human Immunodeficiency Virus Infection

    PubMed Central

    Wang, Laurene H.; Chittick, Gregory E.; McDowell, James A.

    1999-01-01

    Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4+ cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5′-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (Cmax), the area under the concentration-time curve from time zero to infinity (AUC0–∞), time to Cmax (Tmax), and apparent elimination half-life (t1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the mean Cmax of ZDV by approximately 20% (from 1.5 to 1.2 μg/ml), delayed the median Tmax for ZDV by 0.5 h, increased the mean AUC0–∞ for GZDV by up to 40% (from 11.8 to 16.5 μg · h/ml), and delayed the median Tmax for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0–∞ for 3TC by approximately 15% (from 5.1 to 4.3 μg · h/ml), decreased the mean Cmax by approximately 35% (from 1.4 to 0.9 μg/ml), and delayed the median Tmax by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are

  15. 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

  16. Metabolic Outcomes in a Randomized Trial of Nucleoside, Nonnucleoside and Protease Inhibitor-Sparing Regimens for Initial HIV Treatment

    PubMed Central

    Haubrich, Richard H.; Riddler, Sharon A.; DiRienzo, A. Gregory; Komarow, Lauren; Powderly, William G.; Klingman, Karin; Garren, Kevin W.; Butcher, David L.; Rooney, James F.; Haas, David W.; Mellors, John W.; Havlir, Diane V.

    2009-01-01

    Background The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection. Methods Open-label study in 753 subjects randomized equally to: efavirenz or lopinavir/ritonavir(r) plus two NRTI versus the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96-weeks were lipoatrophy, defined as ≥20% loss of extremity fat, and fasting serum lipids. Results Lipoatrophy by DEXA at week 96 occurred in 32% (95% confidence interval 25%, 39%) of subjects in the efavirenz plus two NRTI arm, 17% (12%,24%) in the lopinavir/r plus two NRTI arm, and 9% (5,14%) in the NRTI-sparing arm (p≤0.023 for all comparisons). Varying the definition of lipoatrophy (≥10% to ≥40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (p<0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dL) compared to the other two arms (+32-33 mg/dL, p<.001). Use of lipid lowering agents was more common (25% versus 11-13%) in the NRTI-sparing arm. Conclusion Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid lowering agents. PMID:19417580

  17. Novel drug resistance pattern associated with the mutations K70G and M184V in human immunodeficiency virus type 1 reverse transcriptase.

    PubMed

    Bradshaw, D; Malik, S; Booth, C; Van Houtte, M; Pattery, T; Waters, A; Ainsworth, J; Geretti, A M

    2007-12-01

    We describe an unusual pathway of human immunodeficiency virus type 1 reverse transcriptase resistance during therapy with tenofovir-emtricitabine, characterized initially by the mutations K70E and M184V and later by K70G and M184V, with the two mutations coexisting on the same viral genome. Phenotypic resistance to lamivudine, emtricitabine, abacavir, didanosine, and tenofovir was observed, whereas susceptibility to zidovudine and stavudine was preserved. PMID:17876005

  18. HBsAg seroconversion after pegylated interferon alfa 2a rescue in a lamivudine-resistant patient with HBeAg-negative chronic hepatitis B and favourable IL28-B genotype.

    PubMed

    Stanzione, Maria; Stornaiuolo, Gianfranca; Rizzo, Viviana; Pontarelli, Agostina; Gaeta, Giovanni Battista

    2016-06-01

    Hepatitis B virus (HBV) surface antigen (HBsAg) seroconversion to anti-HBs antibody is the best final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely achieved with the currently applied therapeutic approaches. Here we describe the case of an anti-HBe-positive CHB patient who was successfully treated with a particular therapeutic schedule. The patient was initially treated with lamivudine (LAM) for nine years. Breakthrough was observed after eight years of LAM therapy. HBV-DNA was 3x10E4 IU/mL and LAM resistance mutations were present. Subcutaneous pegylated interferon (PEG-IFN) alfa 2a, 180 mcg/week, was added to LAM and after 4 weeks LAM was discontinued and PEG-IFN alone was continued up to week 52. HBV-DNA became undetectable at week 4 of therapy; serum HBsAg started to decline from week 4 and became undetectable at week 36, with the subsequent appearance of anti-HBs antibodies. IL28-B was genotyped at the polymorphic site rs12979860 and the CC allele was detected. Rescue therapy with Peg-IFN may be an option for selected patients with resistance to nucleos(t)ide analogues. PMID:27367326

  19. Evaluation of cardiovascular biomarkers in a randomized trial of fosamprenavir/ritonavir vs. efavirenz with abacavir/lamivudine in underrepresented, antiretroviral-naïve, HIV-infected patients (SUPPORT): 96-week results

    PubMed Central

    2013-01-01

    Background Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy. Methods This 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naïve, HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios. Results This study enrolled 101 patients (51 receiving fosamprenavir/ritonavir; 50 receiving efavirenz): 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96 weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL (fosamprenavir/ritonavir 63%; efavirenz 66%) by ITT missing-equals-failure analysis. Treatment-related grade 2–4 adverse events were more common

  20. Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3.

    PubMed

    Minuesa, Gerard; Volk, Christopher; Molina-Arcas, Míriam; Gorboulev, Valentin; Erkizia, Itziar; Arndt, Petra; Clotet, Bonaventura; Pastor-Anglada, Marçal; Koepsell, Hermann; Martinez-Picado, Javier

    2009-04-01

    Nucleoside reverse transcriptase inhibitors (NRTIs) need to enter cells to act against the HIV-1. Human organic cation transporters (hOCT1-3) are expressed and active in CD4+ T cells, the main target of HIV-1, and have been associated with antiviral uptake in different tissues. In this study, we examined whether NRTIs interact and are substrates of hOCT in cells stably expressing these transporters. Using [(3)H]N-methyl-4-phenylpyridinium, we found a high-affinity interaction among abacavir [[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]-cyclopent-2-enyl]methanol sulfate] (ABC); <0.08 nM], azidothymidine [3'-azido-3'-deoxythymidine (AZT); <0.4 nM], tenofovir disoproxil fumarate (<1.0 nM), and emtricitabine (<2.5 nM) and hOCTs. Using a wide range of concentrations of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacyitidine (3TC)], we determined two different binding sites for hOCTs: a high-affinity site (K(d1) = 12.3-15.4 pM) and a low-affinity site (K(d2) = 1.9-3.4 mM). Measuring direct uptake of [(3)H]3TC and inhibition with hOCT substrates, we identified 3TC as a novel substrate for hOCT1, 2, and 3, with hOCT1 as the most efficient transporter (K(m) = 1.25 +/- 0.1 mM; V(max) = 10.40 +/- 0.32 nmol/mg protein/min; V(max)/K(m) = 8.32 +/- 0.40 microl/mg protein/min). In drug-drug interaction experiments, we analyzed cis-inhibition of [(3)H]3TC uptake by ABC and AZT and found that 40 to 50% was inhibited at low concentrations of the drugs (K(i) = 22-500 pM). These data reveal that NRTIs experience a high-affinity interaction with hOCTs, suggesting a putative role for these drugs as modulators of hOCT activity. Finally, 3TC is a novel substrate for hOCTs and the inhibition of its uptake at low concentrations of ABC and AZT could have implications for the pharmacokinetics of 3TC. PMID:19141712

  1. 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 Central

    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

    2013-01-01

    Background. The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear. Methods. 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. Results. 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/m2, 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 × 103/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03). Conclusions. ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels. Clinical Trials Registration. NCT00118898. PMID

  2. Lamivudine-resistant rtL180M and rtM204I/V are persistently dominant during combination rescue therapy with entecavir and adefovir for hepatitis B

    PubMed Central

    WANG, YANG; LIU, SHUANG; CHEN, YU; ZHENG, SUJUN; ZHOU, LI; LU, FENGMIN; DUAN, ZHONGPING

    2016-01-01

    Adefovir (ADV) sequential monotherapy was included in the 2005 Asia-Pacific guidelines for the management of patients with lamivudine (LAM) resistance. However, following the development of ADV resistance, the proportion of resistant variants during combined rescue therapy with ADV and entecavir (ETV) were unknown. The present study characterized the dynamics of resistant variants in patients with chronic hepatitis B (CHB) and LAM-resistant variants during antiviral therapy consisting of ADV monotherapy followed by ADV-ETV combination therapy. A total of 3 patients were selected from a cohort of 55 patients with CHB due to developing ADV resistance. The patients had been previously treated with LAM (100 mg daily) for 21–24 months. At the initiation of sequential monotherapy with ADV, LAM-resistant variants (rtM204V/I and rtL180M) were detected in the three patients. These patients developed ADV resistance during 19–30 months of ADV sequential monotherapy, and then switched their antiviral regimen to ADV-ETV combination therapy. During ADV monotherapy and ADV-ETV combination therapy, the patients were monitored every 3 months for the first year of therapy, and then every 6 months thereafter. A total of 30 serum samples were collected from the patients throughout the monitoring period. In total, 10 mutants that were associated with commonly-used antiviral drugs were detected by pyrosequencing. During ADV sequential monotherapy, LAM-resistant variants were gradually decreased, whereas ADV-resistant rtA181V/T and rtN236T variants gradually increased in the viral population. During 30–41 months of ADV-ETV combination therapy, viral load reduction was 2.59–3.28 log10 copies/ml; ADV-resistant variants rtA181T/V and rtN236T were undetectable following 11–24 months of combination therapy; and rtL180M and rtM204I/V remained dominant in the viral population. In conclusion, the results of the present study suggested that, in patients with LAM and ADV

  3. In vivo examination of hydroxyurea and the novel ribonucleotide reductase inhibitors trimidox and didox in combination with the reverse transcriptase inhibitor abacavir: suppression of retrovirus-induced immunodeficiency disease.

    PubMed

    Sumpter, L Ryan; Inayat, Mohammed S; Yost, Erin E; Duvall, William; Hagan, Espen; Mayhew, Christopher N; Elford, Howard L; Gallicchio, Vincent S

    2004-06-01

    Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels. PMID:15130534

  4. Exploratory Analysis for the Evaluation of Estimated Glomerular Filtration Rate, Cholesterol and Triglycerides after Switching from Tenofovir/Emtricitabine plus Atazanavir/Ritonavir (ATV/r) to Abacavir/Lamivudine plus ATV/r in Patients with Preserved Renal Function

    PubMed Central

    Postorino, Maria Concetta; Quiros-Roldan, Eugenia; Maggiolo, Franco; Di Giambenedetto, Simona; Ladisa, Nicoletta; Lapadula, Giuseppe; Lorenzotti, Silvia; Sighinolfi, Laura; Castelnuovo, Filippo; Di Pietro, Massimo; Gotti, Daria; Mazzini, Nicola; Torti, Carlo

    2016-01-01

    Background and Objectives: Renal toxicity due to tenofovir (TDF) has been largely described in patients with HIV infection. However, other antiretroviral drugs (such as atazanavir [ATV], especially when boosted by ritonavir, ATV/r) could perpetuate some degrees of renal impairment with or without TDF co-administration. Also, possible benefits of stopping TDF in patients without renal diseases is not well known. This study aimed at exploring evolution of renal function and lipid profile after switching from tenofovir/emtricitabine (TDF/FTC) to abacavir/lamivudine (ABC/3TC), maintaining the ATV/r component of the regimen. Methods: Patients in the Italian MASTER Cohort, who switched from TDF/FTC plus ATV/r to ABC/3TC plus ATV/r were included, provided that major renal diseases were not diagnosed before switching (i.e., baseline). Serum creatinine, estimated glomerular filtration rate (eGFR), total cholesterol, HDL and triglycerides were evaluated at baseline and at month 18 after switching. Results: 126 patients were selected (80% males). Patients were mostly Italians (92%). 79% had undetectable HIV-RNA and 44% were co-infected by HBV and/or HCV. Median age at switch was 47 years (IQR 43-55). A small but significant decrease in serum creatinine [from 1.06 mg/dl (SD: 0.3) to 0.94 mg/dl (SD: 0.2); p<0.001] with an improvement in eGFR [from 86.8 ml/min (SD: 33) to 96.4 ml/min (SD: 37); p<0.001] were observed in per protocol analysis at month 18. Also ITT analysis showed a decrease in mean serum creatinine [from 1.08 mg/dl (SD: 0.35) to 0.95 mg/dl (SD: 0.24); p<0.001] with an improvement in mean eGFR [from 86.9 ml/min/1.73m2 (SD: 24.11) to 95.8 ml/min/1.73m2 (SD: 19.99); p<0.001]. Total cholesterol increased [from 188 mg/dl (SD: 42) to 206 mg/dl (SD: 44); p<0.001] but also HDL increased as well [from 46 mg/dl (SD: 14) to 54 mg/dl (SD: 19); p=0.015]. An increase in triglycerides concentration was observed [from 162 mg/dl (SD: 144) to 214 mg/dl (SD: 109); p=0.027] in per

  5. Abacavir sulfate, lamivudine, and zidovudine (Trizivir).

    PubMed

    Porche, D

    2001-01-01

    Treatment review is intended to inform and update nurses about treatments relevant to HIV/AIDS. Product information presented in this column does not imply endorsement by the Association of Nurses in Aids Care. PMID:11723917

  6. 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

    2015-12-01

    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. PMID:26565115

  7. 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. PMID:21078938

  8. 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 Central

    2009-01-01

    Summary Background 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. Methods 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. Findings 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). Interpretation 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

  9. Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana

    PubMed Central

    Shapiro, R.L.; Hughes, M.D.; Ogwu, A.; Kitch, D.; Lockman, S.; Moffat, C.; Makhema, J.; Moyo, S.; Thior, I.; McIntosh, K.; van Widenfelt, E.; Leidner, J.; Powis, K.; Asmelash, A.; Tumbare, E.; Zwerski, S.; Sharma, U.; Handelsman, E.; Mburu, K.; Jayeoba, O.; Moko, E.; Souda, S.; Lubega, E.; Akhtar, M.; Wester, C.; Tuomola, R.; Snowden, W.; Martinez-Tristani, M.; Mazhani, L.; Essex, M.

    2010-01-01

    BACKGROUND The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown. METHODS We randomly assigned 560 HIV-1–infected pregnant women (CD4+ count, ≥200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir–ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks’ gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine–lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine. RESULTS The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group. CONCLUSIONS All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.) PMID:20554983

  10. 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. PMID:26910503

  11. 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

  12. Recent availability of two novel, fixed formulations of antiretroviral nucleoside analogues: a 12-month prospective, open-label survey of their practical use and therapeutic perspectives in antiretroviral-naive and -experienced patients.

    PubMed

    Manfredi, Roberto; Calza, Leonardo

    2008-04-01

    The recent introduction of novel, fixed nucleoside-nucleotide reverse transcriptase inhibitor (NRTI) combinations (tenofovir-emtricitabine, and abacavir-lamivudine) expanded the spectrum of available formulations and concurrently increased patients' adherence levels. A prospective survey of the open-label use of these two fixed combinations was performed in 158 patients belonging to our single-center cohort of more than 1,000 HIV-infected subjects enrolled in the last 18 months, and followed for at least 12 months. During the last 18 months, 95 consecutive, evaluable patients (60.1%) received for the first time tenofovir-emtricitabine, or abacavir-lamivudine (63 patients, 39.9%), and were followed for at least 12 months with periodic clinical and laboratory examinations. Among the 53 evaluable patients who were naïve to all antiretrovirals, tenofovir-emtricitabine has been given to 42 subjects (79.2%), mostly associated with efavirenz (26 cases), or different boosted protease inhibitors (16 subjects), whereas abacavir-lamivudine was administered to 11 patients (in 10 cases of 11, together with boosted protease inhibitors). In the remaining 105 patients, tenofovir-emtricitabine or abacavir-lamivudine therapy represented a switch from a prior combination antiretroviral regimen, and was predominantly associated with boosted protease inhibitors (61 patients), versus efavirenz or nevirapine (26 cases), or other drug combinations containing protease inhibitors (the remaining 18 patients). Among the 105 pretreated patients, the prescription of tenofovir-emtricitabine (53 patients) was as frequent as that of abacavir-lamivudine (52 cases), and the therapeutic change was primarily prompted by toxicity or poor tolerability (59 patients), followed by therapeutic failure and viral resistance (46 cases as a whole), and always encompassed a regimen simplification also. Both fixed combinations were well tolerated, and an adherence rate more than 90% was estimated among evaluable

  13. 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

  14. Genotypic and phenotypic analysis of a novel 15-base insertion occurring between codons 69 and 70 of HIV type 1 reverse transcriptase.

    PubMed

    Lobato, Robert L; Kim, Eun-Young; Kagan, Ronald M; Merigan, Thomas C

    2002-07-01

    An HIV-1 isolate possessing a 15-base insertion between codons 69 and 70 of the reverse transcriptase (RT) gene was derived from a patient plasma sample. Investigation of the insertion sequence revealed that this mutation is an ectopic duplication of the first 15 bases of the HIV-1 envelope gene. Phenotypic analysis yielded the following increases in resistance: 371-fold to zidovudine, 84-fold to lamivudine, 32-fold to abacavir, 15-fold to stavudine, 12-fold to didanosine, and 4-fold to zalcitabine. Phenotypic studies suggested that this change does not detract from the overall fitness of the virus. Together, data from this investigation support two conclusions. First, a previously unreported mechanism exists for generating diversity in HIV-1, namely long-distance duplication of genetic material from one portion of the genome to another. Second, large insertions in this region of RT are well tolerated and can confer high levels of resistance to multiple nucleoside analogue reverse transcriptase inhibitors. PMID:12167282

  15. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV.

    PubMed

    De Clercq, Erik

    2009-04-01

    In 2008, 25 years after the human immunodeficiency virus (HIV) was discovered as the then tentative aetiological agent of acquired immune deficiency syndrome (AIDS), exactly 25 anti-HIV compounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir); cell entry inhibitors [fusion inhibitors (FIs: enfuvirtide) and co-receptor inhibitors (CRIs: maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development. PMID:19108994

  16. Low rates of nucleoside reverse transcriptase inhibitor (NRTI) resistance detected in a well monitored cohort in South Africa accessing antiretroviral therapy

    PubMed Central

    Wallis, Carole L; Papathanasopolous, Maria A; Fox, Matthew; Conradie, Francesca; Ive, Prudence; Orrell, Catherine; Zeinecker, Jennifer; Sanne, Ian; Wood, Robin; McIntyre, James; Stevens, Wendy

    2013-01-01

    Background Emergence of complex HIV-1 drug resistance mutations has been linked to the duration of time on a failing antiretroviral (ARV) drug regimen. This study reports on resistance profiles in a closely monitored subtype C infected cohort. Methods A total of 812 participants were enrolled into the CIPRA-SA ‘safeguard the household’ study, viral loads (VLs) were performed 12 weekly for 96 weeks. Virological failure was defined as either <1.5 log drop in VL at week 12 or 2 consecutive VL measurements >1000 RNA copies/ml after week 24. Regimens prescribed were in-line with the South African roll-out program (d4T, 3TC, EFV or NVP). Viral RNA was extracted from patients with virological failure, and pol RT-PCR and sequence analysis were performed to determine drug resistance mutations. Results Eighty three participants experienced virological failure on the first-line regimen during the study period, of which 61 (73%) had HIV-1 drug resistance mutations. The M184V mutation was the most frequent (n=46; 65%), followed by K103N (46%) and Y181C (21%). TAMS were infrequent (1%) and Q151M was not observed. Conclusion Drug resistance profiles were less complex than has been previously reported in South Africa using the same ARV drug regimens. This data suggests that frequent viral load monitoring limits the level and complexity of resistance observed in HIV-1 subtype C, preserving susceptibility to second-line options. PMID:22293461

  17. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis.

    PubMed

    Harris, Kevin S; Brabant, William; Styrchak, Sheila; Gall, Alexander; Daifuku, Richard

    2005-07-01

    We report the activities of a novel nucleoside analog against HIV. This nucleoside (KP-1212) is not a chain terminator but exerts its antiviral effects via mutagenesis of the viral genome. Serial passaging of HIV in the presence of KP-1212 causes an increase in the mutation rate of the virus leading to viral ablation. HIV strains resistant to KP-1212 have not yet been isolated. Quite to the contrary, virus treated with KP-1212 exhibited an increased sensitivity not only to KP-1212 but also to another nucleoside reverse transcriptase inhibitor (NRTI), zidovudine. HIV strains resistant to other NRTIs (e.g. zidovudine, lamivudine, stavudine, abacavir, etc.) exhibited no cross-resistance towards KP-1212. Multiple assays confirmed that KP-1212 has a favorable (low) genotoxicity profile when compared to some approved antiviral nucleosides. In addition, KP-1212 is not toxic to mitochondria nor does it exhibit any inhibitory effects on mitochondrial DNA synthesis. PMID:15890415

  18. Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor-Based HAART During Pregnancy

    PubMed Central

    Kitch, Douglas; Ogwu, Anthony; Hughes, Michael D.; Lockman, Shahin; Leidner, Jean; van Widenfelt, Erik; Moffat, Claire; Moyo, Sikhulile; Makhema, Joseph; Essex, Max; Shapiro, Roger L.

    2011-01-01

    (See the editorial commentary by Kourtis, on pages 493–4.) Background. Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. Methods. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm3 were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. Results. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26–3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. Conclusions. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study. PMID:21791651

  19. Backbones versus core agents in initial ART regimens: one game, two players.

    PubMed

    Llibre, Josep M; Walmsley, Sharon; Gatell, Josep M

    2016-04-01

    The advances seen in ART during the last 30 years have been outstanding. Treatment has evolved from the initial use of single agents as monotherapy. The ability to use HIV RNA as a surrogate marker for clinical outcomes allowed the more rapid evaluation of new therapies. This led to the understanding that triple-drug regimens, including a core agent (an NNRTI or a boosted PI) and two NRTIs, are optimal. These combinations have demonstrated continued improvements in their efficacy and toxicity as initial therapy. However, the need for pharmacokinetic boosting, with potential drug-drug interactions, or residual issues of efficacy or toxicity have persisted for some agents. Most recently, integrase strand transfer inhibitors, particularly dolutegravir, have shown unparalleled safety and efficacy and are currently the core agents of choice. Regimens that included only core agents or only backbone agents have not been as successful as combined therapy in antiretroviral-naive patients. It appears that at least one NRTI is needed for optimal performance and lamivudine and emtricitabine may be the ideal candidates. Several studies are ongoing of agents with longer dosing intervals, lower cost and new NRTI-saving strategies to address unmet needs. PMID:26747092

  20. European Mitochondrial DNA Haplogroups and Metabolic Changes during Antiretroviral Therapy in AIDS Clinical Trials Group Study A5142

    PubMed Central

    Hulgan, Todd; Haubrich, Richard; Riddler, Sharon A.; Tebas, Pablo; Ritchie, Marylyn D.; McComsey, Grace A.; Haas, David W.; Canter, Jeffrey A.

    2010-01-01

    Background Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants. Methods 757 ART-naïve subjects were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Non-randomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white subjects. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup. Results Median age was 39 years, 9% were female, and 37%, 32%, and 30% were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N=10) had higher baseline non-HDL cholesterol (160 mg/dL [interquartile range 137–171] vs. 120 mg/dL [104–136]; p=0.005), a decrease in non-HDL cholesterol over 96 weeks (−14% [−20-+6] vs. +25% [+8-+51]; p<0.001), tended to have more baseline extremity fat, and had more extremity fat loss by DEXA (−13% [−31-+12] vs. +9% [−13-+26]; p=0.08) and lipoatrophy (50% vs. 20%; p=0.04). Haplogroup W (N=5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat (+35.5% [+26.8 - +54.9]; P=0.02). Conclusions Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART. PMID:20871389

  1. 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. PMID:26485011

  2. 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. PMID:16710550

  3. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis

    PubMed Central

    Dumond, Julie B.; Yeh, Rosa F.; Patterson, Kristine B.; Corbett, Amanda H.; Jung, Byung Hwa; Rezk, Naser L.; Bridges, Arlene S.; Stewart, Paul W.; Cohen, Myron S.; Kashuba, Angela D.M.

    2010-01-01

    Objectives To describe first dose and steady state antiretroviral drug exposure in the female genital tract. Design Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women. Method Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA). Results For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%). Conclusions This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates. PMID:17721097

  4. 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

  5. Molecular recognition of the antiretroviral drug abacavir: towards the development of a novel carbazole-based fluorosensor.

    PubMed

    Idzik, Krzysztof Ryszard; Cywinski, Piotr J; Cranfield, Charles G; Mohr, Gerhard J; Beckert, Rainer

    2011-05-01

    Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson-Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, furane, ethylenedioxythiophene, and another uracil; yielding four different derivatives. Photophysical properties of these newly obtained derivatives are described, as are their interactions with the reverse transcriptase inhibitors such as abacavir, zidovudine, lamivudine and didanosine. The influence of each analyte on biosensor fluorescence was assessed on the basis of the Stern-Volmer equation and represented by Stern-Volmer constants. Consequently we have demonstrated that these structures based on carbazole, with a uracil group, may be successfully incorporated into alternative carbazole derivatives to form biosensors for the molecular recognition of antiretroviral drugs. PMID:21222147

  6. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection.

    PubMed

    Menéndez-Arias, Luis; Alvarez, Mar

    2014-02-01

    One to two million people worldwide are infected with the human immunodeficiency virus type 2 (HIV-2), with highest prevalences in West African countries, but also present in Western Europe, Asia and North America. Compared to HIV-1, HIV-2 infection undergoes a longer asymptomatic phase and progresses to AIDS more slowly. In addition, HIV-2 shows lower transmission rates, probably due to its lower viremia in infected individuals. There is limited experience in the treatment of HIV-2 infection and several antiretroviral drugs used to fight HIV-1 are not effective against HIV-2. Effective drugs against HIV-2 include nucleoside analogue reverse transcriptase (RT) inhibitors (e.g. zidovudine, tenofovir, lamivudine, emtricitabine, abacavir, stavudine and didanosine), protease inhibitors (saquinavir, lopinavir and darunavir), and integrase inhibitors (raltegravir, elvitegravir and dolutegravir). Maraviroc, a CCR5 antagonist blocking coreceptor binding during HIV entry, is active in vitro against CCR5-tropic HIV-2 but more studies are needed to validate its use in therapeutic treatments against HIV-2 infection. HIV-2 strains are naturally resistant to a few antiretroviral drugs developed to suppress HIV-1 propagation such as nonnucleoside RT inhibitors, several protease inhibitors and the fusion inhibitor enfuvirtide. Resistance selection in HIV-2 appears to be faster than in HIV-1. In this scenario, the development of novel drugs specific for HIV-2 is an important priority. In this review, we discuss current anti-HIV-2 therapies and mutational pathways leading to drug resistance. PMID:24345729

  7. Susceptibility of the Porcine Endogenous Retrovirus to Reverse Transcriptase and Protease Inhibitors

    PubMed Central

    Qari, Shoukat H.; Magre, Saema; García-Lerma, J. Gerardo; Hussain, Althaf I.; Takeuchi, Yasuhiro; Patience, Clive; Weiss, Robin A.; Heneine, Walid

    2001-01-01

    Porcine xenografts may offer a solution to the shortage of human donor allografts. However, all pigs contain the porcine endogenous retrovirus (PERV), raising concerns regarding the transmission of PERV and the possible development of disease in xenotransplant recipients. We evaluated 11 antiretroviral drugs licensed for human immunodeficiency virus type 1 (HIV-1) therapy for their activities against PERV to assess their potential for clinical use. Fifty and 90% inhibitory concentrations (IC50s and IC90s, respectively) of five nucleoside reverse transcriptase inhibitors (RTIs) were determined enzymatically for PERV and for wild-type (WT) and RTI-resistant HIV-1 reference isolates. In a comparison of IC50s, the susceptibilities of PERV RT to lamivudine, stavudine, didanosine, zalcitabine, and zidovudine were reduced >20-fold, 26-fold, 6-fold, 4-fold, and 3-fold, respectively, compared to those of WT HIV-1. PERV was also resistant to nevirapine. Tissue culture-based, single-round infection assays using replication-competent virus confirmed the relative sensitivity of PERV to zidovudine and its resistance to all other RTIs. A Gag polyprotein-processing inhibition assay was developed and used to assess the activities of protease inhibitors against PERV. No inhibition of PERV protease was seen with saquinavir, ritonavir, indinavir, nelfinavir, or amprenavir at concentrations >200-fold the IC50s for WT HIV-1. Thus, following screening of many antiretroviral agents, our findings support only the potential clinical use of zidovudine. PMID:11134319

  8. Selection and characterization of HIV-1 with a novel S68 deletion in reverse transcriptase.

    PubMed

    Schinazi, Raymond F; Massud, Ivana; Rapp, Kimberly L; Cristiano, Meta; Detorio, Mervi A; Stanton, Richard A; Bennett, Matthew A; Kierlin-Duncan, Monique; Lennerstrand, Johan; Nettles, James H

    2011-05-01

    Resistance to human immunodeficiency virus type 1 (HIV-1) represents a significant problem in the design of novel therapeutics and the management of treatment regimens in infected persons. Resistance profiles can be elucidated by defining modifications to the viral genome conferred upon exposure to novel nucleoside reverse transcriptase (RT) inhibitors (NRTI). In vitro testing of HIV-1LAI-infected primary human lymphocytes treated with β-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68Δ) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68Δ in the HIV-1 genome. The S68Δ HIV-1 RT was phenotyped against various antiviral agents in a heteropolymeric DNA polymerase assay and in human lymphocytes. Drug susceptibility results indicate that the S68Δ displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, β-d-2',3'-oxa-5-fluorocytidine, or 9-(β-D-1,3-dioxolan-4-yl)guanine and remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine (ddI), 1-(β-D-dioxolane)thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the β3-β4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68Δ is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies. PMID:21357304

  9. Triple nucleoside reverse transcriptase inhibitor therapy in children.

    PubMed

    Handforth, Jennifer; Sharland, Mike

    2004-01-01

    develop an early idiosyncratic hypersensitivity reaction - fever, malaise, and mucositis with or without rash, which can progress to more advanced stages of shock and death. A major concern is the apparently inferior virologic control of triple NRTI therapy as demonstrated in the AIDS Clinical Trials Group A5095 study with zidovudine/lamivudine/abacavir (Trizivir) combination in adults. Such a combination should only be considered in special situations. Examples cited include informed patient choice based on anticipated poor adherence on other treatment regimens, or if concomitant drugs such as tuberculosis medication are prescribed. The low pill burden of triple NRTI regimens (especially if combined in a single pill such as Trizivir), offers hope that regimen simplification may still be possible in the future. PMID:15170362

  10. 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

  11. 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

  12. 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

  13. Side Effects of HIV Medicines: HIV and Lactic Acidosis

    MedlinePlus

    ... HIV medicines. All HIV medicines in the nucleoside reverse transcriptase inhibitor (NRTI) drug class may cause lactic acidosis, but ... some HIV medicines. HIV medicines in the nucleoside reverse transcriptase inhibitor (NRTI) drug class can cause the body to ...

  14. In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV.

    PubMed

    Hazen, Richard; Harvey, Robert; Ferris, Robert; Craig, Charles; Yates, Phillip; Griffin, Philip; Miller, John; Kaldor, Istvan; Ray, John; Samano, Vincente; Furfine, Eric; Spaltenstein, Andrew; Hale, Michael; Tung, Roger; St Clair, Marty; Hanlon, Mary; Boone, Lawrence

    2007-09-01

    Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC(50)s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC(50)s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC(50)s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro. PMID:17620375

  15. ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse transcriptase.

    PubMed

    Naeger, Lisa K; Margot, Nicolas A; Miller, Michael D

    2002-07-01

    Removal of nucleoside chain terminator inhibitors mediated by human immunodeficiency virus (HIV) reverse transcriptase (RT) using ATP as an acceptor molecule has been proposed as a novel mechanism of HIV resistance. Recombinant wild-type and mutant HIV type 1 (HIV-1) RT enzymes with thymidine analog resistance mutations D67N, K70R, and T215Y were analyzed for their ability to remove eight nucleoside reverse transcriptase inhibitors in the presence of physiological concentrations of ATP. The order for the rate of removal of the eight inhibitors by the mutant RT enzyme was zidovudine (AZT) > stavudine (d4T) > zalcitabine (ddC) > abacavir > amdoxovir (DAPD) > lamivudine (3TC) > didanosine (ddI) > tenofovir. Thymidine analogs AZT and d4T were the most significantly removed by the mutant enzyme, suggesting that removal of these inhibitors by the ATP-dependent removal mechanism contributes to the AZT and d4T resistance observed in patients with HIV expressing thymidine analog resistance mutations. ATP-dependent removal of tenofovir was 22- to 35-fold less efficient than removal of d4T and AZT, respectively. The addition of ATP and the next complementary deoxynucleoside triphosphate caused a reduction of ATP-mediated removal of d4T, ddC, and DAPD, while AZT and abacavir removal was unaffected. The reduction of d4T, ddC, and DAPD removal in the presence of the deoxynucleoside triphosphate could explain the minor changes in susceptibility to these drugs observed in conventional in vitro phenotypic assays using cells that have higher deoxynucleoside triphosphate pools. The minimal removal of abacavir, ddC, DAPD, 3TC, ddI, and tenofovir is consistent with the minor changes in susceptibility to these drugs observed for HIV mutants with thymidine analog resistance mutations. PMID:12069972

  16. Differential maintenance of the M184V substitution in the reverse transcriptase of human immunodeficiency virus type 1 by various nucleoside antiretroviral agents in tissue culture.

    PubMed

    Petrella, Marco; Oliveira, Maureen; Moisi, Daniela; Detorio, Mervi; Brenner, Bluma G; Wainberg, Mark A

    2004-11-01

    The M184V substitution in human immunodeficiency virus type 1 reverse transcriptase (RT) is rapidly selected in tissue culture following serial passage of wild-type virus in the presence of increasing concentrations of lamivudine (3TC). M184V is also associated with several alterations of RT enzymatic function in vitro that may adversely affect viral fitness or replication capacity, which creates a potential rationale for its maintenance once it has been selected by antiviral chemotherapy. However, the relative effectiveness of nucleoside RT inhibitors that are structurally unrelated to 3TC in selecting and/or maintaining M184V has not been investigated. In the present study, we have studied the abilities of a variety of drugs, i.e., zalcitabine (ddC), didanosine (ddI), abacavir (ABC), and the novel nucleoside SPD754, in addition to 3TC, to maintain the presence of M184V in tissue culture and have shown that SPD754, ABC, and 3TC are able to preserve M184V in mixed dual infections consisting of wild-type viruses and clinical isolates which contained the M184V mutation. Moreover, M184V could also be maintained in these cultures when a subtherapeutic concentration of 3TC (i.e., 0.05 microM) was used. In contrast, neither ddI nor ddC was able to maintain M184V to the same extent as the other drugs after 10 weeks of tissue culture in mixtures of wild-type viruses and isolates containing M184V in different proportions. PMID:15504840

  17. 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

  18. Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial

    PubMed Central

    Nacro, Boubacar; Zoure, Emmanuelle; Hien, Hervé; Tamboura, Hassane; Rouet, François; Ouiminga, Adama; Drabo, Ali; Yameogo, Souleymane; Hien, Alain; Peyriere, Hélène; Mathieu, Olivier; Hirt, Deborah; Treluyer, Jean-Marc; Nicolas, Joëlle; Foulongne, Vincent; Segondy, Michel; van de Perre, Philippe; Diagbouga, Serge

    2011-01-01

    Abstract Objective To assess 12-month survival, pharmacokinetics, immunologic and virologic efficacy, tolerance, compliance and drug resistance in HIV-infected children in Bobo-Dioulasso, Burkina Faso, receiving once-daily highly-active antiretroviral therapy as a combination of didanosine (DDI), lamivudine (3TC) and efavirenz (EFV). Methods In the ANRS 12103 open phase II trial, HIV-infected children were examined at inclusion and monthly thereafter. CD4+ T-lymphocyte (CD4) count, plasma concentration of ribonucleic acid (RNA) of human immunodeficiency virus type 1 (HIV-1) and haematologic and biochemical parameters were measured at baseline and every trimester. HIV-1 resistance testing was performed in case of viral escape. Drug plasma concentrations were determined with high-performance liquid chromatography. Findings From February 2006 to November 2007, 51 children (39% girls) with a mean age of 6.8 years were enrolled and treated for 12 months. At baseline, Z scores for mean weight-for-age and mean height-for-age were −2.01 and −2.12, respectively. Mean CD4% was 9.0. Median plasma HIV-1 RNA viral load was 5.51 log10 copies per millilitre (cp/ml). Two children (3.9%) died and another 11 (22%) suffered 13 severe clinical events. At month 12, mean WAZ had improved by 0.63 (P < 0.001) and mean HAZ by 0.57 (P < 0.001). Mean CD4% had risen to 24 (P < 0.001). Viral load was below 300 RNA cp/ml in 81% of the children; HIV resistance mutations were detected in 11 (21.6%). Conclusion The once-a-day combination of DDI + 3TC + EFV is an alternative first-line treatment for HIV-1-infected children. Dose adjustment should further improve efficacy. PMID:21673861

  19. First-line antiretroviral therapy with nevirapine versus lopinavir-ritonavir based regimens in a resource-limited setting

    PubMed Central

    Clumeck, Nathan; Mwamba, Claude; Kabeya, Kabamba; Matanda, Serge; Vaira, Dolorès; Necsoi, Coca; Kadiebwe, David; Delforge, Marc; Kasamba, Eric; Milolo, Chantal; Ilunga, Joe; Kapend, Liévin

    2014-01-01

    Objective: To compare WHO first-line antiretroviral therapy (ART) with nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen with a boosted protease inhibitor (bPI) regimen in a resource-limited setting regarding treatment outcome and emergence of drug resistance mutations (DRMs). Methods: Treatment-naive adults were randomized to nevirapine (NVP) or ritonavir-boosted lopinavir (LPV/r) regimens each in combination with tenofovir (TDF)/emtricitabine (FTC) or zidovudine (ZDV)/lamivudine (3TC). Primary endpoint was the incidence of therapeutical (clinical and/or virologic) failure at week 48 with follow-up till week 96. Results: Four hundred and twenty-five patients (120 men; 305 women) received at least one dose of the study drug. mITT analysis showed no difference in proportion of therapeutical failure between treatment arms [67/209 (32%) in NVP vs. 63/216 (29%) LPV/r at week 48 (P = 0.53); 88/209 (42%) in NVP vs. 83/216 (38%) in LPV/r at week 96 (P = 0.49)]. Per-protocol analysis demonstrated significantly more virologic failure with NVP than with LPV/r regimens [at week 48: 19/167 (11%) vs. 7/166 (4%), P = 0.014; at week 96: 27/158 (17%) vs. 13/159 (8%), P =  0.019)]. Drug resistance mutations to NNRTI were detected in 19 out of 22 (86.3%) and dual-class resistance to nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI in 15 out of 27 (68.2%) of NVP failing patients. K65R mutation was present in seven out of 14 patients failing NVP-TDF/FTC regimen. No major protease inhibitor-DRM was detected among LPV/r failing patients. Discontinuation for adverse events was similar between treatment groups. Conclusion: In resource-limited settings, first-line NNRTI-NRTI regimen as compared with bPI-based regimen provides similar outcome but is associated with a significantly higher number of virologic failure and resistance mutations in both classes that jeopardize future options for second-line therapy. PMID:25028911

  20. Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase.

    PubMed

    Zhang, Zhijun; Walker, Michelle; Xu, Wen; Shim, Jae Hoon; Girardet, Jean-Luc; Hamatake, Robert K; Hong, Zhi

    2006-08-01

    Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies. PMID:16870771

  1. Use of Nucleoside Reverse Transcriptase Inhibitor Only Regimens in HIV-infected Children and Adolescents

    PubMed Central

    Neely, Michael; Rutstein, Richard; Del Bianco, Gabriela; Heresi, Gloria; Barton, Theresa; Wiznia, Andrew; Wiegand, Ryan; Wheeling, Travis; Bohannon, Beverly; Dominguez, Kenneth

    2013-01-01

    In adults, nucleoside reverse transcriptase inhibitor (NRTI)-only antiretroviral regimens (NOARs) with ≥ three NRTIs are less potent than highly active antiretroviral therapy (HAART). However published pediatric experience with NOARs is limited. Methods We analyzed data from NOAR-treated participants in LEGACY, a multicenter observational cohort study of HIV-infected children and adolescents. NOAR-treated case-participantswere matched to participantswithout prior NOAR who initiated HAART during the same year for comparison. Results Of 575 participants with data from time of HIV diagnosis through 2006, 67 (12%) received NOARs for at least 24 weeks; most (46%) received the fixed dose combination of zidovudine/lamivudine/abacavir. NOAR use peaked in 2001-2002. NOAR-treated participants were significantly older and more treatment-experienced than HAART-treated participants. Virologic outcomes, including the percentage of participants with a plasma HIV RNA viral load <400 copies/mL at week 24 (47% vs. 34%) and the mean 24-week change in log10 plasma HIV RNA viral load from baseline (−0.63 vs. −1.02) were similar between NOAR- and HAART-treated participants, but virologic rebound was more likely in NOAR-treated participants (77% vs. 54%, P = 0.02). Increase in CD4 percentage points from baseline to 24 weeks was negligible in NOAR-treated participants compared with HAART-treated participants (0.95% vs. 10.1%, P <0.001). Anemia and leukopenia were more commonly reported with NOARs than HAART. Discussion Week 24 virologic outcomes were similar between NOAR- and HAART-treated participants, but NOAR durability was poorer and their use was associated with less immunologic reconstitution. NOARs should play a limited role in pediatric and adolescent ART. PMID:24008749

  2. HIV drug resistance interpreted by cumulative versus last genotypes in HIV-infected patients with multiple treatment failures.

    PubMed

    Punyacam, Punthiya; Iemwimangsa, Nareenart; Chantratita, Wasun; Sukasem, Chonlaphat; Sungkanuparph, Somnuek

    2012-04-01

    Genotypic resistance test has been recommended to evaluate HIV drug resistance and guide the effective regimens of antiretroviral therapy (ART) in HIV-infected patients with treatment failure. In patients with multiple treatment failures, drug resistance-associated mutations may disappear due to the loss of selective drug pressure after switching regimens. A cohort study was conducted among HIV-infected patients who had ≥2 genotypic resistance tests during 2003-2011. HIV-1 pol nucleotide sequencing of reverse transcriptase and protease region was carried out using TRUGENE HIV-1 Genotypic Assay. Sequencing data was analyzed using Stanford rule-based interpretation algorithms. Of 54 patients with mean age of 30.1 years, 46.3% were males. HIV-1 subtype A/E was observed in 88.9% of patients. At the latest failure, 55.3% were receiving protease inhibitor-based regimens. Median CD4 and HIV RNA were 167 cells/mm(3) and 22,359 copies/mL. During a median duration of ART of 38.6 months, 72.2%, 22.2%, and 5.6% had 5, 3, and 2 genotype tests, respectively. When compared between using cumulative (CG) and last genotypes (LG), CG interpreted resistance to any drug 59.3% higher than LG did. For NRTI, NNRTI, and PI drug classes, CG interpreted as resistance 42.6%, 27.8%, and 7.4% higher than LG, respectively. The most common drugs that CG interpreted resistance with the higher rate than LG were lamivudine/emtricitabine, nevirapine, efavirenz, etravirine and abacavir. In conclusion, CG interprets HIV drug resistance at a higher rate than LG and may be more accurate to use for selecting the next effective regimen of ART among HIV-infected patients with multiple treatment failures. PMID:22497699

  3. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection.

    PubMed

    Welch, Steve; Sharland, Mike; Lyall, E G Hermione; Tudor-Williams, Gareth; Niehues, Tim; Wintergerst, Uwe; Bunupuradah, Torsak; Hainaut, Marc; Della Negra, Marinella; Pena, Maria José Mellado; Amador, José Tomas Ramos; Gattinara, Guido Castelli; Compagnucci, Alexandra; Faye, Albert; Giaquinto, Carlo; Gibb, Diana M; Gandhi, Kate; Forcat, Silvia; Buckberry, Karen; Harper, Lynda; Königs, Christoph; Patel, Deepak; Bastiaans, Diane

    2009-11-01

    PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: 'When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. 'What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained. PMID:19878352

  4. Efficacy and safety of switching to abacavir/lamivudine (ABC/3TC) plus rilpivirine (RPV) in virologically suppressed HIV-infected patients on HAART.

    PubMed

    Palacios, R; Pérez-Hernández, I A; Martínez, M A; Mayorga, M L; González-Domenech, C M; Omar, M; Olalla, J; Romero, A; Romero, J M; Pérez-Camacho, I; Hernández-Quero, J; Santos, J

    2016-05-01

    We analysed the efficacy and safety of switching from a regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTI) or integrase inhibitors (INI) to ABC/3TC + RPV in virologically suppressed HIV-infected patients. This multicentre, retrospective study comprised asymptomatic HIV-infected patients who switched from 2 NRTI + NNRTI or 2 NRTI + INI to ABC/3TC + RPV between February 2013 and December 2013; all had undetectable HIV viral load prior to switching. Efficacy and safety, and changes in lipids and cardiovascular risk (CVR) were analysed at 48 weeks. Of 85 patients (74.1 % men, mean age 49.5 years), 83 (97.6 %) switched from a regimen based on NNRTI (EFV 74, RPV 5, ETV 2, NVP 2), and 45 (53 %) switched from TDF/FTC to ABC/3TC. The main reasons for switching were toxicity (58.8 %) and convenience (29.4 %). At 48 weeks, 78 (91.8 %) patients continued taking the same regimen; efficacy was 88 % by intention to treat, and 96 % by per protocol. Two patients were lost to follow-up and five ceased the new regimen (4 due to adverse effects and 1 virologic failure). Mean CD4 cell counts increased (744 vs. 885 cells/μL; p = 0.0001), and there were mean decreases in fasting total cholesterol (-15.9 mg/dL; p < 0.0001) and LDL-cholesterol (-11.0 mg/dL; p < 0.004), with no changes in HDL-cholesterol, triglycerides, total cholesterol:HDL-cholesterol ratio, and CVR. ABC/3TC + RPV is effective and safe in virologically-suppressed patients on antiretroviral therapy (ART). Forty-eight weeks after switching the lipid profile improved with decreases in total and LDL cholesterol. PMID:26879392

  5. New developments in anti-HIV chemotherapy.

    PubMed

    De Clercq, E

    2001-11-01

    Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI

  6. New antiretrovirals and new combinations.

    PubMed

    Havlir, D V; Lange, J M

    1998-01-01

    The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to

  7. Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3'-azido-3'-dideoxythymidine.

    PubMed

    Brehm, Jessica H; Koontz, Dianna; Meteer, Jeffrey D; Pathak, Vinay; Sluis-Cremer, Nicolas; Mellors, John W

    2007-08-01

    Recent work indicates that mutations in the C-terminal domains of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) increase 3'-azido-3'-dideoxythymidine (AZT) resistance. Because it is not known whether AZT selects for mutations outside of the polymerase domain of RT, we carried out in vitro experiments in which HIV-1(LAI) or AZT-resistant HIV-1(LAI) (M41L/L210W/T215Y) was passaged in MT-2 cells in increasing concentrations of AZT. The first resistance mutations to appear in HIV-1(LAI) were two polymerase domain thymidine analog mutations (TAMs), D67N and K70R, and two novel mutations, A371V in the connection domain and Q509L in the RNase H domain, that together conferred up to 90-fold AZT resistance. Thereafter, the T215I mutation appeared but was later replaced by T215F, resulting in a large increase in AZT resistance ( approximately 16,000-fold). Mutations in the connection and RNase H domains were not selected starting with AZT-resistant virus (M41L/L210W/T215Y). The roles of A371V and Q509L in AZT resistance were confirmed by site-directed mutagenesis: A371V and Q509L together increased AZT resistance approximately 10- to 50-fold in combination with TAMs (M41L/L210W/T215Y or D67N/K70R/T215F) but had a minimal effect without TAMs (1.7-fold). A371V and Q509L also increased cross-resistance with TAMs to lamivudine and abacavir, but not stavudine or didanosine. These results provide the first evidence that mutations in the connection and RNase H domains of RT can be selected in vitro by AZT and confer greater AZT resistance and cross-resistance to nucleoside RT inhibitors in combination with TAMs in the polymerase domain. PMID:17507476

  8. 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

  9. Changes to antiretroviral drug regimens during integrated TB-HIV treatment: Results of the SAPiT trial

    PubMed Central

    Naidoo, Anushka; Naidoo, Kogieleum; Yende-Zuma, Nonhlanhla; Gengiah, Tanuja N; Padayatchi, Nesri; Gray, Andrew L.; Bamber, Sheila; Nair, Gonasagrie; Karim, Salim S Abdool

    2013-01-01

    Background Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and human immunodeficiency virus (HIV) therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. Methods Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients. Results A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs used, were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate: 2.1 per 100 person-years; 95% (CI): 1.1 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (n= 3; 0.6%), and peripheral neuropathy (n=2; 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study. Conclusion Both drug switches and complete regimen change were uncommon in patients co-treated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change. PMID:24176943

  10. Norfloxacin

    MedlinePlus

    ... side effects.if you are taking antacids containing aluminum hydroxide or magnesium hydroxide (Maalox, Mylanta, Tums, others), didanosine (Videx) sucralfate (Carafate), or supplements or multivitamins that contain iron or zinc, take these medications 2 hours before or 2 ...

  11. Gemifloxacin

    MedlinePlus

    ... side effects.if you are taking antacids containing aluminum hydroxide or magnesium hydroxide (Maalox, Mylanta, Tums, others); didanosine (Videx); sucralfate (Carafate); or vitamin or mineral supplements that contain iron, magnesium, or zinc, take ...

  12. Ofloxacin

    MedlinePlus

    ... side effects.if you are taking antacids containing aluminum, calcium, or magnesium (Maalox, Mylanta, Tums, others); didanosine (Videx); sucralfate (Carafate); or supplements or multivitamins containing iron or zinc, take ofloxacin 2 hours before or 2 hours ...

  13. 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 ...

  14. Emergence of Multiclass Drug–Resistance in HIV-2 in Antiretroviral-Treated Individuals in Senegal: Implications for HIV-2 Treatment in Resouce-Limited West Africa

    PubMed Central

    Gottlieb, Geoffrey S.; Badiane, Ndeye Mery Dia; Hawes, Stephen E.; Fortes, Louise; Toure, Macoumba; Ndour, Cheikh T.; Starling, Alison K.; Traore, Fatou; Sall, Fatima; Wong, Kim G.; Cherne, Stephen L.; Anderson, Donovan J.; Dye, Stefanie A.; Smith, Robert A.; Mullins, James I.; Kiviat, Nancy B.; Sow, Papa Salif

    2013-01-01

    Background The efficacy of various antiretroviral (ARV) therapy regimens for human immunodeficiency virus type 2 (HIV-2) infection remains unclear. HIV-2 is intrinsically resistant to the nonnucleoside reverse-transcriptase inhibitors and to enfuvirtide and may also be less susceptible than HIV-1 to some protease inhibitors (PIs). However, the mutations in HIV-2 that confer ARV resistance are not well characterized. Methods Twenty-three patients were studied as part of an ongoing prospective longitudinal cohort study of ARV therapy for HIV-2 infection in Senegal. Patients were treated with nucleoside reverse-transcriptase inhibitor (NRTI)– and PI (indinavir)–based regimens. HIV-2 pol genes from these patients were genotyped, and the mutations predictive of resistance in HIV-2 were assessed. Correlates of ARV resistance were analyzed. Results Multiclass drug–resistance mutations (NRTI and PI) were detected in strains in 30% of patients; 52% had evidence of resistance to at least 1 ARV class. The reverse-transcriptase mutations M184V and K65R, which confer high-level resistance to lamivudine and emtricitabine in HIV-2, were found in strains from 43% and 9% of patients, respectively. The Q151M mutation, which confers multinucleoside resistance in HIV-2, emerged in strains from 9% of patients. HIV-1–associated thymidine analogue mutations (M41L, D67N, K70R, L210W, and T215Y/F) were not observed, with the exception of K70R, which was present together with K65R and Q151M in a strain from 1 patient. Eight patients had HIV-2 with PI mutations associated with indinavir resistance, including K7R, I54M, V62A, I82F, L90M, L99F; 4 patients had strains with multiple PI resistance–associated mutations. The duration of ARV therapy was positively associated with the development of drug resistance (P = .02). Nine (82%) of 11 patients with HIV-2 with detectable ARV resistance had undetectable plasma HIV-2 RNA loads (<1.4 log10 copies/mL), compared with 3 (25%) of 12

  15. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes.

    PubMed

    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

  16. 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

  17. 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. PMID:12800069

  18. 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

  19. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2005-06-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate

  20. 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

  1. Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility.

    PubMed

    Melikian, George L; Rhee, Soo-Yon; Taylor, Jonathan; Fessel, W Jeffrey; Kaufman, David; Towner, William; Troia-Cancio, Paolo V; Zolopa, Andrew; Robbins, Gregory K; Kagan, Ron; Israelski, Dennis; Shafer, Robert W

    2012-05-01

    Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation. PMID:22330916

  2. Standardized Comparison of the Relative Impacts of HIV-1 Reverse Transcriptase (RT) Mutations on Nucleoside RT Inhibitor Susceptibility

    PubMed Central

    Rhee, Soo-Yon; Taylor, Jonathan; Fessel, W. Jeffrey; Kaufman, David; Towner, William; Troia-Cancio, Paolo V.; Zolopa, Andrew; Robbins, Gregory K.; Kagan, Ron; Israelski, Dennis; Shafer, Robert W.

    2012-01-01

    Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation. PMID:22330916

  3. 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

  4. Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol

    PubMed Central

    Mislak, Andrea C.

    2015-01-01

    Human PrimPol is a newly identified DNA and RNA primase-polymerase of the archaeo-eukaryotic primase (AEP) superfamily and only the second known polymerase in the mitochondria. Mechanistic studies have shown that interactions of the primary mitochondrial DNA polymerase γ (mtDNA Pol γ) with nucleoside reverse transcriptase inhibitors (NRTIs), key components in treating HIV infection, are a major source of NRTI-associated toxicity. Understanding the interactions of host polymerases with antiviral and anticancer nucleoside analog therapies is critical for preventing life-threatening adverse events, particularly in AIDS patients who undergo lifelong treatment. Since PrimPol has only recently been discovered, the molecular mechanism of polymerization and incorporation of natural nucleotide and NRTI substrates, crucial for assessing the potential for PrimPol-mediated NRTI-associated toxicity, has not been explored. We report for the first time a transient-kinetic analysis of polymerization for each nucleotide and NRTI substrate as catalyzed by PrimPol. These studies reveal that nucleotide selectivity limits chemical catalysis while the release of the elongated DNA product is the overall rate-limiting step. Remarkably, PrimPol incorporates four of the eight FDA-approved antiviral NRTIs with a kinetic profile distinct from that of mtDNA Pol γ that may manifest in toxicity. PMID:26552983

  5. 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

  6. Fatal Toxicity from Symptomatic Hyperlactataemia

    PubMed Central

    Leung, Liza; Wilson, Douglas; Manini, Alex F.

    2016-01-01

    Background In many Sub-Saharan African countries, first-line therapy for HIV may include a nucleoside reverse transcriptase inhibitor (NRTI). Long-term NRTI use is associated with symptomatic hyperlactataemia due to inhibition of mitochondrial DNA polymerase γ, a potentially fatal complication. Objective The purpose of the study was to evaluate the factors associated with inhospital fatality for HIV inpatients prescribed NRTIs long term who presented with symptomatic hyperlactataemia. Methods We performed a retrospective cohort study at a 900-bed university hospital in South Africa over 4 years (2005–2008). We included HIV inpatients prescribed NRTIs long term who presented with symptomatic hyperlactataemia (long-term NRTI use; lactate >4.0 mmol/L; absence of infectious source; symptoms requiring admission). Data included demographics, medical history, NRTI duration, blood pressure, symptom duration and relevant laboratory data. Results Of 79 patients who met inclusion criteria (mean age 38.2 ± 10.5 years, 97% female) there were 46 fatalities (58%). Factors significantly associated with fatality were presence of diabetes mellitus (p = 0.04), lactate ≥10 mmol/L (p = 0.003), pH <7.2 (p = 0.002), creatinine ≥200 μmol/L (p = 0.03) and altered mental status (p = 0.03). Conclusions In this study, NRTI-related symptomatic hyperlactataemia occurred predominantly in females. Mortality was associated with severely elevated lactate (≥10 mmol/L), the degree of acidosis, elevated creatinine, history of diabetes and altered mental status on presentation. PMID:21488705

  7. K65R-associated virologic failure in HIV-infected patients receiving tenofovir-containing triple nucleoside/nucleotide reverse transcriptase inhibitor regimens.

    PubMed

    Ruane, Peter J; Luber, Andrew D

    2004-01-01

    High rates of early virologic failure associated with the emergence of the K65R mutation in HIV-1 reverse transcriptase (RT) have been reported among HIV-infected patients who received novel, tenofovir-containing, triple-nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) regimens as their initial therapy. This review surveys the findings of prospective and retrospective studies in this regard, examines the significance of the K65R mutation and other factors associated with reports of early virologic failure among patients receiving tenofovir-containing NRTI/NtRTI regimens, and discusses clinical approaches to preventing and managing HIV drug resistance and treatment failure associated with the K65R mutation. PMID:15266257

  8. Synthesis and anti-HIV activity of some [Nucleoside Reverse Transcriptase Inhibitor]-C5'-linker-[Integrase Inhibitor] heterodimers as inhibitors of HIV replication.

    PubMed

    Sugeac, Elena; Fossey, Christine; Ladurée, Daniel; Schmidt, Sylvie; Laumond, Geraldine; Aubertin, Anne-Marie

    2004-12-01

    Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen. The conjugation of the two different inhibitors (NRTI and INI) was performed using an amino acid (glycine or beta-alanine) as a cleavable linker. PMID:15662954

  9. SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

    PubMed Central

    Ballana, Ester; Badia, Roger; Terradas, Gerard; Torres-Torronteras, Javier; Ruiz, Alba; Pauls, Eduardo; Riveira-Muñoz, Eva; Clotet, Bonaventura; Martí, Ramon

    2014-01-01

    Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase recently recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase (RT). SAMHD1 restriction is counteracted by the human immunodeficiency virus type 2 (HIV-2) accessory protein Vpx, which targets SAMHD1 for proteosomal degradation, resulting in an increased availability of dNTPs and consequently enhanced viral replication. Nucleoside reverse transcriptase inhibitors (NRTI), one of the most common agents used in antiretroviral therapy, compete with intracellular dNTPs as the substrate for viral RT. Consequently, SAMHD1 activity may be influencing NRTI efficacy in inhibiting viral replication. Here, a panel of different RT inhibitors was analyzed for their different antiviral efficacy depending on SAMHD1. Antiviral potency was measured for all the inhibitors in transformed cell lines and primary monocyte-derived macrophages and CD4+ T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTI or the integrase inhibitor raltegravir were observed, but for NRTI, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). The addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation, pointing toward a differential effect of SAMHD1 activity on thymidine. Accordingly, sensitivity to AZT was also reduced in CD4+ T cells infected with HIV-2 compared to infection with the HIV-2ΔVpx strain. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes. PMID:24913159

  10. Drug Resistance Mutations in HIV pol Sequences from Argentinean Patients Under Antiretroviral Treatment: Subtype, Gender, and Age Issues

    PubMed Central

    Moretti, Franco; Calvo, Andrea Y.; Dilernia, Darío A.; Manrique, Julieta M.; Gómez-Carrillo, Manuel; Salomón, Horacio

    2012-01-01

    Abstract We studied drug resistance mutations (DRMs) in 2623 pol sequences. Out of 94,828 amino acid substitutions that were detected, 8749 corresponded to nucleoside reverse transcriptase inhibitor (NRTI), 3765 to nonnucleoside reverse transcriptase inhibitor (NNRTI), and 7141 to protease inhibitor (PI) resistance-associated mutations. The most common DRMs were L10I, I54V, L90M, V82A, A71V, L10V, M46I, M184V, M41L, T215Y, D67N, L210W, K70R, N348I, V118I, K103N, Y181C, G190A, K101E, V108I, L100I, V90I, K101Q, and A98G. As expected, DRMs frequencies depended on viral genotype. The amounts of NRTI and PI resistance mutations among B and BF sequences from children were higher than among sequences from adults. The frequencies of PI and NRTI resistance mutations among B and BF sequences from adult men were higher than among sequences from women. Some of these observations can be explained in light of the available epidemiological information, but some cannot, indicating that further studies are needed to understand the antiretroviral resistance epidemics in Argentina. PMID:21936717

  11. Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy.

    PubMed

    Kallianpur, Asha R; Hulgan, Todd

    2009-04-01

    Peripheral neuropathy is an important complication of antiretroviral therapy. Nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction, inflammation and nutritional factors are implicated in its pathogenesis. Pharmacogenetic and genomic studies investigating NRTI neurotoxicity have only recently become possible via the linkage of HIV clinical studies to large DNA repositories. Preliminary case-control studies using these resources suggest that host mitochondrial DNA haplogroup polymorphisms in the hemochromatosis gene and proinflammatory cytokine genes may influence the risk of peripheral neuropathy during antiretroviral therapy. These putative risk factors await confirmation in other HIV-infected populations but they have strong biological plausibility. Work to identify underlying mechanisms for these associations is ongoing. Large-scale studies incorporating clearly defined and validated methods of neuropathy assessment and the use of novel laboratory models of NRTI-associated neuropathy to clarify its pathophysiology are now needed. Such investigations may facilitate the development of more effective strategies to predict, prevent and ameliorate this debilitating treatment toxicity in diverse clinical settings. PMID:19374518

  12. Non-cirrhotic portal hypertension in human immunodeficiency virus-infected patients: a new challenge in antiretroviral therapy era.

    PubMed

    Alvarez Díaz, Hortensia; Mariño Callejo, Ana; García Rodríguez, José Francisco

    2011-01-01

    Non-cirrhotic portal hypertension (NCPH) has been recently reported as a liver disease in Human Immunodeficiency Virus (HIV)-infected patients under antiretroviral therapy (ART). Combination of non-exclusive mechanisms has been described: primary endothelial damage of terminal portal veins induced by HIV or immunologic disorders, mitochondrial toxicity by didanosine and prothrombotic state. It is characterized by heterogeneous liver histological findings, frequently identified as nodular regenerative hyperplasia and clinical manifestations of portal hypertension with well-preserved liver function. We describe herein two HIV-infected patients with clinical picture suggestive of NCPH. Besides the case reports, we briefly address questions to apply to patient care in clinical practice. PMID:21760875

  13. Non-Cirrhotic Portal Hypertension in Human Immunodeficiency Virus-Infected Patients: A New Challenge in Antiretroviral Therapy Era

    PubMed Central

    Álvarez Díaz, Hortensia; Mariño Callejo, Ana; García Rodríguez, José Francisco

    2011-01-01

    Non-cirrhotic portal hypertension (NCPH) has been recently reported as a liver disease in Human Immunodeficiency Virus (HIV)-infected patients under antiretroviral therapy (ART). Combination of non-exclusive mechanisms has been described: primary endothelial damage of terminal portal veins induced by HIV or immunologic disorders, mitochondrial toxicity by didanosine and prothrombotic state. It is characterized by heterogeneous liver histological findings, frequently identified as nodular regenerative hyperplasia and clinical manifestations of portal hypertension with well-preserved liver function. We describe herein two HIV-infected patients with clinical picture suggestive of NCPH. Besides the case reports, we briefly address questions to apply to patient care in clinical practice. PMID:21760875

  14. Class-Sparing Regimens for Initial Treatment of HIV-1 Infection

    PubMed Central

    Riddler, Sharon A.; Haubrich, Richard; DiRienzo, A. Gregory; Peeples, Lynne; Powderly, William G.; Klingman, Karin L.; Garren, Kevin W.; George, Tania; Rooney, James F.; Brizz, Barbara; Lalloo, Umesh G.; Murphy, Robert L.; Swindells, Susan; Havlir, Diane; Mellors, John W.

    2013-01-01

    BACKGROUND The use of either efavirenz or lopinavir–ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir–ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. METHODS In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir–ritonavir plus two NRTIs (lopinavir–ritonavir group), and lopinavir–ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups. RESULTS At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir–ritonavir group (P = 0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir–ritonavir group, and 83% in the NRTI-sparing group (P = 0.003 for the comparison between the efavirenz group and the lopinavir–ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. CONCLUSIONS Virologic failure was less likely in the efavirenz group than in the lopinavir–ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895.) PMID:18480202

  15. Clinical Response and Tolerability to and Safety of Saquinavir with Low-Dose Ritonavir in Human Immunodeficiency Virus Type 1-Infected Mothers and Their Infants▿ †

    PubMed Central

    Zorrilla, Carmen D.; Van Dyke, Russell; Bardeguez, Arlene; Acosta, Edward P.; Smith, Betsy; Hughes, Michael D.; Huang, Sharon; Watts, D. Heather; Heckman, Barbara; Jiménez, Eleanor; McSherry, George; Mofenson, Lynne

    2007-01-01

    Saquinavir boosted with low-dose ritonavir given with zidovudine and lamivudine was well tolerated by pregnant women and their infants. All mothers had <400 human immunodeficiency virus type 1 RNA copies/ml at delivery. Two had elevated liver transaminases and amylase. Seven infant adverse events were possibly treatment related (anemia, neutropenia, and hyperbilirubinemia). PMID:17420209

  16. Novel treatment options for hepatitis B virus infection.

    PubMed

    Kumar, Rakesh; Agrawal, Babita

    2004-02-01

    Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators. PMID:15043391

  17. Combination therapy with a nucleos(t)ide analogue and interferon for chronic hepatitis B: simultaneous or sequential.

    PubMed

    Enomoto, Masaru; Tamori, Akihiro; Nishiguchi, Shuhei; Kawada, Norifumi

    2013-09-01

    Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated. PMID:23338486

  18. Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

    PubMed Central

    Cohen, O J; Pantaleo, G; Holodniy, M; Schnittman, S; Niu, M; Graziosi, C; Pavlakis, G N; Lalezari, J; Bartlett, J A; Steigbigel, R T

    1995-01-01

    Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue. Images Fig. 1 Fig. 2 Fig. 3 PMID:7597072

  19. HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

    PubMed Central

    Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick CK; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher KC; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

    2014-01-01

    Introduction First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line. Results A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥2 TAMs; and 32 with M184V+≥1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤200 cells/µL at genotyping (OR=4.43, 95% CI [1.59–12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39–16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ≥95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43–35.81), p=0.001). Measures of patient

  20. Resistance issues with new nucleoside/nucleotide backbone options.

    PubMed

    Wainberg, Mark A; Turner, Dan

    2004-09-01

    The nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) remain an enduring feature of combination therapy. As NRTI/NtRTI options continue to expand, questions arise about how best to combine these agents to create effective dual NRTI/NtRTI backbones in antiretroviral regimens while avoiding treatment-emergent drug resistance. Clinicians must consider how NRTIs/NtRTIs such as tenofovir DF (TDF), abacavir (ABC), and emtricitabine (FTC), as well as new once-daily and coformulated NRTIs/NtRTIs, interact with older agents when combined in novel regimens and how sequencing the new NRTIs can preserve future treatment options. Resistance data from clinical trials have revealed important information on the patterns, prevalence, and effects of resistance seen among patients experiencing virologic failure. In recent years, the prevalence of some mutations such as M184V and Q151M has remained relatively constant, while the L74V mutation, the 69 insertions, and thymidine analogue mutations have decreased in prevalence. Other mutations such as K65R and Y115F, while still relatively uncommon, are increasing in prevalence. This increase may be due to the use of new treatment combinations that select for these mutations at a higher rate. Clinical trials suggest that new regimens containing TDF or ABC select for K65R and that this mutation is observed more frequently with TDF; in contrast, L74V is observed more frequently in ABC-containing regimens but is not commonly selected by TDF-containing regimens. Several lines of evidence are converging to suggest that the presence of zidovudine may decrease the risk of L74V and K65R in ABC- or TDF-containing regimens. This review summarizes the clinical implications of resistance profiles associated with new NRTI/NtRTI regimens in current use and in advanced clinical studies. PMID:15319668

  1. Chronic binge alcohol consumption does not diminish effectiveness of continuous antiretroviral suppression of viral load in SIV-infected macaques

    PubMed Central

    Molina, Patricia E.; Amedee, Angela M.; Veazey, Ron; Dufour, Jason; Volaufova, Julia; Bagby, Gregory J.; Nelson, Steve

    2015-01-01

    Background Alcohol use disorders (AUD) are a frequent comorbidity in a large percentage of people living with HIV/AIDS (PLWHA). PLWHA with comorbid AUDs are consistently found to perform poorly at most levels of the HIV treatment cascade, resulting in a higher likelihood of virologic non-suppression. This has been partly attributed to lower rates of persistence with and adherence to antiretroviral therapies (ART). Focus groups of in-care PLWHA identify the need to suspend ART on drinking days because of the potential for toxicity and/or lack of therapeutic effectiveness. The aim of this study was to examine whether chronic binge alcohol (CBA) consumption decreases the effectiveness of uninterrupted ART, specifically that of nucleoside reverse transcriptase inhibitors (NRTI) tenofovir and emtricitabine in suppressing viral replication, or results in drug toxicity in simian immunodeficiency virus (SIV) infected rhesus macaques. Methods Daily CBA or isocaloric sucrose (SUC) administration was initiated three months prior to intrarectal SIVmac251 inoculation and continued throughout the study period. ART was initiated 2.5 months after SIV infection and continued through the study period. Results CBA administration did not prevent or delay the ART-mediated reduction in viral load. Following ART, circulating levels of total protein and creatinine were significantly higher than baseline values in both sucrose- and alcohol-treated animals, but still within a normal range. No evidence of ART toxicity was observed in either CBA- or SUC-administered macaques. Conclusions These findings indicate that CBA does not attenuate effectiveness of NRTI suppression of viral load, nor does it appear to interact with NRTI to produce toxicity during the initial 2 months of treatment. We conclude that while efforts to reduce AUD in PLWHA should be a priority, and that counseling on the importance of adherence to ART even on drinking days should also be promoted. PMID:25257285

  2. Prevalence and Evolution of Low Frequency HIV Drug Resistance Mutations Detected by Ultra Deep Sequencing in Patients Experiencing First Line Antiretroviral Therapy Failure

    PubMed Central

    Recordon-Pinson, Patricia; Reigadas, Sandrine; Bidet, Yannick; Bruyand, Mathias; Bonnet, Fabrice; Lazaro, Estibaliz; Neau, Didier; Fleury, Hervé; Dabis, François; Morlat, Philippe; Masquelier, Bernard

    2014-01-01

    Objectives Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs) is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS) before antiretroviral therapy (ART) and at virological failure (VF), in HIV-1 infected patients experiencing VF on first-line ART. Methods Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL) >500 copies/ml or one VL >1000 copies/ml) were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS) and UDS at baseline (before ART initiation) and VF. Results Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001) compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF. Conclusion Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first-line ART can increase the overall burden of resistance to PI, NRTI and NNRTI. PMID:24475178

  3. Antiretroviral Treatment Regimen Outcomes Among HIV-Infected Prisoners

    PubMed Central

    Springer, Sandra A.; Friedland, Gerald H.; Doros, Gheorghe; Pesanti, Edward; Altice, Frederick L.

    2008-01-01

    Background Despite the high prevalence of HIV in correctional settings, the duration of therapy and response to various highly active antiretroviral therapy (HAART) regimens in this setting is unknown. Method Using a retrospective cohort study (1997−2002) of HIV-infected prisoners in Connecticut that linked demographic, pharmacy, and laboratory data, we compared HIV-1 RNA (VL) and CD4 lymphocyte responses to four treatment strategies at baseline and at the end of incarceration. Results Using an analysis of 1,044 incarceration periods or 1,099 subjects for whom ≥6 months of continuous data were available, HAART regimens that included a triple NRTI, two NRTIs + either a PI or NNRTI, or a three-class (NRTI+NNRTI+PI) strategy demonstrated no difference in virological and immunological outcomes. The proportion of subjects who were initiated with NRTI, NNRTI, PI, or three-class regimens were 14%, 32%, 46%, and 8%, respectively. For all study groups, the mean change from baseline in CD4 and VL was +74 cells/μL and −0.93 log10 copies/mL (p < .0001), respectively. Overall, 59% of subjects had an HIV-1 RNA level below the level of detection (<400 copies/mL) by the end of their incarceration. Using Kaplan-Meier curves to examine the time to change in the initial HAART strategy over the incarceration period, the three-class strategy was significantly more likely to be changed earlier than all others (p < .05). Conclusion Although the three-class strategy was less durable, initiating HAART with any strategy resulted in similar and impressive virological and immunological outcomes by the end of incarceration, further supporting prison as an important site for the initiation and provision of effective antiretroviral therapy. PMID:17720660

  4. Impact of protease inhibitors on intracellular concentration of tenofovir-diphosphate among HIV-1 infected patients

    PubMed Central

    Lahiri, Cecile D.; Tao, Sijia; Jiang, Yong; Sheth, Anandi N.; Acosta, Edward P.; Marconi, Vincent C.; Armstrong, Wendy S.; Schinazi, Raymond F.; Vunnava, Aswani; Sanford, Sara; Ofotokun, Ighovwerha

    2015-01-01

    Intracellular nucleoside reverse transcriptase inhibitor (NRTI) concentrations are associated with plasma HIV-1 response. Coadministration of protease inhibitors with NRTIs can affect intra-cellular concentrations due to protease inhibitor inhibition of efflux transporters. Tenofovir-diphosphate (TFV-DP) concentrations within peripheral blood mononuclear cells were compared among individuals receiving either atazanavir or darunavir-based regimens. There was a trend towards higher TFV-DP concentrations among women and among participants receiving atazanavir. TFV-DP intracellular concentrations were positively associated with undetectable plasma HIV-1 RNA. PMID:25870991

  5. Immunologic response in treatment-naïve HIV-2-infected patients: the IeDEA West Africa cohort

    PubMed Central

    Balestre, Eric; Ekouevi, Didier Koumavi; Tchounga, Boris; Eholie, Serge Paul; Messou, Eugène; Sawadogo, Adrien; Thiébaut, Rodolphe; May, Margaret T; Sterne, Jonathan Ac; Dabis, François

    2016-01-01

    Introduction Response to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa. Methods This prospective cohort study enrolled treatment-naïve HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens. Results Of 422 HIV-2-infected patients, 285 (67.5%) were treated with a boosted PI-based regimen, 104 (24.6%) with an unboosted PI-based regimen and 33 (7.8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.5% female) and median age at ART initiation (45.3 years; interquartile range 38.3 to 51.8). Treatment groups differed by clinical stage (21.2%, 16.8% and 17.3% at CDC Stage C or World Health Organization Stage IV for the triple NRTI, boosted PI and unboosted PI groups, respectively, p=0.02), median length of follow-up (12.9, 17.7 and 44.0 months for the triple NRTI, the boosted PI and the unboosted PI groups, respectively, p<0.001) and baseline median CD4 count (192, 173 and 129 cells/µl in the triple NRTI, the boosted PI and the unboosted PI-based regimen groups, respectively, p=0.003). CD4 count recovery at 12 months was higher for patients treated with boosted PI-based regimens than those treated with three NRTIs or with unboosted PI-based regimens (191 cells/µl, 95% CI 142 to 241; 110 cells/µl, 95% CI 29 to 192; 133 cells/µl, 95% CI 80 to 186, respectively, p=0.004). Conclusions In this observational study using African data, boosted PI-containing regimens had better immunological response compared to triple NRTI combinations and unboosted PI-based regimens at 12 months. A randomized clinical trial is still required to determine

  6. Mutation detection in the drug-resistant hepatitis B virus polymerase gene using nanostructured reverse micelles.

    PubMed

    Park, Lian-Chun; Maruyama, Tatsuo; Kamiya, Noriho; Goto, Masahiro; Kuma, Hiroyuki; Hamasaki, Naotaka

    2004-11-01

    The emergence of drug-resistant hepatitis B virus (HBV) has been reported in patients with prolonged administration of lamivudine, which is a potent drug for the prevention of HBV infection. Lamivudine-resistant HBV has several types of mutations at the YMDD motif of its DNA polymerase. We successfully demonstrated that monitoring the hybridization behavior in nanostructured reverse micelles enables us to detect single nucleotide polymorphisms (SNPs). With the aid of reverse micelles, a model 40-mer oligonucleotide containing a single-base substitution was clearly distinguished from the normal, complementary oligonucleotide. In addition, we extended this technique to a high-throughput analysis. The results obtained with a 96-well micro-plate reader indicated the possibility of SNPs detection toward multiple samples of patients. PMID:15566158

  7. Legal, ethical, and economic implications of breaking down once-daily fixed-dose antiretroviral combinations into their single components for cost reduction.

    PubMed

    Ramiro, Miguel A; Llibre, Josep M

    2014-11-01

    The availability of generic lamivudine in the context of the current economic crisis has raised a new issue in some European countries: breaking up the once-daily fixed-dose antiretroviral combinations (FDAC) of efavirenz/tenofovir/emtricitabine, tenofovir/emtricitabine, or abacavir/lamivudine, in order to administer their components separately, thereby allowing the use of generic lamivudine instead of branded emtricitabine or lamivudine. The legal, ethical, and economic implications of this potential strategy are reviewed, particularly in those patients receiving a once-daily single-tablet regimen. An unfamiliar change in antiretroviral treatment from a successful patient-friendly FDAC into a more complex regimen including separately the components to allow the substitution of one (or some) of them for generic surrogates (in the absence of a generic bioequivalent FDAC) could be discriminatory because it does not guarantee access to equal excellence in healthcare to all citizens. Furthermore, it could violate the principle of non-maleficence by potentially causing harm both at the individual level (hindering adherence and favouring treatment failure and resistance), and at the community level (hampering control of disease transmission and transmission of HIV-1 resistance). Replacing a FDAC with the individual components of that combination should only be permitted when the substituting medication has the same qualitative and quantitative composition of active ingredients, pharmaceutical form, method of administration, dosage and presentation as the medication being replaced, and a randomized study has demonstrated its non-inferiority. Finally, a strict pharma-economic study supporting this change, comparing the effectiveness and the cost of a specific intervention with the best available alternative, should be undertaken before its potential implementation. PMID:24139337

  8. Therapy of chronic viral hepatitis: a critical view.

    PubMed

    Rizzetto, M

    1999-11-01

    Many oral nucleoside analogues that are potent inhibitors of hepatitis B virus have recently been developed for the treatment of hepatitis B. The problems with these drugs are bioavailability, toxicity and the time-dependent emergence of resistant hepatitis B virus mutants. Lamivudine appears to be the most useful in terms of clinical benefit, safety and tolerance. It is active on wild type hepatitis B virus as well as on HBeAg-minus variants of the virus. However, although hepatitis B virus is consistently repressed while on therapy, only a minority of patients are cured or remain in remission after Lamivudine withdrawal. Maintenance therapy would appear to be in order, but the long-term use of Lamivudine is precluded by the emergence of polymerase gene-mutants which may rekindle disease. Combination with other antivirals (Adefovir?) active also against Lamivudine escape mutants opens promising new prospects. There is, as yet, no valid therapy for chronic hepatitis D virus hepatitis. Attempts to improve the results of alpha-interferon therapy in chronic hepatitis C with new interferons, or the manipulation of interferon monotherapy so as to obtain the maximum results compatible with tolerance, have not produced significantly better results than the classic protocols of alpha-interferon monotherapy. A more concrete improvement has been achieved by the combination of interferon with Ribavirin, with the overall rate of response increasing three times compared to interferon monotherapy. Anaemia, however, is a common additional side-effect induced by Ribavirin. Combination therapy has become the treatment of choice for interferon naive patients as well as for interferon relapses; it is not efficacious in patients who have not responded to interferon. PMID:10730571

  9. Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia

    PubMed Central

    Toscanini, Federica; De Leo, Pasqualina; Calcagno, Giuseppe; Malfatti, Federica; Grasso, Alessandro; Anselmo, Marco

    2011-01-01

    Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only. PMID:25954538

  10. Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1.

    PubMed

    Kasirye, P; Kendall, L; Adkison, K K; Tumusiime, C; Ssenyonga, M; Bakeera-Kitaka, S; Nahirya-Ntege, P; Mhute, T; Kekitiinwa, A; Snowden, W; Burger, D M; Gibb, D M; Walker, A S

    2012-02-01

    The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)(0-12) and peak concentration (C(max)) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC(0-12) were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC(0-12) dnGMR = 1.58 (1.37-1.81), C(max) dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations. PMID:22190066

  11. Prophylaxis against de novo hepatitis B for liver transplantation utilizing hep B core (+) donors: does hepatitis B immunoglobulin provide a survival advantage?

    PubMed

    Brock, Guy N; Mostajabi, Farida; Ferguson, Nicole; Carrubba, Christopher J; Eng, Mary; Buell, Joseph F; Marvin, Michael R

    2011-06-01

    Donor liver allografts with positive serology for hepatitis B core antibody [HBc (+)] have been increasingly used for liver transplantation. However, the optimal prophylactic regimen to prevent development of de novo hepatitis B has not been determined. To evaluate this, we screened United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) registry data for adult recipients of HBc (+) organs who were HBsAg (-), and evaluated the effects of using prophylactic anti-viral therapies (HBIG and lamivudine) on patient and graft survival. Out of a total cohort of 958 patients transplanted since 2004, 61 received HBIG alone, 116 received lamivudine alone, 66 both, 509 neither and 206 were missing this information. Based on several multivariable Cox regression models, patients receiving HBIG therapy-only were observed to have a statistically significant (approximately 70%) reduction in risk of mortality compared with patients receiving lamivudine-only therapy [HR=0.29, 95% CI (0.10, 0.86), P=0.026], and a nonstatistically significant reduction in risk of graft failure. However, no graft failures were attributed to de novo hepatitis B, suggesting that any improved graft/patient survival possibly associated with HBIG therapy occurs independently of de novo hepatitis B virus (HBV) reduction. While this study cannot prove that HBIG therapy is protective for graft and patient survival after liver transplantation, these findings do highlight the need to further examine and study prophylactic use in recipients of HBc (+) donors. PMID:21401727

  12. PROPHYLAXIS AGAINST DENOVO HEPATITIS B FOR LIVER TRANSPLANTATION UTILIZING HEP B CORE (+) DONORS: DOES HBIG PROVIDE A SURVIVAL ADVANTAGE?

    PubMed Central

    Brock, Guy N.; Mostajabi, Farida; Ferguson, Nicole; Carrubba, Christopher J; Eng, Mary; Buell, Joseph F.; Marvin, Michael R.

    2011-01-01

    Donor liver allografts with positive serology for Hepatitis B core antibody (HBc (+)) have been increasingly used for liver transplantation. However the optimal prophylactic regimen to prevent development of denovo hepatitis B has not been determined. To evaluate this, we screened UNOS STAR registry data for adult recipients of HBc (+) organs who were HBsAg (-), and evaluated the effects of using prophylactic anti-viral therapies (HBIG and Lamivudine) on patient and graft survival. Out of a total cohort of 958 patients transplanted since 2004, 61 received HBIG alone, 116 received Lamivudine alone, 66 both, 509 neither and 206 were missing this information. Based on several multivariable Cox regression models, patients receiving HBIG therapy-only were observed to have a statistically significant (~70%) reduction in risk of mortality compared to patients receiving Lamivudine-only therapy (HR = 0.29, 95% CI (0.10, 0.86), p=0.026), and a non-statistically significant reduction in risk of graft failure. However, no graft failures were attributed to denovo hepatitis B, suggesting that any improved graft/patient survival possibly associated with HBIG therapy occurs independently of denovo HBV reduction. While this study cannot prove that HBIG therapy is protective for graft and patient survival after liver transplantation, these findings do highlight the need to further examine and study prophylactic use in recipients of HBc (+) donors. PMID:21401727

  13. Review of tenofovir use in HIV-infected children.

    PubMed

    Aurpibul, Linda; Puthanakit, Thanyawee

    2015-04-01

    Tenofovir disoproxil fumarate (TDF) is approved by the Food and Drug Administration for use in children ages 2 years and older and is recommended by the World Health Organization for use as a preferred first-line nucleotide reverse transcriptase inhibitor in adults and adolescents ages 10 years and older. The simplicity of once daily dosing, few metabolic side effects and efficacy against hepatitis B virus make TDF suitable for use in a large scale program. Unlike thymidine analoge nucleoside reverse transcriptase inhibitors (NRTIs); tenofovir does not induce multi-NRTI resistance mutations, so more NRTI options are available for future second-line-regimens. Fixed-dose combinations of TDF with other ARVs as a single tablet regimen are now widely available for adults and adolescents, but none are available for young children. Current information on TDF including the pharmacokinetics, safety and tolerability in children and adolescents was reviewed. A dosing regimen according to body-weight-band has been established for pediatric use. Safety concerns of TDF mainly relate to its effects on renal function and bone mineral density. Regular monitoring of renal function in high-risk patients, including those on other nephrotoxic drugs, may be warranted to detect adverse renal effects. Long-term-data on renal and bone outcomes among HIV-infected children is needed. Lessons learned from clinical studies will help clinicians balance the risks and benefits of TDF and design appropriate antiretroviral regimens for children in different circumstances. PMID:25247583

  14. Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

    PubMed Central

    Adebiyi, Oluwafeyisetan O.; Adebiyi, Olubunmi A.; Owira, Peter M. O.

    2015-01-01

    Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy. PMID:26690471

  15. Oral administration of stavudine induces hyperalgesia without affecting activity in rats.

    PubMed

    Weber, Juliane; Mitchell, Duncan; Kamerman, Peter R

    2007-12-01

    We have investigated whether long-term oral administration of the nucleoside reverse transcriptase inhibitor (NRTI) stavudine affects nociception in Sprague-Dawley rats, and whether any changes of nociception are accompanied by deterioration in activity and appetite. Stavudine (50 mg kg(-1)) was administered to rats orally once daily for six weeks in gelatine cubes. Mechanical hyperalgesia of the tail was assessed using a bar algometer, and thermal hyperalgesia by tail immersion in 49 degrees C water. Withdrawal latencies were compared to those of rats receiving placebo gelatine cubes. Withdrawal latencies to the noxious thermal challenge were not affected by stavudine, but those to the mechanical challenge were significantly decreased in rats receiving stavudine, compared to rats receiving placebo, from week three to week six of drug administration (P<0.05, ANCOVA with Newman Keuls post-hoc comparisons). The overall condition of the rats was assessed by recording daily voluntary wheel running distance and maximum running speed, food intake and body mass. Daily stavudine administration did not adversely affect voluntary running activity, appetite or growth. We have shown that long-term daily oral administration of the NRTI stavudine results in mechanical hyperalgesia in rats within three weeks without affecting appetite, growth and physical activity. PMID:17632188

  16. Molecular epidemiology of HIV in a cohort of men having sex with men from Istanbul.

    PubMed

    Alpsar, Dilek; Agacfidan, Ali; Lübke, Nadine; Verheyen, Jens; Eraksoy, Haluk; Cağatay, Atahan; Bozkaya, Emel; Kaiser, Rolf; Akgül, Baki

    2013-06-01

    In Turkey, the first HIV/AIDS case was reported in 1985. Since then the number of persons with HIV infection has increased, HIV is getting a public health problem. The aim of this study was to determine HIV-1 subtype diversity, drug resistance and gag cleavage site mutations among 20 HIV-infected men having sex with men from Istanbul, Turkey. The most prevalent subtype was found to be subtype B (50 %), but also the non-B subtypes A1, C and CRF02_AG, CRF03_AB and CRF06_cpx were found. Resistance-associated mutations were found in 6 patients (30 %) with 2/6 patients being therapy-experienced and 4/6 therapy-naïve at the time-point of analysis. In these patients, the nucleoside reverse transcriptase inhibitor (NRTI)-associated resistance mutations M41L, T215C, V75I, T69N, the non-NRTI associated mutations V106I, E138A, K103N and the protease inhibitor associated mutations Q58E and V82I were detected. Two virus strains also presented Gag cleavage site mutations. With increasing numbers of HIV-infected Turkish patients that require anti-retroviral treatment, HIV-1 drug-resistance testing is strongly recommended in order to choose the most active drug combination for therapy to achieve better clinical outcomes. PMID:23296905

  17. Viraemia and HIV-1 drug resistance mutations among patients receiving antiretroviral treatment in Mozambique.

    PubMed

    Maldonado, F; Biot, M; Roman, F; Masquelier, C; Anapenge, M; Bastos, R; Chuquela, H C; Arendt, V; Schmit, J C; Zachariah, R

    2009-06-01

    This study was conducted among individuals taking first-line antiretroviral treatment (ART) for at least 12 months under programme conditions in Maputo, Mozambique in order to report on the level of detectable viraemia and the proportion and types of drug resistance mutations among those with detectable viral loads. HIV-1 RNA viral load levels (lower detection limit <50 copies/ml) were measured, and resistance mutations were sequenced. One hundred and forty-nine consecutive patients (69% females, median age 36 years) were included after a mean follow-up time of 23 months. One hundred and seven (72%; 95% CI 64-79) had undetectable viral load, while in 42 (28%, 95% CI 21-36) viral load was detectable (range 50-58884 copies/ml). From 15 patients with viral load >1000 copies/ml, 12 viruses were sequenced: eight were C subtypes and four were circulating recombinant forms (CRF08). Eight (5%; 95% CI 2-9) patients with detectable viral load had one or more major resistance mutations. Nucleoside reverse transcriptase inhibitor (NRTI) and non-NRTI mutations were observed. There were no major mutations for resistance to protease inhibitors. In Maputo, the level of detectable viraemia is reassuringly low. While embarking on ART scale-up, wider surveillance is warranted to monitor programme quality and limit the development of drug resistance, which remains a major potential challenge for the future of ART in Africa. PMID:18804251

  18. Low rate of transmitted drug resistance may indicate low access to antiretroviral treatment in Maranhão State, northeast Brazil.

    PubMed

    Moura, Maria Edileuza Soares; Reis, Mônica Nogueira da Guarda; Lima, Yanna Andressa Ramos; Eulálio, Kelsen Dantas; Cardoso, Ludimila Paula Vaz; Stefani, Mariane Martins de Araújo

    2015-02-01

    The Brazilian AIDS epidemic is characterized by significant geographic contrasts: a reduction in incidence and mortality in the epicenter (southeast) and an increase in the northeast. HIV-1-transmitted drug resistance (TDR) and genetic diversity were investigated among 106 antiretroviral (ARV)-naive patients from Maranhão State, northeast. The HIV-1 protease (PR) and reverse transcriptase (RT) regions were sequenced; subtypes were assigned by REGA/phylogenetic analysis. TDR to the nucleoside/nonnucleoside reverse transcriptase inhibitor (NRTI/NNRTI) and protease inhibitor (PI) was identified by the Calibrated Population Resistance tool (Stanford). The median age was 31 years (range 18-72), with 54.7% women, 78.3% heterosexual transmission, and 17.9% men who have sex with men (MSM). Around 30% had <350 CD4(+) T cells/μl and 47.2% had plasma viral loads ≤10,000 copies/ml. The TDR rate was 3.8% (4/106; CI 95%, 1.2-8.9%) (three males, two of them MSM). Only single class mutations to NRTI (M184V; T215S) or NNRTI (K103S/N) were detected. Subtype B represented 81.1% (86/106), F1 1.9% (2/106), and C 2.8% (3/106); 14.2% were mosaics: 13 BF1 and 2 BC. Surveillance of TDR and HIV-1 genetic diversity is important to improve control strategies regionally. PMID:25411830

  19. Characterization of HIV-1 Resistance to Tenofovir Alafenamide In Vitro.

    PubMed

    Margot, Nicolas A; Johnson, Audun; Miller, Michael D; Callebaut, Christian

    2015-10-01

    Tenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection of in vitro resistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFV in vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R(2) = 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observed in vivo suggests that TAF may retain activity against TDF-resistant mutant viruses. PMID:26149983

  20. Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications.

    PubMed

    Adebiyi, Oluwafeyisetan O; Adebiyi, Olubunmi A; Owira, Peter M O

    2015-12-01

    Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin's effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy. PMID:26690471

  1. Trends in Decline of Antiretroviral Resistance among ARV-Experienced Patients in the HIV Outpatient Study: 1999–2008

    PubMed Central

    Buchacz, Kate; Baker, Rose; Ward, Douglas J.; Palella, Frank J.; Chmiel, Joan S.; Young, Benjamin; Yangco, Bienvenido G.; Novak, Richard M.; Brooks, John T.

    2012-01-01

    Background. Little is known about temporal trends in frequencies of clinically relevant ARV resistance mutations in HIV strains from U.S. patients undergoing genotypic testing (GT) in routine HIV care. Methods. We analyzed cumulative frequency of HIV resistance among patients in the HIV Outpatient Study (HOPS) who, during 1999–2008 and while prescribed antiretrovirals, underwent GT with plasma HIV RNA >1,000 copies/mL. Exposure ≥4 months to each of three major antiretroviral classes (NRTI, NNRTI and PI) was defined as triple-class exposure (TCE). Results. 906 patients contributed 1,570 GT results. The annual frequency of any major resistance mutations decreased during 1999–2008 (88% to 79%, P = 0.05). Resistance to PIs decreased among PI-exposed patients (71% to 46%, P = 0.010) as exposure to ritonavir-boosted PIs increased (6% to 81%, P < 0.001). Non-significant declines were observed in resistance to NRTIs among NRTI-exposed (82% to 67%), and triple-class-resistance among TCE patients (66% to 41%), but not to NNRTIs among NNRTI-exposed. Conclusions. HIV resistance was common but declined in HIV isolates from subgroups of ARV-experienced HOPS patients during 1999–2008. Resistance to PIs among PI-exposed patients decreased, possibly due to increased representation of patients whose only PI exposures were to boosted PIs. PMID:22611484

  2. [d4U]-spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase

    PubMed Central

    Younis, Yassir; Hunter, Roger; Muhanji, Clare I; Hale, Ian; Singh, Rajinder; Bailey, Christopher M.; Sullivan, Todd S.; Anderson, Karen S.

    2010-01-01

    Four double-drug HIV NRTI / NNRTI inhibitors 15a-d of the type [d4U]-spacer-[HI-236] in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer. PMID:20605472

  3. Emergent HIV-1 Drug Resistance Mutations Were Not Present at Low-Frequency at Baseline in Non-Nucleoside Reverse Transcriptase Inhibitor-Treated Subjects in the STaR Study

    PubMed Central

    Porter, Danielle P.; Daeumer, Martin; Thielen, Alexander; Chang, Silvia; Martin, Ross; Cohen, Cal; Miller, Michael D.; White, Kirsten L.

    2015-01-01

    At Week 96 of the Single-Tablet Regimen (STaR) study, more treatment-naïve subjects that received rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) developed resistance mutations compared to those treated with efavirenz (EFV)/FTC/TDF by population sequencing. Furthermore, more RPV/FTC/TDF-treated subjects with baseline HIV-1 RNA >100,000 copies/mL developed resistance compared to subjects with baseline HIV-1 RNA ≤100,000 copies/mL. Here, deep sequencing was utilized to assess the presence of pre-existing low-frequency variants in subjects with and without resistance development in the STaR study. Deep sequencing (Illumina MiSeq) was performed on baseline and virologic failure samples for all subjects analyzed for resistance by population sequencing during the clinical study (n = 33), as well as baseline samples from control subjects with virologic response (n = 118). Primary NRTI or NNRTI drug resistance mutations present at low frequency (≥2% to 20%) were detected in 6.6% of baseline samples by deep sequencing, all of which occurred in control subjects. Deep sequencing results were generally consistent with population sequencing but detected additional primary NNRTI and NRTI resistance mutations at virologic failure in seven samples. HIV-1 drug resistance mutations emerging while on RPV/FTC/TDF or EFV/FTC/TDF treatment were not present at low frequency at baseline in the STaR study. PMID:26690199

  4. Long-Term Exposure to AZT, but not d4T, Increases Endothelial Cell Oxidative Stress and Mitochondrial Dysfunction

    PubMed Central

    Kline, Erik R.; Bassit, Leda; Hernandez-Santiago, Brenda I.; Detorio, Mervi A.; Liang, Bill; Kleinhenz, Dean J.; Walp, Erik R.; Dikalov, Sergey; Jones, Dean P.; Schinazi, Raymond F.

    2009-01-01

    Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT) and stavudine (d4T), cause toxicities to numerous tissues, including the liver and vasculature. While much is known about hepatic NRTI toxicity, the mechanism of toxicity in endothelial cells is incompletely understood. Human aortic endothelial and HepG2 liver cells were exposed to 1 μM AZT or d4T for up to 5 weeks. Markers of oxidative stress, mitochondrial function, NRTI phosphorylation, mitochondrial DNA (mtDNA) levels, and cytotoxicity were monitored over time. In endothelial cells, AZT significantly oxidized glutathione redox potential, increased total cellular and mitochondrial-specific superoxide, decreased mitochondrial membrane potential, increased lactate release, and caused cell death from weeks 3 through 5. Toxicity occurred in the absence of di- and tri-phosphorylated AZT and mtDNA depletion. These data show that oxidative stress and mitochondrial dysfunction in endothelial cells occur with a physiologically relevant concentration of AZT, and require long-term exposure to develop. In contrast, d4T did not induce endothelial oxidative stress, mitochondrial dysfunction, or cytotoxicity despite the presence of d4T-triphosphate. Both drugs depleted mtDNA in HepG2 cells without causing cell death. Endothelial cells are more susceptible to AZT-induced toxicity than HepG2 cells, and AZT caused greater endothelial dysfunction than d4T because of its pro-oxidative effects. PMID:19067249

  5. Emergent HIV-1 Drug Resistance Mutations Were Not Present at Low-Frequency at Baseline in Non-Nucleoside Reverse Transcriptase Inhibitor-Treated Subjects in the STaR Study.

    PubMed

    Porter, Danielle P; Daeumer, Martin; Thielen, Alexander; Chang, Silvia; Martin, Ross; Cohen, Cal; Miller, Michael D; White, Kirsten L

    2015-12-01

    At Week 96 of the Single-Tablet Regimen (STaR) study, more treatment-naïve subjects that received rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) developed resistance mutations compared to those treated with efavirenz (EFV)/FTC/TDF by population sequencing. Furthermore, more RPV/FTC/TDF-treated subjects with baseline HIV-1 RNA >100,000 copies/mL developed resistance compared to subjects with baseline HIV-1 RNA ≤100,000 copies/mL. Here, deep sequencing was utilized to assess the presence of pre-existing low-frequency variants in subjects with and without resistance development in the STaR study. Deep sequencing (Illumina MiSeq) was performed on baseline and virologic failure samples for all subjects analyzed for resistance by population sequencing during the clinical study (n = 33), as well as baseline samples from control subjects with virologic response (n = 118). Primary NRTI or NNRTI drug resistance mutations present at low frequency (≥2% to 20%) were detected in 6.6% of baseline samples by deep sequencing, all of which occurred in control subjects. Deep sequencing results were generally consistent with population sequencing but detected additional primary NNRTI and NRTI resistance mutations at virologic failure in seven samples. HIV-1 drug resistance mutations emerging while on RPV/FTC/TDF or EFV/FTC/TDF treatment were not present at low frequency at baseline in the STaR study. PMID:26690199

  6. Comparison of genotypic and virtual phenotypic drug resistance interpretations with laboratory-based phenotypes among CRF01_AE and subtype B HIV-infected individuals.

    PubMed

    Jiamsakul, Awachana; Chaiwarith, Romanee; Durier, Nicolas; Sirivichayakul, Sunee; Kiertiburanakul, Sasisopin; Van Den Eede, Peter; Ditangco, Rossana; Kamarulzaman, Adeeba; Li, Patrick C K; Ratanasuwan, Winai; Sirisanthana, Thira

    2016-02-01

    HIV drug resistance assessments and interpretations can be obtained from genotyping (GT), virtual phenotyping (VP) and laboratory-based phenotyping (PT). We compared resistance calls obtained from GT and VP with those from PT (GT-PT and VP-PT) among CRF01_AE and subtype B HIV-1 infected patients. GT predictions were obtained from the Stanford HIV database. VP and PT were obtained from Janssen Diagnostics BVBA's vircoType(TM) HIV-1 and Antivirogram®, respectively. With PT assumed as the "gold standard," the area under the curve (AUC) and the Bland-Altman plot were used to assess the level of agreement in resistance interpretations. A total of 80 CRF01_AE samples from Asia and 100 subtype B from Janssen Diagnostics BVBA's database were analysed. CRF01_AE showed discordances ranging from 3 to 27 samples for GT-PT and 1 to 20 samples for VP-PT. The GT-PT and VP-PT AUCs were 0.76-0.97 and 0.81-0.99, respectively. Subtype B showed 3-61 discordances for GT-PT and 2-75 discordances for VP-PT. The AUCs ranged from 0.55 to 0.95 for GT-PT and 0.55 to 0.97 for VP-PT. Didanosine had the highest proportion of discordances and/or AUC in all comparisons. The patient with the largest didanosine FC difference in each subtype harboured Q151M mutation. Overall, GT and VP predictions for CRF01_AE performed significantly better than subtype B for three NRTIs. Although discrepancies exist, GT and VP resistance interpretations in HIV-1 CRF01_AE strains were highly robust in comparison with the gold-standard PT. PMID:26147742

  7. Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review.

    PubMed

    Oliveira, Natalia Mejias; Ferreira, Felipe Augusto Yamauti; Yonamine, Raquel Yumi; Chehter, Ethel Zimberg

    2014-01-01

    In HIV-seropositive individuals, the incidence of acute pancreatitis may achieve 40% per year, higher than the 2% found in the general population. Since 1996, when combined antiretroviral therapy, known as HAART (highly active antiretroviral therapy), was introduced, a broad spectrum of harmful factors to the pancreas, such as opportunistic infections and drugs used for chemoprophylaxis, dropped considerably. Nucleotide analogues and metabolic abnormalities, hepatic steatosis and lactic acidosis have emerged as new conditions that can affect the pancreas. To evaluate the role of antiretroviral drugs to treat HIV/AIDS in a scenario of high incidence of acute pancreatitis in this population, a systematic review was performed, including original articles, case reports and case series studies, whose targets were HIV-seropositive patients that developed acute pancreatitis after exposure to any antiretroviral drugs. This association was confirmed after exclusion of other possible etiologies and/or a recurrent episode of acute pancreatitis after re-exposure to the suspected drug. Zidovudine, efavirenz, and protease inhibitors are thought to lead to acute pancreatitis secondary to hyperlipidemia. Nucleotide reverse transcriptase inhibitors, despite being powerful inhibitors of viral replication, induce a wide spectrum of side effects, including myelotoxicity and acute pancreatitis. Didanosine, zalcitabine and stavudine have been reported as causes of acute and chronic pancreatitis. They pose a high risk with cumulative doses. Didanosine with hydroxyurea, alcohol or pentamidine are additional risk factors, leading to lethal pancreatitis, which is not a frequent event. In addition, other drugs used for prophylaxis of AIDS-related opportunistic diseases, such as sulfamethoxazole-trimethoprim and pentamidine, can produce necrotizing pancreatitis. Despite comorbidities that can lead to pancreatic involvement in the HIV/AIDS population, antiretroviral drug-induced pancreatitis

  8. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

    PubMed

    Jones, J; Colquitt, J; Shepherd, J; Harris, P; Cooper, K

    2010-05-01

    by lamivudine has an incremental cost-effective ratio (ICER) of 9940 pounds per quality-adjusted life-year (QALY) gained, compared with lamivudine followed by tenofovir. A more appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,619 pounds per QALY gained, compared with lamivudine followed by tenofovir. For HBeAg-negative patients, tenofovir followed by lamivudine has an ICER of 9811 pounds per QALY gained, compared with best supportive care. A more clinically appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,854 pounds per QALY gained, compared with tenofovir followed by lamivudine. The ERG uncovered a number of errors in the submission and these ICERs approximately doubled when the analysis was corrected and reran. The guidance issued by NICE on 22 July 2009 states that tenofovir disoproxil, within its marketing authorization is recommended as an option for the treatment of people with chronic HBe-Ag-positive or HBe-Ag-negative hepatitis B in whom antiviral treatment is indicated. PMID:20507800

  9. High frequency of antiviral drug resistance and non-b subtypes in HIV-1 patients failing antiviral therapy in Cuba

    PubMed Central

    Kouri, Vivian; Alemán, Yoan; Pérez, Lissette; Pérez, Jorge; Fonseca, Carlos; Correa, Consuelo; Aragonés, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Vinken, Lore; Limia, Celia; Soto, Yudira; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2014-01-01

    Introduction Emergence of HIV-1 drug resistance may limit the sustained benefits of antiretroviral therapy (ART) in settings with limited laboratory monitoring and drug options. The objective is to implement the surveillance of drug resistance and subtypes in HIV-1 patients failing ART in Cuba. Methods This study compiled clinical and genotypic drug resistance data 588 ART-experienced HIV-1 patients attending a clinical center in Havana in 2009–2013. Drug resistance testing was performed as part of routine clinical care. Drug resistance mutations and levels were determined using Rega version 8.0.2. Results Eighty-three percent received solely ART containing at least three drugs. Patients from 2009 to 2010 were longer treated (median: 4.9 vs 2.7 years) and exposed to more ART regimens (median: 4 vs 2 regimens) compared to patients from 2011–2013. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside RTI (NNRTI) and PI mutations were present in 83.5, 77.4 and 52.0%. Full-class resistance (FCR) to NRTI, NNRTI, PI and multidrug resistance (MDR) were detected in 25.0, 33.7, 11.4 and 6.3%. FCR to NRTI, NNRTI, PI and MDR were present in 12.8, 28.7, 0 and 0% after first-line failure (164 patients) and in 23.1, 34.6, 3.8 and 3.1% after second-line failure (130 patients). Subtype B (32.5%), BG recombinants (19.6%) and CRF19_cpx (16.2%) were the most prevalent genetic forms. Subtype distribution did not change significantly between 2009–2010 and 2011–2013, except for BG recombinants that increased from 12.2 to 21.3% (p=0.002). Conclusions Our study found a high prevalence of drug resistance and supports the need for appropriate laboratory monitoring in clinical practice and access to drug options in case of virological failure. PMID:25397499

  10. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing

    PubMed Central

    Rhee, Soo-Yon; Jordan, Michael R.; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U.; Mukui, Irene; Hosseinipour, Mina C.; Frenkel, Lisa M.; Ndembi, Nicaise; Hamers, Raph L.; Rinke de Wit, Tobias F.; Wallis, Carole L.; Gupta, Ravindra K.; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M.; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F.; De Oliveira, Tulio; Wensing, Annemarie M. J.; Gallant, Joel E.; Wainberg, Mark A.; Richman, Douglas D.; Fitzgibbon, Joseph E.; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W.

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  11. Profile of the HIV epidemic in Cape Verde: molecular epidemiology and drug resistance mutations among HIV-1 and HIV-2 infected patients from distinct islands of the archipelago.

    PubMed

    de Pina-Araujo, Isabel Inês M; Guimarães, Monick L; Bello, Gonzalo; Vicente, Ana Carolina P; Morgado, Mariza G

    2014-01-01

    HIV-1 and HIV-2 have been detected in Cape Verde since 1987, but little is known regarding the genetic diversity of these viruses in this archipelago, located near the West African coast. In this study, we characterized the molecular epidemiology of HIV-1 and HIV-2 and described the occurrence of drug resistance mutations (DRM) among antiretroviral therapy naïve (ARTn) patients and patients under treatment (ARTexp) from different Cape Verde islands. Blood samples, socio-demographic and clinical-laboratory data were obtained from 221 HIV-positive individuals during 2010-2011. Phylogenetic and bootscan analyses of the pol region (1300 bp) were performed for viral subtyping. HIV-1 and HIV-2 DRM were evaluated for ARTn and ARTexp patients using the Stanford HIV Database and HIV-GRADE e.V. Algorithm Homepage, respectively. Among the 221 patients (169 [76.5%] HIV-1, 43 [19.5%] HIV-2 and 9 [4.1%] HIV-1/HIV-2 co-infections), 67% were female. The median ages were 34 (IQR = 1-75) and 47 (IQR = 12-84) for HIV-1 and HIV-2, respectively. HIV-1 infections were due to subtypes G (36.6%), CRF02_AG (30.6%), F1 (9.7%), URFs (10.4%), B (5.2%), CRF05_DF (3.0%), C (2.2%), CRF06_cpx (0.7%), CRF25_cpx (0.7%) and CRF49_cpx (0.7%), whereas all HIV-2 infections belonged to group A. Transmitted DRM (TDRM) was observed in 3.4% (2/58) of ARTn HIV-1-infected patients (1.7% NRTI, 1.7% NNRTI), but not among those with HIV-2. Among ARTexp patients, DRM was observed in 47.8% (33/69) of HIV-1 (37.7% NRTI, 37.7% NNRTI, 7.4% PI, 33.3% for two classes) and 17.6% (3/17) of HIV-2-infections (17.6% NRTI, 11.8% PI, 11.8% both). This study indicates that Cape Verde has a complex and unique HIV-1 molecular epidemiological scenario dominated by HIV-1 subtypes G, CRF02_AG and F1 and HIV-2 subtype A. The occurrence of TDRM and the relatively high level of DRM among treated patients are of concern. Continuous monitoring of patients on ART, including genotyping, are public policies to be implemented

  12. Profile of the HIV Epidemic in Cape Verde: Molecular Epidemiology and Drug Resistance Mutations among HIV-1 and HIV-2 Infected Patients from Distinct Islands of the Archipelago

    PubMed Central

    de Pina-Araujo, Isabel Inês M.; Guimarães, Monick L.; Bello, Gonzalo; Vicente, Ana Carolina P.; Morgado, Mariza G.

    2014-01-01

    HIV-1 and HIV-2 have been detected in Cape Verde since 1987, but little is known regarding the genetic diversity of these viruses in this archipelago, located near the West African coast. In this study, we characterized the molecular epidemiology of HIV-1 and HIV-2 and described the occurrence of drug resistance mutations (DRM) among antiretroviral therapy naïve (ARTn) patients and patients under treatment (ARTexp) from different Cape Verde islands. Blood samples, socio-demographic and clinical-laboratory data were obtained from 221 HIV-positive individuals during 2010–2011. Phylogenetic and bootscan analyses of the pol region (1300 bp) were performed for viral subtyping. HIV-1 and HIV-2 DRM were evaluated for ARTn and ARTexp patients using the Stanford HIV Database and HIV-GRADE e.V. Algorithm Homepage, respectively. Among the 221 patients (169 [76.5%] HIV-1, 43 [19.5%] HIV-2 and 9 [4.1%] HIV-1/HIV-2 co-infections), 67% were female. The median ages were 34 (IQR = 1–75) and 47 (IQR = 12–84) for HIV-1 and HIV-2, respectively. HIV-1 infections were due to subtypes G (36.6%), CRF02_AG (30.6%), F1 (9.7%), URFs (10.4%), B (5.2%), CRF05_DF (3.0%), C (2.2%), CRF06_cpx (0.7%), CRF25_cpx (0.7%) and CRF49_cpx (0.7%), whereas all HIV-2 infections belonged to group A. Transmitted DRM (TDRM) was observed in 3.4% (2/58) of ARTn HIV-1-infected patients (1.7% NRTI, 1.7% NNRTI), but not among those with HIV-2. Among ARTexp patients, DRM was observed in 47.8% (33/69) of HIV-1 (37.7% NRTI, 37.7% NNRTI, 7.4% PI, 33.3% for two classes) and 17.6% (3/17) of HIV-2-infections (17.6% NRTI, 11.8% PI, 11.8% both). This study indicates that Cape Verde has a complex and unique HIV-1 molecular epidemiological scenario dominated by HIV-1 subtypes G, CRF02_AG and F1 and HIV-2 subtype A. The occurrence of TDRM and the relatively high level of DRM among treated patients are of concern. Continuous monitoring of patients on ART, including genotyping, are public policies to be

  13. Deep sequencing analysis of HIV-1 reverse transcriptase at baseline and time of failure in patients receiving rilpivirine in the phase III studies ECHO and THRIVE.

    PubMed

    Van Eygen, Veerle; Thys, Kim; Van Hove, Carl; Rimsky, Laurence T; De Meyer, Sandra; Aerssens, Jeroen; Picchio, Gaston; Vingerhoets, Johan

    2016-05-01

    Minority variants (1.0-25.0%) were evaluated by deep sequencing (DS) at baseline and virological failure (VF) in a selection of antiretroviral treatment-naïve, HIV-1-infected patients from the rilpivirine ECHO/THRIVE phase III studies. Linkage between frequently emerging resistance-associated mutations (RAMs) was determined. DS (llIumina®) and population sequencing (PS) results were available at baseline for 47 VFs and time of failure for 48 VFs; and at baseline for 49 responders matched for baseline characteristics. Minority mutations were accurately detected at frequencies down to 1.2% of the HIV-1 quasispecies. No baseline minority rilpivirine RAMs were detected in VFs; one responder carried 1.9% F227C. Baseline minority mutations associated with resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 8/47 VFs (17.0%) and 7/49 responders (14.3%). Baseline minority nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs M184V and L210W were each detected in one VF (none in responders). At failure, two patients without NNRTI RAMs by PS carried minority rilpivirine RAMs K101E and/or E138K; and five additional patients carried other minority NNRTI RAMs V90I, V106I, V179I, V189I, and Y188H. Overall at failure, minority NNRTI RAMs and NRTI RAMs were found in 29/48 (60.4%) and 16/48 VFs (33.3%), respectively. Linkage analysis showed that E138K and K101E were usually not observed on the same viral genome. In conclusion, baseline minority rilpivirine RAMs and other NNRTI/NRTI RAMs were uncommon in the rilpivirine arm of the ECHO and THRIVE studies. DS at failure showed emerging NNRTI resistant minority variants in seven rilpivirine VFs who had no detectable NNRTI RAMs by PS. J. Med. Virol. 88:798-806, 2016. © 2015 Wiley Periodicals, Inc. PMID:26412111

  14. Surveillance of HIV Transmitted Drug Resistance in Latin America and the Caribbean: A Systematic Review and Meta-Analysis

    PubMed Central

    Avila-Rios, Santiago; Sued, Omar; Rhee, Soo-Yon; Shafer, Robert W.; Reyes-Teran, Gustavo; Ravasi, Giovanni

    2016-01-01

    Background HIV transmitted drug resistance (TDR) remains at moderate level in Latin America and the Caribbean (LAC). However, different epidemiologic scenarios could influence national and sub-regional TDR levels and trends. Methods and Findings We performed a systematic review of currently available publications on TDR in antiretroviral treatment-naïve adults in LAC. Ninety-eight studies published between January 2000 and June 2015 were included according to critical appraisal criteria and classified by sub-region: Brazil (50), Mesoamerica (17), Southern Cone (16), Andean (8) and Caribbean (7). From these, 81 studies encompassing 11,441 individuals with data on DR mutation frequency were included in a meta-analysis. Overall TDR prevalence in LAC was 7.7% (95% CI: 7.2%-8.2%). An increasing trend was observed for overall TDR when comparing 2000–2005 (6.0%) and 2006–2015 (8.2%) (p<0.0001), which was associated with significant NNRTI TDR increase (p<0.0001). NRTI TDR decreased (4.5% vs. 2.3%, p<0.0001). NNRTI TDR increase was associated mainly with K101E, K103N and G190A. NRTI TDR decrease was associated mainly with M184V, K70R and T215Y. All sub-regions reached moderate overall TDR levels. The rapid increase in TDR to all antiretroviral classes in the Caribbean is notable, as well as the significant increase in NNRTI TDR reaching moderate levels in the Southern Cone. NRTI TDR was dominant in 2000–2005, mainly in the Caribbean, Mesoamerica and Brazil. This dominance was lost in 2006–2015 in all sub-regions, with the Southern Cone and the Caribbean switching to NNRTI dominance. PI TDR remained mostly constant with a significant increase only observed in the Caribbean. Conclusions Given the high conceptual and methodological heterogeneity of HIV TDR studies, implementation of surveys with standardized methodology and national representativeness is warranted to generate reliable to inform public health policies. The observed increasing trend in NNRTI TDR

  15. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

    PubMed

    Rhee, Soo-Yon; Jordan, Michael R; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U; Mukui, Irene; Hosseinipour, Mina C; Frenkel, Lisa M; Ndembi, Nicaise; Hamers, Raph L; Rinke de Wit, Tobias F; Wallis, Carole L; Gupta, Ravindra K; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F; De Oliveira, Tulio; Wensing, Annemarie M J; Gallant, Joel E; Wainberg, Mark A; Richman, Douglas D; Fitzgibbon, Joseph E; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  16. Long-term efficacy of nucleoside monotherapy in preventing HBV infection in HBsAg-negative recipients of anti-HBc-positive donor livers

    PubMed Central

    Chotiyaputta, Watcharasak; Pelletier, Shawn J.; Fontana, Robert J.

    2010-01-01

    Background and aim Transmission of hepatitis B virus (HBV) infection occurs in up to 87.5% of HBsAg-negative recipients of anti-HBc-positive donor livers in the absence of HBV prophylaxis. There is no standardized prophylactic regimen to prevent HBV infection in this setting. The aim of this study was to determine the long-term efficacy of nucleoside analogue to prevent HBV infection in this setting. Methods A retrospective study of HBsAg-negative patients receiving liver transplantation (LT) from anti-HBc-positive donors during a 10-year period. Results Twenty patients were studied, mean age was 50.2 ± 8.3 years, 40% were men, and 90% were Caucasian. The median MELD score at the time of LT was 18 (12–40). None of the patients received hepatitis B immune globulin. Eighteen patients received nucleoside analogue monotherapy: 10 received lamivudine and 8 received entecavir. None of these 18 patients developed HBV infection after a median follow up of 32 (1–75) months. One patient received a second course of hepatitis B vaccine 50 months after LT with anti-HBs titer above 1,000 mIU/mL. Lamivudine was discontinued and the patient remained HBsAg negative 18 months after withdrawal of lamivudine. Two patients who were anti-HBs positive before LT were not started on HBV prophylaxis after LT; both developed HBV infection after LT. Conclusions Nucleoside monotherapy is sufficient in preventing HBV infection in HBsAg-negative recipients of anti-HBc-positive donor livers. HBV prophylaxis is necessary in anti-HBs-positive recipients of anti-HBc-positive donor livers. PMID:21286341

  17. Identification of transformation products of antiviral drugs formed during biological wastewater treatment and their occurrence in the urban water cycle.

    PubMed

    Funke, Jan; Prasse, Carsten; Ternes, Thomas A

    2016-07-01

    The fate of five antiviral drugs (abacavir, emtricitabine, ganciclovir, lamivudine and zidovudine) was investigated in biological wastewater treatment. Investigations of degradation kinetics were accompanied by the elucidation of formed transformation products (TPs) using activated sludge lab experiments and subsequent LC-HRMS analysis. Degradation rate constants ranged between 0.46 L d(-1) gSS(-1) (zidovudine) and 55.8 L d(-1) gSS(-1) (abacavir). Despite these differences of the degradation kinetics, the same main biotransformation reaction was observed for all five compounds: oxidation of the terminal hydroxyl-moiety to the corresponding carboxylic acid (formation of carboxy-TPs). In addition, the oxidation of thioether moieties to sulfoxides was observed for emtricitabine and lamivudine. Antiviral drugs were detected in influents of municipal wastewater treatment plants (WWTPs) with concentrations up to 980 ng L(-1) (emtricitabine), while in WWTP effluents mainly the TPs were found with concentration levels up to 1320 ng L(-1) (carboxy-abacavir). Except of zidovudine none of the original antiviral drugs were detected in German rivers and streams, whereas the concentrations of the TPs ranged from 16 ng L(-1) for carboxy-lamivudine up to 750 ng L(-1) for carboxy-acyclovir. These concentrations indicate an appreciable portion from WWTP effluents present in rivers and streams, as well as the high environmental persistence of the carboxy-TPs. As a result three of the carboxylic TPs were detected in finished drinking water. PMID:27082694

  18. Establishment of drug-resistant HBV small-animal models by hydrodynamic injection

    PubMed Central

    Cheng, Junjun; Han, Yanxing; Jiang, Jian-Dong

    2014-01-01

    In antiviral therapy of hepatitis B virus (HBV) infection, drug resistance remains a huge obstacle to the long-term effectiveness of nucleoside/tide analogs (NAs). Primary resistance mutation (rtM204V) contributes to lamivudine (LAM)-resistance, and compensatory mutations (rtL180M and rtV173L) restore viral fitness and increase replication efficiency. The evaluation of new anti-viral agents against drug-resistant HBV is limited by the lack of available small-animal models. We established LAM-resistance HBV replication mice models based on clinical LAM-resistant HBV mutants. Double (rtM204V+rtL180M) or triple (rtM204V+rtL180M+rtV173L) lamivudine-resistant mutations were introduced into HBV expression vector, followed by hydrodynamic injection into tail vein of NOD/SCID mice. Viremia was detected on days 5, 9, 13 and 17 and liver HBV DNA was detected on day 17 after injection. The serum and liver HBV DNA levels in LAM-resistant model carrying triple mutations are the highest among the models. Two NAs, LAM and entecavir (ETV), were used to test the availability of the models. LAM and ETV inhibited viral replication on wild-type model. LAM was no longer effective on LAM-resistant models, but ETV retains a strong activity. Therefore, these models can be used to evaluate anti-viral agents against lamivudine-resistance, affording new opportunities to establish other drug-resistant HBV small-animal models. PMID:26579395

  19. Changes in First-Line cART Regimens and Short-Term Clinical Outcome between 1996 and 2010 in The Netherlands

    PubMed Central

    Smit, Mikaela; Smit, Colette; Geerlings, Suzanne; Gras, Luuk; Brinkman, Kees; Hallett, Timothy B.; de Wolf, Frank

    2013-01-01

    Objectives Document progress in HIV-treatment in the Netherlands since 1996 by reviewing changing patterns of cART use and relating those to trends in patients' short-term clinical outcomes between 1996 and 2010. Design and Methods 1996–2010 data from 10,278 patients in the Dutch ATHENA national observational cohort were analysed. The annual number of patients starting a type of regimen was quantified. Trends in the following outcomes were described: i) recovery of 150 CD4 cells/mm3 within 12 months of starting cART; ii) achieving viral load (VL) suppression ≤1,000 copies/ml within 12 months of starting cART; iii) switching from first-line to second-line regimen within three years of starting treatment; and iv) all-cause mortality rate per 100 person-years within three years of starting treatment. Results Between 1996 and 2010, first-line regimens changed from lamivudine/zidovudine-based or lamivudine/stavudine-based regimens with unboosted-PIs to tenofovir with either emtricitabine or lamivudine with NNRTIs. Mortality rates did not change significantly over time. VL suppression and CD4 recovery improved over time, and the incidence of switching due to virological failure and toxicity more than halved between 1996 and 2010. These effects appear to be related to the use of new regimens rather than improvements in clinical care. Conclusion The use of first-line cART in the Netherlands closely follows changes in guidelines, to the benefit of patients. While there was no significant improvement in mortality, newer drugs with better tolerability and simpler dosing resulted in improved immunological and virological recovery and reduced incidences of switching due to toxicity and virological failure. PMID:24098764

  20. HIV transmission and 24-month survival in a randomized trial of HAART to prevent MTCT during pregnancy and breastfeeding in Botswana (The Mma Bana Study)

    PubMed Central

    Shapiro, Roger L.; Kitch, Douglas; Ogwu, Anthony; Hughes, Michael D.; Lockman, Shahin; Powis, Kathleen; Souda, Sajini; Moffat, Claire; Moyo, Sikhulile; McIntosh, Kenneth; van Widenfelt, Erik; Zwerski, Sheryl; Mazhani, Loeto; Makhema, Joseph; Essex, Max

    2014-01-01

    Objectives Highly active antiretroviral therapy (HAART) for prevention of mother-to-child HIV transmission (MTCT) may impact long-term survival of mothers and children. Design Randomized clinical trial. Methods HIV–infected pregnant women with CD4 ≥200 cells/mm3 were randomly assigned to abacavir, zidovudine, lamivudine (Arm A) or lopinavir–ritonavir, zidovudine–lamivudine (Arm B) from week 26–34 gestation through planned weaning by 6 months postpartum. Women with baseline CD4 <200 received nevirapine–zidovudine–lamivudine indefinitely (Obs arm), as did randomized women later qualifying for treatment. Results Among 560 randomized and 170 observational women enrolled, there were 14 deaths (1.9%); 1 antenatally (Obs), 3 from delivery though 6 months postpartum (1 Arm A, 2 Obs), and 10 from 6–24 months postpartum (5 Arm A, 3 Arm B, 2 Obs). Time to death or CD4 <200 was shorter in Arm A vs. B (p=0.03). Of 709 live-born children, 97% breastfed for median 5.8 months. Of 37 (5.2%) deaths by 24 months, 9 were before breastfeeding initiated (3 Arm A, 2 Arm B, 4 Obs); 6 while breastfeeding (1 Arm A, 2 Arm B, 3 Obs); and 22 after weaning (9 Arm A, 11 Arm B, 2 Obs). Only 8 children (1.1%) were HIV-infected at 24 months (6 Arm A, 1 Arm B, 1 Obs), all before 6 months. Conclusions Low MTCT was maintained through extended follow-up in all arms. Disease progression appeared slower after discontinuing protease inhibitor-based HAART, but a concerning number of maternal deaths occurred after stopping either regimen. Strategies to improve maternal and child survival in the post-intervention period are required. PMID:24180000

  1. New antivirals - mechanism of action and resistance development.

    PubMed

    Balzarini, J; Naesens, L; De Clercq, E

    1998-10-01

    In recent years, several novel treatment modalities emerged for a number of virus infections, including lamivudine for hepatitis B virus, abacavir, adefovir dipivoxyl and apropovir disprometil for human immunodeficiency virus, cidofovir for cytomegalovirus, and famciclovir (the oral prodrug of penciclovir) and cidofovir for other herpesviruses (i.e. herpes simplex virus and varicella-zoster virus). For all drugs, resistance eventually develops upon prolonged administration to the infected individuals, albeit at a varying extent. In addition, new mutations related to multidrug resistance have recently been identified. PMID:10066527

  2. Combination antiretroviral studies for patients with primary biliary cirrhosis.

    PubMed

    Lytvyak, Ellina; Montano-Loza, Aldo J; Mason, Andrew L

    2016-01-01

    Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label

  3. [Ergotism due to simultaneous use of ergot alkaloids and high activity antiretroviral therapy].

    PubMed

    Cifuentes M, Daniel; Blanco L, Sergio; Ramírez F, Camila

    2016-06-01

    High activity antiretroviral therapy may exacerbate the activity of ergot alkaloids due to an inhibition of cytochrome P450. We report a 57 years old female with AIDS treated with lamivudine, zidovudine, atazanavir, ritonavir and cotrimoxazole presenting with ischemic signs in the four limbs. There was acrocyanosis and weak radial and ulnar pulses. A family member referred that the patient used ergot alkaloids for headaches. An ergotism due to the simultaneous use of ergot alkaloids and antiretroviral therapy was suspected. The latter was discontinued and intravenous nitroglycerin, nifedipine and pentoxifyline were started with good results. PMID:27598502

  4. Co-occurrence of chronic hepatitis B virus infection and autoimmune hepatitis in a young Senegalese girl.

    PubMed

    Nobili, Valerio; Marcellini, Matilde; Devito, Rita; Comparcola, Donatella; Vento, Sandro

    2006-08-01

    We report the case of a 9-year-old Senegalese girl with co-occurring wild-type (HBeAg-positive) chronic hepatitis B and antinuclear antibody-positive autoimmune hepatitis. Her HLA haplotype was A1, B8, DRB1*04, DQB1*02. Steriod and lamivudine therapy led to biochemical remission, and reactivation occurred when the patient stopped steroids. Persistent HBV infection due to wild-type virus (likely acquired vertically or early in life, as the mother was HBsAg positive) may have acted as a trigger for autoimmune hepatitis in this young girl. PMID:16825914

  5. Prevention of hepatitis B recurrence after liver transplantation.

    PubMed

    Polak, Wojciech G; Gładysz, Andrzej; Rotter, Katarzyna

    2005-01-01

    Over the last decade significant improvement in patient and graft survival has been observed after liver transplantation for hepatitis B virus (HBV)-related liver disease, mostly because of efficient prophylaxis against hepatitis B reinfection. This review discusses different approches in prevention of hepatitis B recurrence in liver recipients including new concepts as vaccination against hepatitis B after liver transplantation. Based on available data combined prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine is currently recommended prophylaxis for HBV recurrence after liver transplantation. PMID:16617660

  6. Effect of various pyrimidines possessing the 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] moiety, able to mimic natural 2'-deoxyribose, on wild-type and mutant hepatitis B virus replication.

    PubMed

    Kumar, Rakesh; Semaine, Wassila; Johar, Monika; Tyrrell, D Lorne J; Agrawal, Babita

    2006-06-15

    Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Development of drug resistance against clinical anti-HBV drug lamivudine due to long-term use and rebound of viral DNA after cessation of treatment has been a major setback of the current therapy. We have synthesized a series of pyrimidine nucleosides possessing a variety of substituents at the C-5 position, and a 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] flexible acyclic glycosyl moiety at the N-1 position, that have the ability to mimic the natural 2'-deoxyribosyl moiety. Some of these potential antiviral compounds included variations at both C-5 and C-6 positions of the uracil base. Other variations of the uracil derivatives were the 6-aza congeners. 4-Amino and 4-methoxy pyrimidine derivatives were also made. Compounds in which the base moiety was substituted by 5-chloro- (25), 5-(2-bromovinyl)- (32), or 5-bromo-6-methyl- (37) groups possess significant activity against duck-HBV, wild-type human HBV (2.2.15 cells), and lamivudine-resistant HBV containing single and double mutations. No cytotoxicity was seen in host HepG2 and Vero cells, up to the highest concentration tested. The anti-HBV activity exhibited by compounds 25, 32, and 37 was superior for human HBV and comparable for DHBV to that of the corresponding purine nucleoside, ganciclovir. Further, they were only 10-15-fold less inhibitory against human HBV in 2.2.15 cells than the reference drug, lamivudine. Other compounds in the series were moderately inhibitory against DHBV and wild-type human HBV. The size of the halogen and the electronegativity of the substituents at the 5- and 6-positions are important for antiviral activity toward HBV. These compounds were also evaluated for their antiviral activity for West Nile virus, respiratory syncytial virus, SARS-coronavirus, and hepatitis C virus. They were generally inactive in these antiviral assay systems (at concentrations up to 100 microg/mL). 1-[(2-Hydroxy-1

  7. Combination antiretroviral studies for patients with primary biliary cirrhosis

    PubMed Central

    Lytvyak, Ellina; Montano-Loza, Aldo J; Mason, Andrew L

    2016-01-01

    Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label

  8. Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

    PubMed Central

    Bailey, Christopher M.; Sullivan, Todd J.; Iyidogan, Pinar; Tirado-Rives, Julian; Chung, Raymond; Ruiz-Caro, Juliana; Mohamed, Ebrahim; Jorgensen, William; Hunter, Roger; Anderson, Karen S.

    2013-01-01

    Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication. PMID:23659183

  9. Premature and accelerated aging: HIV or HAART?

    PubMed

    Smith, Reuben L; de Boer, Richard; Brul, Stanley; Budovskaya, Yelena; van Spek, Hans

    2012-01-01

    Highly active antiretroviral therapy (HAART) has significantly increased life expectancy of the human immunodeficiency virus (HIV)-positive population. Nevertheless, the average lifespan of HIV-patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated aging of HIV-patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-γ. Besides NRTIs, other antiretroviral drug classes such as protease inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favor of the use of Caenorhabditis elegans as a novel model system for studying these effects. PMID:23372574

  10. Premature and accelerated aging: HIV or HAART?

    PubMed Central

    Smith, Reuben L.; de Boer, Richard; Brul, Stanley; Budovskaya, Yelena; van Spek, Hans

    2013-01-01

    Highly active antiretroviral therapy (HAART) has significantly increased life expectancy of the human immunodeficiency virus (HIV)-positive population. Nevertheless, the average lifespan of HIV-patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated aging of HIV-patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-γ. Besides NRTIs, other antiretroviral drug classes such as protease inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favor of the use of Caenorhabditis elegans as a novel model system for studying these effects. PMID:23372574

  11. Antiretroviral Regimens and CD4/CD8 Ratio Normalization in HIV-Infected Patients during the Initial Year of Treatment: A Cohort Study

    PubMed Central

    De Salvador-Guillouët, F.; Sakarovitch, C.; Durant, J.; Risso, K.; Demonchy, E.; Roger, P. M.; Fontas, E.

    2015-01-01

    Background As CD4/CD8 ratio inversion has been associated with non-AIDS morbidity and mortality, predictors of ratio normalization after cART need to be studied. Here, we aimed to investigate the association of antiretroviral regimens with CD4/CD8 ratio normalization within an observational cohort. Methods We selected, from a French cohort at the Nice University Hospital, HIV-1 positive treatment-naive patients who initiated cART between 2000 and 2011 with a CD4/CD8 ratio <1. Association between cART and ratio normalization (>1) in the first year was assessed using multivariate logistic regression models. Specific association with INSTI-containing regimens was examined. Results 567 patients were included in the analyses; the median CD4/CD8 ratio was 0.36. Respectively, 52.9%, 29.6% and 10.4% initiated a PI-based, NNRTI-based or NRTI-based cART regimens. About 8% of the population started an INSTI-containing regimen. 62 (10.9%) patients achieved a CD4/CD8 ratio ≥1 (N group). cART regimen was not associated with normalization when coded as PI-, NNRTI- or NRTI-based regimen. However, when considering INSTI-containing regimens alone, there was a strong association with normalization [OR, 7.67 (2.54–23.2)]. Conclusions Our findings suggest an association between initiation of an INSTI-containing regimen and CD4/CD8 ratio normalization at one year in naïve patients. Should it be confirmed in a larger population, it would be another argument for their use as first-line regimen as it is recommended in the recent update of the “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents”. PMID:26485149

  12. Drug-resistant reverse transcriptase genotyping and phenotyping of B and non-B subtypes (F and A) of human immunodeficiency virus type I found in Brazilian patients failing HAART.

    PubMed

    Caride, E; Brindeiro, R; Hertogs, K; Larder, B; Dehertogh, P; Machado, E; de Sá, C A; Eyer-Silva, W A; Sion, F S; Passioni, L F; Menezes, J A; Calazans, A R; Tanuri, A

    2000-09-15

    Development of drug resistance is the inevitable consequence of incomplete suppression of virus plasma levels in HIV-1-infected patients treated with highly active antiretroviral therapy. Resistance mutations previously characterized have been found in B subtype viruses of developed countries. Moreover, mutation profiles for non-B and more divergent B subtype viruses found in developing countries shall be analyzed together with their ex vivo phenotyping in order to establish an exact correlation between the genotyping data and the clinical management counseling for those uncommon virus subtypes. In the present study, we evaluated the mutation profile for individuals infected with B subtype and non-B subtype viruses. Viral DNA fragments corresponding to the RT gene were amplified, sequenced, and subtyped. Phenotyping analysis for reverse transcriptase nucleoside (NRTI) and nonnucleoside inhibitor susceptibility was performed using the recombinant virus assay technology. Brazilian non-B subtypes (subtype F, n = 4, and subtype A, n = 1) isolates showed essentially the same B subtype mutation profile, presenting an NRTI drug resistance with similar MIC50% and MIC90% values for all drugs analyzed regardless of their subtypes. A strong cross-resistance phenotype among AZT, 3TC, and abacavir could be seen in all isolates analyzed. A novel result was that some RT sequences not only revealed the presence of G333D/E mutations but also correlated to the presence of mutation T386I that could abrogate the M184V-surpassing effect of L210W or L210W plus G333D/E. These findings suggest that Brazilian non-B subtype HIV-1 strains use an identical RT drug resistance mutation pattern when compared to B isolates and will contribute to the validation of the genotypic and phenotypic tests in these predominant worldwide-spread viral variants. PMID:11017792

  13. Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race–ethnicity determine the degree of regimen complexity

    PubMed Central

    Tashima, Karen T.; Mollan, Katie R.; Na, Lumine; Gandhi, Rajesh T.; Klingman, Karin L.; Fichtenbaum, Carl J.; Andrade, Adriana; Johnson, Victoria A.; Eron, Joseph J.; Smeaton, Laura; Haubrich, Richard H.

    2015-01-01

    Background Regimen selection for highly treatment-experienced patients is complicated. Methods Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3–4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. Results A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR]=2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR=6.2) or boosted protease inhibitor (PI, OR=6.6), prior use of integrase strand transfer inhibitor (INSTI, OR=25), and race–ethnicity (all P≤0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR=0.5) and Hispanic participants from the continental US (OR=0.2) were less likely to start a complex regimen, compared to white non-Hispanics. Conclusions In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race–ethnicity were key factors in decisions to select a more complex regimen. PMID:26212575

  14. Decreasing population selection rates of resistance mutation K65R over time in HIV-1 patients receiving combination therapy including tenofovir

    PubMed Central

    Theys, K.; Snoeck, J.; Vercauteren, J.; Abecasis, A. B.; Vandamme, A.-M.; Camacho, R. J.

    2013-01-01

    Objectives The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. Methods In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. Results The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non-nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. Discussion Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovir. PMID:23027713

  15. HIV-1 Genetic Diversity and Drug Resistance among Senegalese Patients in the Public Health System

    PubMed Central

    Thiam, Moussa; Diop-Ndiaye, Halimatou; Diouf, Aminata Diaw; Vidal, Nicole; Ndiaye, Ousseynou; Ndiaye, Ibrahima; Ngom-Gueye, Ndeye Fatou; Diallo, Sada; Diongue, Oumy Diop; Camara, Makhtar; Seck, Abdoulaye; Mboup, Souleymane

    2013-01-01

    In this study, we investigated the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations and genetic variability among Senegalese patients undergoing highly active antiretroviral therapy (ART) in the public health system. We conducted a cross-sectional study of 72 patients with suspected therapeutic failure. HIV-1 genotyping was performed with Viroseq HIV-1 Genotyping System v2.0 or the procedure developed by the ANRS AC11 resistance study group, and a phylogenetic analysis was performed. The median follow-up visit was at 40 (range, 12 to 123) months, and the median viral load was 4.67 (range, 3.13 to 6.94) log10 copies/ml. The first-line therapeutic regimen was nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (EFV) or NRTIs plus nevirapine (NVP) (54/72 patients; 75%), and the second-line therapy was NRTIs plus a protease inhibitor (PI/r) (18/72; 25%). Fifty-five patients (55/72; 76.39%) had at least one drug resistance mutation. The drug resistance rates were 72.22 and 88.89% for the first-line and second-line ARTs, respectively. In NRTI mutations, thymidine analog mutations (TAMs) were found in 50.79% and the M184V mutation was found in 34.92% of the samples. For non-NRTI resistance, we noted a predominance of the K103N mutation (46.27%). For PI/r, several cases of mutations were found with a predominance of M46I and L76V/F at 24% each. The phylogenetic analysis revealed CRF02_AG as the predominant circulating recombinant form (43/72; 59.72%). We found a high prevalence of resistance mutations and a high rate of TAMs among Senegalese patients in the public health system. These findings emphasize the need to improve virological monitoring in resource-limited settings. PMID:23241378

  16. HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China

    PubMed Central

    He, Jianmei; Zheng, Jun; Chiarella, Jennifer; Kozal, Michael J.

    2016-01-01

    Objective Determine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF). Methods 29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs (Stanford DRMs with an algorithm value ≥15, include low-, intermediate and high-level resistance) by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels. Results DS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×104 c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency (26 NNRTI, 12 NRTI and 2 PI) and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1–4% and 24 (60%) at levels of 5–19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS. Conclusions DS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects. PMID:26895182

  17. Antiretroviral drug resistance mutations in naïve and experienced patients in Shiraz, Iran, 2014.

    PubMed

    Naziri, Hamed; Baesi, Kazem; Moradi, Abdolvahab; Aghasadeghi, Mohammad R; Tabarraei, Alijan; McFarland, Willi; Davarpanah, Mohamad Ali

    2016-09-01

    Resistance to antiretroviral agents is a significant concern in the clinical management of HIV-infected individuals, particularly in areas of the world where treatment options are limited. In this study, we aimed to identify HIV drug-resistance-associated mutations in 40 drug-naïve patients and 62 patients under antiretroviral therapy (ART) referred to the Shiraz HIV/AIDS Research Center - the first such data available for the south of Iran. HIV reverse transcriptase and protease genes were amplified and sequenced to determine subtypes and antiretroviral- resistance-associated mutations (RAMs). Subtype CRF35-AD recombinant was the most prevalent in all patients (98 of 102, 96 %), followed by subtype A1, and subtype B (one each, 2 %). Among the 40 ART-naïve patients, two mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance (two with Y115F and T215I) and three associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (two with G190S and Y181C, four with V179T) were found. Among ART-experienced patients, four mutations associated with resistance to NRTI, four with NNRTI, and five with protease inhibitors (PI) were found. Twenty patients with high levels of resistance were already on second-line therapy. We document for the first time in this region of Iran high levels of ART resistance to multiple drugs. Our findings call for more vigilant systematic ART resistance surveillance, increased resistance testing, careful management of patients with existing regimens, and strong advocacy for expansion of available drugs in Iran. PMID:27368990

  18. Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa.

    PubMed

    Manasa, Justen; Danaviah, Siva; Lessells, Richard; Elshareef, Muna; Tanser, Frank; Wilkinson, Eduan; Pillay, Sureshnee; Mthiyane, Hloniphile; Mwambi, Henry; Pillay, Deenan; de Oliveira, Tulio

    2016-08-01

    As more human immunodeficiency virus (HIV)-infected patients access combination antiretroviral therapy (cART), higher proportions of newly infected patients may be infected with drug-resistant viruses. Regular surveillance of transmitted drug resistance (TDR) is required in southern Africa where high rates of transmission persist despite rapid expansion of ART. Dried blood spot samples from cART-naive participants from two rounds of an annual population-based HIV surveillance program in rural KwaZulu-Natal were tested for HIV RNA, and samples with HIV RNA >10,000 copies/ml were genotyped for drug resistance. The 2009 surveillance of drug resistance mutation (SDRM) list was used for drug resistance interpretation. The data were added to previously published data from the same program, and the χ(2) test for trend was used to test for trend in estimated prevalence of any TDR. Seven hundred and one participants' data were analyzed: 67 (2010), 381 (2011), and 253 (2012). No TDR was detected in 2010. Years 2011 and 2012 had 18 participants with SDRMs 4.7% and 7.1%, respectively (p = .02, χ(2) test for trend). The nonnucleoside reverse transcriptase inhibitor mutation, K103N, was the most common mutation, occurring in 27 (3.8%) of the participants, while nucleoside reverse transcriptase inhibitor (NRTI) SDRMs were detected in 10 (1.4%) of the participants, of whom eight had only a single NRTI SDRM. The increase in levels of drug resistance observed in this population could be a signal of increasing transmission of drug-resistant HIV. Thus, continued surveillance is critical to inform public health policies around HIV treatment and prevention. PMID:27002368

  19. Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa

    PubMed Central

    Danaviah, Siva; Lessells, Richard; Elshareef, Muna; Tanser, Frank; Wilkinson, Eduan; Pillay, Sureshnee; Mthiyane, Hloniphile; Mwambi, Henry; Pillay, Deenan; de Oliveira, Tulio

    2016-01-01

    Abstract As more human immunodeficiency virus (HIV)–infected patients access combination antiretroviral therapy (cART), higher proportions of newly infected patients may be infected with drug-resistant viruses. Regular surveillance of transmitted drug resistance (TDR) is required in southern Africa where high rates of transmission persist despite rapid expansion of ART. Dried blood spot samples from cART-naive participants from two rounds of an annual population-based HIV surveillance program in rural KwaZulu-Natal were tested for HIV RNA, and samples with HIV RNA >10,000 copies/ml were genotyped for drug resistance. The 2009 surveillance of drug resistance mutation (SDRM) list was used for drug resistance interpretation. The data were added to previously published data from the same program, and the χ2 test for trend was used to test for trend in estimated prevalence of any TDR. Seven hundred and one participants' data were analyzed: 67 (2010), 381 (2011), and 253 (2012). No TDR was detected in 2010. Years 2011 and 2012 had 18 participants with SDRMs 4.7% and 7.1%, respectively (p = .02, χ2 test for trend). The nonnucleoside reverse transcriptase inhibitor mutation, K103N, was the most common mutation, occurring in 27 (3.8%) of the participants, while nucleoside reverse transcriptase inhibitor (NRTI) SDRMs were detected in 10 (1.4%) of the participants, of whom eight had only a single NRTI SDRM. The increase in levels of drug resistance observed in this population could be a signal of increasing transmission of drug-resistant HIV. Thus, continued surveillance is critical to inform public health policies around HIV treatment and prevention. PMID:27002368

  20. Baseline Natural Killer and T Cell Populations Correlation with Virologic Outcome after Regimen Simplification to Atazanavir/Ritonavir Alone (ACTG 5201)

    PubMed Central

    McKinnon, John E.; Mailliard, Robbie B.; Swindells, Susan; Wilkin, Timothy J.; Borowski, LuAnn; Roper, Jillian M.; Bastow, Barbara; Kearney, Mary; Wiegand, Ann; Mellors, John W.; Rinaldo, Charles R.

    2014-01-01

    Objectives Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92–55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration ClinicalTrials.gov NCT00084019 PMID:24802242

  1. Transmission dynamics of HIV-1 subtype B in the Basque Country, Spain.

    PubMed

    Patiño-Galindo, J A; Thomson, Michael M; Pérez-Álvarez, Lucía; Delgado, Elena; Cuevas, María Teresa; Fernández-García, Aurora; Nájera, Rafael; Iribarren, José A; Cilla, Gustavo; López-Soria, Leyre; Lezaun, María J; Cisterna, Ramón; González-Candelas, F

    2016-06-01

    This work was aimed to study the HIV-1 subtype B epidemics in the Basque Country, Spain. 1727 HIV-1 subtype B sequences comprising protease and reverse transcriptase (PR/RT) coding regions, sampled between 2001 and 2008, were analyzed. 156 transmission clusters were detected by means of phylogenetic analyses. Most of them comprised less than 4 individuals and, in total, they included 441 patients. Six clusters comprised 10 or more patients and were further analyzed in order to study their origin and diversification. Four clusters included men who had unprotected homosexual sex (MSM), one group was formed by intravenous drug users (IDUs), and another included both IDUs and people infected through unprotected heterosexual sex (HTs). Most of these clusters originated from the mid-1980s to the mid-1990s. Only one cluster, formed by MSM, originated after 2000. The time between infections was significantly lower in MSM groups than in those containing IDUs (P-value <0.0001). Nucleoside RT and non-nucleoside RT inhibitor (NRTI and NNRTI)-resistance mutations to antiretroviral treatment were found in these six clusters except the most recent MSM group, but only the IDU clusters presented protease inhibitor (PI)-resistance mutations. The most prevalent mutations for each inhibitor class were PI L90M, NRTI T215D/Y/F, and NNRTI K103N, which were also among the most prevalent resistant variants in the whole dataset. In conclusion, while most infections occur as isolated introductions into the population, the number of infections found to be epidemiologically related within the Basque Country is significant. Public health control measures should be reinforced to prevent the further expansion of transmission clusters and resistant mutations occurring within them. PMID:26921800

  2. Vaginal microbicide film combinations of two reverse transcriptase inhibitors, EFdA and CSIC, for the prevention of HIV-1 sexual transmission

    PubMed Central

    Zhang, Wei; Hu, Minlu; Shi, Yuan; Gong, Tiantian; Dezzutti, Charlene S.; Moncla, Bernard; Sarafianos, Stefan G.; Parniak, Michael A.; Rohan, Lisa C.

    2015-01-01

    Purpose EFdA is a potent nucleoside reverse transcriptase inhibitor (NRTI) with activity against a wide spectrum of wild-type and drug resistant HIV-1 variants. CSIC is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with demonstrated anti-HIV properties important for use in topical prevention of HIV transmission. The objective of this study was to develop and characterize film-formulated EFdA and CSIC for use as a female-controlled vaginal microbicide to prevent sexual transmission of HIV. Methods Assessments of EFdA- and CSIC-loaded films included physicochemical characteristics, in vitro cytotoxicity, epithelia integrity studies, compatibility with the normal vaginal Lactobacillus flora and anti-HIV bioactivity evaluations. Results No significant change in physicochemical properties or biological activity of the combination films were noted during 3 months storage. In vitro cytotoxicity and bioactivity testing showed that 50% cytotoxic concentration (CC50) of either EFdA or CSIC was several orders of magnitude higher than the 50% effective concentration (EC50) values. Film-formulated EFdA and CSIC combination showed additive inhibitory activity against wild type and drug-resistant variants of HIV. Epithelial integrity studies demonstrated that the combination vaginal film had a much lower toxicity to HEC-1A monolayers compared to that of VCF®, a commercial vaginal film product containing nonoxynol-9. Polarized ectocervical explants showed films with drug alone or in combination were effective at preventing HIV infection. Conclusions Our data suggest that vaginal microbicide films containing a combination of the NRTI EFdA and the NNRTI CSIC have potential to prevent HIV-1 sexual transmission. PMID:25794967

  3. Increase of Transmitted Drug Resistance among HIV-Infected Sub-Saharan Africans Residing in Spain in Contrast to the Native Population

    PubMed Central

    Yebra, Gonzalo; de Mulder, Miguel; Pérez-Elías, María Jesús; Pérez-Molina, José Antonio; Galán, Juan Carlos; Llenas-García, Jara; Moreno, Santiago; Holguín, África

    2011-01-01

    Background The prevalence of transmitted HIV drug resistance (TDR) is stabilizing or decreasing in developed countries. However, this trend is not specifically evaluated among immigrants from regions without well-implemented antiretroviral strategies. Methods TDR trends during 1996–2010 were analyzed among naïve HIV-infected patients in Spain, considering their origin and other factors. TDR mutations were defined according to the World Health Organization list. Results Pol sequence was available for 732 HIV-infected patients: 292 native Spanish, 226 sub-Saharan Africans (SSA), 114 Central-South Americans (CSA) and 100 from other regions. Global TDR prevalence was 9.7% (10.6% for Spanish, 8.4% for SSA and 7.9% for CSA). The highest prevalences were found for protease inhibitors (PI) in Spanish (3.1%), for non-nucleoside reverse transcriptase inhibitors (NNRTI) in SSA (6.5%) and for nucleoside reverse transcriptase inhibitors (NRTI) in both Spanish and SSA (6.5%). The global TDR rate decreased from 11.3% in 2004–2006 to 8.4% in 2007–2010. Characteristics related to a decreasing TDR trend in 2007-10 were Spanish and CSA origin, NRTI- and NNRTI-resistance, HIV-1 subtype B, male sex and infection through injection drug use. TDR remained stable for PI-resistance, in patients infected through sexual intercourse and in those carrying non-B variants. However, TDR increased among SSA and females. K103N was the predominant mutation in all groups and periods. Conclusion TDR prevalence tended to decrease among HIV-infected native Spanish and Central-South Americans, but it increased up to 13% in sub-Saharan immigrants in 2007–2010. These results highlight the importance of a specific TDR surveillance among immigrants to prevent future therapeutic failures, especially when administering NNRTIs. PMID:22046345

  4. Boosted Lopinavir– Versus Boosted Atazanavir–Containing Regimens and Immunologic, Virologic, and Clinical Outcomes: A Prospective Study of HIV-Infected Individuals in High-Income Countries

    PubMed Central

    2015-01-01

    Background. Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience. Methods. We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004–2013. Antiretroviral therapy–naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the ‘intention-to-treat’ effect for atazanavir vs lopinavir regimens on each of the outcomes. Results. A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53–.91) for death, 0.67 (95% CI, .55–.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84–.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, −.13 to 16.43) cells/µL higher in the atazanavir group. Estimates differed by NRTI backbone. Conclusions. Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens. PMID:25567330

  5. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

    PubMed Central

    Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van de Vijver, David A. M. C.; Åsjö, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leondios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Zidovec Lepej, Snjezana; Boucher, Charles A. B.; Schmit, Jean-Claude; Wensing, Annemarie M. J.

    2016-01-01

    Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)–infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%–9.5%) in 2008–2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected. PMID:26620652

  6. Tenofovir-associated renal dysfunction in clinical practice: An observational cohort from western India

    PubMed Central

    Patel, Ketan K.; Patel, Atul K.; Ranjan, Rajiv R.; Patel, Apurva R.; Patel, Jagdish K.

    2010-01-01

    Background: Tenofovir (TDF) is preferred nucleoside reverse transcriptase inhibitors (NRTI) for the treatment of human immunodeficiency virus infection because of its potency and safety. Renal toxicity with TDF use is low and comparable with other NRTI in clinical trials, but there are many case studies and small case series of renal dysfunction with TDF. Materials and Methods: This is an observational longitudinal cohort of patients started on a TDF-based regimen from January 2007 to April 2010. Patients were evaluated at baseline and with every follow-up visit for serum creatinine and calculated creatinine clearance (Cockroft-Gault formula). In addition to this, the patients were also subjected to test for serum potassium, phosphorous and urine examinations as and when indicated. Renal dysfunction was defined as rise in serum creatinine to more than the upper level of normal (>1.2 mg%). Results: Of 1,271 patients started on a TDF-containing antiretroviral treatment (ART) 83 (6.53%) developed renal dysfunction, of which 79 had impaired serum creatinine and five had Fanconi’s syndrome. Renal dysfunction was more common with boosted a protease inhibitor (PI) (9.44%)-based regimen as compared to a non- nucleoside reverse transcriptase inhibitors (NNRTI) (5.01%)-based regimen (P = 0.003). The mean decline in creatinine clearance from baseline was 22.27 ml/min. The median time to develop renal dysfunction was 154 (15–935) days. Serum creatinine returned to normal in all the patients after stopping TDF. Five patients presented with features suggestive of Fanconi’s syndrome without alteration in serum creatinine. Conclusion: TDF-based treatment is associated with mild but reversible renal dysfunction. Patients receiving PI/r are at a higher risk of renal dysfunction compared to those receiving NNRTI-based ART. Clinicians should be adviced to have intensive renal monitoring, including creatinine clearance, urine examination, K+ and phosphate levels at baseline and

  7. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

    PubMed Central

    Van Dyke, Russell B.; Chadwick, Ellen Gould; Hazra, Rohan; Williams, Paige L.; Seage, George R.

    2016-01-01

    The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13

  8. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs.

    PubMed

    Van Dyke, Russell B; Chadwick, Ellen Gould; Hazra, Rohan; Williams, Paige L; Seage, George R

    2016-01-01

    The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13

  9. Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

    PubMed

    Sleasman, J W; Robbins, B L; Cross, S J; Lindsey, J C; Kraimer, J M; Heckman, B E; Sprenger, H L; Tustin, N B; Rose, C H; Poston, P A; Neal, E F; Pakes, G E; Nikanjam, M; Capparelli, E V

    2009-04-01

    The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults. PMID:19118380

  10. The Reason for Regimen Change Among HIV/AIDS Patients Initiated on First Line Highly Active Antiretroviral Therapy in Southern Ethiopia

    PubMed Central

    Woldemedhin, Beharu; Wabe, Nasir Tajure

    2012-01-01

    Background: Highly active antiretroviral therapy (HAART) has markedly decreased the morbidity and mortality due to HIV disease. However, toxicities, comorbidity, pregnancy, and treatment failure, among others, would result in frequent initial HAART regimen change. Aim: The study was designed to assess the causes of initial highly active antiretroviral therapeutic regimen changes among patients on HAART. Materials and Methods: The study was conducted using a retrospective institution-based study, by reviewing the patient information sheet and physician diagnosis cards. Patient cards that showed a change in the initial treatment regimen were assessed and analyzed, to identify the common reason that resulted in a change from the initial treatment regimen. The data was analyzed using SPSS version 16.0. Results: A total of 340 patient cards were assessed. The majority of the patients (69.29%) were females. The most common first regimen, before the first switch, was stavudine / lamivudine / nevirapine (D4T/3TC/NVP) (54.70%) and stavudine / lamivudine / Efavirenz (D4T/3TC/EFV) (20.88%). The main reasons for modification were toxicity, comorbidity, pregnancy, and treatment failure. The main types of toxicities observed were peripheral neuropathy (36.52%), rash (17.83%), and anemia (17.39%). Conclusion: Toxicity was the main reason for the modification of initial HAART among the study population. Efavirenz-based regimens had the lowest hazard for change relatively, except in pregnancy-related cases. PMID:22393543

  11. [How to use viral genomic analysis in clinical practice: chronic hepatitis B and C].

    PubMed

    Izumi, Namiki

    2006-04-01

    Viral genomic analysis has been developed recently, and is utilized in clinical practice. The genotype of HB virus has the most important clinical implication, and in Japan, genotype C shows worse prognosis than genotype B. Basic core promoter (BCP) mutation is associated with hepatic fibrosis, and HBe antigen seronegativity is frequently observed after lamivudine administration than wild type. Polymerase domain B mutation was shown to be associated with lamivudine resistance concomitantly with domain C mutation. In the treatment of chronic hepatitis C genotype 1b infection, peginterferon and ribavirin combination therapy was introduced, and this combination therapy has been shown to induce 50% sustained virological response (SVR). To predict the virological response to combination therapy, monitoring viral decline provides the most important information. Real-time PCR is expensive, therefore, highly sensitive core antigen quantitation is valuable in clinical practice. When patients treated by combination therapy achieve a 2 log drop in HCV antigen until twelve weeks, they are estimated to have obtained 75% SVR by monitoring the amount of serum core antigen. PMID:16722459

  12. Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma

    PubMed Central

    2014-01-01

    Background Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established. Methods In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation. Results Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb- patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine. Discussion This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation. PMID:24533834

  13. Selection of hepatitis B surface "escape" mutants during passive immune prophylaxis following liver transplantation: potential impact of genetic changes on polymerase protein function

    PubMed Central

    Shields, P; Owsianka, A; Carman, W; Boxall, E; Hubscher, S; Shaw, J; O'Donnell, K; Elias, E; Mutimer, D

    1999-01-01

    CASE REPORT—A patient is described who developed hepatitis B virus (HBV) reinfection five months following liver transplantation. Failure of hepatitis B immunoglobulin prophylaxis was associated with the emergence of mutations. HBV gene sequencing identified nucleotide substitutions associated with amino acid changes, one within the major hydrophilic region (MHR) of the HBV surface antigen at amino acid position 144 and one outside the MHR. Because of the overlapping reading frames of surface and polymerase genes, the latter surface antigen change was associated with an amino acid change in the polymerase protein. The patient developed significant allograft hepatitis and was treated with lamivudine (3TC) 100 mg daily. Rapid decline of serum HBV DNA was observed with loss of HBV e antigen and HBV surface antigen from serum. There was normalisation of liver biochemistry, and liver immunohistochemistry showed a reduction in HBV core and disappearance of HBs antigen staining.
CONCLUSION—Surface antigen encoding gene mutations associated with HBIg escape may be associated with alteration of the polymerase protein. The polymerase changes may affect sensitivity to antiviral treatment. Selection pressure on one HBV reading frame (for example, HBIg pressure on HBsAg, or nucleoside analogue pressure on polymerase protein) may alter the gene product of the overlapping frame. Such interactions are relevant to strategies employing passive immune prophylaxis and antiviral treatment.


Keywords: liver transplantation; prophylaxis; escape mutants; lamivudine PMID:10403747

  14. Co-occurrence of Photochemical and Microbiological Transformation Processes in Open-Water Unit Process Wetlands.

    PubMed

    Prasse, Carsten; Wenk, Jannis; Jasper, Justin T; Ternes, Thomas A; Sedlak, David L

    2015-12-15

    The fate of anthropogenic trace organic contaminants in surface waters can be complex due to the occurrence of multiple parallel and consecutive transformation processes. In this study, the removal of five antiviral drugs (abacavir, acyclovir, emtricitabine, lamivudine and zidovudine) via both bio- and phototransformation processes, was investigated in laboratory microcosm experiments simulating an open-water unit process wetland receiving municipal wastewater effluent. Phototransformation was the main removal mechanism for abacavir, zidovudine, and emtricitabine, with half-lives (t1/2,photo) in wetland water of 1.6, 7.6, and 25 h, respectively. In contrast, removal of acyclovir and lamivudine was mainly attributable to slower microbial processes (t1/2,bio = 74 and 120 h, respectively). Identification of transformation products revealed that bio- and phototransformation reactions took place at different moieties. For abacavir and zidovudine, rapid transformation was attributable to high reactivity of the cyclopropylamine and azido moieties, respectively. Despite substantial differences in kinetics of different antiviral drugs, biotransformation reactions mainly involved oxidation of hydroxyl groups to the corresponding carboxylic acids. Phototransformation rates of parent antiviral drugs and their biotransformation products were similar, indicating that prior exposure to microorganisms (e.g., in a wastewater treatment plant or a vegetated wetland) would not affect the rate of transformation of the part of the molecule susceptible to phototransformation. However, phototransformation strongly affected the rates of biotransformation of the hydroxyl groups, which in some cases resulted in greater persistence of phototransformation products. PMID:26562588

  15. Determination of the composition of counterfeit Heptodin tablets by near infrared chemical imaging and classical least squares estimation.

    PubMed

    Lopes, Marta B; Wolff, Jean-Claude; Bioucas-Dias, José M; Figueiredo, Mário A T

    2009-05-01

    According to the WHO definition for counterfeit medicines, several categories can be established, e.g., medicines containing the correct active pharmaceutical ingredient (API) but different excipients, medicines containing low levels of API, no API or even a substitute API. Obviously, these different scenarios will have different detrimental effects on a patient's health. Establishing the degree of risk to the patient through determination of the composition of counterfeit medicines found in the market place is thus of paramount importance. In this work, classical least squares was used for predicting the composition of counterfeit Heptodin tablets found in a market survey. Near infrared chemical imaging (NIR-CI) was used as a non-destructive measurement technique. No prior knowledge about the origin and composition of the tablets was available. Good API (i.e., lamivudine) predictions were obtained, especially for tablets containing a high API (close to the authentic) dose. Concentration maps of each pure material, i.e., the API (lamivudine) and the excipients microcrystalline cellulose, sodium starch glycollate, rice starch and talc, were estimated. Below 1% of the energy was not explained by the model (residuals percentage) for every pixel in all 12 counterfeit tablets. The similarities among tablets with respect to the total API percentage determined, as well as the corresponding concentration maps, support the classification of the tablets into the different groups obtained in previous work. PMID:19393365

  16. Molecular characterization of hepatitis B virus and a 9-year clinical profile in a patient infected with genotype I.

    PubMed

    Osiowy, Carla; Kaita, Kelly; Solar, Kaarina; Mendoza, Kenneth

    2010-05-01

    An unusual hepatitis B virus (HBV) variant, assigned provisionally to genotype I, was recently reported, characterized by an anomalous genotyping pattern and putative recombination; however, the natural history of this unusual strain is unknown. This study analyzed longitudinal sera collected over a 9-year period from a patient infected with this variant to investigate the clinical profile and intrahost viral evolution over time. The patient, who had immigrated to Canada in 1998 from Vietnam, was treated with lamivudine in 2000. Approximately 4-5 years following the withdrawal of lamivudine therapy, a genomic "shift" occurred coincident with ALT flares and increasing HBV viral load, resulting in numerous stable nucleotide substitutions within the core coding region, suggesting altered immune control that may provide a selective advantage to the virus. Analysis of quasispecies diversity over time demonstrated further this shift, with two sequence clusters associated with time points either prior to or following relapse observed, including increased diversity among quasispecies prior to relapse. In keeping with the complex nature of genotype I strains, majority population genomes had a mean genetic distance from genotype C of 7.6 +/- 0.1%, although large genomic segments lacked significant homology with any HBV genotype. Further study is needed to understand the evolutionary origin and natural history of infection with this unique HBV variant. PMID:20419807

  17. Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice

    PubMed Central

    Afdhal, Nezam H.; Bacon, Bruce R.; Brown, Robert S.

    2011-01-01

    A number of agents can reduce viral replication in patients with chronic hepatitis B, but most patients do not undergo a curative response to these drugs and therefore require long-term therapy. Thus, recent studies have investigated the long-term safety, efficacy, and resistance profiles of several antiviral nucleotide/nucleoside agents: lamivudine, telbivudine, adefovir dipivoxil, entecavir, and tenofovir. The most recent data have revealed that lamivudine and telbivudine produce high rates of resistance when treatment is continued for 2–5 years; as a result, these agents are no longer preferred for first-line monotherapy. Entecavir and tenofovir, on the other hand, appear to have favorable safety and efficacy profiles when used as monotherapy, with very low rates of resistance over 5 years. In order to help clinicians incorporate these data into clinical practice, this monograph will review recently published data on hepatitis B antiviral medications, as well as explore when to consider cessation of therapy. The treatment of special patient populations and the need to screen patients for hepatocellular carcinoma will also be discussed. PMID:22557938

  18. Single-Pass Intestinal Perfusion (SPIP) and prediction of fraction absorbed and permeability in humans: A study with antiretroviral drugs.

    PubMed

    Dezani, Thaisa Marinho; Dezani, André Bersani; Junior, João Batista da Silva; Serra, Cristina Helena Dos Reis

    2016-07-01

    In recent years, the prediction of oral drug absorption in humans has been a challenge for researchers and many techniques for permeability studies have been developed for several purposes, including biowaiver processes. The Single-Pass Intestinal Perfusion (SPIP) method performed in rats can provide permeability results closest to in vivo condition. The purpose of the present study was to evaluate the intestinal permeability of the antiretroviral drugs lamivudine, stavudine and zidovudine using the SPIP method in rats and to predict their permeability (Peff,humans) and fraction absorbed (Fa) in humans. Metoprolol and fluorescein were used as marker compounds of high and low permeability, respectively. The effective permeability (Peff) results showed that stavudine and zidovudine have high permeability characteristics while lamivudine presented the lowest result. From Peff values obtained in rats, the Peff,humans and Fa were calculated. The use of SPIP in rats and calculations for absorption prediction in humans may indicate the transport mechanisms and/or pre-systemic metabolism involved on permeation processes of drugs, since this model is the closest to in vivo conditions. PMID:27130787

  19. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2002-12-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, adalimumab, AERx morphine sulphate, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, almotriptan, amprenavir, aripiprazole, atenolol, atorvastatin calcium; BSYX-A110; Cantuzumab mertansine, capravirine, CDP-571, CDP-870, celecoxib; Delavirdine mesilate, docetaxel, dofetilide, donepezil hydrochloride, duloxetine hydrochloride, dutasteride, dydrogesterone; Efavirenz, emtricitabine, enjuvia, enteryx, epristeride, erlotinib hydrochloride, escitalopram oxalate, etanercept, etonogestrel, etoricoxib; Fesoterodine, finasteride, flt3ligand; Galantamine hydrobromide, gemtuzumab ozogamicin, genistein, gepirone hydrochloride; Indinavir sulfate, infliximab; Lamivudine, lamivudine/zidovudine/abacavir sulfate, leteprinim potassium, levetiracetam, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, losartan potassium; MCC-465, MRA; Nebivolol, nesiritide, nevirapine; Olanzapine, OROS(R)-Methylphenidate hydrochloride; Peginterferon alfa-2a, peginterferon alfa-2b, Pimecrolimus, polyethylene glycol 3350, pramlintide acetate, pregabalin, PRO-2000; Risedronate sodium, risperidone, ritonavir, rituximab, rivastigmine tartrate, rofecoxib, rosuvastatin calcium; Saquinavir mesilate, Stavudine; Tacrolimus, tadalafil, tamsulosin hydrochloride, telmisartan, tomoxetine hydrochloride, treprostinil sodium, trimegestone, trimetrexate; Valdecoxib, venlafaxine hydrochloride; Zoledronic acid monohydrate. PMID:12616965

  20. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor {gamma}, controls hepatitis B virus replication

    SciTech Connect

    Yoon, Sarah; Jung, Jaesung; Kim, Taeyeung; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

    2011-01-20

    In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein {alpha} (C/EBP{alpha}), peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), adiponectin, liver X receptor {alpha} (LXR{alpha}), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPAR{gamma} and C/EBP{alpha}. Conversely, HBV replication was upregulated by adiponectin and PPAR{gamma} agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.

  1. Noncirrhotic portal hypertension in a human immunodeficiency virus (HIV) infected adolescent

    PubMed Central

    Gouvêa, Aída de Fátima Thomé Barbosa; Machado, Daisy Maria; Beltrão, Suênia Cordeiro de Vasconcelos; do Carmo, Fabiana Bononi; Mattar, Regina Helena Guedes Motta; Succi, Regina Célia de Menezes

    2015-01-01

    OBJECTIVE: To alert the pediatrician who is following up HIV-infected patients about the possibility of non-cirrhotic portal hypertension (NCPH) in this period of life, in order to avoid the catastrophic consequences of this disease as bleeding esophageal varices. CASE DESCRIPTION: A 13 years old HIV-infected patient by vertical route was receiving didanosine (ddI) for 12 years. Although the HIV viral load had been undetectable for 12 years, this patient showed gradual decrease of CD4+ T cells, prolonged thrombocytopenia and high alkaline phosphatase. Physical examination detected splenomegaly, which triggered the investigation that led to the diagnosis of severe liver fibrosis by transient elastography, probably due to hepatic toxicity by prolonged use of ddI. COMMENTS: This is the first case of NCPH in HIV-infected adolescent described in Brazil. Although, the NCPH is a rare disease entity in seropositive patients in the pediatric age group, it should be investigated in patients on long-term ddI or presenting clinical and laboratories indicators of portal hypertension, as splenomegaly, thrombocytopenia and increased alkaline phosphatase. PMID:25913495

  2. Fanconi syndrome induced by tenofovir: A case report.

    PubMed

    Lify, Bouchra; Dabo, G; Nascimento, O; Iraqui, S; Elkhayat, S; Zamd, M; Medkouri, G; Benghanem, M; Ramdani, B; Sodqi, M M; Marih, L; Chakib, A; El FilaliMarhoum, K

    2016-01-01

    Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor discovered in the USA in 2001. It is currently the treatment of choice for patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus. Its antiretroviral efficacy and good tolerance are responsible for the higher frequency of prescriptions compared with other nucleoside analogs. However, it can induce acute renal toxicity causing impairment of the proximal tubular function of the kidney. This is highly dependent on factors such as associated co-prescription didanosine or a protease inhibitor "boosted" with ritonavir, preexisting renal insufficiency, low body weight, or presence of associated diabetes. In contrast, long-term renal toxicity remains highly debated. Some studies describe a decrease in estimated glomerular filtration rate during prolonged treatment with TDF. Others reported renal safety even during prolonged use. The differences between patients enrolled in the different studies, the measured parameters and their interpretation could explain these discrepancies. We describe a case of a patient infected with HIV, who presented with Fanconi syndrome with acute renal failure six months after starting antiretroviral treatment including tenofovir. PMID:27424704

  3. The Combined Use of Known Antiviral Reverse Transcriptase Inhibitors AZT and DDI Induce Anticancer Effects at Low Concentrations

    PubMed Central

    Aschacher, Thomas; Sampl, Sandra; Käser, Lisa; Bernhard, David; Spittler, Andreas; Holzmann, Klaus; Bergmann, Michael

    2012-01-01

    A hallmark of tumor cell survival is the maintenance of elongated telomeres. It is known that antiviral reverse transcriptase inhibitors (RTIs) such as azidothymidine (AZT) and didanosine (ddI) lead to telomere shortening at high, potentially toxic concentrations. We hypothesized that those drugs might have synergistic effects enabling successful therapy with low, nontoxic concentrations. Biologic effects of AZT and ddI were analyzed at concentrations that correspond to minimal plasma levels achieved during human immunodeficiency virus therapy. Long-term coapplication of low-dose AZT and ddI induced a significant shortening of telomeres in the tumor cell lines HCT-116, SkMel-28, MelJuso, and Jurkat. Treatment of cells with both RTI, but not with single RTI, led to a significant accumulation of γH2AX, to p53 phosphorylation, and to cell apoptosis in all cell lines. Oral low-dose dual RTI application but not low-dose single RTI application was associated with a significantly reduced tumor growth of HCT-116 cells in mice. This antiproliferative activity of the combined use of AZT and ddI at low, clinically applicable concentrations warrants clinical testing in human solid cancer. PMID:22355273

  4. ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy

    PubMed Central

    Para, Michael F.; Meehan, Patricia; Holden-Wiltse, Jeanne; Fischl, Margaret; Morse, Gene; Shafer, Robert; Demeter, Lisa M.; Wood, Kenneth; Nevin, Tom; Virani-Ketter, Nzeera; Freimuth, William W.

    1999-01-01

    ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 μM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance. PMID:10348755

  5. Incidence of Pancreatitis in HIV-1–Infected Individuals Enrolled in 20 Adult AIDS Clinical Trials Group Studies

    PubMed Central

    Reisler, Ronald B.; Murphy, Robert L.; Redfield, Robert R.; Parker, Robert A.

    2005-01-01

    Objective To report on the incidence of clinical- and laboratory-defined pancreatitis in HIV-1–infected individuals treated with antiretrovirals (ARVs). Methods Pancreatitis incidence rates were calculated based on a Poisson distribution for subjects enrolled in 1 or more of 20 Adult AIDS Clinical Trials Group studies from October 1989 through July 1999. Results A total of 8451 subjects were enrolled. The overall pancreatitis rates were 0.61 per 100 person-years (PYs) clinical and 2.23 per 100 PYs clinical/laboratory. Pancreatitis rates for single, dual, and triple nucleoside reverse transcriptase inhibitors (NRTIs) were similar. Rates of pancreatitis in didanosine (ddI) arms seemed to be dose dependent. Pancreatitis rates in ddI/hydroxyurea (HU) arms were not significantly different from the rates for ddI alone. Overall pancreatitis rates for ddI/stavudine (d4T) trials were high at 4.16 per 100 PYs clinical and 6.25 per 100 PYs clinical/laboratory. The highest rates were seen with the combination of indinavir (IDV)/ddI/d4Twith or without HU. Conclusions The combination of NRTIs and definition has an impact on the incidence of pancreatitis. Standardization of definition and more comprehensive evaluations are needed to determine how much of this pancreatitis is directly caused by ARVs and how much is attributable to preexisting comorbidities and other known risk factors. PMID:15905731

  6. Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease.

    PubMed Central

    Lamarre, D; Croteau, G; Wardrop, E; Bourgon, L; Thibeault, D; Clouette, C; Vaillancourt, M; Cohen, E; Pargellis, C; Yoakim, C; Anderson, P C

    1997-01-01

    Palinavir is a potent inhibitor of the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) proteases. Replication of laboratory strains (HIV-1, HIV-2, and simian immunodeficiency virus) and HIV-1 clinical isolates is inhibited by palinavir with 50% effective concentrations ranging from 0.5 to 30 nM. The average cytotoxic concentration of palinavir (35 microM) in the various target cells indicates a favorable therapeutic index. Potent antiviral activity is retained with increased doses of virus and with clinical isolates resistant to zidovudine (AZT), didanosine (ddI), or nevirapine. Combinations of palinavir with either AZT, ddI, or nevirapine demonstrate synergy or additivity in the inhibition of HIV-1 replication. Palinavir retains anti-HIV-1 activity when administered postinfection until times subsequent to the reverse transcription step. In chronically infected CR-10 cells, palinavir blocks Gag precursor polyprotein processing completely, reducing greater than 99% of infectious particle production. The results indicate that the antiviral activity of palinavir is specific to inhibition of the viral protease and occurs at a late stage in the replicative cycle of HIV-1. On the basis of the potent in vitro activity, low-level cytotoxicity, and other data, palinavir was selected for in-depth preclinical evaluation. PMID:9145853

  7. Quantification of mitochondrial toxicity in HIV-infected individuals by quantitative PCR compared to flow cytometry

    PubMed Central

    Wagner, Thor A.; Lin, Chen-Han; Tobin, Nicole H.; Côté, Hélène C.F.; Sloan, Derek D.; Jerome, Keith R.; Frenkel, Lisa M.

    2014-01-01

    Background Non-invasive diagnostic assays to evaluate mitochondrial toxicity could have significant clinical utility for HIV-infected individuals on antiretroviral therapy (ART). Methods This study compared the ratio of mitochondrial to nuclear DNA determined by quantitative PCR to the ratio of mitochondrial to nuclear-encoded proteins by flow cytometry, in peripheral blood mononuclear cells from 73 HIV-infected individuals with and without risk factors for mitochondrial toxicity. Results PCR detected similar mitochondrial/nuclear DNA in HIV-infected individuals without a history of ART, and those receiving ART with lipodystrophy, lipoatrophy or a history of suspected lactic acidosis. However, the ratio was significantly greater in ART-untreated compared to those receiving either stavudine or didanosine. In contrast, flow cytometry did not detect any differences in mitochondrial/nuclear protein (1). There was no correlation between the assays (rho = −0.05, p = 0.65). Conclusions Assessment of the mitochondrial/nuclear DNA ratio by quantitative PCR performed better than the mitochondrial/nuclear-encoded protein ratio by flow cytometry to detect adverse effects of nucleoside analogues on mitochondria. PMID:23044657

  8. A case of non-cirrhotic portal hypertension associated with anti-retroviral therapy in a Japanese patient with human immunodeficiency virus infection.

    PubMed

    Yajima, Keishiro; Uehira, Tomoko; Otera, Hiroshi; Koizumi, Yusuke; Watanabe, Dai; Kodama, Yoshinori; Kuzushita, Noriyoshi; Nishida, Yasuharu; Mita, Eiji; Mano, Masayuki; Shirasaka, Takuma

    2014-09-01

    The diagnosis of non-cirrhotic portal hypertension (NCPH), a rare but potentially life-threatening complication in human immunodeficiency virus (HIV)-positive individuals, often occurs only after the emergence of fatal manifestations such as bleeding of esophageal varices. We herein report a female Japanese HIV patient who developed NCPH approximately 4 years after discontinuation of 65 months of didanosine (ddI) administration. The patient presented with severe ascites, bloody bowel discharge, extreme abdominal swelling, and symptoms of portal hypertension but no sign of liver cirrhosis. Examination revealed esophageal varices, oozing-like bleeding from a wide part of the colon, significant atrophy of the right lobe of the liver, and arterio-portal shunting and recanalization from the left medial segment branch of the portal vein to a paraumbilical vein, but no visible obstruction of the main trunk of the portal vein. Treatment for esophageal varices consisted of coagulation therapy with argon plasma after enforcement by endoscopic sclerotherapy and oral administration of β-blockers for elevated portal blood pressure. The patient has not experienced gastrointestinal bleeding in the approximately 5 years since the diagnosis of NCPH. Reviewing this case suggests the importance of suspecting NCPH in HIV patients with liver dysfunction of unknown etiology with a history of ddI and other purine analogs use, as well as the importance of controlling portal hypertension and esophageal varices in the treatment of NCPH. PMID:25034388

  9. The combined use of known antiviral reverse transcriptase inhibitors AZT and DDI induce anticancer effects at low concentrations.

    PubMed

    Aschacher, Thomas; Sampl, Sandra; Käser, Lisa; Bernhard, David; Spittler, Andreas; Holzmann, Klaus; Bergmann, Michael

    2012-01-01

    A hallmark of tumor cell survival is the maintenance of elongated telomeres. It is known that antiviral reverse transcriptase inhibitors (RTIs) such as azidothymidine (AZT) and didanosine (ddI) lead to telomere shortening at high, potentially toxic concentrations. We hypothesized that those drugs might have synergistic effects enabling successful therapy with low, nontoxic concentrations. Biologic effects of AZT and ddI were analyzed at concentrations that correspond to minimal plasma levels achieved during human immunodeficiency virus therapy. Long-term coapplication of low-dose AZT and ddI induced a significant shortening of telomeres in the tumor cell lines HCT-116, SkMel-28, MelJuso, and Jurkat. Treatment of cells with both RTI, but not with single RTI, led to a significant accumulation of γH2AX, to p53 phosphorylation, and to cell apoptosis in all cell lines. Oral low-dose dual RTI application but not low-dose single RTI application was associated with a significantly reduced tumor growth of HCT-116 cells in mice. This antiproliferative activity of the combined use of AZT and ddI at low, clinically applicable concentrations warrants clinical testing in human solid cancer. PMID:22355273

  10. Antiviral therapy: current concepts and practices.

    PubMed Central

    Bean, B

    1992-01-01

    Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future. PMID:1576586

  11. A case of figurate urticaria by etanercept.

    PubMed

    Sessa, Maurizio; Sullo, Maria Giuseppa; Mascolo, Annamaria; Cimmaruta, Daniela; Romano, Francesca; Puca, Rosa Valentina; Capuano, Annalisa; Rossi, Francesco; Schiavo, Ada Lo

    2016-01-01

    Etanercept is a competitive inhibitor of tumor necrosis factor-alpha (TNF-α) a polypeptide hormone, involved in the development of the immune system, in host defense and immune surveillance. Even if the etanercept mechanism of action is not completely understood, it is supposed that it negatively modulates biological responses mediated by molecules (cytokines, adhesion molecules, or proteinases) induced or regulated by TNF. For this reason, it is widely used in the treatment of immunologicals diseases, such as rheumatoid and psoriatic arthritis, polyarticular juvenile idiopathic active, ankylosing spondylitis, and plaque psoriasis. Etanercept has a good tolerability profile. Adverse events related to skin are rare, arising usually in about 5% of patients treated with anti-TNF α. In this scenario, we describe a case of figurate urticaria arose after the re-administration of etanercept in a patient affected by psoriasis and hepatitis B. A 65-year-old man, affected by psoriasis, was hospitalized in September 2014 to the Regional Center for the treatment of psoriasis and Biological Drugs of Second University of Naples for progressive extension of psoriatic skin lesions. The laboratory analysis detected positivity for hepatitis B virus (HBV) antigens. For this reason, it was administered to him lamivudine 100 mg/die about 30 days before to start etanercept treatment. The etanercept therapy has resulted in a progressive improving of skin manifestations, and the patient decided individually to stop the therapy. Afterwards, for worsening of the psoriatic lesions, he was again hospitalized and treated with the same therapeutic schedule (lamivudine followed by etanercept). Ten days after the start of therapy, the patient showed the onset of urticarial rash. Due to this, the treatment with lamivudine and etanercept was suspended and the patient's clinical conditions improved. It is probably that immunological disorders due to etanercept therapy and HBV infection could

  12. A simultaneous determination of related substances by high performance liquid chromatography in a drug product using quality by design approach.

    PubMed

    Tol, Trupti; Kadam, Nilesh; Raotole, Nilesh; Desai, Anita; Samanta, Gautam

    2016-02-01

    The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high

  13. Hepatitis B in HIV patients: what is the current treatment and what are the challenges?

    PubMed

    Soriano, Vincent; Tuma, Paula; Vispo, Eugenia; Labarga, Pablo; Fernández, José Vicente; Medrano, José; Barreiro, Pablo

    2009-03-01

    Chronic hepatitis B affects 5-10% of HIV patients in Western countries. Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV co-infected patients, given its limited antiviral potency and high risk of selection of resistance, which further results in wide cross-resistance to all other nucleoside analogues. Recent reports of transmission of lamivudine-resistant HBV in HIV patients are of especial concern, and large surveillance studies suggest that it may occur in up to 10% of new HBV infections in Western countries. Another worrisome aspect of the selection of lamivudine-resistant HBV is the potential for selection of vaccine escape mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV co-infected patients in whom antiretroviral therapy is advised. Its co-formulation with emtricitabine (Truvada) is particularly convenient for treating both HIV and HBV in co-infected individuals. While pegIFN-alpha monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT), it is clear that very few coinfected patients fulfill these criteria. In HBeAg-negative HIV patients, adefovir may be an option but the relatively low antiviral potency of this drug discourages its wide use. Given its potential anti-HIV activity, both entecavir and telbivudine must only be prescribed with antiretroviral agents. Lack of information about potential pharmacodynamic interactions between entecavir and abacavir (both are guanosine analogues) or between telbivudine and zidovudine or stavudine (all are thymidine analogues) further discourages their concomitant use. At this time, most experts agree that early introduction of anti-HBV active HAART is the best strategy for the treatment of chronic hepatitis B in HIV patients, and Truvada must be part of the triple regimen. PMID:19731560

  14. A case of figurate urticaria by etanercept

    PubMed Central

    Sessa, Maurizio; Sullo, Maria Giuseppa; Mascolo, Annamaria; Cimmaruta, Daniela; Romano, Francesca; Puca, Rosa Valentina; Capuano, Annalisa; Rossi, Francesco; Schiavo, Ada Lo

    2016-01-01

    Etanercept is a competitive inhibitor of tumor necrosis factor-alpha (TNF-α) a polypeptide hormone, involved in the development of the immune system, in host defense and immune surveillance. Even if the etanercept mechanism of action is not completely understood, it is supposed that it negatively modulates biological responses mediated by molecules (cytokines, adhesion molecules, or proteinases) induced or regulated by TNF. For this reason, it is widely used in the treatment of immunologicals diseases, such as rheumatoid and psoriatic arthritis, polyarticular juvenile idiopathic active, ankylosing spondylitis, and plaque psoriasis. Etanercept has a good tolerability profile. Adverse events related to skin are rare, arising usually in about 5% of patients treated with anti-TNF α. In this scenario, we describe a case of figurate urticaria arose after the re-administration of etanercept in a patient affected by psoriasis and hepatitis B. A 65-year-old man, affected by psoriasis, was hospitalized in September 2014 to the Regional Center for the treatment of psoriasis and Biological Drugs of Second University of Naples for progressive extension of psoriatic skin lesions. The laboratory analysis detected positivity for hepatitis B virus (HBV) antigens. For this reason, it was administered to him lamivudine 100 mg/die about 30 days before to start etanercept treatment. The etanercept therapy has resulted in a progressive improving of skin manifestations, and the patient decided individually to stop the therapy. Afterwards, for worsening of the psoriatic lesions, he was again hospitalized and treated with the same therapeutic schedule (lamivudine followed by etanercept). Ten days after the start of therapy, the patient showed the onset of urticarial rash. Due to this, the treatment with lamivudine and etanercept was suspended and the patient's clinical conditions improved. It is probably that immunological disorders due to etanercept therapy and HBV infection could

  15. High Viral Load and Elevated Angiogenic Markers Associated with Increased Risk of Preeclampsia among Women Initiating Highly Active Antiretroviral Therapy (HAART) in Pregnancy in the Mma Bana Study, Botswana

    PubMed Central

    Powis, Kathleen M; McElrath, Thomas F; Hughes, Michael D; Ogwu, Anthony; Souda, Sajini; Datwyler, Saul A; von Widenfelt, Erik; Moyo, Sikhulile; Nádas, Marisa; Makhema, Joseph; Machakaire, Esther; Lockman, Shahin; Essex, Max; Shapiro, Roger L

    2013-01-01

    Background Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after HAART initiation have not been studied. Methods The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts ≥ 200 cells/mm3 between 26–34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts < 200 cells/mm3 initiated nevirapine/zidovudine/lamivudine between 18–34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining722 Mma Bana participants who delivered, using logistic regression. Plasma samples drawn at HAART initiation and one month later from 60 women without preeclampsia and at HAART initiation for all11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1), Results Pre-HAART viral load > 100,000 copies/ml was associated with preeclampsia (OR 5.8; 95% CI 1.8, 19.4; p = 0.004). Median pre-HAART PlGF level was lower and sFLT-1 was higher in women who developed preeclampsia versus those who did not (130 vs 992 pg/ml, p=0.001; 17.5 vs 9.4 pg/ml, p=0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women. Conclusions Pre-HAART viral load > 100,000 copies/ml and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 one month into treatment. PMID:23344545

  16. Factors associated with suboptimal adherence to antiretroviral therapy in Asia

    PubMed Central

    Jiamsakul, Awachana; Kumarasamy, Nagalingeswaran; Ditangco, Rossana; Li, Patrick CK; Phanuphak, Praphan; Sirisanthana, Thira; Sungkanuparph, Somnuek; Kantipong, Pacharee; Lee, Christopher KC; Mustafa, Mahiran; Merati, Tuti; Kamarulzaman, Adeeba; Singtoroj, Thida; Law, Matthew

    2014-01-01

    Introduction Adherence to antiretroviral therapy (ART) plays an important role in treatment outcomes. It is crucial to identify factors influencing adherence in order to optimize treatment responses. The aim of this study was to assess the rates of, and factors associated with, suboptimal adherence (SubAdh) in the first 24 months of ART in an Asian HIV cohort. Methods As part of a prospective resistance monitoring study, the TREAT Asia Studies to Evaluate Resistance Monitoring Study (TASER-M) collected patients’ adherence based on the World Health Organization-validated Adherence Visual Analogue Scale. SubAdh was defined in two ways: (i) <100% and (ii) <95%. Follow-up time started from ART initiation and was censored at 24 months, loss to follow-up, death, treatment switch, or treatment cessation for >14 days. Time was divided into four intervals: 0–6, 6–12, 12–18 and 18–24 months. Factors associated with SubAdh were analysed using generalized estimating equations. Results Out of 1316 patients, 32% ever reported <100% adherence and 17% ever reported <95%. Defining the outcome as SubAdh <100%, the rates of SubAdh for the four time intervals were 26%, 17%, 12% and 10%. Sites with an average of >2 assessments per patient per year had an odds ratio (OR)=0.7 (95% confidence interval (CI) (0.55 to 0.90), p=0.006), compared to sites with ≤2 assessments per patient per year. Compared to heterosexual exposure, SubAdh was higher in injecting drug users (IDUs) (OR=1.92, 95% CI (1.23 to 3.00), p=0.004) and lower in homosexual exposure (OR=0.52, 95% CI (0.38 to 0.71), p<0.001). Patients taking a nucleoside transcriptase inhibitor and protease inhibitor (NRTI+PI) combination were less likely to report adherence <100% (OR=0.36, 95% CI (0.20 to 0.67), p=0.001) compared to patients taking an NRTI and non-nucleoside transcriptase inhibitor (NRTI+NNRTI) combination. SubAdh decreased with increasing time on ART (all p<0.001). Similar associations were found with adherence

  17. Randomized trial of DRV/r or LPV/r QD monotherapy vs maintaining a PI/r-based antiretroviral regimen in persons with suppressed HIV replication

    PubMed Central

    Pinnetti, Carmela; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Sandrine, Ottou; Tommasi, Chiara; Zaccarelli, Mauro; Federico Perno, Carlo; Rosaria Capobianchi, Maria; Girardi, Enrico; Antinori, Andrea; Ammassari, Adriana

    2014-01-01

    Introduction PI/r monotherapy has been suggested as an attainable maintenance strategy in patients achieving stable HIV suppression in plasma. The objective of trial was to compare the virological outcome of two different PI/r QD monotherapy strategies (LPV/r or DRV/r) with maintaining a triple PI/r-based ARV regimen. Material and Methods Phase III, open-label, non-inferiority (−12% margin), randomized trial of HIV adults with HIV-RNA <50 cp/mL for at least 48 weeks while on PI/r-based cART, CD4 nadir >100 cell/mm3, without previous PIs virological failure. Eligible patients were randomized to continue PI/r+2NRTIs (Arm A), to switch to LPV/r 800/200 mg QD monotherapy (Arm B), or to switch to DRV/r 800/100 mg QD monotherapy (Arm C). Primary endpoint was proportion of patients with plasma HIV-1 RNA <50 cp/mL (TLOVR) at 48w by intent to treat (ITT) analysis (missing/re-induction=failure). FDA snapshot and ITT switch-included analysis (ITT-SI) were also used. In ITT-SI, patients who had <50 copies/mL at 96w were counted as successes even if they had confirmed HIV-RNA elevations and had subsequently successfully intensified by NRTI. Results Due to slow recruitment, only 103 patients were included. No differences were observed between the three arms with respect to gender, age, HIV transmission, CD4 nadir and at screening. At randomization, 61 patients were receiving TDF/FTC (60%), 19 ZDV/3TC (18%), 8 ABV/3TC (8%), 75 LPV/r (73%), 13 ATV/r (13%), 4 DRV/r (4%). Differences in proportion of virological success by groups using Arm A as comparator according to FDA TLOVR were reported in Figure 1. Similar results were obtained by Snapshot analysis. Of 14 patients with virological failure, 8 patients restarted triple therapy with 2NRTI and 7/8 regained a VL <50 cp/mL over time. According to ITT-SI analysis, 96 week differences [95% CI] were −5.7 [−29.6; +18.2] in Arm B, and +19.6 [−1.6; +40.8] in Arm C. A GRT was performed in 6/14 patients (one not amplifiable; four

  18. Nuke-sparing regimens as a main simplification strategy and high level of toxicity resolution after antiretroviral switch: the SWITCHART Study

    PubMed Central

    Carrero-Gras, Ana; Antela, Antonio; Muñoz-Rodríguez, Jessica; Díaz-Menéndez, Marta; Viciana, Pompeyo; Torrella-Domingo, Adriadna; Sanz-Moreno, José; Jesús Téllez-Molina, María; Moreno, Javier; Hernández-Quero, José; Pérez-Hernández, Isabel A; Domingo-Pedrol, Pere

    2014-01-01

    Background The advent of combined antiretroviral therapy (ART) in the past decade has led to HIV suppression in most cases. Virological failure was the main reason for ART switch a few years ago; however, toxicity and treatment simplification have now gained importance due to the availability of more effective and convenient drugs. This study assessed the reasons for ART switch in daily practice. Material and Methods Observational retrospective study that included patients whose ART was switched between January 2011 and July 2012. Patients with any other switch during the follow-up period (until September 2013) were excluded. Results A total of 246 patients were included. Main reasons for ART switch were simplification (33%) and toxicity (31%), followed by clinical trial inclusion (13%), virological failure (6%), drug interaction (4%), patient decision (3%), lack of adherence (2%), pregnancy (1%) and other (8%). Eighty patients switched to a simpler regimen (median age 48 [40–53], mean CD4 count 608±265 cells/cl, 89% <50 copies/ml, mean number of previous regimens 6±5, mean time on previous ART 3±2 years). In this case, previous ART mostly included 2NRTI+1PI/r (54%) (Figure 1). The simplification strategy mainly contained nuke-sparing regimens (60%) based on PI (DRV/r 48%): monotherapy 46%, dual therapy 13% (PI/r+maraviroc 9%, PI/r+NNRTI 4%) and triple therapy 1% (PI/r+maraviroc+raltegravir). The second preferred simplification option was 2NRTI+1NNRTI (24%). Seventy-seven patients switched due to toxicities (median age 47 [43–53], mean CD4 count 606±350 cells/μl, <50 copies/ml 82%, mean number of previous regimens 4±3, mean time on previous ART 3±3 years). Renal (25%) and CNS (18%) toxicities were the main reasons for ART switch, followed by diarrhoea (16%), liver enzyme elevation (ALT 10%; AST 9%; bilirubin 7%), lipid elevation (cholesterol 5%; triglycerides 8%), nausea (7%) and other (=5%) (Figure 2). All patients with renal toxicity were under TDF and

  19. High Prevalence of HIV Low Abundance Drug-Resistant Variants in a Treatment-Naive Population in North Rift Kenya.

    PubMed

    Cheriro, Winfrida; Kiptoo, Michael; Kikuvi, Gideon; Mining, Simeon; Emonyi, Wilfred; Songok, Elijah

    2015-12-01

    The advent of antiretroviral treatment (ART) has resulted in a dramatic reduction in AIDS-related morbidity and mortality. However, the emergence and spread of antiretroviral drug resistance (DR) threaten to negatively impact treatment regimens and compromise efforts to control the epidemic. It is recommended that surveillance of drug resistance occur in conjunction with scale-up efforts to ensure that appropriate first-line therapy is offered relative to the resistance that exists. However, standard resistance testing methods used in Sub-Saharan Africa rely on techniques that do not include low abundance DR variants (LADRVs) that have been documented to contribute to treatment failure. The use of next generation sequencing (NGS) has been shown to be more sensitive to LADRVS. We have carried out a preliminary investigation using NGS to determine the prevalence of LDRVS among a drug-naive population in North Rift Kenya. Antiretroviral-naive patients attending a care clinic in North Rift Kenya were requested to provide and with consent provided blood samples for DR analysis. DNA was extracted and amplified and nested PCR was conducted on the pol RT region using primers tagged with multiplex identifiers (MID). Resulting PCR amplicons were purified, quantified, and pyrosequenced using a GS FLX Titanium PicoTiterPlate (Roche). Valid pyrosequencing reads were aligned with HXB-2 and the frequency and distribution of nucleotide and amino acid changes were determined using an in-house Perl script. DR mutations were identified using the IAS-USA HIV DR mutation database. Sixty samples were successfully sequenced of which 26 were subtype A, 9 were subtype D, 2 were subtype C, and the remaining were recombinants. Forty-six (76.6%) had at least one drug resistance mutation, with 25 (41.6%) indicated as major and the remaining 21 (35%) indicated as minor. The most prevalent mutation was NRTI position K219Q/R (11/46, 24%) followed by NRTI M184V (5/46, 11%) and NNRTI K103N (4/46, 9

  20. Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens

    PubMed Central

    Van Zyl, Gert U.; Liu, Tommy F.; Claassen, Mathilda; Engelbrecht, Susan; de Oliveira, Tulio; Preiser, Wolfgang; Wood, Natasha T.; Travers, Simon; Shafer, Robert W.

    2013-01-01

    Objectives South Africa’s national antiretroviral (ARV) treatment program expanded in 2010 to include the nucleoside reverse transcriptase (RT) inhibitors (NRTI) tenofovir (TDF) for adults and abacavir (ABC) for children. We investigated the associated changes in genotypic drug resistance patterns in patients with first-line ARV treatment failure since the introduction of these drugs, and protease inhibitor (PI) resistance patterns in patients who received ritonavir-boosted lopinavir (LPV/r)-containing therapy. Methods We analysed ARV treatment histories and HIV-1 RT and protease mutations in plasma samples submitted to the Tygerberg Academic Hospital National Health Service Laboratory. Results Between 2006 and 2012, 1,667 plasma samples from 1,416 ARV-treated patients, including 588 children and infants, were submitted for genotypic resistance testing. Compared with 720 recipients of a d4T or AZT-containing first-line regimen, the 153 recipients of a TDF-containing first-line regimen were more likely to have the RT mutations K65R (46% vs 4.0%; p<0.001), Y115F (10% vs. 0.6%; p<0.001), L74VI (8.5% vs. 1.8%; p<0.001), and K70EGQ (7.8% vs. 0.4%) and recipients of an ABC-containing first-line regimen were more likely to have K65R (17% vs 4.0%; p<0.001), Y115F (30% vs 0.6%; p<0.001), and L74VI (56% vs 1.8%; p<0.001). Among the 490 LPV/r recipients, 55 (11%) had ≥1 LPV-resistance mutations including 45 (9.6%) with intermediate or high-level LPV resistance. Low (20 patients) and intermediate (3 patients) darunavir (DRV) cross resistance was present in 23 (4.6%) patients. Conclusions Among patients experiencing virological failure on a first-line regimen containing two NRTI plus one NNRTI, the use of TDF in adults and ABC in children was associated with an increase in four major non- thymidine analogue mutations. In a minority of patients, LPV/r-use was associated with intermediate or high-level LPV resistance with predominantly low-level DRV cross-resistance. PMID

  1. HIV Drug Resistance Surveillance in Honduras after a Decade of Widespread Antiretroviral Therapy

    PubMed Central

    Tapia-Trejo, Daniela; Meza, Rita I.; Nuñez, Sandra M.; Parham, Leda; Flores, Norma A.; Valladares, Diana; Pineda, Luisa M.; Flores, Dixiana; Motiño, Roxana; Umanzor, Víctor; Carbajal, Candy; Murillo, Wendy; Lorenzana, Ivette; Palou, Elsa Y.; Reyes-Terán, Gustavo

    2015-01-01

    Introduction We assessed HIV drug resistance (DR) in individuals failing ART (acquired DR, ADR) and in ART-naïve individuals (pre-ART DR, PDR) in Honduras, after 10 years of widespread availability of ART. Methods 365 HIV-infected, ART-naïve, and 381 ART-experienced Honduran individuals were enrolled in 5 reference centres in Tegucigalpa, San Pedro Sula, La Ceiba, and Choluteca between April 2013 and April 2015. Plasma HIV protease-RT sequences were obtained. HIVDR was assessed using the WHO HIVDR mutation list and the Stanford algorithm. Recently infected (RI) individuals were identified using a multi-assay algorithm. Results PDR to any ARV drug was 11.5% (95% CI 8.4–15.2%). NNRTI PDR prevalence (8.2%) was higher than NRTI (2.2%) and PI (1.9%, p<0.0001). No significant trends in time were observed when comparing 2013 and 2014, when using a moving average approach along the study period or when comparing individuals with >500 vs. <350 CD4+ T cells/μL. PDR in recently infected individuals was 13.6%, showing no significant difference with PDR in individuals with longstanding infection (10.7%). The most prevalent PDR mutations were M46IL (1.4%), T215 revertants (0.5%), and K103NS (5.5%). The overall ADR prevalence in individuals with <48 months on ART was 87.8% and for the ≥48 months on ART group 81.3%. ADR to three drug families increased in individuals with longer time on ART (p = 0.0343). M184V and K103N were the most frequent ADR mutations. PDR mutation frequency correlated with ADR mutation frequency for PI and NNRTI (p<0.01), but not for NRTI. Clusters of viruses were observed suggesting transmission of HIVDR both from ART-experienced to ART-naïve individuals and between ART-naïve individuals. Conclusions The global PDR prevalence in Honduras remains at the intermediate level, after 10 years of widespread availability of ART. Evidence of ADR influencing the presence of PDR was observed by phylogenetic analyses and ADR/PDR mutation frequency correlations

  2. Psychosocial Predictors of Non-Adherence and Treatment Failure in a Large Scale Multi-National Trial of Antiretroviral Therapy for HIV: Data from the ACTG A5175/PEARLS Trial

    PubMed Central

    Safren, Steven A.; Biello, Katie B.; Smeaton, Laura; Mimiaga, Matthew J.; Walawander, Ann; Lama, Javier R.; Rana, Aadia; Nyirenda, Mulinda; Kayoyo, Virginia M.; Samaneka, Wadzanai; Joglekar, Anjali; Celentano, David; Martinez, Ana; Remmert, Jocelyn E.; Nair, Aspara; Lalloo, Umesh G.; Kumarasamy, Nagalingeswaran; Hakim, James; Campbell, Thomas B.

    2014-01-01

    Background PEARLS, a large scale trial of antiretroviral therapy (ART) for HIV (n = 1,571, 9 countries, 4 continents), found that a once-daily protease inhibitor (PI) based regimen (ATV+DDI+FTC), but not a once-daily non-nucleoside reverse transcriptase inhibitor/nucleoside reverse transcriptase inhibitor (NNRTI/NRTI) regimen (EFV+FTC/TDF), had inferior efficacy compared to a standard of care twice-daily NNRTI/NRTI regimen (EFV+3TC/ZDV). The present study examined non-adherence in PEARLS. Methods Outcomes: non-adherence assessed by pill count and by self-report, and time to treatment failure. Longitudinal predictors: regimen, quality of life (general health perceptions  =  QOL-health, mental health  =  QOL-mental health), social support, substance use, binge drinking, and sexual behaviors. “Life-Steps” adherence counseling was provided. Results In both pill-count and self-report multivariable models, both once-a-day regimens had lower levels of non-adherence than the twice-a-day standard of care regimen; although these associations attenuated with time in the self-report model. In both multivariable models, hard-drug use was associated with non-adherence, living in Africa and better QOL-health were associated with less non-adherence. According to pill-count, unprotected sex was associated with non-adherence. According to self-report, soft-drug use was associated with non-adherence and living in Asia was associated with less non-adherence. Both pill-count (HR = 1.55, 95% CI: 1.15, 2.09, p<.01) and self-report (HR = 1.13, 95% CI: 1.08, 1.13, p<.01) non-adherence were significant predictors of treatment failure over 72 weeks. In multivariable models (including pill-count or self-report nonadherence), worse QOL-health, age group (younger), and region were also significant predictors of treatment failure. Conclusion In the context of a large, multi-national, multi-continent, clinical trial there were variations in adherence over time, with more

  3. [Data on rilpivirine in treatment-naïve patients. Lessons from ECHO, THRIVE and STaR].

    PubMed

    Domingo, Pere; Ribera, Esteban

    2013-06-01

    Rilpivirine (RPV) is a new, second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been recently approved for use in the initial antiretroviral therapy (ART) of treatment-naïve HIV-infected patients, combined with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). The approved dose is 25mg once daily with food. RPV has been assessed in a phase IIb study (TMC278-C204) and in three phase III trials (ECHO, THRIVE and STaR). In all of them, RPV was compared with the gold standard, efavirenz (EFV); these studies enrolled a large number of patients (n=1,349 on RPV). RPV was non-inferior to EFV at 48 and 96 weeks. In all the studies and study arms, the tolerability of RPV was better than that of EFV, especially for neuropsychiatric adverse effects, rash, and lipid profile. An analysis of the combined data from the ECHO and THRIVE trials showed marked differences, depending on baseline viral load. The therapeutic efficacy of RPV was superior to that of EFV in patients with a baseline viral load ≤ 100,000 copies/mL, due to a similar virological efficacy and a better tolerability profile. However, in patients with a baseline viral load ≥ 100,000 copies/mL, virological failure was more frequent in the RPV arm, especially in patients with a viral load ≥ 500,000 copies/mL. Emerging resistance mutations to RPV were commonly detected in patients with virological failure, especially in those with a higher baseline viral load. In view of these results, the European Medications Agency and the US Food and Drug Administration have approved the use of RPV in treatment-naïve patients with a baseline viral load ≤ 100,000 copies/mL. Some treatment guidelines have already included RPV among their recommendations. The guidelines of the US Department of Health and Human Services (DHSS) and the International Antiviral Society-USA ((IAS-USA), while awaiting additional data, consider RPV-based regimens as an alternative regimen. The Gesida

  4. HIV-1 Transmitted Drug Resistance Mutations in Newly Diagnosed Antiretroviral-Naive Patients in Turkey.

    PubMed

    Sayan, Murat; Sargin, Fatma; Inan, Dilara; Sevgi, Dilek Y; Celikbas, Aysel K; Yasar, Kadriye; Kaptan, Figen; Kutlu, Selda; Fisgin, Nuriye T; Inci, Ayse; Ceran, Nurgul; Karaoglan, Ilkay; Cagatay, Atahan; Celen, Mustafa K; Koruk, Suda T; Ceylan, Bahadir; Yildirmak, Taner; Akalın, Halis; Korten, Volkan; Willke, Ayse

    2016-01-01

    HIV-1 replication is rapid and highly error-prone. Transmission of a drug-resistant HIV-1 strain is possible and occurs within the HIV-1-infected population. In this study, we aimed to determine the prevalence of transmitted drug resistance mutations (TDRMs) in 1,306 newly diagnosed untreated HIV-1-infected patients from 21 cities across six regions of Turkey between 2010 and 2015. TDRMs were identified according to the criteria provided by the World Health Organization's 2009 list of surveillance drug resistance mutations. The HIV-1 TDRM prevalence was 10.1% (133/1,306) in Turkey. Primary drug resistance mutations (K65R, M184V) and thymidine analogue-associated mutations (TAMs) were evaluated together as nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations. NRTI TDRMs were found in 8.1% (107/1,306) of patients. However, TAMs were divided into three categories and M41L, L210W, and T215Y mutations were found for TAM1 in 97 (7.4%) patients, D67N, K70R, K219E/Q/N/R, T215F, and T215C/D/S mutations were detected for TAM2 in 52 (3.9%) patients, and M41L + K219N and M41L + T215C/D/S mutations were detected for the TAM1 + TAM2 profile in 22 (1.7%) patients, respectively. Nonnucleoside reverse transcriptase inhibitor-associated TDRMs were detected in 3.3% (44/1,306) of patients (L100I, K101E/P, K103N/S, V179F, Y188H/L/M, Y181I/C, and G190A/E/S) and TDRMs to protease inhibitors were detected in 2.3% (30/1,306) of patients (M46L, I50V, I54V, Q58E, L76V, V82A/C/L/T, N83D, I84V, and L90M). In conclusion, long-term and large-scale monitoring of regional levels of HIV-1 TDRMs informs treatment guidelines and provides feedback on the success of HIV-1 prevention and treatment efforts. PMID:26414663

  5. Comparisons of Primary HIV-1 Drug Resistance between Recent and Chronic HIV-1 Infection within a Sub-Regional Cohort of Asian Patients

    PubMed Central

    Kiertiburanakul, Sasisopin; Chaiwarith, Romanee; Sirivichayakul, Sunee; Ditangco, Rossana; Jiamsakul, Awachana; Li, Patrick C. K.; Kantipong, Pacharee; Lee, Christopher; Ratanasuwan, Winai; Kamarulzaman, Adeeba; Sohn, Annette H.; Sungkanuparph, Somnuek

    2013-01-01

    Background The emergence and transmission of HIV-1 drug resistance (HIVDR) has raised concerns after rapid global antiretroviral therapy (ART) scale-up. There are limited data on the epidemiology of primary HIVDR in resource-limited settings in Asia. We aimed to determine the prevalence and compare the distribution of HIVDR in a cohort of ART-naïve Asian patients with recent and chronic HIV-1 infection. Methods Multicenter prospective study was conducted in ART-naïve patients between 2007 and 2010. Resistance-associated mutations (RAMs) were assessed using the World Health Organization 2009 list for surveillance of primary HIVDR. Results A total of 458 patients with recent and 1,340 patients with chronic HIV-1 infection were included in the analysis. The overall prevalence of primary HIVDR was 4.6%. Recently infected patients had a higher prevalence of primary HIVDR (6.1% vs. 4.0%, p = 0.065) and frequencies of RAMs to protease inhibitors (PIs; 3.9% vs. 1.0%, p<0.001). Among those with recent infection, the most common RAMs to nucleoside reverse transcriptase inhibitors (NRTIs) were M184I/V and T215D/E/F/I/S/Y (1.1%), to non-NRTIs was Y181C (1.3%), and to PIs was M46I (1.5%). Of patients with chronic infection, T215D/E/F/I/S/Y (0.8%; NRTI), Y181C (0.5%; non-NRTI), and M46I (0.4%; PI) were the most common RAMs. K70R (p = 0.016) and M46I (p = 0.026) were found more frequently among recently infected patients. In multivariate logistic regression analysis in patients with chronic infection, heterosexual contact as a risk factor for HIV-1 infection was less likely to be associated with primary HIVDR compared to other risk categories (odds ratio 0.34, 95% confidence interval 0.20–0.59, p<0.001). Conclusions The prevalence of primary HIVDR was higher among patients with recent than chronic HIV-1 infection in our cohort, but of borderline statistical significance. Chronically infected patients with non-heterosexual risks for HIV were more likely to have

  6. Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

    PubMed Central

    Deuzing, Ilona P.; Charpentier, Charlotte; Wright, David W.; Matheron, Sophie; Paton, Jack; Frentz, Dineke; van de Vijver, David A.; Coveney, Peter V.; Descamps, Diane; Boucher, Charles A. B.

    2014-01-01

    ABSTRACT Infection with HIV-2 can ultimately lead to AIDS, although disease progression is much slower than with HIV-1. HIV-2 patients are mostly treated with a combination of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and protease inhibitors designed for HIV-1. Many studies have described the development of HIV-1 resistance to NRTIs and identified mutations in the polymerase domain of RT. Recent studies have shown that mutations in the connection and RNase H domains of HIV-1 RT may also contribute to resistance. However, only limited information exists regarding the resistance of HIV-2 to NRTIs. In this study, therefore, we analyzed the polymerase, connection, and RNase H domains of RT in HIV-2 patients failing NRTI-containing therapies. Besides the key resistance mutations K65R, Q151M, and M184V, we identified a novel mutation, V111I, in the polymerase domain. This mutation was significantly associated with mutations K65R and Q151M. Sequencing of the connection and RNase H domains of the HIV-2 patients did not reveal any of the mutations that were reported to contribute to NRTI resistance in HIV-1. We show that V111I does not strongly affect drug susceptibility but increases the replication capacity of the K65R and Q151M viruses. Biochemical assays demonstrate that V111I restores the polymerization defects of the K65R and Q151M viruses but negatively affects the fidelity of the HIV-2 RT enzyme. Molecular dynamics simulations were performed to analyze the structural changes mediated by V111I. This showed that V111I changed the flexibility of the 110-to-115 loop region, which may affect deoxynucleoside triphosphate (dNTP) binding and polymerase activity. IMPORTANCE Mutation V111I in the HIV-2 reverse transcriptase enzyme was identified in patients failing therapies containing nucleoside analogues. We show that the V111I change does not strongly affect the sensitivity of HIV-2 to nucleoside analogues but increases the fitness of viruses with drug

  7. The management of chronic viral hepatitis: A Canadian consensus conference 2004

    PubMed Central

    Sherman, Morris; Bain, Vincent; Villeneuve, Jean-Pierre; Myers, Robert P; Cooper, Curtis; Martin, Steven; Lowe, Catherine

    2004-01-01

    Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care. PMID:18159509

  8. In Vitro Evolution of the Human Immunodeficiency Virus Type 1 Gag-Protease Region and Maintenance of Reverse Transcriptase Resistance following Prolonged Drug Exposure†

    PubMed Central

    La Seta Catamancio, Simona; De Pasquale, Maria Pia; Citterio, Paola; Kurtagic, Semir; Galli, Massimo; Rusconi, Stefano

    2001-01-01

    We studied the human immunodeficiency virus type 1 phenotypic and genotypic profiles of a dual drug-resistant isolate (isolate 14aPost-DR) selected for zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or KNI-272. The IDV-treated virus was highly resistant to 3TC, ZDV, and IDV and accumulated protease mutations at positions M46I and V82F. A change from alanine to valine was observed in 4 of 10 clones in the P2 position of the p7-p1 Gag-protease cleavage site, linked to position M46I in the dominant viral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions. PMID:11230439

  9. Management of hepatitis B reactivation in patients receiving cancer chemotherapy

    PubMed Central

    Huang, Yi-Wen

    2012-01-01

    Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) testing should be performed in patients who require cancer chemotherapy. Four meta-analyses support lamivudine prophylaxis for HBV reactivation during chemotherapy in HBsAg-positive patients. Randomized controlled trials to compare different HBV antiviral agents are needed to define optimal regimens for the prevention and treatment of HBV reactivation in patients receiving cancer chemotherapy. PMID:22973419

  10. Theoretical and experimental studies of the stability of drug-drug interact.

    PubMed

    Soares, Monica F R; Alves, Lariza D S; Nadvorny, Daniela; Soares-Sobrinho, José L; Rolim-Neto, Pedro J

    2016-11-01

    Several factors can intervene in the molecular properties and consequently in the stability of drugs. The molecular complexes formation often occur due to favor the formation of hydrogen bonds, leading the system to configuration more energy stable. This work we aim to investigate through theoretical and experimental methods the relation between stability and properties of molecular complexes the molecular complex formed between the drugs, efavirenz (EFV), lamivudine (3TC) and zidovudine (AZT). With this study was possible determining the most stable complex formed between the compounds evaluated. In addition the energy and structural properties of the complex formed in relation to its individual components allowed us to evaluate the stability of the same. PMID:27267283

  11. HIV Drug Resistance Surveillance Among Jamaican Men Who Have Sex with Men Should Be Prioritized for Reducing HIV Transmission.

    PubMed

    Collins-Fairclough, Aneisha M; Dennis, Ann M; Nelson, Julie A E; Weir, Sharon S; Figueroa, J Peter

    2015-08-01

    The prevalence of human immunodeficiency virus type 1 (HIV-1) is highest among men who have sex with men (MSM) in Jamaica but no genotypic data are available on the virus strains that are responsible for the epidemic among this key population. HIV-1 polymerase (pol) genes from 65 MSM were sequenced and used to predict drug resistance mutations. An HIV drug resistance prevalence of 28% (minimum 13%) was observed among this cohort, with the most frequent mutations conferring resistance to efavirenz, nevirapine, and lamivudine. Phylogenetic analysis of the sequences revealed 10 times the number of linked HIV infections among this cohort than respondent reporting. HIV treatment and prevention efforts in Jamaica could benefit significantly from Pol genotyping of the HIV strains infecting socially vulnerable MSM prior to initiating antiretroviral therapy (ART), as this would guide suppressive ART and unearth HIV transmission clusters to enable more effective delivery of treatment and prevention programs. PMID:26133540

  12. [Chronic hepatitis B: current therapy].

    PubMed

    Buffet, Catherine

    2008-11-01

    HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication. PMID:19445377

  13. HIV Drug Resistance Surveillance Among Jamaican Men Who Have Sex with Men Should Be Prioritized for Reducing HIV Transmission

    PubMed Central

    Dennis, Ann M.; Nelson, Julie A.E.; Weir, Sharon S.; Figueroa, J. Peter

    2015-01-01

    Abstract The prevalence of human immunodeficiency virus type 1 (HIV-1) is highest among men who have sex with men (MSM) in Jamaica but no genotypic data are available on the virus strains that are responsible for the epidemic among this key population. HIV-1 polymerase (pol) genes from 65 MSM were sequenced and used to predict drug resistance mutations. An HIV drug resistance prevalence of 28% (minimum 13%) was observed among this cohort, with the most frequent mutations conferring resistance to efavirenz, nevirapine, and lamivudine. Phylogenetic analysis of the sequences revealed 10 times the number of linked HIV infections among this cohort than respondent reporting. HIV treatment and prevention efforts in Jamaica could benefit significantly from Pol genotyping of the HIV strains infecting socially vulnerable MSM prior to initiating antiretroviral therapy (ART), as this would guide suppressive ART and unearth HIV transmission clusters to enable more effective delivery of treatment and prevention programs. PMID:26133540

  14. [Efficacy of dolutegravir in treatment-naïve patients. The SPRING-1, SPRING-2, SINGLE and FLAMINGO trials].

    PubMed

    Bernardino, José I; Antela, Antonio

    2015-03-01

    The efficacy of dolutegravir (DTG) in treatment-naïve patients has been analyzed in the SPRING 1 and 2, SINGLE and FLAMINGO trials, which compared dolutegravir with the agents currently recommended as the drugs of choice in clinical practice guidelines in treatment-naïve patients: efavirenz, raltegravir and darunavir/ritonavir. These trials confirmed the superiority (SINGLE and FLAMINGO) or the non-inferiority (SPRING-2) of dolutegravir. More than 2,000 patients were included in these 4 studies, lending value to their results and reinforcing the view of dolutegravir as the drug of choice in treatment-naïve patients, accompanied either by abacavir/lamivudine (Kivexa(®)) or tenofovir/emtricitabine (Truvada®). PMID:25858607

  15. [Position of dolutegravir in the treatment of HIV infection].

    PubMed

    Martínez, Esteban; Gatell, José M

    2015-03-01

    Initial treatment with dolutegravir offers higher efficacy than treatment with efavirenz, darunavir/ritonavir and even with raltegravir in patients with a high viral load. Like ritonavir-boosted protease inhibitors, dolutegravir will probably have a high genetic barrier to resistance and prior genetic testing will not be required in integrase inhibitor-naïve patients. The drug is well tolerated and associated with few treatment discontinuations. It can be administered once daily and the tablet size is small. A fixed-dose combination tablet containing dolutegravir, abacavir and lamivudine will soon be available. Dolutegravir has few interactions with commonly-used drugs. It does not require pharmacological boosting and has no food or time of day restrictions. Because of these characteristics, dolutegravir has a unique profile and is the ideal drug for most HIV-infected patients. PMID:25858610

  16. Evaluation of chemically modified hydrophobic sago starch as a carrier for controlled drug delivery.

    PubMed

    Singh, Akhilesh Vikram; Nath, Lila Kanta

    2013-04-01

    The present investigation deals with the development of controlled release tablets of lamivudine using acetylated sago starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated sago starch was tested for acute toxicity and drug-excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, % friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in the case of higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion processes. 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® which proves the controlled release property of acetylated sago starch. PMID:23960835

  17. Evaluation of chemically modified hydrophobic sago starch as a carrier for controlled drug delivery

    PubMed Central

    Singh, Akhilesh Vikram; Nath, Lila Kanta

    2012-01-01

    The present investigation deals with the development of controlled release tablets of lamivudine using acetylated sago starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated sago starch was tested for acute toxicity and drug–excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, % friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in the case of higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion processes. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir® which proves the controlled release property of acetylated sago starch. PMID:23960835

  18. Use of lopinavir/ritonavir associated with ergotamine resulting in foot amputation: brief communication.

    PubMed

    Ferry, Fernando Raphael de Almeida; Da Silva, Guilherme Almeida Rosa; Motta, Rogerio Neves; Carvalho, Ricardo de Souza; De Sá, Carlos Alberto Morais

    2014-01-01

    A 32-year-old female, was diagnosed in 2004 with a C1 HIV1 infection, using zidovudine/lamivudine 300/150 mg BID and lopinavir/ritonavir 400/100 mg BID, in addition to prophylaxis with trimethoprim-sulfamethoxazole 800/160 mg QD, but no prophylaxis with macrolide antibiotics. The patient presented with a severe headache and was prescribed two capsules of the anti-migraine drug Ormigrein™, which contained ergotamine tartrate 1 mg, caffeine 100 mg, paracetamol 220 mg, hyoscyamine sulfate 87.5 mcg, and atropine sulfate 12.5 mcg. Afterwards she was prescribed one capsule of Ormigrein every 30 minutes for a total of six capsules a day. The patient took the medication as prescribed but developed a pain in her left ankle three days later, which evolved to the need for amputation. PMID:24879006

  19. Sustained seroconversion of chronic hepatitis B infection after stem cell transplantation.

    PubMed

    Serap, Aksoylar; Funda, Ozgenc; Bengu, Kadioglu; Mehmet, Kantar; Nazan, Cetingul; Rasit, Yagci; Savas, Kansoy

    2011-08-01

      We present an 18-yr-old adolescent with acute lymphocytic leukemia, who underwent peripheral blood SCT with serologically and histologically documented chronic hepatitis B infection. Prior and during the transplant process, lamivudine was administered orally and he underwent SCT with a twofold decrease in viral load at the time of transplant from his HLA full matched, HBV natural immune (anti-HBs and anti-HBc positive) donor. Successful engraftment was achieved and three months after SCT, HBV seroconversion was documented accompanied with an ALT flare. Chronic graft-versus-host disease coincided after the transplantation, and he has been on immunosuppressive treatment for 25 months with sustained HBV seroconversion. We assume that adoptive immunity transfer combined with antiviral treatment might also constitute sustained seroconversion in chronic HBV, besides the reported risk of reactivation. PMID:20102530

  20. The Epi-TAF for Tenofovir Disoproxil Fumarate?

    PubMed

    Walensky, Rochelle P; Horn, Tim H; Paltiel, A David

    2016-04-01

    Approximately 84% of human immunodeficiency virus (HIV)-infected US residents on antiretroviral therapy currently receive some form of tenofovir disoproxil fumarate (TDF) as part of their HIV treatment regimen. The TDF analogue tenofovir alafenamide (TAF) has demonstrated equal efficacy but with decreased renal injury and bone mineral density loss compared with TDF. We examine how much more society ought to be willing to pay for TAF over TDF, in exchange for its improved toxicity profile. Using cost-effectiveness methods, we find that current conditions warrant an annual premium of up to $1000 over the average wholesale price (AWP) of TDF. Once generic coformulations of tenofovir/lamivudine become accessible, however, the appropriate premium for TAF will likely merit a downward adjustment, using generic TDF-based costs as the benchmark. PMID:26658300

  1. Challenges to treatment of leukemia in HIV-positive children.

    PubMed

    Stefan, D Cristina; Dippenaar, Anel; De Bruin, Gerhard; Uys, Ronelle; van Toorn, Ronald

    2012-12-01

    We describe the challenges to treatment of leukemia in three cases of human immunodeficiency virus (HIV)-infected children with multiple infections and complications. Two of the three patients had acute myeloid leukemia and the other one acute lymphoblastic leukemia. Two of the patients were known with HIV infection; the third was diagnosed on admission. All patients received antiretroviral therapy with standard doses of lamivudine, stavudine and efavirenz or lopinavir/retonavir. All three were diagnosed with Mycobacterium tuberculosis on one or more occasions: pulmonary or miliary involvement or tuberculous meningitis. One patient developed spinal paraplegia and needed an urgent laminectomy. Later he recovered almost completely. The interaction between antiretroviral and antituberculosis treatments combined with chemotherapy, antibiotics and supportive care is not known. Despite the severity and the complexity of several associated diseases, the outcome of the patients was rewarding and encouraging. PMID:22421805

  2. Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients

    PubMed Central

    Baril, Jean-Guy; Angel, Jonathan B.; Gill, M. John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

    2016-01-01

    Objective We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. Methods A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Results Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. Conclusions The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here

  3. Case Report: Stevens-Johnson syndrome following a single double dosing of nevirapine-containing regimen once in an HIV-infected woman on long-term antiretroviral therapy.

    PubMed Central

    Kakande, Betty; Isaacs, Thuraya; Muloiwa, Rudzani; Dlamini, Sipho; Lehloenya, Rannakoe

    2015-01-01

    A 31-year old HIV-infected African woman on nevirapine, tenofovir and lamivudine for more than 4 years presented with an 8-day history of symptoms and signs of Stevens-Johnson syndrome. She was on no other medication. Her viral load was undetectable and she had maintained a CD4 count of between 356 and 387cells/mm 3 in the preceding 2½ years. She missed her antiretrovirals 10 days before the onset of her symptoms and subsequently doubled her daily dose the following day. She had been on no other medication in the preceding 8 weeks. Her ARVs were stopped and she fully re-epithelialized with the exception of the lips, over the following 10 days. She was started on a daily single tablet of Odimune® (a fixed drug combination antiretroviral containing tenofovir, emtricitabine and efavirenz). Nevirapine is the most common offender in cases of antiretroviral-associated SJS in published literature. Lamivudine is very rarely implicated while there are no similar reports with tenofovir.  We concluded that nevirapine was by far the most likely offender in this case. Nevirapine toxicity is associated with high CD4 counts, undetectable viral load and high drug plasma level. We postulate that the sudden increase of the plasma levels of nevirapine in a patient with a high CD4 count and undetectable viral load created a perfect storm for the development of SJS in our patient, who had been on the NVP-containing regimen for many years. Clinicians should be aware that severe adverse drug reactions are dynamic and can occur even when the drug has been in use for a long time. PMID:26629333

  4. [In Process Citation].

    PubMed

    Horváth, Gábor; Gerlei, Zsuzsanna; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Rókusz, László; Szalay, Ferenc; Tornai, István; Werling, Klára; Hunyady, Béla

    2015-12-15

    Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2016 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous ente- cavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2015, 156(Suppl. 2) 25-36. PMID:26667112

  5. [Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline].

    PubMed

    Horváth, Gábor; Hunyady, Béla; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Szalay, Ferenc; Telegdy, László; Tornai, István

    2014-03-01

    Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. PMID:24631887

  6. [In Process Citation].

    PubMed

    Horváth, Gábor; Gerlei, Zsuzsanna; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Rókusz, László; Szalay, Ferenc; Telegdy, László; Tornai, István; Werling, Klára; Hunyady, Béla

    2015-03-01

    Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2015, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2015, 156(Suppl. 1), 25-35. PMID:26039414

  7. Application of Bayesian Approach to Cost-Effectiveness Analysis of Antiviral Treatments in Chronic Hepatitis B

    PubMed Central

    Zhang, Hua; Huo, Mingdong; Chao, Jianqian; Liu, Pei

    2016-01-01

    Background Hepatitis B virus (HBV) infection is a major problem for public health; timely antiviral treatment can significantly prevent the progression of liver damage from HBV by slowing down or stopping the virus from reproducing. In the study we applied Bayesian approach to cost-effectiveness analysis, using Markov Chain Monte Carlo (MCMC) simulation methods for the relevant evidence input into the model to evaluate cost-effectiveness of entecavir (ETV) and lamivudine (LVD) therapy for chronic hepatitis B (CHB) in Jiangsu, China, thus providing information to the public health system in the CHB therapy. Methods Eight-stage Markov model was developed, a hypothetical cohort of 35-year-old HBeAg-positive patients with CHB was entered into the model. Treatment regimens were LVD100mg daily and ETV 0.5 mg daily. The transition parameters were derived either from systematic reviews of the literature or from previous economic studies. The outcome measures were life-years, quality-adjusted lifeyears (QALYs), and expected costs associated with the treatments and disease progression. For the Bayesian models all the analysis was implemented by using WinBUGS version 1.4. Results Expected cost, life expectancy, QALYs decreased with age. Cost-effectiveness increased with age. Expected cost of ETV was less than LVD, while life expectancy and QALYs were higher than that of LVD, ETV strategy was more cost-effective. Costs and benefits of the Monte Carlo simulation were very close to the results of exact form among the group, but standard deviation of each group indicated there was a big difference between individual patients. Conclusions Compared with lamivudine, entecavir is the more cost-effective option. CHB patients should accept antiviral treatment as soon as possible as the lower age the more cost-effective. Monte Carlo simulation obtained costs and effectiveness distribution, indicate our Markov model is of good robustness. PMID:27574976

  8. Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B.

    PubMed

    Kim, Jeong Tae; Jeong, Hye Won; Choi, Ki Hwa; Yoon, Tae Young; Sung, Nohyun; Choi, Young Ki; Kim, Eun Ha; Chae, Hee Bok

    2014-11-14

    Several clinical trials have demonstrated the potent antiviral efficacy of entecavir (ETV), and this relatively new nucleoside analogue drug has rapidly become a frequently prescribed therapy for chronic hepatitis B (CHB) worldwide. While the studies have also shown a good overall safety profile for ETV, adverse drug reactions (ADRs) in patients with advanced cirrhosis have been reported and represent a broad spectrum of drug-induced injuries, including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses (i.e., allergic reactions). Cutaneous ADRs associated with ETV are very rare, with only two case reports in the publicly available literature; both of these cases were classified as unspecified hypersensitivity allergic (type I) ADR, but neither were reported as pathologically proven or as evaluated by cytokine release analysis. Here, we report the case of a 45-year-old woman who presented with a generalized maculopapular rash after one week of ETV treatment for lamivudine-resistant CHB. The patient reported having experienced a similar skin eruption during a previous three-month regimen of ETV, for which she had self-discontinued the medication. Histopathological analysis of a skin biopsy showed acanthotic epidermis with focal parakeratosis and a perivascular lymphocytic infiltrate admixed with interstitial eosinophils in the papillary and reticular dermis, consistent with a diagnosis of drug sensitivity. A lymphocyte stimulation test showed significantly enhanced IL-4, indicating a classification of type IVb delayed hypersensitivity. The patient was switched to an adefovir-lamivudine combination regimen and the skin eruption resolved two weeks after the ETV withdrawal. This case represents the first pathologically and immunologically evidenced ETV-induced delayed type hypersensitivity skin reaction reported to date. Physicians should be aware of the potential, although rare

  9. CLEFT PALATE IN HIV-EXPOSED NEWBORNS OF MOTHERS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

    PubMed Central

    James, Ayotunde; Oluwatosin, Babatunde; Njideka, Georgina; Babafemi; Benjamin, Onyekwere George; Olufemi, David; Leo, Robert; Folorunso, Isaac; Phylis; Olusina, Olusegun

    2014-01-01

    Aims Cleft lip/palate, though rare, is the commonest head and neck congenital malformation. Both genetic and environmental factors have been implicated in the aetiopathogenesis but the role of in-utero exposure to human immunodeficiency virus (HIV) and highly active antiretroviral therapy (HAART) is still being investigated. This short communication reports the occurrence of cleft palate in three newborns exposed in-utero to HIV and HAART. Material and methods This is a case series of HIV-exposed newborns observed to have cleft palate among a larger cohort of HIV-exposed and unexposed newborns in a study evaluating the effect of HIV infection and HAART on newborn hearing. The Risk Ratio (RR) was calculated to detect a potential association between in-utero exposure to Efavirenz containing ART and cleft palate. Results Three HIV-exposed newborns with cleft palate were identified during hearing screening performed on 126 HIV-exposed and 121 HIV unexposed newborns. Two had exposure to tenofovir+lamivudine+efavirenz (TDF+3TC+EFV) while the third had exposure to zidovudine+lamivudine+nevirapine (ZDV+3TC+NVP) during the first trimester. There was no statistically significant association between presence of cleft palate and exposure to an EFV containing HAART regimen (p=0.07, RR=10.95 [0.94-126.84]). Conclusions This communication highlights the possible aetiologic role of HAART in cleft palate, the need for further prospective follow-up studies and establishment of antiretroviral pregnancy, birth and neonatal registries. PMID:25653715

  10. Mutational analysis of reverse transcriptase and surface proteins of patients with partial virological response during mono and combination antiviral therapies in genotype D chronic hepatitis B

    PubMed Central

    Mahabadi, Mostafa; Alavian, Seyed Moayed; Norouzi, Mehdi; Keyvani, Hossein; Mahmoudi, Mahmood; Jazayeri, Seyed Mohammad

    2016-01-01

    Introduction The mutational pattern of chronic Hepatitis B virus (HBV) is unclear in patients who show incomplete response to antiviral therapy. The aims of this study were 1) to determine the benefit of combination therapy with adefovir dipivoxil (ADV) and Lamivudine (LAM) versus ADV or LAM alone in maintaining virological, biochemical and histological responses and 2) to investigate the patterns of mutations in the reverse transcriptase and surface proteins of HBV with LAM and/or ADF-resistant in partially-responded chronic hepatitis B (CHB) patients. Methods The study group consisted of 186 chronic HBV carriers who were admitted to the Tehran Hepatitis Network from 2010 to 2013. We retrospectively selected 86 patients who partially responded to different nucleoside analogue regimens. After 48 weeks of therapy, five groups of patients were defined including eight Lamivudine (LAM) Group (I), 30 Adefovir (ADV) Group (II), 16 ADV add on LAM Group (III), 32 ADV+LAM Group (IV), and 100 controls (no therapy). Reverse transcriptase (RT) and surface genes were amplified and sequenced for mutational analysis. Results All groups showed differences between mean values for age, gender, alanine transaminase (ALT), aspartate transaminase (AST), and HBV DNA levels groups showed significant differences than other groups (p < 0.05). The mutation frequencies for groups were I (1.7%), II (1.39%), III (2.28%), IV (2.0%), and V (0.38%). T54N, L80I/V, I91L/V, L180M, M204I/V, Q215P/S, and F221Y/S showed the highest number of mutations in all groups with different frequencies. Four new, unreported mutations were found. Conclusion Those patients who failed to respond in the first 48 weeks, whether they were receiving mono or combination therapy, should be tested genotypically, for the early modification of treatment. PMID:27504160

  11. Structure of the HIV-1 reverse transcriptase Q151M mutant: insights into the inhibitor resistance of HIV-1 reverse transcriptase and the structure of the nucleotide-binding pocket of Hepatitis B virus polymerase

    SciTech Connect

    Nakamura, Akiyoshi; Tamura, Noriko; Yasutake, Yoshiaki

    2015-10-23

    The structure of the HIV-1 reverse transcriptase Q151M mutant was determined at a resolution of 2.6 Å in space group P321. Hepatitis B virus polymerase (HBV Pol) is an important target for anti-HBV drug development; however, its low solubility and stability in vitro has hindered detailed structural studies. Certain nucleotide reverse transcriptase (RT) inhibitors (NRTIs) such as tenofovir and lamivudine can inhibit both HBV Pol and Human immunodeficiency virus 1 (HIV-1) RT, leading to speculation on structural and mechanistic analogies between the deoxynucleotide triphosphate (dNTP)-binding sites of these enzymes. The Q151M mutation in HIV-1 RT, located at the dNTP-binding site, confers resistance to various NRTIs, while maintaining sensitivity to tenofovir and lamivudine. The residue corresponding to Gln151 is strictly conserved as a methionine in HBV Pol. Therefore, the structure of the dNTP-binding pocket of the HIV-1 RT Q151M mutant may reflect that of HBV Pol. Here, the crystal structure of HIV-1 RT Q151M, determined at 2.6 Å resolution, in a new crystal form with space group P321 is presented. Although the structure of HIV-1 RT Q151M superimposes well onto that of HIV-1 RT in a closed conformation, a slight movement of the β-strands (β2–β3) that partially create the dNTP-binding pocket was observed. This movement might be caused by the introduction of the bulky thioether group of Met151. The structure also highlighted the possibility that the hydrogen-bonding network among amino acids and NRTIs is rearranged by the Q151M mutation, leading to a difference in the affinity of NRTIs for HIV-1 RT and HBV Pol.

  12. Antiretroviral Genotypic Resistance Mutations in HIV-1 Infected Korean Patients with Virologic Failure

    PubMed Central

    Chin, Bum Sik; Choi, Ju-Yeon; Choi, Jin Young; Kim, Gab Jung; Kee, Mee-Kyung; Kim, June Myung

    2009-01-01

    Resistance assays are useful in guiding decisions for patients experiencing virologic failure (VF) during highly-active antiretroviral therapy (HAART). We investigated antiretroviral resistance mutations in 41 Korean human immunodeficiency virus type 1 (HIV-1) infected patients with VF and observed immunologic/virologic response 6 months after HAART regimen change. Mean HAART duration prior to resistance assay was 45.3±27.5 months and commonly prescribed HAART regimens were zidovudine/lamivudine/nelfinavir (22.0%) and zidovudine/lamivudine/efavirenz (19.5%). Forty patients (97.6%) revealed intermediate to high-level resistance to equal or more than 2 antiretroviral drugs among prescribed HAART regimen. M184V/I mutation was observed in 36 patients (87.7%) followed by T215Y/F (41.5%) and M46I/L (34%). Six months after resistance assay and HAART regimen change, median CD4+ T cell count increased from 168 cells/µL (interquartile range [IQR], 62-253) to 276 cells/µL (IQR, 153-381) and log viral load decreased from 4.65 copies/mL (IQR, 4.18-5.00) to 1.91 copies/mL (IQR, 1.10-3.60) (P<0.001 for both values). The number of patients who accomplished viral load <400 copies/mL was 26 (63.4%) at 6 months follow-up. In conclusion, many Korean HIV-1 infected patients with VF are harboring strains with multiple resistance mutations and immunologic/virologic parameters are improved significantly after genotypic resistance assay and HAART regimen change. PMID:19949656

  13. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-04-01

    (+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin

  14. Incidence and predictors of severe anemia in Asian HIV-infected children using first-line antiretroviral therapy

    PubMed Central

    Bunupuradah, Torsak; Kariminia, Azar; Chan, Kwai-Cheng; Ramautarsing, Reshmie; Huy, Bui Vu; Han, Ning; Nallusamy, Revathy; Hansudewechakul, Rawiwan; Saphonn, Vonthanak; Sirisanthana, Virat; Chokephaibulkit, Kulkanya; Kurniati, Nia; Kumarasamy, Nagalingeswaran; Yusoff, Nik Khairulddin Nik; Razali, Kamarul; Fong, Siew Moy; Sohn, Annette H.; Lumbiganon, Pagakrong

    2014-01-01

    Objective There are limited data on treatment-related anemia in Asian HIV-infected children. Methods Data from Asian HIV-infected children aged <18 years on first-line highly active antiretroviral therapy (HAART) were used. Children who had preexisting severe anemia at baseline were excluded. Anemia was graded by using the DAIDS 2004 table. Potential risk factors of severe anemia were assessed by logistic regression. Results Data from 1,648 children (51.9% female, 62.8% WHO stage 3/4) were analyzed. Median (IQR) age was 6.8 (3.7–9.6) years, CD4% was 9 (3–16)% and plasma HIV-RNA was 5.2 (4.7–5.6) log10 copies/ml at HAART initiation in those with available testing. The most common regimens were stavudine/lamivudine/nevirapine (42%) and zidovudine/lamivudine/nevirapine (25%). Severe anemia was identified in 47 (2.9%) children after a median time of 6 months after HAART initiation with an incidence rate of 5.4 per 100 child-years. Mild anemia or moderate anemia at baseline (p=0.024 and p=0.005, respectively), previous or current use of zidovudine (p<0.0001 and p=0.013, respectively), and male sex (p=0.008) were associated with severe anemia. Higher weight-for-age z-score (p=0.004) was protective. Conclusions The incidence of severe anemia in Asian HIV-infected children after HAART initiation was low and mainly occurred during the first few months after HAART initiation. Mild to moderate anemia at baseline and using AZT were independent risk factors of developing severe anemia. PMID:23764352

  15. Cystatin C-Based Renal Function Changes After Antiretroviral Initiation: A Substudy of a Randomized Trial

    PubMed Central

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

    2014-01-01

    Background.  The effects of antiretrovirals on cystatin C-based renal function estimates are unknown. Methods.  We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz. Results.  Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were −8.3 (−14.0, −2.6) mL/min with Cockcroft-Gault; −14.9 (−19.7, −10.1) mL/min per 1.732 with Modification of Diet in Renal Disease; −12.8 (−16.5, −9.0) mL/min per 1.732 with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.732 with 2012 CKD-EPI cystatin C; and −1.2 (−5.1, 2.6) mL/min per 1.732 with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation. Conclusions.  Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used. PMID:25734077

  16. Hepatitis B Virus Reactivation After Three-Dimensional Conformal Radiotherapy in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma

    SciTech Connect

    Kim, Ji Hoon; Park, Joong-Won Kim, Tae Hyun; Koh, Dong Wook; Lee, Woo Jin; Kim, Chang-Min

    2007-11-01

    Purpose: To investigate whether three-dimensional conformal radiotherapy (3D-CRT) influences hepatitis B virus (HBV) reactivation and chronic hepatitis B (CHB) exacerbation in patients with HBV-related hepatocellular carcinoma (HCC). Methods and Materials: Of the 48 HCC patients with HBV who underwent 3D-CRT to the liver, 16 underwent lamivudine therapy before and during 3D-CRT (Group 1) and 32 did not receive antiviral therapy before 3D-CRT (Group 2). To analyze spontaneous HBV reactivation, we included a control group of 43 HCC patients who did not receive any specific treatment for HCC or CHB. Results: The cumulative rate of radiation-induced liver disease for Groups 1 and 2 was 12.5% (2 of 16) and 21.8% (7 of 32), respectively (p > 0.05). The cumulative rate of HBV reactivation was significantly greater in Group 2 (21.8%, 7 of 32) than in Group 1 (0%, 0/16) or the control group (2.3%, 1 of 43; p < 0.05 each). The cumulative rate of CHB exacerbation, however, did not differ significantly between Groups 2 (12.5%, 4 of 32) and 1 (0%, 0 of 16) or the control group (2.3%, 1 of 43; p > 0.05 each). The CHB exacerbations in the 4 Group 2 patients had radiation-induced liver disease features but were differentiated by serum HBV DNA changes. Two of these patients required antiviral therapy and effectively recovered with lamivudine therapy. Conclusions: In patients with HBV-related HCC undergoing 3D-CRT, HBV reactivation and consequent CHB exacerbation should be considered in the differential diagnosis of radiation-induced liver disease, and antiviral therapy might be considered for the prevention of liver function deterioration after RT.

  17. Executive summary of the GESIDA/National AIDS Plan Consensus Document on Antiretroviral Therapy in Adults Infected by the Human Immunodeficiency Virus (Updated January 2016).

    PubMed

    2016-01-01

    In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise 3 drugs, namely, 2 nucleoside reverse transcriptase inhibitors (NRTI), and 1 drug from another family. Four of the recommended regimens, all of which have an integrase strand transfer inhibitor (INSTI) as the third drug, are considered a preferred regimen; a further 6 regimens, which are based on an INSTI, a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with cobicistat or ritonavir (PI/COBI, PI/r), are considered alternatives. The reasons and criteria for switching ART are presented both for patients with an undetectable PVL and for patients who experience virological failure, in which case the rescue regimen should include 3 (or at least 2) drugs that are fully active against HIV. The specific criteria for ART in special situations (acute infection, HIV-2 infection, pregnancy) and comorbid conditions (tuberculosis and other opportunistic infections, kidney disease, liver disease, and cancer) are updated. PMID:27068257

  18. In Utero Exposure of Female CD-1 Mice to AZT and/or 3TC: I. Persistence of Microscopic Lesions in Cardiac Tissue

    PubMed Central

    Torres, Salina M.; March, Thomas H.; Carter, Meghan M.; McCash, Consuelo L.; Seilkop, Steven K.; Poirier, Miriam C.; Walker, Dale M.

    2010-01-01

    The current study was designed to delineate temporal changes in cardiomyocytes and mitochondria at the light and electron microscopic levels in hearts of mice exposed transplacentally to commonly used nucleoside analogs (NRTIs). Pregnant CD-1 mice were given 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during the last 7 days of gestation, and hearts from female mouse pups were examined at 13 and 26 weeks postpartum for histopathological or ultrastructural changes in cross-sections of both the ventricles and the interventricular septum. Using light microscopy and special staining techniques, transplacental exposure to AZT, 3TC, or AZT/3TC was shown to induce significant histopathological changes in myofibrils; these changes were more widespread at 13 weeks than at 26 weeks postpartum. While most light microscopic lesions resolved, some became more severe between 13 and 26 weeks postpartum. Transplacental NRTI exposure also resulted in progressive drug-specific changes in the number and ultrastructural integrity of cardiac mitochondria. These light and electron microscopic findings show that a subset of changes in cardiac mitochondria and myofibrils persisted and progressed months after transplacental exposure of an animal model to NRTIs, with combined AZT/3TC exposure yielding additive effects compared with either drug alone. PMID:20101476

  19. Antiretroviral Therapy-Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase-γ Inhibition

    PubMed Central

    Selvaraj, Shanmugapriya; Ghebremichael, Musie; Li, Min; Foli, Yram; Langs-Barlow, Allison; Ogbuagu, Arit; Barakat, Lydia; Tubridy, Elizabeth; Edifor, Regina; Lam, Wing; Cheng, Yung-Chi; Paintsil, Elijah

    2014-01-01

    We hypothesized that competition between NRTI-triphosphate and endogenous deoxyribonucleoside triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of Pol-γ inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV-infected with mitochondrial toxicity, 25 HIV-infected positive controls, and 25 HIV-negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median RN pool was 10062 (IQR, 7090 – 12590), 4360 (IQR, 3058 –6838), and 2968 (IQR, 2538 – 4436) pmol/106 cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mtDNA copy number compared to negative controls (p<0.05). Cases had significantly higher expression of Pol-γ, nucleoside transporters, cellular kinases, and ABC compared to controls. Antiretroviral therapy perturbs ribonucleotide and deoxyribonucleotide pools. Depletion of RN and dRN pools may be associated with ART-induced mitochondrial toxicity independent of Pol-γ inhibition. PMID:24637942

  20. Molecular Characterization of the Human Immunodeficiency Virus Type 1 in Women and Their Vertically Infected Children.

    PubMed

    Vaz, Sara Nunes; Giovanetti, Marta; Rego, Filipe Ferreira de Almeida; Oliveira, Tulio de; Danaviah, Siva; Gonçalves, Maria Luiza Freire; Alcantara, Luiz Carlos Junior; Brites, Carlos

    2015-10-01

    Approximately 35 million people worldwide are infected with human immunodeficiency virus (HIV) around 3.2 million of whom are children under 15 years. Mother-to-child-transmission (MTCT) of HIV-1 accounts for 90% of all infections in children. Despite great advances in the prevention of MTCT in Brazil, children are still becoming infected. Samples from 19 HIV-1-infected families were collected. DNA was extracted and fragments from gag, pol, and env were amplified and sequenced directly. Phylogenetic reconstruction was performed. Drug resistance analyses were performed in pol and env sequences. We found 82.1% of subtype B and 17.9% of BF recombinants. A prevalence of 43.9% drug resistance-associated mutations in pol sequences was identified. Of the drug-naive children 33.3% presented at least one mutation related to protease inhibitor/nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NRTI/NNRTI) resistance. The prevalence of transmitted drug resistance mutations was 4.9%. On env we found a low prevalence of HR1 (4.9%) and HR2 (14.6%) mutations. PMID:26200738

  1. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    PubMed

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs. PMID:22998569

  2. Efficacy of Tenofovir 1% Vaginal Gel in Reducing the Risk of HIV-1 and HSV-2 Infection

    PubMed Central

    McConville, Christopher; Boyd, Peter; Major, Ian

    2014-01-01

    Human Immunodeficiency Virus (HIV) is a retrovirus that can result in rare opportunistic infections occurring in humans. The onset of these infections is known as Acquired Immune Deficiency Syndrome (AIDS). Sexual transmission is responsible for the majority of infections 1, resulting in transmission of HIV due to infected semen or vaginal and cervical secretions containing infected lymphocytes. HIV microbicides are formulations of chemical or biological agents that can be applied to the vagina or rectum with the intention of reducing the acquisition of HIV. Tenofovir is an NRTI that is phosphorylated by adenylate kinase to tenofovir diphosphate, which in turn competes with deoxyadeosine 5’-triphosphate for incorporation into newly synthesized HIV DNA. Once incorporated, tenofovir diphosphate results in chain termination, thus inhibiting viral replication. Tenofovir has been formulated into a range of vaginal formulations, such as rings, tablets gels and films. It has been shown to safe and effective in numerous animal models, while demonstrating safety and acceptability in numerous human trials. The most encouraging results came from the CAPRISA 004 clinical trial which demonstrated that a 1% Tenofovir vaginal gel reduced HIV infection by approximately 39%. PMID:24741339

  3. The Nucleoside Analog D-carba T Blocks HIV-1 Reverse Transcription

    PubMed Central

    Boyer, Paul L.; Vu, B. Christie; Ambrose, Zandrea; Julias, John G.; Warnecke, Svenja; Liao, Chenzhong; Meier, Chris; Marquez, Victor E.; Hughes, Stephen H.

    2009-01-01

    A major pathway for HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) involves reverse transcriptase (RT) mutations that enhance ATP-dependent pyrophosphorolysis, which excises NRTIs from the end of viral DNA. We analyzed novel NRTIs for their ability to inhibit DNA synthesis of excision-proficient HIV-1 RT mutants. D-carba T is a carbocyclic nucleoside that has a 3′ hydroxyl on the pseudosugar. The 3′ hydroxyl group allows RT to incorporate additional dNTPs, which should protect D-carba TMP from excision. D-carba T can be converted to the triphosphate form by host cell kinases with moderate efficiency. D-carba T-TP is efficiently incorporated by HIV-1 RT; however, the next dNTP is added slowly to a D-carba TMP at the primer terminus. D-carba T effectively inhibits viral vectors that replicate using NRTI-resistant HIV-1 RTs, and there is no obvious toxicity in cultured cells. NRTIs based on the carbocyclic pseudosugar may offer an effective approach for the treatment of HIV-1 infections. PMID:19678643

  4. Synthesis, Activity and Structural Analysis of Novel α-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

    PubMed Central

    Chung, Suhman; Himmel, Daniel M.; Jiang, Jian-Kang; Wojtak, Krzysztof; Bauman, Joseph D.; Rausch, Jason W.; Wilson, Jennifer A.; Beutler, John A.; Thomas, Craig J.; Arnold, Eddy; Le Grice, Stuart F.J.

    2011-01-01

    The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one) potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating α-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified α-hydroxytropolones exhibit antiviral activity at non-cytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogs can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use. PMID:21568335

  5. Synthesis Activity and Structural Analysis of Novel alpha-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

    SciTech Connect

    S Chung; D Himmel; J Jiang; K Wojtak; J Bauman; J Rausch; J Wilson; J Beutler; C Thomas; et al.

    2011-12-31

    The {alpha}-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating {alpha}-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified {alpha}-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved {alpha}-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

  6. HIV Infection and Antiretroviral Therapy Have Divergent Effects on Mitochondria in Adipose Tissue

    PubMed Central

    Morse, Caryn G.; Voss, Joachim G.; Rakocevic, Goran; McLaughlin, Mary; Vinton, Carol L.; Huber, Charles; Hu, Xiaojun; Yang, Jun; Huang, Da Wei; Logun, Carolea; Danner, Robert L.; Rangel, Zoila G.; Munson, Peter J.; Orenstein, Jan M.; Rushing, Elisabeth J.; Lempicki, Richard A.; Dalakas, Marinos C.; Kovacs, Joseph A.

    2012-01-01

    Background. Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited. Methods. Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)–based ART, and HIV-negative controls. Results. The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+/HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes. Conclusions. HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART. PMID:22476717

  7. Basolateral Uptake of Nucleosides by Sertoli Cells Is Mediated Primarily by Equilibrative Nucleoside Transporter 1

    PubMed Central

    Klein, David M.; Evans, Kristen K.; Hardwick, Rhiannon N.; Dantzler, William H.; Wright, Stephen H.

    2013-01-01

    The blood-testis barrier (BTB) prevents the entry of many xenobiotic compounds into seminiferous tubules thereby protecting developing germ cells. Understanding drug transport across the BTB may improve drug delivery into the testis. Members of one class of drug, nucleoside reverse transcriptase inhibitors (NRTIs), do penetrate the BTB, presumably through interaction with physiologic nucleoside transporters. By investigating the mechanism of nucleoside transport, it may be possible to design other drugs to bypass the BTB in a similar manner. We present a novel ex vivo technique to study transport at the BTB that employs isolated, intact seminiferous tubules. Using this system, we found that over 80% of total uptake by seminiferous tubules of the model nucleoside uridine could be inhibited by 100 nM nitrobenzylmercaptopurine riboside (NBMPR, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine), a concentration that selectively inhibits equilibrative nucleoside transporter 1 (ENT1) activity. In primary cultured rat Sertoli cells, 100 nM NBMPR inhibited all transepithelial transport and basolateral uptake of uridine. Immunohistochemical staining showed ENT1 to be located on the basolateral membrane of human and rat Sertoli cells, whereas ENT2 was located on the apical membrane of Sertoli cells. Transepithelial transport of uridine by rat Sertoli cells was partially inhibited by the NRTIs zidovudine, didanosine, and tenofovir disoproxil fumarate, consistent with an interaction between these drugs and ENT transporters. These data indicate that ENT1 is the primary route for basolateral nucleoside uptake into Sertoli cells and a possible mechanism for nucleosides and nucleoside-based drugs to undergo transepithelial transport. PMID:23639800

  8. Gateways to Clinical Trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, and provides information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abiciximab, acetylcholine chloride, acetylcysteine, alefacept, alemtuzumab, alicaforsen, alteplase, aminopterin, amoxicillin sodium, amphotericin B, anastrozole, argatroban monohydrate, arsenic trioxide, aspirin, atazanavir, atorvastatin, augmerosen, azathioprine; Benzylpenicillin, BMS-284756, botulinum toxin type A, botulinum toxin type B, BQ-123, budesonide, BXT-51072; Calcium folinate, carbamazepine, carboplatin, carmustine, ceftriaxone sodium, cefuroxime axetil, chorionic gonadotropin (human), cimetidine, ciprofloxacin hydrochloride, cisplatin, citalopram hydrobromide, cladribine, clarithromycin, clavulanic acid, clofarabine, clopidogrel hydrogensulfate, clotrimazole, CNI-1493, colesevelam hydrochloride, cyclophosphamide, cytarabine; Dalteparin sodium, daptomycin, darbepoetin alfa, debrisoquine sulfate, dexrazoxane, diaziquone, didanosine, docetaxel, donezepil, doxorubicin hydrochloride liposome injection, DX-9065a; Eberconazole, ecogramostim, eletriptan, enoxaparin sodium, epoetin, epoprostenol sodium, erlizumab, ertapenem sodium, ezetimibe; Fampridine, fenofibrate, filgrastim, fluconazole, fludarabine phosphate, fluorouracil, 5-fluorouracil/epinephrine, fondaparinux sodium, formoterol fumarate; Gabapentin, gemcitabine, gemfibrozil, glatiramer; Heparin sodium, homoharringtonine; Ibuprofen, iloprost, imatinib mesilate, imiquimod, interferon alpha-2b, interferon alpha-2c, interferon-beta; KW-6002; Lamotrigine, lanoteplase, metoprolol tartrate, mitoxantrone hydrochloride; Naproxen sodium, naratriptan, Natalizumab, nelfinavir mesilate

  9. Investigation of Super Learner Methodology on HIV-1 Small Sample: Application on Jaguar Trial Data

    PubMed Central

    Houssaïni, Allal; Assoumou, Lambert; Marcelin, Anne Geneviève; Molina, Jean Michel; Calvez, Vincent; Flandre, Philippe

    2012-01-01

    Background. Many statistical models have been tested to predict phenotypic or virological response from genotypic data. A statistical framework called Super Learner has been introduced either to compare different methods/learners (discrete Super Learner) or to combine them in a Super Learner prediction method. Methods. The Jaguar trial is used to apply the Super Learner framework. The Jaguar study is an “add-on” trial comparing the efficacy of adding didanosine to an on-going failing regimen. Our aim was also to investigate the impact on the use of different cross-validation strategies and different loss functions. Four different repartitions between training set and validations set were tested through two loss functions. Six statistical methods were compared. We assess performance by evaluating R2 values and accuracy by calculating the rates of patients being correctly classified. Results. Our results indicated that the more recent Super Learner methodology of building a new predictor based on a weighted combination of different methods/learners provided good performance. A simple linear model provided similar results to those of this new predictor. Slight discrepancy arises between the two loss functions investigated, and slight difference arises also between results based on cross-validated risks and results from full dataset. The Super Learner methodology and linear model provided around 80% of patients correctly classified. The difference between the lower and higher rates is around 10 percent. The number of mutations retained in different learners also varys from one to 41. Conclusions. The more recent Super Learner methodology combining the prediction of many learners provided good performance on our small dataset. PMID:22550568

  10. In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells▿

    PubMed Central

    Vidal, Francesc; Domingo, Joan Carles; Guallar, Jordi; Saumoy, Maria; Cordobilla, Begoña; Sánchez de la Rosa, Rainel; Giralt, Marta; Álvarez, Maria Luisa; López-Dupla, Miguel; Torres, Ferran; Villarroya, Francesc; Cihlar, Tomas; Domingo, Pere

    2006-01-01

    We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P = 0.002) and TFV (P = 0.0001). The combination of 10 μM RTV and 40 μM LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs. PMID:16940060

  11. New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs.

    PubMed Central

    Pauwels, R; Andries, K; Debyser, Z; Kukla, M J; Schols, D; Breslin, H J; Woestenborghs, R; Desmyter, J; Janssen, M A; De Clercq, E

    1994-01-01

    Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces. Images PMID:7535037

  12. Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 1. Stability studies for hairless rat skin permeation.

    PubMed

    Kim, D D; Chien, Y W

    1995-09-01

    The stability of dideoxynucleoside-type anti-HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia-Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37 degrees C for at least 30 h. However, DDC and DDI degraded in the extract of the dermis following first-order kinetics at both 25 and 37 degrees C, while AZT was stable at 37 degrees C for at least 30 h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor, i.e., p-chloromercuribenzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin. PMID:8537882

  13. Factors involved in continuance of atazanavir-based regimens: Results from a cohort of HIV1-positive patients.

    PubMed

    Giacomelli, Andrea; Oreni, Letizia; Franzetti, Marco; Di Cristo, Valentina; Colella, Elisa; Ridolfo, Anna Lisa; Galli, Massimo; Rusconi, Stefano

    2016-05-01

    We evaluated predictive factors involved in durability and therapeutic failure of atazanavir (ATV)-based antiretroviral regimens with or without ritonavir (r) in real life setting. This retrospective study of HIV-1-positive patients evaluated the factors related to ATV continuance and the time-dependent probability of therapeutic failure (HIV-RNA >200 copies/mL and concomitant discontinuation of ATV). We also investigated the rate of therapeutic failure and the variations in total bilirubin levels from starting unboosted ATV-based regimens. The study involved 1030 patients: 183 treatment-naïve patients (17.8%) started ATV/r (17 subsequently switched to unboosted ATV); 653 (63.4%) switched to ATV/r from previous antiretroviral regimens (121 subsequently switched to unboosted ATV); and 194 (18.8%) switched to unboosted ATV from previous ATV-free regimens. The median ATV follow-up was 28 months (interquartile range 7-56). The risk of ATV discontinuation was significantly lower in patients switched to unboosted ATV from ATV/r (HR 0.45; p < 0.0001). The discontinuation of ATV correlated with female gender (HR 1.26; p = 0.035), use of a zidovudine/didanosine/stavudine containing backbone (HR 1.8; p = 0.004), and a baseline CD4+ cell counts of <200/μL (HR 1.54; p = 0.003), the last of which was also associated with a higher risk of therapeutic failure (HR 2.42; p = 0.001). Total bilirubin levels were significantly lower in the patients switching from ATV/r to unboosted ATV. Unboosted ATV-based therapies are safe and effective options in patients whose immuno-virological conditions are stable, and allow the long-term survival of ATV-containing regimeans. PMID:26902109

  14. Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study

    PubMed Central

    Rasmussen, Line D.; Mathiesen, Elisabeth R.; Kronborg, Gitte; Pedersen, Court; Gerstoft, Jan; Obel, Niels

    2012-01-01

    Objective In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals. Methods We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996–2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses. Results In the period 1996–1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57–5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03–5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42–7.39). In the period 1999–2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72–1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21–0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine. Conclusion Native HIV–infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM. PMID:22984529

  15. Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir.

    PubMed

    Masiá, Mar; Padilla, Sergio; Robledano, Catalina; López, Natividad; Ramos, José Manuel; Gutiérrez, Felix

    2012-03-01

    Initiation of combined antiretroviral therapy (cART) is associated with bone loss, which may be more intense with regimens including tenofovir. The underlying mechanisms are not well understood. Cross-sectional data have linked tenofovir with higher parathyroid hormone (PTH) concentrations in patients with vitamin D deficiency. We performed a longitudinal study with a 48-week follow-up to evaluate sequential changes in PTH and 25-hydroxyvitamin D [25(OH)D] levels in patients starting cART with either tenofovir/emtricitabine or abacavir/lamivudine. Fifty-seven patients were included, 31 initiating tenofovir/emtricitabine and 26 initiating abacavir/lamivudine. Median PTH levels turned out to be significantly higher among tenofovir/emtricitabine users at week 4 (p=0.01), week 24 (p=0.008), and week 36 (p=0.02), and were above the upper limits of normal values (ULN) at weeks 24, 36, and 48 only in patients receiving tenofovir/emtricitabine. 25(OH)D, serum and urine calcium and phosphate, and renal-tubular maximum reabsorption of phosphate to the glomerular filtration rate (TmP/GFR) levels did not differ between the two treatment arms over the study period. Among tenofovir/emtricitabine users, median (interquartile range) PTH concentrations were significantly higher in patients with suboptimal 25(OH)D levels (<30 μg/liter) at week 24 [63 (57.8-82.4) ng/liter vs. 54.3 (34.4-63.067.5) ng/liter, p=0.05] and week 48 [67.5 (59.6-86.0) ng/liter vs. 41.9 (37.3-68.8) ng/liter, p=0.03]. A multivariable logistic regression model showed that tenofovir/emtricitabine use was an independent predictor of high PTH levels (≥53 ng/liter). Starting cART with tenofovir regimens is associated with an elevation in PTH plasma concentrations soon after introducing the drug. Suboptimal baseline 25(OH)D levels increase the risk of developing secondary hyperparathyroidism among tenofovir users. PMID:21639815

  16. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-03-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulfate, abatacept, adalimumab, ademetionine, adjuvanted influenza vaccine, alefacept, alemtuzumab, amlodipine, amphotericin B, anakinra, aripiprazole, aspirin, axitinib; Betamethasone dipropionate, bevacizumab, biphasic insulin aspart, bortezomib, bosentan, botulinum toxin type B, BQ-123; Calcium folinate, canertinib dihydrochloride, carboplatin, carmustine, cetirizine hydrochloride, cetuximab, cholecalciferol, ciclesonide, ciclosporin, cinacalcet hydrochloride, cisplatin, clarithromycin, clofazimine, cold-adapted influenza vaccine trivalent, CpG-7909; Darbepoetin alfa, darifenacin hydrobromide, DB-289, desloratadine, Dexamet, dicycloverine hydrochloride, dimethyl fumarate, docetaxel, dolastatin 10, drospirenone, drospirenone/estradiol, duloxetine hydrochloride; Ecogramostim, edotecarin, efaproxiral sodium, enalapril maleate, epoetin beta, epoprostenol sodium, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, estradiol, etanercept; Fluconazole, fludarabine phosphate, fluorouracil; Gefitinib, gemcitabine, Ghrelin (human), glibenclamide, glimepiride, GTI-2040; Haloperidol, human insulin, hydrocortisone probutate; Imatinib mesylate, indisulam, influenza vaccine, inhaled insulin, insulin aspart, insulin glulisine, insulin lispro, irinotecan, ispronicline; Lamivudine, lamivudine/zidovudine/abacavir sulfate, lapatinib, letrozole, levocetirizine, lomustine, lonafarnib, lumiracoxib;Magnesium sulfate, MD-1100, melphalan, metformin hydrochloride, methotrexate, metoclopramide hydrochloride, mitiglinide calcium hydrate, monophosphoryl lipid A, montelukast sodium, motexafin gadolinium

  17. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study

    PubMed Central

    2016-01-01

    Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma

  18. Outcomes in a Cohort of Patients Started on Antiretroviral Treatment and Followed up for a Decade in an Urban Clinic in Uganda

    PubMed Central

    Castelnuovo, Barbara; Kiragga, Agnes; Musaazi, Joseph; Sempa, Joseph; Mubiru, Frank; Wanyama, Jane; Wandera, Bonnie; Kamya, Moses Robert; Kambugu, Andrew

    2015-01-01

    Background Short-medium term studies from sub-Saharan Africa show that, despite high early mortality, substantial loss to program, and high rates toxicity, patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However, these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. Objectives We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. Methods We report 10-years outcomes including mortality, retention, CD4-count response, virological outcomes, ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. Results Of 559 patients, 69.1% were female, median age (IQR) was 38 (33–44) years, median CD4-count (IQR) 98 (21–163) cell/μL; 74% were started on stavudine, lamivudine and nevirapine, 26% on zidovudine, lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15, 95%, CI 0.12–0.18). The median CD4 count increased from 98 to 589 cell/μL (IQR: 450–739 cell/μL) with a median increase of 357 cells/μL (IQR: 128–600 cells/μL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI-based regimen due to confirmed treatment failure. Conclusions Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging, particularly the remarkable and incremental immune-recovery and a satisfactory rate of virologic suppression. PMID:26642214

  19. Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation

    PubMed Central

    Lee, Jeonghwan; Cho, Jang-Hee; Lee, Jong Soo; Ahn, Dong-Won; Kim, Chan-Duck; Ahn, Curie; Jung, In Mok; Han, Duck Jong; Lim, Chun Soo; Kim, Yon Su; Kim, Young Hoon; Lee, Jung Pyo

    2016-01-01

    Abstract Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs. Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 ± 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation. Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155–4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289–6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341–3.426; P = 0.001). KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver

  20. Central nervous system penetration-effectiveness rank does not reliably predict neurocognitive impairment in HIV-infected individuals

    PubMed Central

    Libertone, Raffaella; Lorenzini, Patrizia; Balestra, Pietro; Pinnetti, Carmela; Ricottini, Martina; Maddalena Plazzi, Maria; Menichetti, Samanta; Zaccarelli, Mauro; Nicastri, Emanuele; Bellagamba, Rita; Ammassari, Adriana; Antinori, Andrea

    2014-01-01

    Introduction Central nervous system (CNS) penetration-effectiveness (CPE) rank was proposed in 2008 as an estimate of penetration of ARV regimen into the CNS, and validated as predictor of CSF HIV-1 replication. Results on predictive role of CPE on neurocognitive and clinical outcome were conflicting. Materials and Methods Retrospective, cross-sectional analysis of neurocognitive profile in HIV-infected cART-treated patients. All patients underwent neuropsychological (NP) assessment by standardized battery of 14 tests on 5 different domains. People were classified as having NCI if they scored >1 standard deviation (SD) below the normal mean in at least two tests, or >2 SD below in one test. Linear and logistic regression analyses were fitted using as outcome Npz8 and impaired/not impaired respectively. Results A total of 660 HIV-infected cART-treated individuals from 2009 to 2014, contributing a total of 1003 tests (mean age 49 (IQR 43–56), male 82%; median current CD4 586/mm3; 18% HCV infected; HIV-RNA <40 cp/mL in 84%). Current ARV regimen was 2NRTIs+1NNRTI 50.3%, 2NRTI+1PI/r in 32.6%, NRTI sparing in 11.1%. Mean CPE of current regimens was 6.6 (95% CI 6.5–6.7). As per test multivariable analysis, higher CPE values were associated to poor NP tasks (Beta=−0,09; 95% CI −0,14 −0,03; p=0.002 at multivariable linear regression). The association between higher CPE and increased NCI risk was confirmed at multivariable logistic regression, with a 1.24-fold risk of NCI occurrence for each point increase of CPE of current regimen at the time of NP testing (see Table 1). In a sensitivity analysis performed only on patients at the first NP test, the association between higher CPE and poor NP tasks and enhanced NCI risk was only marginally confirmed (Beta=−0,05; [−0,12–0,02]; p=0,19; OR 1,13 [0,95–1,34]; p=0.17). Older age, longer time from HIV diagnosis, current CD4 count <350 cell/mm3 and lower education level were all associated to an increased risk of

  1. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years

    PubMed Central

    Strehlau, Renate; Donati, Anamaria Pena; Arce, Pedro Martinez; Lissens, Jurgen; Yang, Rong; Biguenet, Sophie; Cambilargiu, Daniela; Hardy, Hélène; Correll, Todd

    2015-01-01

    Introduction PRINCE-1 is an ongoing prospective, international, multicentre, nonrandomized, two-stage clinical trial assessing safety and efficacy of once-daily atazanavir (ATV) powder boosted with ritonavir (RTV) liquid plus optimized dual nucleoside reverse-transcriptase inhibitor (NRTI) background therapy in antiretroviral (ARV)-naïve and -experienced children with HIV-1 infection aged ≥3 months to <6 years. Methods Children with HIV-1 infection without prior ATV exposure and with a screening HIV-1 RNA ≥1000 copies/mL were enrolled. The dosing of ATV powder, boosted with 80 mg RTV liquid, was based on three baseline weight bands (5 to <10 kg=150 mg, 10 to <15 kg=200 mg and 15 to <25 kg=250 mg). Results Of the 56 treated patients, 46 completed 48 weeks of therapy, 67.9% were from Africa and 60.7% were ART-naïve. Median ages at baseline were 6, 35 and 55 months, and proportions with HIV-1 RNA >100,000 were 85.7, 52.6 and 25% in the three baseline weight bands, respectively. No unexpected safety events occurred and no deaths were reported. Over 48 weeks, upper respiratory tract infections, diarrhoea, vomiting and Grade 3 to 4 hyperbilirubinaemia occurred in 35.7, 35.7, 28.6, and 9.4% of patients, respectively; five patients (8.9%) discontinued due to adverse events (AEs); and 11 patients (19.6%) experienced serious adverse events. At Week 48, using a modified intent-to-treat analysis (two patients were excluded because they switched to ATV capsules before Week 48), 61.1 and 74.1% of patients overall had an HIV-1 RNA level <50 copies/mL and <400 copies/mL, respectively. Virologic suppression rates increased across the lowest to highest baseline weight bands (47.6, 68.4 and 71.4% had HIV-1 RNA <50 copies/mL, and 66.7, 73.7 and 85.7% had HIV-RNA <400 copies/mL, respectively) but did not differ meaningfully between ARV-naïve and -experienced patients. Overall, the median change from baseline in CD4 cell count was +363 cells/mm3, and the median change from

  2. Emergence of Resistance to Protease Inhibitor Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients: Selection of Four Alternative Viral Protease Genotypes and Influence of Viral Susceptibility to Coadministered Reverse Transcriptase Nucleoside Inhibitors

    PubMed Central

    Maguire, Michael; Shortino, Denise; Klein, Astrid; Harris, Wendy; Manohitharajah, Varsha; Tisdale, Margaret; Elston, Robert; Yeo, Jane; Randall, Sharon; Xu, Fan; Parker, Hayley; May, Jackie; Snowden, Wendy

    2002-01-01

    Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I+I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P = 0.014 and P = 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure. PMID:11850255

  3. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection.

    PubMed

    Greig, Sarah L; Deeks, Emma D

    2016-06-01

    Tenofovir alafenamide (tenofovir AF) is a novel oral prodrug of the nucleos(t)ide reverse transcriptase inhibitor (NRTI) tenofovir that has several pharmacological advantages over tenofovir disoproxil fumarate (tenofovir DF), including increased plasma stability and reduced tenofovir systemic exposure. Tenofovir AF has been coformulated with elvitegravir, cobicistat and emtricitabine as a once-daily, single-tablet regimen (elvitegravir/cobicistat/emtricitabine/tenofovir AF; Genvoya(®)) for the treatment of adults and adolescents with HIV-1 infection. With regard to establishing and/or maintaining virological suppression over 48 weeks in randomized, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF was noninferior to elvitegravir/cobicistat/emtricitabine/tenofovir DF in antiretroviral therapy (ART)-naive adults, and statistically superior (subsequent to established noninferiority) to ongoing treatment with tenofovir DF-containing regimens in ART-experienced adults with virological suppression. In single-arm, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF also provided high rates of virological suppression among ART-naive adolescents and ART-experienced adults with stable renal impairment. In general, elvitegravir/cobicistat/emtricitabine/tenofovir AF was well tolerated and associated with more favourable renal and bone parameters, but a less favourable lipid profile, than tenofovir DF-containing regimens. Thus, elvitegravir/cobicistat/emtricitabine/tenofovir AF is an alternative single-tablet regimen for adults and adolescents with HIV-1 infection, particularly those with an estimated creatinine clearance of ≥30 to <50 mL/min or an increased risk of tenofovir DF-related bone toxicity. PMID:27189707

  4. Detecting primary drug-resistant mutations in Korean HIV patients using ultradeep pyrosequencing.

    PubMed

    Cho, Min-Chul; Park, Chang-Wook; Park, Borae G; Oh, Heung-Bum; Choi, Sang-Ho; Choi, Sung-Eun; Cho, Nam-Sun

    2016-08-01

    HIV primary resistance, drug resistance in treatment-naïve patients, is an emerging public health issue. The prevalence of HIV primary resistance mutations down to the level of 1% minor variants was investigated using ultradeep pyrosequencing (UDPS) in HIV-positive Korean blood donors and in treatment naïve chronic patients for the comparison. The entire pol region was sequenced from 25 HIV-positive blood donors, and 18 treatment-naïve chronic HIV patients. UDPS was successful in 19 blood donors and 18 chronic patients. In total, 1,011,338 sequence reads were aligned, and 28,093 sequence reads were aligned on average per sample. The prevalence of HIV primary resistance mutations in the HIV-positive blood donors and chronic HIV patients were 63.2% and 44.4% according to UDPS, respectively. Protease inhibitor (PI) drugs demonstrated different patterns in HIV-positive blood donors and chronic HIV patients, whereas non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI), and integrase inhibitor (INI) drugs showed similar patterns between the two groups. Higher level of primary resistance prevalence was observed mainly because UDPS method could detect mutations in minor variants with 1-10% frequency. The higher resistance prevalence was observed in HIV-positive blood donors than in chronic patients. Considering that treatments for HIV-infected patients were recently amended to start at an earlier stage, information about degree of drug resistance to each drug between the two groups would help to establish future policies, design additional clinical trials, assess HIV patient care in Korea. PMID:27109046

  5. Dyslipidemia and Cardiovascular Disease Risk Factor Management in HIV-1-Infected Subjects Treated with HAART in the Spanish VACH Cohort

    PubMed Central

    Domingo, Pere; Suarez-Lozano, Ignacio; Teira, Ramón; Lozano, Fernando; Terrón, Alberto; Viciana, Pompeyo; González, Juan; Galindo, Mª José; Geijo, Paloma; Vergara, Antonio; Cosín, Jaime; Ribera, Esteban; Roca, Bernardino; Garcia-Alcalde, Mª Luisa; Sánchez, Trinitario; Torres, Ferran; Lacalle, Juan Ramón; Garrido, Myriam

    2008-01-01

    Background: There is increasing evidence that metabolic adverse effects associated with antiretroviral therapy may translate into an increased cardiovascular risk in HIV-1-infected patients. Objectives: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-1-infected persons, and to investigate any association between them, stage of HIV-1 disease, and use of antiretroviral therapies. Methods: Multicentric, cross-sectional analysis of CVD risk factors of treated patients in the VACH cohort. The data collected includes: demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidemia, body mass index, stage of HIV-1 infection, and antiretroviral therapy. Results: The analysis included 2358 patients. More than 18% of the study population was at an age of appreciable risk of CVD. 1.7% had previous CVD and 59.2% were smokers. Increased prevalence of elevated total cholesterol was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 3.34; 95% confidence interval (CI), 1.77–6.31], PI but no NNRTI (OR, 4.04; 95% CI, 2.12–7.71), or NNRTI + PI (OR, 17.77; 95% CI, 7.24–43.59) compared to patients treated only with nucleoside reverse transcriptase inhibitors (NRTI). Higher CD4 cell count, lower plasma HIV-1 RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated cholesterol levels. The use of lipid lowering agents was very low among our patients. Conclusion: Patients in the VACH cohort present multiple known risk factors for CVD, and a very low rate of lipid lowering therapy use. NNRTI and/or PI-based antiretroviral therapies are associated with the worst lipid profile. This is more frequent in older subjects with greater CD4 counts and controlled HIV-1 replication. PMID:18923695

  6. Cellular HIV-1 DNA quantitation in patients during simplification therapy with protease inhibitor-sparing regimens.

    PubMed

    Sarmati, Loredana; Parisi, Saverio Giuseppe; Nicastri, Emanuele; d'Ettorre, Gabriella; Andreoni, Carolina; Dori, Luca; Gatti, Francesca; Montano, Marco; Buonomini, Anna Rita; Boldrin, Caterina; Palù, Giorgio; Vullo, Vincenzo; Andreoni, Massimo

    2007-07-01

    Simplified regimens containing protease-inhibitors (PI)-sparing combinations were used in patients with virological suppression after prolonged highly active antiretroviral therapy. This study evaluated the total HIV-1 DNA quantitation as a predictor of long-term success for PI-sparing simplified therapy. Sixty-two patients were enrolled in a prospective non-randomized cohort. All patients have been receiving a triple-therapy regimen, two nucleoside reverse transcriptase inhibitors (NRTIs) plus one PI, for at least 9 months and were characterized by undetectable plasma HIV-1 RNA levels (<50 cp/ml) for at least 6 months. Patients were changed to a simplified PI-sparing regimen to overcome PI-associated adverse effects. HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and at the end of follow-up. Patients with proviral DNA levels below the median value (226 copies/10(6) PBMCs) had a significant higher CD4 cell count at nadir (P = 0.003) and at enrolment (P = 0.001) with respect to patients with HIV-DNA levels above the median value. At month 18, 53 out of 62 (85%) patients on simplified regimen showed virological success, 4 (6.4%) patients experienced virological failure and 5 (8%) patients showed viral blip. At logistic regression analysis, HIV-DNA levels below 226 copies/10(6) PBMCs at baseline were associated independently to a reduced risk of virological failure or viral blip during simplified therapy (OR 0.002, 95% CI 0.001-0.46, P = 0.025). The substitution of PI with NRTI or non-NRTIs may represent an effective treatment option. Indeed, treatment failure or viral blip were experienced by 6% and 8% of the patients on simplified therapy, respectively. In addition, sustained suppression of the plasma viral load was significantly correlated with low levels of proviral DNA before treatment simplification. PMID:17516532

  7. The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study

    PubMed Central

    2013-01-01

    Objective To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. Design Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration. Methods Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the ‘intention-to-treat’ effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting. Results A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens. Conclusions Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine. PMID:22546987

  8. The prevalence of transmitted drug resistance in newly diagnosed HIV-infected individuals in Croatia: the role of transmission clusters of men who have sex with men carrying the T215S surveillance drug resistance mutation.

    PubMed

    Grgic, Ivana; Lepej, Snjezana Zidovec; Lunar, Maja M; Poljak, Mario; Vince, Adriana; Vrakela, Ivana Baca; Planinic, Ana; Seme, Katja; Begovac, Josip

    2013-02-01

    The aim of this study was to determine the prevalence of transmitted drug resistance (TDR) in newly diagnosed and treatment-naive HIV-infected patients from Croatia and evaluate a possible contribution of transmission clusters to the spread of resistant virus. The study enrolled treatment-naive HIV-infected patients that entered clinical care at the Croatian Reference Center for HIV/AIDS between 2006 and 2008. The protease gene and a part of the reverse transcriptase gene of the HIV-1 genome were sequenced by using the Trugene HIV-1 Genotyping System. The prevalence of transmitted drug resistance was analyzed by using the surveillance drug resistance mutations (SDRM) list recommended by the WHO in 2009. We report findings for 118 of 180 eligible patients (65.6% coverage). SDRM were detected in 26 of 118 patients (22.0%) who were infected with subtype B and belonged mostly to the men having sex with men (MSM). The majority of patients with primary resistance carried SDRM associated with resistance to nucleoside analogues reverse transcriptase inhibitors (NRTIs, 23 of 118 patients, 19.5%). The most frequently found NRTI SDRM was T215S (17 of 118 patients, 14.4%). SDRM associated with resistance to nonnucleoside reverse transcriptase inhibitors were detected in three (2.5%) patients and primary resistance to protease inhibitors was not detected. Non-B subtypes were detected in 13/118 patients (11%). A total of 12 transmission pairs and eight distinct transmission clusters were identified with the largest cluster harboring sequences from 19 patients; among them all but two were carrying the T215S mutation. This study showed a high prevalence of TDR in newly diagnosed MSM from Croatia and is an important contribution concerning the relationship between local transmission clusters and the spread of resistant virus. PMID:22906365

  9. The prevalence and determinants of drug-resistance-associated mutations in the HIV-1-infected MSM population of Henan Province in China.

    PubMed

    Hou, Li-Juan; Wang, Hong-Wei; Duan, Shu-Peng; Zhuo, Ya; Zhou, Yan-Cai; Wu, Hong-Jie; Shen, Bao-Sheng

    2015-08-01

    To estimate the prevalence of human immunodeficiency virus (HIV) drug resistance (DR) in a population of men who have sex with men (MSM) from Henan Province of China and to identify the DR-associated HIV-1 mutations in these MSM. The HIV-positive status of the MSM subjects in this study was confirmed using ELISA and Western blotting. The MSM subjects were classified into non-treatment group (n = 106) and treatment group (n = 313). CD4(+) T-lymphocyte counts were obtained by flow cytometry, and viral load was measured by branched DNA (bDNA) signal amplification assay. HIV-1 genotypic resistance tests were performed by sequence analysis of the HIV-1 protease and reverse transcriptase genes. In the non-treatment group, 15 patients (14.2 %) displayed DR to non-nucleoside reverse transcriptase inhibitor (NNRTI). In the treatment group, the failure rate of viral suppression was 38.33 % and the DR rate was 33.2 %, which was higher than the rate observed in the non-treatment group (P < 0.05). The incidence of mutations corresponding to NNRTI resistance was significantly higher than the incidence of mutations corresponding to nucleoside reverse transcriptase inhibitor (NRTI) resistance (32.9 % vs. 26.5 %) in the cohort. After antiretroviral therapy (ART), the frequencies of K103N, G190A, Y181C, and V106A mutations were highly elevated. Logistic regression analysis results showed that duration of treatment, poor treatment compliance, drug abuse and homosexual orientation are the major risk factors for DR in this MSM population (all P < 0.05). Our results showed that DR-associated mutations in the HIV-1-infected MSM population increased significantly after ART. Furthermore, duration of treatment, poor treatment compliance, drug abuse and homosexual orientation were identified as the risk factors for DR in the MSM population from Henan Province in China. PMID:26077516

  10. Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening.

    PubMed

    La, Jennifer; Latham, Catherine F; Tinetti, Ricky N; Johnson, Adam; Tyssen, David; Huber, Kelly D; Sluis-Cremer, Nicolas; Simpson, Jamie S; Headey, Stephen J; Chalmers, David K; Tachedjian, Gilda

    2015-06-01

    Fragment-based screening methods can be used to discover novel active site or allosteric inhibitors for therapeutic intervention. Using saturation transfer difference (STD) NMR and in vitro activity assays, we have identified fragment-sized inhibitors of HIV-1 reverse transcriptase (RT) with distinct chemical scaffolds and mechanisms compared to nonnucleoside RT inhibitors (NNRTIs) and nucleoside/nucleotide RT inhibitors (NRTIs). Three compounds were found to inhibit RNA- and DNA-dependent DNA polymerase activity of HIV-1 RT in the micromolar range while retaining potency against RT variants carrying one of three major NNRTI resistance mutations: K103N, Y181C, or G190A. These compounds also inhibit Moloney murine leukemia virus RT but not the Klenow fragment of Escherichia coli DNA polymerase I. Steady-state kinetic analyses demonstrate that one of these fragments is a competitive inhibitor of HIV-1 RT with respect to deoxyribonucleoside triphosphate (dNTP) substrate, whereas a second compound is a competitive inhibitor of RT polymerase activity with respect to the DNA template/primer (T/P), and consequently also inhibits RNase H activity. The dNTP competing RT inhibitor retains activity against the NRTI-resistant mutants K65R and M184V, demonstrating a drug resistance profile distinct from the nucleotide competing RT inhibitors indolopyridone-1 (INDOPY-1) and 4-dimethylamino-6-vinylpyrimidine-1 (DAVP-1). In antiviral assays, the T/P competing compound inhibits HIV-1 replication at a step consistent with an RT inhibitor. Screening of additional structurally related compounds to the three fragments led to the discovery of molecules with improved potency against HIV-1 RT. These fragment inhibitors represent previously unidentified scaffolds for development of novel drugs for HIV-1 prevention or treatment. PMID:26038551

  11. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy.

    PubMed

    Karamchand, Sumanth; Leisegang, Rory; Schomaker, Michael; Maartens, Gary; Walters, Lourens; Hislop, Michael; Dave, Joel A; Levitt, Naomi S; Cohen, Karen

    2016-03-01

    Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged. PMID:26945366

  12. National Prevalence and Trends of HIV Transmitted Drug Resistance in Mexico

    PubMed Central

    Avila-Ríos, Santiago; García-Morales, Claudia; Garrido-Rodríguez, Daniela; Ormsby, Christopher E.; Hernández-Juan, Ramón; Andrade-Villanueva, Jaime; González-Hernández, Luz A.; Torres-Escobar, Indiana; Navarro-Álvarez, Samuel; Reyes-Terán, Gustavo

    2011-01-01

    Background Transmitted drug resistance (TDR) remains an important concern for the management of HIV infection, especially in countries that have recently scaled-up antiretroviral treatment (ART) access. Methodology/Principal Findings We designed a study to assess HIV diversity and transmitted drug resistance (TDR) prevalence and trends in Mexico. 1655 ART-naïve patients from 12 Mexican states were enrolled from 2005 to 2010. TDR was assessed from plasma HIV pol sequences using Stanford scores and the WHO TDR surveillance mutation list. TDR prevalence fluctuations over back-projected dates of infection were tested. HIV subtype B was highly prevalent in Mexico (99.9%). TDR prevalence (Stanford score>15) in the country for the study period was 7.4% (95% CI, 6.2∶8.8) and 6.8% (95% CI, 5.7∶8.2) based on the WHO TDR surveillance mutation list. NRTI TDR was the highest (4.2%), followed by NNRTI (2.5%) and PI (1.7%) TDR. Increasing trends for NNRTI (p = 0.0456) and PI (p = 0.0061) major TDR mutations were observed at the national level. Clustering of viruses containing minor TDR mutations was observed with some apparent transmission pairs and geographical effects. Conclusions TDR prevalence in Mexico remains at the intermediate level and is slightly lower than that observed in industrialized countries. Whether regional variations in TDR trends are associated with differences in antiretroviral drug usage/ART efficacy or with local features of viral evolution remains to be further addressed. PMID:22110765

  13. Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase

    PubMed Central

    Boyer, Paul L.; Das, Kalyan; Arnold, Eddy

    2015-01-01

    Although anti-human immunodeficiency virus type 1 (HIV-1) therapies have become more sophisticated and more effective, drug resistance continues to be a major problem. Zidovudine (azidothymidine; AZT) was the first nucleoside reverse transcriptase (RT) inhibitor (NRTI) approved for the treatment of HIV-1 infections and is still being used, particularly in the developing world. This drug targets the conversion of single-stranded RNA to double-stranded DNA by HIV-1 RT. However, resistance to the drug quickly appeared both in viruses replicating in cells in culture and in patients undergoing AZT monotherapy. The primary resistance pathway selects for mutations of T215 that change the threonine to either a tyrosine or a phenylalanine (T215Y/F); this resistance pathway involves an ATP-dependent excision mechanism. The pseudo-sugar ring of AZT lacks a 3′ OH; RT incorporates AZT monophosphate (AZTMP), which blocks the end of the viral DNA primer. AZT-resistant forms of HIV-1 RT use ATP in an excision reaction to unblock the 3′ end of the primer strand, allowing its extension by RT. The T215Y AZT resistance mutation is often accompanied by two other mutations, M41L and L210W. In this study, the roles of these mutations, in combination with T215Y, were examined to determine whether they affect polymerization and excision by HIV-1 RT. The M41L mutation appears to help restore the DNA polymerization activity of RT containing the T215Y mutation and also enhances AZTMP excision. The L210W mutation plays a similar role, but it enhances excision by RTs that carry the T215Y mutation when ATP is present at a low concentration. PMID:26324274

  14. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

    PubMed Central

    Karamchand, Sumanth; Leisegang, Rory; Schomaker, Michael; Maartens, Gary; Walters, Lourens; Hislop, Michael; Dave, Joel A.; Levitt, Naomi S.; Cohen, Karen

    2016-01-01

    Abstract Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10–1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged. PMID:26945366

  15. Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case–control study using centralized ultrasensitive 454 pyrosequencing

    PubMed Central

    Cozzi-Lepri, Alessandro; Noguera-Julian, Marc; Di Giallonardo, Francesca; Schuurman, Rob; Däumer, Martin; Aitken, Sue; Ceccherini-Silberstein, Francesca; D'Arminio Monforte, Antonella; Geretti, Anna Maria; Booth, Clare L.; Kaiser, Rolf; Michalik, Claudia; Jansen, Klaus; Masquelier, Bernard; Bellecave, Pantxika; Kouyos, Roger D.; Castro, Erika; Furrer, Hansjakob; Schultze, Anna; Günthard, Huldrych F.; Brun-Vezinet, Francoise; Paredes, Roger; Metzner, Karin J.; Paredes, Roger; Metzner, Karin J.; Cozzi-Lepri, Alessandro; Schuurman, Rob; Brun-Vezinet, Francoise; Günthard, Huldrych; Ceccherini-Silberstein, Francesca; Kaiser, Rolf; Geretti, Anna Maria; Brockmeyer, Norbert; Masquelier, Bernard; Dabis, F.; Bruyand, M.; Chêne, G.; Dabis, F.; Lawson-Ayayi, S.; Thiébaut, R.; Wittkop, L.; André, K.; Bonnal, F.; Bonnet, F.; Bernard, N.; Caunègre, L.; Cazanave, C.; Ceccaldi, J.; Chossat, I.; Courtaud, K.; Dauchy, F. A.; De Witte, S.; Dupon, M.; Dupont, A.; Duffau, P.; Dutronc, H.; Farbos, S.; Gaborieau, V.; Gemain, M. C.; Gerard, Y.; Greib, C.; Hessamfar, M.; Lacoste, D.; Lataste, P.; Lazaro, E.; Longy-Boursier, M.; Malvy, D.; Meraud, J. P.; Mercié, P.; Monlun, E.; Morlat, P.; Neau, D.; Ochoa, A.; Pellegrin, J. L.; Pistone, T.; Receveur, M. C.; Schmeltz, J. Roger; Tchamgoué, S.; Vandenhende, M. A.; Vareil, M.O.; Viallard, J. F.; Moreau, J. F.; Pellegrin, I.; Fleury, H.; Lafon, M. E.; Masquelier, B.; Reigadas, S.; Trimoulet, P.; Bouchet, S.; Breilh, D.; Molimard, M.; Titier, K.; Haramburu, F.; Miremont-Salamé., G.; Blaizeau, M. J.; Decoin, M.; Delaune, J.; Delveaux, S.; D'Ivernois, C.; Hanapier, C.; Leleux, O.; Lenaud, E.; Uwamaliya-Nziyumvira, B.; Sicard, X.; Geffard, S.; Le Marec, F.; Conte, V.; Frosch, A.; Leray, J.; Palmer, G.; Touchard, D.; Bonnet, F.; Breilh, D.; Chêne, G.; Dabis, F.; Dupon, M.; Fleury, H.; Malvy, D.; Mercié, P.; Morlat, P.; Neau, D.; Pellegrin, I.; Pellegrin, J. L.; Bouchet, S.; Gaborieau, V.; Lacoste, D.; Tchamgoué, S.; Thiébaut, R.; Losso, M.; Kundro, M.; Ramos Mejia, J. M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Skinhøj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Katlama, C.; Viard, J. P.; Girard, P. M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Bogner, J.; Fätkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; HassounRambam, G.; Elinav, H.; HaouziHadassah, M.; EspositoI, R.; Mazzotta, F.; Vullo, V.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Monforte, A. D'Arminio; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Antinori, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Puoti, M.; Quiros Roldan, E.; Rusconi, S.; Cozzi-Lepri, A.; Cicconi, P.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Carletti, F.; Carrara, S.; Castrogiovanni, A.; Di Caro, A.; Petrone, F.; Prota, G.; Quartu, S.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Vanino, E.; Verucchi, G.; Castelli, F.; Quiros Roldan, E.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Lo Caputo, S.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Bonfanti, P.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; D'Arminio Monforte, A.; Ridolfo, A. L.; Piolini, R.; Castagna, A.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Marchetti, G.; Mussini, C.; Puzzolante, C.; Gori, A.

    2015-01-01

    Objectives It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. Methods This Europe-wide case–control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%–25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. Results Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35–5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76–6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12–5.18, P = 0.024). A dose–effect relationship between virological failure and mutational load was found. Conclusions Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART. PMID:25336166

  16. Learning from past treatments and their outcome improves prediction of in vivo response to anti-HIV therapy.

    PubMed

    Saigo, Hiroto; Altmann, Andre; Bogojeska, Jasmina; Müller, Fabian; Nowozin, Sebastian; Lengauer, Thomas

    2011-01-01

    Infections with the human immunodeficiency virus type 1 (HIV-1) are treated with combinations of drugs. Unfortunately, HIV responds to the treatment by developing resistance mutations. Consequently, the genome of the viral target proteins is sequenced and inspected for resistance mutations as part of routine diagnostic procedures for ensuring an effective treatment. For predicting response to a combination therapy, currently available computer-based methods rely on the genotype of the virus and the composition of the regimen as input. However, no available tool takes full advantage of the knowledge about the order of and the response to previously prescribed regimens. The resulting high-dimensional feature space makes existing methods difficult to apply in a straightforward fashion. The machine learning system proposed in this work, sequence boosting, is tailored to exploiting such high-dimensional information, i.e. the extraction of longitudinal features, by utilizing the recent advancements in data mining and boosting. When applied to predicting the latest treatment outcome for 3,759 treatment-experienced patients from the EuResist integrated database, sequence boosting achieved superior performance compared to SVMs with RBF kernels. Moreover, sequence boosting allows an easy access to the discriminative treatment information. Analysis of feature importance values provided by our model confirmed known facts regarding HIV treatment. For instance, application of potent and recently licensed drugs was beneficial for patients, and, conversely, the patient group that was subject to NRTI mono-therapies in the past had poor treatment perspectives today. Furthermore, our model revealed novel biological insights. More precisely, the combination of previously used drugs with their in vivo response is more informative than the information of previously used drugs alone. Using this information improves the performance of systems for predicting therapy outcome. PMID:21291416

  17. Aging and HIV/AIDS: pathogenetic role of therapeutic side effects

    PubMed Central

    Torres, Rebecca A; Lewis, William

    2014-01-01

    The intersection of aging and HIV/AIDS is a looming ‘epidemic within an epidemic.’ This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active anti-retroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies. PMID:24336070

  18. Suboptimal adherence associated with virological failure and resistance mutations to first-line highly active antiretroviral therapy (HAART) in Bangalore, India

    PubMed Central

    Ekstrand, Maria L.; Shet, Anita; Chandy, Sara; Singh, Girija; Shamsundar, Ranjani; Madhavan, Vidya; Saravanan, Shanmugam; Heylen, Elsa; Kumarasamy, Nagalingeswaran

    2010-01-01

    This study was conducted to examine the relationship between adherence, viral load (VL) and resistance among outpatients receiving highly active antiretroviral therapy (HAART) in Bangalore, India. In total, 552 outpatients were recruited and VL testing was conducted for all study participants. HIV-1 genotypic resistance testing was performed for 92 participants with a VL ≥ 1000 copies/ml. Interpretation of resistance mutations was performed according to the Stanford database. Past-month adherence and treatment interruptions for >48 h were assessed via self-report. At baseline, 34 participants (6%) reported <95% past-month adherence and 110 (20%) reported a history of >48 h treatment interruptions. Combining the two adherence measures, 22% of participants were classified as ‘suboptimally adherent’. In total, 24% of study participants (n = 132) had a detectable VL. Among the 92 samples sent for resistance testing, 68% had at least one nucleoside reverse transcriptase inhibitor (NRTI) mutation, with M184V being the most common (62%) and with 48% having thymidine analogue mutations. Moreover, 72% had at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation and 23% had three or more NNRTI mutations. Both adherence measures were significantly associated with VL (P < 0.001). Suboptimal adherence was significantly associated with resistance mutations (P < 0.02). The findings illustrate for the first time the strong association between suboptimal adherence, treatment failure and drug resistance to first-line HAART in India. The predictive value of standard adherence measures was improved by including treatment interruption data. The observed mutations can jeopardise future treatment options, especially in light of limited access to second-line treatments. To develop effective adherence interventions, research is needed to examine culturally-specific reasons for treatment interruptions. PMID:21516199

  19. Foscarnet, zidovudine and dolutegravir combination efficacy and tolerability for late stage HIV salvage therapy: A case-series experience.

    PubMed

    Delory, Tristan; Papot, Emmanuelle; Rioux, Christophe; Charpentier, Charlotte; Auge-Courtoi, Claire; Michard, Florence; Peytavin, Gilles; Descamps, Diane; Matheron, Sophie; Yazdanpanah, Yazdan

    2016-07-01

    Salvage therapy including foscarnet (PFA), zidovudine (ZDV) and an optimized background ART (OBT) has been shown to be effective in patients with advanced HIV infection, and no therapeutic options. Dolutegravir (DTG) may offer a more active combination. Objective was to describe efficacy and tolerability of PFA-ZDV-DTG containing regimen. In our cohort, we identified patients who: (i) had plasma HIV-1 RNA load (pVL) >50 c/ml (>100 for HIV-2) on combination ART (cART); (ii) had at least 1 PI/r, 1 NRTI, 1 NNRTI (for HIV-1), and at least 1 raltegravir resistance mutations; (iii) were naive to DTG; and (iv) initiated on a PFA-ZDV-DTG containing-regimen with 48 weeks (W48) of follow-up. Out of 5 patients, 2 were infected with HIV-2. At PFA-ZDV-DTG initiation, CD4 cell count was (/mm(3) ) of 64, 40, 10, in HIV-1, and 37, 199, in HIV-2 infected patients; and pVL (log10 c/ml) of 4.8, 5.1, 4.4, in HIV-1, and 3.6, 4.2, in HIV-2 infected patients, respectively. Median OBT genotypic sensitivity score was 1.5 [1-2]. PFA was discontinued in one patient, due to an acute renal failure. At W48, one HIV-1 infected patient had a pVL <50 c/ml and two <200 c/ml; the two HIV-2 infected patients had pVL >100 c/ml. No lack of treatment adherence was observed. In treatment experienced HIV-infected patients, failing cART and without other therapeutic options, a PFA-ZDV-DTG combination therapy could be effective. Renal adverse events should be monitored. J. Med. Virol. 88:1204-1210, 2016. © 2015 Wiley Periodicals, Inc. PMID:26636432

  20. Monitoring and Switching of First-line Antiretroviral Therapy in sub-Saharan Africa: Collaborative Analysis of Adult Treatment Cohorts

    PubMed Central

    Haas, Andreas D.; Keiser, Olivia; Balestre, Eric; Brown, Steve; Bissagnene, Emmanuel; Chimbetete, Cleophas; Dabis, François; Davies, Mary-Ann; Hoffmann, Christopher J.; Oyaro, Patrick; Parkes-Ratanshi, Rosalind; Reynolds, Steven J.; Sikazwe, Izukanji; Wools-Kaloustian, Kara; Zannou, Djimon Marcel; Wandeler, Gilles; Egger, Matthias

    2015-01-01

    Background HIV-1 viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not universally available. We examined monitoring of first-line and switching to second-line ART in sub-Saharan Africa, 2004–2013. Methods Adult HIV-1 infected patients starting combination ART in 16 countries were included. Switching was defined as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to a protease inhibitor (PI)-based regimen, with a change of ≥1 NRTI. Virological and immunological failures were defined per World Health Organization criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% confidence intervals (CI) comparing routine VL monitoring, targeted VL monitoring, CD4 cell monitoring and clinical monitoring, adjusted for programme and individual characteristics. Findings Of 297,825 eligible patients, 10,352 patients (3·5%) switched during 782,412 person-years of follow-up. Compared to CD4 monitoring hazard ratios for switching were 3·15 (95% CI 2·92–3·40) for routine VL, 1·21 (1·13–1·30) for targeted VL and 0·49 (0·43–0·56) for clinical monitoring. Overall 58.0% of patients with confirmed virological and 19·3% of patients with confirmed immunological failure switched within 2 years. Among patients who switched the percentage with evidence of treatment failure based on a single CD4 or VL measurement ranged from 32·1% with clinical to 84.3% with targeted VL monitoring. Median CD4 counts at switching were 215 cells/µl under routine VL monitoring but lower with other monitoring (114–133 cells/µl). Interpretation Overall few patients switched to second-line ART and switching occurred late in the absence of routine viral load monitoring. Switching was more common and occurred earlier with targeted or routine viral load testing. PMID:26423252

  1. HIV-1 Group O Genotypes and Phenotypes: Relationship to Fitness and Susceptibility to Antiretroviral Drugs.

    PubMed

    Tebit, Denis M; Patel, Hamish; Ratcliff, Annette; Alessandri, Elodie; Liu, Joseph; Carpenter, Crystal; Plantier, Jean-Christophe; Arts, Eric J

    2016-07-01

    Despite only 30,000 group O HIV-1 infections, a similar genetic diversity is observed among the O subgroups H (head) and T (tail) (previously described as subtypes A, B) as in the 9 group M subtypes (A-K). Group O isolates bearing a cysteine at reverse transcriptase (RT) position 181, predominantly the H strains are intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, their susceptibility to newer antiretroviral drugs such as etravirine, maraviroc, raltegravir (RAL), and elvitegravir (EVG) remains relatively unknown. We tested a large collection of HIV-1 group O strains for their susceptibility to four classes of antiretroviral drugs namely nucleoside RT, non-nucleoside RT, integrase, and entry inhibitors knowing in advance the intrinsic resistance to NNRTIs. Drug target regions were sequenced to determine various polymorphisms and were phylogenetically analyzed. Replication kinetics and fitness assays were performed in U87-CD4(+)CCR5 and CXCR4 cells and peripheral blood mononuclear cells. With all antiretroviral drugs, group O HIV-1 showed higher variability in IC50 values than group M HIV-1. The mean IC50 values for entry and nucleoside reverse transcriptase inhibitor (NRTI) were similar for group O and M HIV-1 isolates. Despite similar susceptibility to maraviroc, the various phenotypic algorithms failed to predict CXCR4 usage based on the V3 Env sequences of group O HIV-1 isolates. Decreased sensitivity of group O HIV-1 to integrase or NNRTIs had no relation to replicative fitness. Group O HIV-1 isolates were 10-fold less sensitive to EVG inhibition than group M HIV-1. These findings suggest that in regions where HIV-1 group O is endemic, first line treatment regimens combining two NRTIs with RAL may provide more sustained virologic responses than the standard regimens involving an NNRTI or protease inhibitors. PMID:26861573

  2. Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

    PubMed Central

    Gunawardana, Manjula; Remedios-Chan, Mariana; Miller, Christine S.; Fanter, Rob; Yang, Flora; Marzinke, Mark A.; Hendrix, Craig W.; Beliveau, Martin; Moss, John A.; Smith, Thomas J.

    2015-01-01

    Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day−1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml−1; interquartile range [IQR], 0.60 to 1.50 ng ml−1) and tenofovir (TFV; median, 15.0 ng ml−1; IQR, 8.8 to 23.3 ng ml−1), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/106 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. PMID:25896688

  3. Altered Strand Transfer Activity of a Multi-drug-resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutant with a Dipeptide Fingers Domain Insertion

    PubMed Central

    Nguyen, Laura A.; Daddacha, Waaqo; Rigby, Sean; Bambara, Robert A.; Kim, Baek

    2013-01-01

    Prolonged highly active anti-retroviral therapy (HAART) with multiple nucleoside reverse transcriptase inhibitors (NRTI) for the treatment of human immunodeficiency virus type 1 (HIV-1) infected patients can induce the development of an HIV-1 RT harboring a dipeptide insertion at the RT fingers domain with a background thymidine analog mutation (TAM). This mutation renders viral resistance to multiple NRTIs. We investigated the effect of the dipeptide fingers domain insertion mutation on strand transfer activity using two clinical RT variants isolated during pre- and post-treatment of an infected patient, termed pre-drug RT without the dipeptide insertion and post-drug RT with the Ser-Gly insertion mutation, respectively. First, the post-drug RT displayed elevated strand transfer activity, compared to the pre-drug RT, with two different RNA templates. Second, the post-drug RT exhibited less RNA template degradation than the pre-drug RT, but higher polymerization-dependent RNase H activity. Third, the post-drug RT had a faster association rate for template binding (kon) and lower equilibrium binding constant KD to template, leading to the tighter template binding affinity than the pre-drug RT. The koff rates for pre-drug RT and post-drug RTs were similar. Finally, the removal of the dipeptide insertion from the post-drug RT abolished the elevated strand transfer activity and RNase H activity in addition to the loss of AZT resistance. These biochemical data suggests that the dipeptide insertion mutation elevates strand transfer activity by increasing the interaction of the RT with RNA donor template, promoting cleavage that generates more invasion site for the acceptor template during DNA synthesis. PMID:22100453

  4. Molecular diversity of HIV-1 and surveillance of transmitted drug resistance variants among treatment Naïve patients, 5 years after active introduction of HAART in Kuala Lumpur, Malaysia.

    PubMed

    Ong, Lai Yee; Razak, Siti Nur Humaira; Lee, Yeat Mei; Sri La Sri Ponnampalavanar, Sasheela; Syed Omar, Sharifah Faridah; Azwa, Raja Iskandar; Tee, Kok Keng; Kamarulzaman, Adeeba

    2014-01-01

    Expansion of antiretroviral treatment programs have led to the growing concern for the development of antiretroviral drug resistance. The aims were to assess the prevalence of drug resistant HIV-1 variants and to identify circulating subtypes among HAART-naïve patients. Plasma specimens from N = 100 HIV+ HAART-naïve adult were collected between March 2008 and August 2010 and viral RNA were extracted for nested PCR and sequenced. PR-RT sequences were protein aligned and checked for transmitted drug resistance mutations. Phylogenetic reconstruction and recombination analysis were performed to determine the genotypes. Based on the WHO consensus guidelines, none of the recruited patients had any transmitted drug resistance mutations. When analyzed against the Stanford guidelines, 35% of patients had at least one reported mutation that may reduce drug susceptibility to PI (24%), NRTI (5%), and NNRTI (14%). The commonly detected mutation that may affect current first line therapy was V179D (3%), which may lead to reduced susceptibility to NNRTI. The predominant circulating HIV-1 genotypes were CRF01_AE (51%) and CRF33_01B (17%). The prevalence of unique recombinant forms (URF) was 7%; five distinct recombinant structures involving CRF01_AE and subtype B' were observed, among them a cluster of three isolates that could form a novel circulating recombinant form (CRF) candidate. Transmitted drug resistance prevalence among HAART-naïve patients was low in this cohort of patients in Kuala Lumpur despite introduction of HAART 5 years ago. Owing to the high genetic diversity, continued molecular surveillance can identify the persistent emergence of HIV-1 URF and novel CRF with significant epidemiological impact. PMID:24127302

  5. Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening

    PubMed Central

    La, Jennifer; Latham, Catherine F.; Tinetti, Ricky N.; Johnson, Adam; Tyssen, David; Huber, Kelly D.; Sluis-Cremer, Nicolas; Simpson, Jamie S.; Headey, Stephen J.; Chalmers, David K.; Tachedjian, Gilda

    2015-01-01

    Fragment-based screening methods can be used to discover novel active site or allosteric inhibitors for therapeutic intervention. Using saturation transfer difference (STD) NMR and in vitro activity assays, we have identified fragment-sized inhibitors of HIV-1 reverse transcriptase (RT) with distinct chemical scaffolds and mechanisms compared to nonnucleoside RT inhibitors (NNRTIs) and nucleoside/nucleotide RT inhibitors (NRTIs). Three compounds were found to inhibit RNA- and DNA-dependent DNA polymerase activity of HIV-1 RT in the micromolar range while retaining potency against RT variants carrying one of three major NNRTI resistance mutations: K103N, Y181C, or G190A. These compounds also inhibit Moloney murine leukemia virus RT but not the Klenow fragment of Escherichia coli DNA polymerase I. Steady-state kinetic analyses demonstrate that one of these fragments is a competitive inhibitor of HIV-1 RT with respect to deoxyribonucleoside triphosphate (dNTP) substrate, whereas a second compound is a competitive inhibitor of RT polymerase activity with respect to the DNA template/primer (T/P), and consequently also inhibits RNase H activity. The dNTP competing RT inhibitor retains activity against the NRTI-resistant mutants K65R and M184V, demonstrating a drug resistance profile distinct from the nucleotide competing RT inhibitors indolopyridone-1 (INDOPY-1) and 4-dimethylamino-6-vinylpyrimidine-1 (DAVP-1). In antiviral assays, the T/P competing compound inhibits HIV-1 replication at a step consistent with an RT inhibitor. Screening of additional structurally related compounds to the three fragments led to the discovery of molecules with improved potency against HIV-1 RT. These fragment inhibitors represent previously unidentified scaffolds for development of novel drugs for HIV-1 prevention or treatment. PMID:26038551

  6. Comparative Fitness of Multi-Dideoxynucleoside-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) in an In Vitro Competitive HIV-1 Replication Assay

    PubMed Central

    Kosalaraksa, Pope; Kavlick, Mark F.; Maroun, Victor; Le, Richard; Mitsuya, Hiroaki

    1999-01-01

    We examined whether human immunodeficiency virus type 1 (HIV-1) fitness was altered upon the acquisition of a set or subset of five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the pol gene, which confers resistance to multiple dideoxynucleosides (MDR), as well as the zidovudine resistance-associated mutation T215Y, using a competitive HIV-1 replication assay in a setting of an HXB2D genetic background. Target H9 cells were exposed to a 50:50 mixture of paired infectious molecular clones, and HIV-1 in the culture supernatant was transmitted to new cultures every 7 to 10 days. The polymerase-encoding region of the virus was sequenced at various time points, and the relative proportion of the two viral populations was determined. In the absence of drugs, the comparative order for replicative fitness was HIV-162/75/77/116/151 > HIV-177/116/151 > HIV-1151 > wild-type HIV-1 (HIV-1wt) > HIV-175/77/116/151 > HIV-1151/215 > HIV-1215. In the presence of zidovudine or didanosine, the order was HIV-162/75/77/116/151 > HIV-177/116/151 > HIV-175/77/116/151 > HIV-1151 > HIV-1215. HIV-1215S(TCC), a putative intermediate infectious clone for HIV-1215, replicated comparably to HIV-1wt, while two putative intermediates for HIV-1151 [HIV-1151L(CTG) and HIV-1151K(AAG)] replicated much less efficiently than HIV-1wt and HIV-1151, suggesting that for HIV-1151 to develop, two base substitutions are likely to occur concurrently or within a short interval. These data may illustrate the molecular basis by which HIV-1151 emerges much less frequently than HIV-1215. The present data also demonstrate that several MDR HIV-1 variants are more fit than HIV-1wt in the absence of drugs and that resistance-associated mutations and drug pressure are critical variates for HIV-1 fitness. PMID:10364282

  7. Antiretroviral treatment interruption and loss to follow-up in two HIV cohorts in Australia and Asia: implications for 'test and treat' prevention strategy.

    PubMed

    Guy, Rebecca; Wand, Handan; McManus, Hamish; Vonthanak, Saphonn; Woolley, Ian; Honda, Miwako; Read, Tim; Sirisanthana, Thira; Zhou, Julian; Carr, Andrew

    2013-12-01

    Both antiretroviral treatment interruption (TI) and cessation have been strongly discouraged since 2006. We describe the incidence, duration, and risk factors for TI and loss-to-follow-up (LTFU) rates across 13 countries. All 4689 adults (76% men) in two large HIV cohorts in Australia and Asia commencing combination antiretroviral therapy (ART) to March 2010 were included. TI was defined by ART cessation >30 days, then recommencement, and loss to follow-up (LTFU) by no visit since 31 March 2009 and no record of death. Survival analysis and Poisson regression methods were used. With median follow-up of 4.4 years [interquartile range (IQR):2.1-6.5], TI incidence was 6.7 per 100 person years (PY) (95% CI:6.1-7.3) pre-2006, falling to 2.0 (95% CI:1.7-2.2) from 2006 (p<0.01). LTFU incidence was 3.5 per 100 PY (95% CI:3.1-3.9) pre-2006, and 4.1 (95% CI:3.5-4.9) from 2006 (p=0.22). TIs accounted for 6.4% of potential time on ART pre-2006 and 1.2% from 2006 (p<0.01), and LTFU 4.7% of potential time on ART pre-2006 and 6.6% from 2006 (p<0.01). Median TI duration was 163 (IQR: 75-391) days pre-2006 and 118 (IQR: 67-270) days from 2006 (p<0.01). Independent risk factors for the first TI were: Australia HIV Observational Database participation; ART initiation pre-2006; ART regimens including stavudine and didanosine; three nucleoside analogue reverse transcriptase inhibitors; ≥7 pills per day; and ART with food restrictions (fasting or with food). In conclusion, since 2006, 7.8% of patients had significant time off treatment, which has the potential to compromise any 'test and treat' policy as during the interruption viral load will rebound and increase the risk of transmission. PMID:24320013

  8. Weight-based dosing in medication use: what should we know?

    PubMed Central

    Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan

    2016-01-01

    Background Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance. Methods A literature search was conducted using PubMed. Results Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always

  9. Les neuropathies liées au VIH/SIDA: une étude clinique chez les patients infectés par le VIH au Centre d'Excellence VIH/SIDA de l'Université de Lubumbashi

    PubMed Central

    Kabongo, Joe Katabwa; Kaputu-Kalala-Malu, Célestin; Luboya, Oscar; Mutombo, Valerien; Ntambwe, Abel; Mapatano, Mala Ali; Mukendi, Kavulu Mayamba

    2015-01-01

    Introduction En vue d'améliorer la prise en charge des patients souffrant de neuropathie (NP) associées à l'infection HIV, nous avons essayé de déterminer le profil clinique des personnes souffrant de NP au cours du suivi thérapeutique de leur infection HIV. Méthodes Il s'agit d'une étude transversale (n= 101) menée au centre d'excellence depuis 1 an. Notre analyse est essentiellement clinique. Par un examen clinique minutieux, nous avons recherché tous les symptômes et signes cliniques des NP. Subjectivement, les douleurs dominent le tableau. Pour affiner leur diagnostic, nous avons utilisé l’échelle DN4 (Diagnostic des douleurs neuropathiques) et l’échelle EVA (Evaluation de la gravité des douleurs). Nous avons ensuite analysé nos données en fonction de certains autres facteurs épidémiologiques tels que le taux des CD4, le traitement anti-HIV etc. Résultats Les 101 patients représentent 3,12% de la cohorte générale; 53,3% des patients présentent une abolition des réflexes ostéotendineux des membres inférieurs; 77,89% présentent une hypoesthésie thermo algique en chaussette et en gants; 25% ont présenté une amyotrophie des membres inférieurs; 76,5% ont été soumis à un traitement antirétroviral contenant la stavudine; 11,7% ont pris la didanosine (DDI) et Abacavir (ABC). 84% ont une moyenne de CD4 de 292 cel/mm3. Conclusion La NP altère la qualité de vie de nos patients et diminue l'adhérence au traitement antirétroviral. Plusieurs facteurs sont incriminés dans la survenue de la NP, l'effet direct des antirétroviraux, l'effet inflammatoire dysimmunitaire, l'effet infectieux lié aux infections opportunistes. D'autres facteurs seront recherchés et analysés ultérieurement. PMID:26185582

  10. Antiretroviral Treatment Interruption and Loss to Follow-Up in Two HIV Cohorts in Australia and Asia: Implications for ‘Test and Treat’ Prevention Strategy

    PubMed Central

    Wand, Handan; McManus, Hamish; Vonthanak, Saphonn; Woolley, Ian; Honda, Miwako; Read, Tim; Sirisanthana, Thira; Zhou, Julian; Carr, on behalf of Australia HIV Observational Database (AHOD) and Treat Asia HIV Observation Database (TAHOD), Andrew

    2013-01-01

    Abstract Both antiretroviral treatment interruption (TI) and cessation have been strongly discouraged since 2006. We describe the incidence, duration, and risk factors for TI and loss-to-follow-up (LTFU) rates across 13 countries. All 4689 adults (76% men) in two large HIV cohorts in Australia and Asia commencing combination antiretroviral therapy (ART) to March 2010 were included. TI was defined by ART cessation >30 days, then recommencement, and loss to follow-up (LTFU) by no visit since 31 March 2009 and no record of death. Survival analysis and Poisson regression methods were used. With median follow-up of 4.4 years [interquartile range (IQR):2.1–6.5], TI incidence was 6.7 per 100 person years (PY) (95% CI:6.1–7.3) pre-2006, falling to 2.0 (95% CI:1.7–2.2) from 2006 (p<0.01). LTFU incidence was 3.5 per 100 PY (95% CI:3.1–3.9) pre-2006, and 4.1 (95% CI:3.5–4.9) from 2006 (p=0.22). TIs accounted for 6.4% of potential time on ART pre-2006 and 1.2% from 2006 (p<0.01), and LTFU 4.7% of potential time on ART pre-2006 and 6.6% from 2006 (p<0.01). Median TI duration was 163 (IQR: 75–391) days pre-2006 and 118 (IQR: 67–270) days from 2006 (p<0.01). Independent risk factors for the first TI were: Australia HIV Observational Database participation; ART initiation pre-2006; ART regimens including stavudine and didanosine; three nucleoside analogue reverse transcriptase inhibitors; ≥7 pills per day; and ART with food restrictions (fasting or with food). In conclusion, since 2006, 7.8% of patients had significant time off treatment, which has the potential to compromise any ‘test and treat’ policy as during the interruption viral load will rebound and increase the risk of transmission. PMID:24320013

  11. Efficacy and safety of three second-line antiretroviral regimens in HIV-infected patients in Africa

    PubMed Central

    Ciaffi, Laura; Koulla-Shiro, Sinata; Sawadogo, Adrien; le Moing, Vincent; Eymard-Duvernay, Sabrina; Izard, Susanne; Kouanfack, Charles; Ngom Gueye, Ndeye Fatou; Fobang, Avelin Aghokeng; Reynes, Jacques; Calmy, Alexandra; Delaporte, Eric

    2015-01-01

    Objective: WHO recommends ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors in HIV-infected patients failing non-nucleoside reverse transcriptase inhibitor-based first-line treatment. Here, we aimed to provide more evidence for the choice of nucleoside reverse transcriptase inhibitor and boosted protease inhibitor. Design: ANRS 12169 is a 48-week, randomized, open-label, non-inferiority trial in three African cities, comparing efficacy and safety of three second-line regimens. Methods: Patients failing non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy with confirmed plasma HIV-1 viral load above 1000 copies/ml were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (control group as per WHO recommendations), abacavir + didanosine + lopinavir/ritonavir (ABC/ddI group) or tenofovir/emtricitabine + darunavir/ritonavir (DRV group) regimens. The primary endpoint was the proportion of patients with plasma vral load below 50 copies/ml at week 48 in the modified intention-to-treat population. Non-inferiority was pre-specified with a 15% margin. Results: Of the 454 randomized patients, 451 were included in the analysis. Globally, 294 (65.2%) and 375 (83.2%) patients had viral load below 50 and 200 copies/ml, respectively, at week 48. The primary endpoint was achieved in 105 (69.1%) control group patients versus 92 (63.4%) in the ABC/ddI (difference 5.6%, 95% confidence interval –5.1 to 16.4) and 97 (63.0%) in the DRV (difference 6.1%, 95% confidence interval –4.5 to 16.7) groups (non-inferiority not shown). Overall, less number of patients with baseline viral load at least 100 000 copies/ml (n = 122) had a viral load below 50 copies/ml at week 48 (37.7 versus 75.4%; P < 0.001). Conclusions: The three second-line regimens obtained similar and satisfactory virologic control and confirmed the WHO recommendation (TDF/FTC/LPVr) as a valid option. However, the suboptimal

  12. Anti-hepatitis B virus activities of Geranium carolinianum L. extracts and identification of the active components.

    PubMed

    Li, Jiyang; Huang, Hai; Zhou, Wei; Feng, Meiqing; Zhou, Pei

    2008-04-01

    The ethanol extract of Geranium carolinianum L., a domestic plant grown in China, was subjected to sequential extractions with different organic solvents. The extracts were assayed for anti-hepatitis B virus (HBV) activities. The ethyl acetate fraction was found to contain the highest level of anti-HBV activity. In order to identify the active ingredients, the ethyl acetate fraction was further fractionated by column chromatography. Seven compounds were identified including ellagic acid, geraniin, quercitrin, hyperin, hirsutrin, quercetin, and kaempferol, whose structures were determined by NMR. The presence of the anti-HBV compounds geraniin, ellagic acid and hyperin in G. carolinianum L. may account for the effectiveness of this folk medicine in the treatment of HBV infections. Geraniin inhibited hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion by more than 85.8% and 63.7%, respectively, at the non-cytotoxic concentration of 200 microg/ml. The inhibitions of HBsAg and HBeAg secretion by geraniin were higher than the inhibition by the positive control Lamivudine, 33.5% and 32.2% respectively, at the same concentration. Since HBeAg is involved in immune tolerance during HBV infection, the newly identified anti-HBV compound geraniin might be a candidate agent to overcome the immune tolerance in HBV-infected individuals. This is the first report of the anti-HBV effects of geraniin and hyperin, the active substances derived from G. carolinianum L. PMID:18379075

  13. The efficacy of tenofovir-based therapy in patients showing suboptimal response to entecavir-adefovir combination therapy

    PubMed Central

    Kim, Jeong Han; Ahn, Sung Hyun; Ko, Soon Young; Choe, Won Hyeok; Kim, Kyun-Hwan; Kwon, So Young

    2016-01-01

    Background/Aims: Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination. Methods: We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy. Results: The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy. Conclusions: The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases. PMID:27304549

  14. Virological and Immunological Status of the People Living with HIV/AIDS Undergoing ART Treatment in Nepal.

    PubMed

    Ojha, Chet Raj; Shakya, Geeta; Dumre, Shyam Prakash

    2016-01-01

    Antiretroviral therapy (ART) has increased the life span of the people living with HIV (PLHIV), but their virological and immunological outcomes are not well documented in Nepal. The study was conducted at a tertiary care center including 826 HIV-1 seropositive individuals undergoing ART for at least six months. Plasma viral load (HIV-1 RNA) was detected by Real Time PCR and CD4(+) T-lymphocyte (CD4(+)) counts were estimated by flow cytometry. The mean CD4(+) count of patients was 501 (95% CI = 325-579) cells/cumm, but about 35% of patients had CD4(+) T cell counts below 350 cells/cumm. With increasing age, average CD4(+) count was found to be decreasing (p = 0.005). Of the total cases, 82 (9.92%) were found to have virological failure (viral load: >1000 copies/ml). Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV), the frequently used ART regimen in Nepal, showed virological failure in 11.34% and immunological failure in 37.17% of patients. Virological failure rate was higher among children < 15 years (14.5%) (p = 0.03); however, no association was observed between ART outcomes and gender or route of transmission. The study suggests there are still some chances of virological and immunological failures despite the success of highly active ART (HAART). PMID:27547761

  15. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    PubMed Central

    Restrepo Valencia, Piedad

    2015-01-01

    Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. PMID:26600625

  16. Metabolism of deoxypyrimidines and deoxypyrimidine antiviral analogs in isolated brain mitochondria

    PubMed Central

    McCann, Kathleen A.; Williams, David W.; McKee, Edward E.

    2012-01-01

    The goal of this project was to characterize deoxypyrimidine salvage pathways used to maintain deoxynucleoside triphosphate pools in isolated brain mitochondria and to determine the extent that antiviral pyrimidine analogs utilize or affect these pathways. Mitochondria from rat brains were incubated in media with labeled and unlabeled deoxynucleosides and deoxynucleoside analogs. Products were analyzed by HPLC coupled to an inline UV monitor and liquid scintillation counter. Isolated mitochondria transported thymidine and deoxycytidine into the matrix, and readily phosphorylated both of these to mono-, di, and tri-phosphate nucleotides. Rates of phosphorylation were much higher than rates observed in mitochondria from heart and liver. Deoxyuridine was phosphorylated much more slowly than thymidine and only to dUMP. AZT, an antiviral thymidine analog, was phosphorylated to AZT-MP as readily as thymidine was phosphorylated to TMP, but little if any AZT-DP or AZT-TP was observed. AZT at 5.5 ± 1.7 μM was shown to inhibit thymidine phosphorylation by 50%, but was not observed to inhibit deoxycytidine phosphorylation except at levels > 100 μM. Stavudine and lamivudine were inert when incubated with isolated brain mitochondria. The kinetics of phosphorylation of thymidine, dC and AZT were significantly different in brain mitochondria compared to mitochondria from liver and heart. PMID:22530558

  17. [Evaluation of multidrug-resistant tuberculosis treatment in Ivory Coast from 2008 to 2010].

    PubMed

    Ahui, B J-M; Horo, K; Bakayoko, A S; Kouassi, A B; Anon, J C; Brou-Gode, V C; Koffi, M O; Itchy, M V; N'Gom, A S; N'Goran, N B; Aka-Danguy, E

    2013-12-01

    This is a retrospective study conducted from January 2008 to December 2010 on sectional descriptive analysis of records of patients treated for MDR-TB and whose follow-up was in the thoracic department of Centre Hospitalier Universitaire (CHU) of Cocody in Abidjan Côte d'Ivoire. We selected eight patients who met the inclusion criteria of 21 MDR-TB patients registered during the study period. The average age was 29.25years ranging from 21 to 39. Males accounted for 75% of the patients (6 males and 2 females). The students represented the professional social layer most affected with 37.5% of the patients. All patients had a history of tuberculosis and only one patient was HIV positive under anti-retroviral (zidovudin, lamivudin and efavirenz). All cultures found Mycobacterium tuberculosis. The resistance profile in addition to isoniazid and rifampicin, found two cases of resistance to ethambutol and streptomycin. The chest radiograph at the time of initiation of second-line treatment showed essentially excavations in 75% of cases and infiltrates in 25%. The lesions were bilateral in 7 of 8 patients (87.5%). The main side effects observed during treatment were limited to cochleovestibular disorders (2 patients) and neuropsychiatric disorders (2 patients) and digestive disorders in half of the patients with removal of the offending molecule kanamycin. After 24months of treatment, it was numbered five cures (62.5%), two failures and one death. PMID:24183291

  18. Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

    PubMed Central

    Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A.; Bolshakov, Oleg; Adesina, Simeon; Gugssa, Ayele; Anderson, Winston A.; Nekhai, Sergei; Akala, Emmanuel O.

    2016-01-01

    Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs. PMID:27013886

  19. The Deleterious Influence of Tenofovir-Based Therapies on the Progression of Atherosclerosis in HIV-Infected Patients

    PubMed Central

    Aragonès, Gerard; Pardo-Reche, Pedro; Fernández-Sender, Laura; Rull, Anna; Beltrán-Debón, Raúl; Rodríguez-Gallego, Esther; Camps, Jordi; Joven, Jorge; Alonso-Villaverde, Carlos

    2012-01-01

    We investigated the potential differential effects of antiretroviral therapies on unbalanced chemokine homeostasis and on the progression of atherosclerosis in HIV-infected patients. A two-year prospective study was performed in 67 consecutive HIV-infected patients initiating antiretroviral therapy with abacavir/lamivudine or tenofovir/emtricitabine. Circulating levels of inflammatory biomarkers, progression of subclinical atherosclerosis and expression levels of selected chemokines genes in circulating leukocytes were assessed. Control subjects showed significantly lower plasma concentrations of CRP, tPA, IL-6, and MCP-1 than HIV-infected patients at a baseline. After two years of followup, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1, tPA, and IL-6. The decrease in plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving TDF-based therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression. However, the expression levels of selected genes in blood cells only showed associations with the viral load and total and HDL-cholesterol levels. Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis. PMID:22645407

  20. Poly(lactic-co-glycolic) Acid-Chitosan Dual Loaded Nanoparticles for Antiretroviral Nanoformulations.

    PubMed

    Makita-Chingombe, Faithful; Kutscher, Hilliard L; DiTursi, Sara L; Morse, Gene D; Maponga, Charles C

    2016-01-01

    Poly(lactic-co-glycolic acid) (PLGA) chitosan (CS) coated nanoparticles (NPs) were loaded with two antiretrovirals (ARVs) either lamivudine (LMV) which is hydrophilic or nevirapine (NVP) which is hydrophobic or both LMV and NVP. These ARVs are of importance in resource-limited settings, where they are commonly used in human immunodeficiency virus (HIV-1) treatment due to affordability and accessibility. NPs prepared by a water-oil-water emulsion and reduced pressure solvent evaporation technique were determined to have a positive zeta potential, a capsule-like morphology, and an average hydrodynamic diameter of 240 nm. Entrapment of NVP as a single ARV had a notable increase in NP size compared to LMV alone or in combination with LMV. NPs stored at room temperature in distilled water maintained size, polydispersity (PDI), and zeta potential for one year. No changes in size, PDI, and zeta potential were observed for NPs in 10% sucrose in lyophilized or nonlyophilized states stored at 4°C and -20°C, respectively. Freezing NPs in the absence of sucrose increased NP size. Drug loading, encapsulation efficiency, and kinetic release profiles were quantified by high performance liquid chromatography (HPLC). Our novel nanoformulations have the potential to improve patient outcomes and expand drug access in resource-limited countries for the treatment of HIV-1. PMID:27190651

  1. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report.

    PubMed

    Despotovic, A; Savic, B; Salemovic, D; Ranin, J; Jevtovic, Dj

    2016-01-01

    Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB) was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART) was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS). The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment. PMID:26603644

  2. Total laparoscopic intestinal vaginoplasty as neovaginal reconstruction in an HIV-positive transgender woman.

    PubMed

    van der Sluis, Wouter B; Verweij, Stephan P; Özer, Mujde; Meijerink, Wilhelmus J; Bouman, Mark-Bram

    2016-07-01

    A 46-year-old, HIV-positive transgender woman of South American ethnicity consulted our outpatient clinic to discuss the possibilities of a surgical, secondary neovaginal reconstruction because of complete stenosis of her inverted penile skin-lined neovagina. She was taking abacavir/lamivudine and nevirapine as antiretroviral therapy. We successfully performed a total laparoscopic sigmoid vaginoplasty without any complications. There was no short-term morbidity and no complications were reported after 15 months of follow-up. To our knowledge, this is the first report of laparoscopic sigmoid vaginoplasty as vaginal reconstruction in a HIV-positive transgender woman. Worldwide, transgender women have a high burden of HIV infection. This report shows that intestinal vaginoplasty is a feasible surgical option for HIV-positive transgender women in need of vaginal reconstruction. Because patients are again able to engage in penetrative sexual intercourse, we emphasise the importance of practicing safe sex and early initiation of adequate antiretroviral therapy in this patient population. PMID:26037643

  3. Chemical Incorporation of Chain-Terminating Nucleoside Analogs as 3'-Blocking DNA Damage and Their Removal by Human ERCC1-XPF Endonuclease.

    PubMed

    Yamamoto, Junpei; Takahata, Chiaki; Kuraoka, Isao; Hirota, Kouji; Iwai, Shigenori

    2016-01-01

    Nucleoside/nucleotide analogs that lack the 3'-hydroxy group are widely utilized for HIV therapy. These chain-terminating nucleoside analogs (CTNAs) block DNA synthesis after their incorporation into growing DNA, leading to the antiviral effects. However, they are also considered to be DNA damaging agents, and tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme, is reportedly able to remove such CTNA-modifications of DNA. Here, we have synthesized phosphoramidite building blocks of representative CTNAs, such as acyclovir, abacavir, carbovir, and lamivudine, and oligonucleotides with the 3'-CTNAs were successfully synthesized on solid supports. Using the chemically synthesized oligonucleotides, we investigated the excision of the 3'-CTNAs in DNA by the human excision repair cross complementing protein 1-xeroderma pigmentosum group F (ERCC1-XPF) endonuclease, which is one of the main components of the nucleotide excision repair pathway. A biochemical analysis demonstrated that the ERCC1-XPF endonuclease cleaved 2-7 nt upstream from the 3'-blocking CTNAs, and that DNA synthesis by the Klenow fragment was resumed after the removal of the CTNAs, suggesting that ERCC1-XPF participates in the repair of the CTNA-induced DNA damage. PMID:27294910

  4. Comparison of three quantification methods for the TZM-bl pseudovirus assay for screening of anti-HIV-1 agents.

    PubMed

    Xing, Liying; Wang, Shunyi; Hu, Qin; Li, Jingtao; Zeng, Yi

    2016-07-01

    The TZM-bl pseudovirus assay is commonly used to evaluate the efficacy of neutralizing antibodies and small molecular inhibitors in HIV-1 research. Here, to determine the optimal measurement method for screening anti-HIV-1 inhibitors, we compared three measurement methods based on firefly luciferase and β-galactosidase activities. The 50% tissue culture infective doses (TCID50) of the pseudoviruses were determined using the luciferase, β-galactosidase colorimetric, and 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining assays. Three commercial reverse-transcriptase inhibitors (azidothymidine, nevirapine, and lamivudine) were tested as reference drugs to compare the reproducibility, linear correlation, and half maximal inhibitory concentration (IC50) values determined using these methods. In the TCID50 assay, the sensitivity of β-galactosidase colorimetric assay was almost 562 times lower than that of the other two methods. Reproducible dose-response curves were obtained for the inhibitors with all methods; the IC50 values of the inhibitors were not significantly different. Linear regression analysis showed linear correlation between methods. Compared to the β-galactosidase colorimetric assay, the other two methods have the advantage of high sensitivity and are less affected by interference. In conclusion, the luciferase and X-gal staining assays, which can be applied either alone or combined, are recommended for anti-HIV-1 inhibitor screening. PMID:27016178

  5. Roles of hepatocyte nuclear factors in hepatitis B virus infection.

    PubMed

    Kim, Doo Hyun; Kang, Hong Seok; Kim, Kyun-Hwan

    2016-08-21

    Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB. PMID:27610013

  6. Prevalence of Past and Reactivated Viral Infections and Efficacy of Cyclosporine A as Monotherapy or in Combination in Patients with Psoriatic Arthritis—Synergy Study: A Longitudinal Observational Study

    PubMed Central

    Colombo, Delia; Grossi, Paolo; Marchesoni, Antonio; Di Nuzzo, Sergio; Griseta, Vito; Gargiulo, Anna; Parodi, Aurora; Bellia, Gilberto

    2014-01-01

    We have prospectively evaluated psoriatic arthritis (PsA) patients for (1) seropositivity for former viral infections and seroconversion and (2) efficacy of cyclosporine A (CsA) alone or in combination with other immunosuppressants in a time period of 12 months. Screening included HBV antibodies and antigens, HCV antibodies and RNA, HSV 1-2, HZV, EBV, and CMV IgG, and IgM, HHV-6 DNA, and HIV 1-2 antibodies. PsA was evaluated by the Psoriasis Area Severity Index (PASI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Visual Analogue Scale (VAS). At baseline, 126 (56%) out of 225 evaluable patients had 2 or more seropositivities indicative of former infections, and 31 patients (13.8%) presented seropositivity for HCV, HBV, HSV-1 and -2, HHV-6, EBV, or parvovirus infection; one of them, positive for HBAg, was treated with lamivudine, while the remaining 30 received no specific treatment. None of the 31 patients developed virus reactivation. A reduction (P < 0.001) of PASI, BASDAI, and VAS scores was observed at 6 and 12 months. The treatment of PsA with CsA as monotherapy or in combination was safe and effective. In vitro experiments and clinical findings, including those from our study, suggest that CsA as monotherapy or in combination with biologics might be the treatment of choice in PsA HCV-positive patients. PMID:24804261

  7. Human immunodeficiency virus postexposure prophylaxis for occupational exposure in a medical school hospital in Thailand.

    PubMed

    Hiransuthikul, N; Hiransuthikul, P; Kanasuk, Y

    2007-12-01

    This is a retrospective review of occupational exposure to human immunodeficiency virus (HIV) and subsequent postexposure prophylaxis (PEP) among healthcare workers (HCWs) in King Chulalongkorn Memorial Hospital (KCMH), Bangkok, Thailand. From January 2002 to December 2004, data were collected from incident reports, the hospital's infectious diseases unit and the emergency department. There were 315 reported episodes of occupational exposure among 306 HCWs. Nurses (34.0%) were the HCWs most frequently exposed and percutaneous injury (91.4%) was the most common type of exposure. One-third of the source patients tested were infected with HIV. PEP was initiated following 200 (63.5%) of the 315 exposures and was started within 24h in >95% of cases. The most commonly prescribed PEP regimen was zidovudine, lamivudine and nelfinavir. Fifty-six percent of HCWs given PEP completed a four-week course but the remainder discontinued PEP prematurely due to side-effects, or after negative results from the source, or following informed risk reassessment or from their own accord. No exposed HCW acquired HIV during the study period. Appropriate counselling and careful risk assessment are important in achieving effective HIV PEP among HCWs. PMID:18023920

  8. Durable survival after chemotherapy in a HIV patient with Burkitt's lymphoma presenting with massive upper gastrointestinal bleeding.

    PubMed

    Law, Man F; Chan, Hay N; Pang, Chun Y; Lai, Ho K; Ha, Chung Y; Ng, Celia; Ho, Rita; Wong, Cheuk K; Yeung, Yiu M; Yip, Sze F

    2016-07-01

    Massive upper gastrointestinal bleeding is an uncommon presentation of Burkitt's lymphoma in a patient with HIV/AIDS, and is seldom reported in the literature. A 39-year-old man who has sex with men presented with abdominal pain and massive haematemesis and a rapid drop in haemoglobin level to 4.8 g/dL. Upper gastrointestinal endoscopy showed a large blood clot in the stomach, and an emergency laparotomy was performed because of unstable haemodynamics. This showed active bleeding from multiple tumours in the fundus and body of the stomach. The patient underwent gastrectomy and gastric biopsy confirmed Burkitt's lymphoma. Further tests showed lymphoma involvement in bone marrow and central nervous system. The patient tested positive for HIV, and had a CD4 count of 212 cells/mm(3) and viral load of 18,000 copies/mL at diagnosis. He was commenced on a chemotherapy regimen of CODOX-M/IVAC, and highly active antiretroviral therapy consisting of indinavir, stavudine and lamivudine. The major side effect was peripheral neuropathy. Infective complications during chemotherapy were controlled by broad-spectrum antibiotics and anti-fungal agents. Complete remission of the lymphoma was achieved after the chemotherapy and remission was maintained for more than 14 years. PMID:26185043

  9. Approved Antiviral Drugs over the Past 50 Years.

    PubMed

    De Clercq, Erik; Li, Guangdi

    2016-07-01

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

  10. Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1.

    PubMed

    Duwal, S; Sunkara, V; von Kleist, M

    2016-07-01

    While HIV-1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target-cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir-diphosphate builds up too slowly to halt infection when taken "on demand" and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy. PMID:27439573

  11. Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

    PubMed Central

    Weinberg, Adriana; Forster, Jeri E.; Levin, Myron J.; Davies, Jill; Pappas, Jennifer; Kinzie, Kay; Barr, Emily; Paul, Suzanne; McFarland, Elizabeth J.

    2016-01-01

    Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade ≥1 AE and grade ≥3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade ≥ 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE. PMID:27127401

  12. Multiscale Systems‐Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV‐1

    PubMed Central

    Sunkara, V

    2016-01-01

    While HIV‐1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target‐cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir‐diphosphate builds up too slowly to halt infection when taken “on demand” and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy. PMID:27439573

  13. Care of Patients With HIV Infection: Antiretroviral Drug Regimens.

    PubMed

    Bolduc, Philip; Roder, Navid; Colgate, Emily; Cheeseman, Sarah H

    2016-04-01

    The advent of combination antiretroviral drug regimens has transformed HIV infection from a fatal illness into a manageable chronic condition. All patients with HIV infection should be considered for antiretroviral therapy, regardless of CD4 count or HIV viral load, for individual benefit and to prevent HIV transmission. Antiretroviral drugs affect HIV in several ways: entry inhibitors block HIV entry into CD4 T cells; nucleotide and nucleoside reverse transcriptase inhibitors prevent reverse transcription from RNA to DNA via chain-terminating proteins; nonnucleoside reverse transcriptase inhibitors prevent reverse transcription through enzymatic inhibition; integrase strand transfer inhibitors block integration of viral DNA into cellular DNA; protease inhibitors block maturation and production of the virus. Current guidelines recommend six combination regimens for initial therapy. Five are based on tenofovir and emtricitabine; the other uses abacavir and lamivudine. Five include integrase strand transfer inhibitors. HIV specialists should assist with treating patients with complicated HIV infection, including patients with treatment-resistant HIV infection, coinfection with hepatitis B or C virus, pregnancy, childhood infections, severe opportunistic infections, complex drug interactions, significant drug toxicity, or comorbidities. Family physicians can treat most patients with HIV infection effectively by choosing appropriate treatment regimens, monitoring patients closely, and retaining patients in care. PMID:27092564

  14. Hepatitis B Reactivation with Novel Agents in Non-Hodgkin’s Lymphoma and Prevention Strategies

    PubMed Central

    Ozoya, Oluwatobi O.; Sokol, Lubomir; Dalia, Samir

    2016-01-01

    Abstract Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines. Non-Hodgkin’s lymphoma is the most common hematological malignancy, and certain patients undergoing therapy are at increased risk of HBV reactivation. Rituximab, a monoclonal antibody, is well studied in HBV reactivation, but newer agents have been implicated as well. Here, we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation. Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin’s lymphoma. Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation, and HBV reactivation rates have decreased with increased awareness. HBV reactivation is uncommon when using other novel agents. Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients. In conclusion, the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation, especially in patients treated with anti-CD20 antibody. Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. Lastly, large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation. PMID:27350944

  15. Depression in Hepatitis B and C, and Its Correlation With Hepatitis Drugs Consumption (Interfron/Lamivodin/Ribaverin)

    PubMed Central

    Alian, Shahriar; Masoudzadeh, Abbas; Khoddad, Talayeh; Dadashian, Amir; Ali Mohammadpour, Reza

    2013-01-01

    Objective: Chronic infection of hepatitis B and hepatitis C are considered as the most important infectious diseases, which lead to drastic consequences such as liver dysfunction. Depression is a psychiatric disorder which is concomitantly present in these patients, and decreases the patients’ quality of life. It may lead to suicide, homicide or intentional transmission of infectious to others. Medical treatment with interferon can also lead to depression which is comparable to the depression caused by disease. Methods: We performed a cross sectional study on 205 patients with hepatitis B and hepatitis C infection. We aimed to determine the prevalence of depression via Beck Depression Inventory (BDI), and its correlates with hepatitis drugs. Results: Of 205 patients, 154 cases had hepatitis B and 51 cases had hepatitis C infection. The frequency of depression was 68% in hepatitis B and 86% in hepatitis C infected patients (p<0.05). The frequency of mild depression was 14%, moderate depression was 57.3% and severe depression was 28.7% (p<0.05). Depression frequency in Interferon recipients was 100%, in interferon-ribavirin recipients was 94.4%, in lamivudine recipients was 64%, and in patients that receive no drug was 66.7%. Depression prevalence was significantly higher among those on interferon therapy (p<0.05). Conclusion: There is a high prevalence of depression among patients with hepatitis B and hepatitis C infection, especially patients on interferon therapy. Hence these patients should be repeatedly evaluated for depression. Declaration of Interest: None. PMID:24644496

  16. Evaluation of microwave assisted grafted sago starch as controlled release polymeric carrier.

    PubMed

    Singh, Akhilesh Vikram; Nath, Lila Kanta

    2013-09-01

    In the present investigation an attempt has been made to develop a new co-polymeric material for controlled release tablet formulations. The acrylamide grafting was successfully performed on the backbone of sago starch. The modified starch was tested for acute toxicity and drug-excipient compatibility study. The grafted material was used in making of controlled release tablets of lamivudine. The formulations were evaluated for physical characteristics such as hardness, friability, %drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi model and the release mechanism of the optimized formulation predominantly exhibited 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(®) was observed. The pharmacokinetics parameters were showed controlled pattern and better bioavailability. The optimized formulation exhibited good stability and release profile at the accelerated stability conditions. PMID:23707750

  17. Green tea polyphenol, epigallocatechin-3-gallate, possesses the antiviral activity necessary to fight against the hepatitis B virus replication in vitro *

    PubMed Central

    Pang, Jing-yao; Zhao, Kui-jun; Wang, Jia-bo; Ma, Zhi-jie; Xiao, Xiao-he

    2014-01-01

    Although several antiviral drugs and vaccines are available for use against hepatitis B virus (HBV), hepatitis caused by HBV remains a major public health problem worldwide, which has not yet been resolved, and new anti-HBV drugs are in great demand. The present study was performed to investigate the anti-HBV activity of epigallocatechin-3-gallate (EGCG), a natural-origin compound, in HepG2 2.2.15 cells. The antiviral activity of EGCG was examined by detecting the levels of HBsAg and HBeAg in the supernatant and extracellular HBV DNA. EGCG effectively suppressed the secretion of HBsAg and HBeAg from HepG2 2.2.15 cells in a dose- and time-dependent manner, and it showed stronger effects at the level of 0.11–0.44 μmol/ml (50–200 μg/ml) than lamivudine (3TC) at 0.87 μmol/ml (200 μg/ml). EGCG also suppressed the amount of extracellular HBV DNA. The data indicated that EGCG possessed anti-HBV activity and suggested the potential of EGCG as an effective anti-HBV agent with low toxicity. PMID:24903990

  18. [Efficacy of initial antiretroviral therapy based on lopinavir/ritonavir plus 2 nucleoside/nucleotide analogs in patients with human immunodeficiency virus type 1 infection].

    PubMed

    Zamora, Laura; Gatell, José M

    2014-11-01

    Triple combination regimens consisting of lopinavir/ritonavir (LPV/r) plus 2 nucleoside/nucleotide analogs continue to be a valid option in initial antiretroviral therapy. Other protease inhibitors boosted with ritonavir (and in future with cobicistat) have been introduced, as well as other non-nucleoside analogs (rilpivirin) and 3 integrase inhibitors. None of the new regimens have shown superiority over LPV/r or comparisons are lacking. Therefore, regimens including LPV/r continue to be recommended as initial first-line or alternative strategies in most treatment guidelines. Dual combinations with LPV/r (plus raltegravir or lamivudine) are described in another article and can provide a similar response rate to triple combinations, better tolerance, and an improved cost-efficacy ratio, both for initial therapy and in simplification strategies. In contrast, LPV/r or darunavir/r monotherapy does not seem an acceptable option in treatment-naïve patients and is becoming increasingly less acceptable in simplification strategies. PMID:25542868

  19. Occult hepatitis B virus infection among Mexican human immunodeficiency virus-1-infected patients

    PubMed Central

    Alvarez-Muñoz, Ma Teresa; Maldonado-Rodriguez, Angelica; Rojas-Montes, Othon; Torres-Ibarra, Rocio; Gutierrez-Escolano, Fernanda; Vazquez-Rosales, Guillermo; Gomez, Alejandro; Muñoz, Onofre; Torres, Javier; Lira, Rosalia

    2014-01-01

    AIM: To determine the frequency of occult hepatitis B infection (OHBI) in a group of human immunodeficiency virus (HIV)-1+/ hepatitis B surface antigen negative (HBsAg)- patients from Mexico. METHODS: We investigated the presence of OHBI in 49 HIV-1+/HBsAg- patients. Hepatitis B virus (HBV) DNA was analyzed using nested PCR to amplify the Core (C) region and by real-time PCR to amplify a region of the S and X genes. The possible associations between the variables and OHBI were investigated using Pearson’s χ2 and/or Fisher’s exact test. RESULTS: We found that the frequency of OHBI was 49% among the group of 49 HIV-1+/HBsAg- patients studied. The presence of OHBI was significantly associated with the HIV-1 RNA viral load [odds ratio (OR) = 8.75; P = 0.001; 95%CI: 2.26-33.79] and with HIV-antiretroviral treatment with drugs that interfere with HBV replication (lamivudine, tenofovir or emtricitabine) (OR = 0.25; P = 0.05; 95%CI: 0.08-1.05). CONCLUSION: The OHBI frequency is high among 49 Mexican HIV-1+/HBsAg- patients and it was more frequent in patients with detectable HIV RNA, and less frequent in patients who are undergoing HIV-ARV treatment with drugs active against HBV. PMID:25309083

  20. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-05-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole

  1. Favorable therapeutic response with an antiretroviral salvage regimen in an HIV-1-positive subject infected with a CRF11-cpx virus.

    PubMed

    Tau, Pamela; Mancon, Alessandro; Mileto, Davide; Di Nardo Stuppino, Silvia; Bottani, Giulia; Gismondo, Maria Rita; Galli, Massimo; Micheli, Valeria; Rusconi, Stefano

    2014-05-01

    HIV drug resistance still represents a crucial problem in antiretroviral therapy. We report a case of a naive patient, harboring a CRF11-cpx virus, which showed drug resistance mutations in the reverse transcriptase. A drug resistance genotyping test was performed for the pol (protease, reverse transcriptase, and integrase) and V3 regions. The initial clinical parameter results showed a 4 log level of HIV-RNA (12,090 cp/ml) and a very low CD4(+) cell count (35 cells/μl). We designed an initial highly active antiretroviral therapy (HAART) regimen including lamivudine (3TC)+abacavir (ABC)+booster ritonavir (DRV/r). The virus was highly resistant to all nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) except for ABC, tenofovir (TDF), and efavirenz (EFV) and was susceptible to all protease inhibitors (PIs) and integrase inhibitors (INIs). A salvage regimen including raltegravir (RAL)+DRV/r was started. Ten months later, the immunovirological status shows CD4(+) 142/μl and HIV-RNA <37 cp/ml. Our results demonstrate the effectiveness of a treatment combination that includes RAL+DRV/r in a patient infected with a complex X4-tropic CRF11-cpx virus. PMID:24279648

  2. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

    PubMed

    Huprikar, S; Danziger-Isakov, L; Ahn, J; Naugler, S; Blumberg, E; Avery, R K; Koval, C; Lease, E D; Pillai, A; Doucette, K E; Levitsky, J; Morris, M I; Lu, K; McDermott, J K; Mone, T; Orlowski, J P; Dadhania, D M; Abbott, K; Horslen, S; Laskin, B L; Mougdil, A; Venkat, V L; Korenblat, K; Kumar, V; Grossi, P; Bloom, R D; Brown, K; Kotton, C N; Kumar, D

    2015-05-01

    Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended. PMID:25707744

  3. Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment.

    PubMed

    Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A; Bolshakov, Oleg; Adesina, Simeon; Gugssa, Ayele; Anderson, Winston A; Nekhai, Sergei; Akala, Emmanuel O

    2016-01-01

    Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs. PMID:27013886

  4. Clinical Pharmacokinetics of Antiretroviral Drugs in Older Persons

    PubMed Central

    Schoen, John C.; Erlandson, Kristine Mace

    2013-01-01

    Introduction Combination antiretroviral therapy has enabled HIV infected persons to reach older ages in high numbers. Hepatic and renal changes that normally occur with advancing age occur earlier and with higher incidence in HIV-infected individuals. A limited number of prospective controlled studies have demonstrated small reductions (17% to 41%) in lopinavir, atazanavir, and lamivudine clearance in older versus younger adults. A much larger number of retrospective studies in adults (age range ~20 to 60 years), including all antiretroviral drugs, have evaluated age as a covariate for pharmacokinetics. Most studies did not detect substantial associations between drug exposures and age. Areas Covered This review summarizes antiretroviral drug pharmacokinetics in older persons. The authors review articles from PubMed (search terms: elderly, antiretroviral, pharmacokinetics) in addition to the bibliographies of those selected. Expert Opinion The evidence to date does not support major pharmacokinetic changes in adults between ~20 and 60 years of age. However, additional prospective, well-controlled studies are needed in more persons > 60 years, including those with frailty and comorbidities, with assessment of unbound drug clearance, and incorporation of adherence, pharmacogenetics, and concomitant medications. Until then, guidelines for drug-drug interactions and dosing in renal and hepatic impairment should be followed in older HIV infected individuals. PMID:23514375

  5. Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS

    PubMed Central

    Taha, Huda; Das, Archik; Das, Satyajit

    2015-01-01

    Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI), which has now been licensed to be used in different countries including the UK. Earlier studies have demonstrated that DTG when used with nucleoside backbone in treatment-naïve and - experienced patients has been well tolerated and demonstrated virological suppression comparable to other INSTIs and superiority against other first-line agents, including efavirenz and boosted protease inhibitors. Like other INSTIs, DTG uses separate metabolic pathways compared to other antiretrovirals and is a minor substrate for CYP-450. It does not appear to have a significant interaction with drugs, which uses the CYP-450 system. Nonetheless, it uses renal solute transporters that may potentially inhibit the transport of other drugs and can have an effect on the elimination of other drugs. However, the impact of this mechanism appears to be very minimal and insignificant clinically. The side effect profiles of DTG are similar to raltegravir and have been found to be well tolerated. DTG has a long plasma half-life and is suitable for once daily use without the need for a boosting agent. DTG has all the potential to be used as a first-line drug in combination with other nucleoside backbones, especially in the form of a single tablet in combination with abacavir and lamivudine. The purpose of this review article is to present the summary of the available key information about the clinical usefulness of DTG in the treatment of HIV infection. PMID:26491363

  6. Poly(lactic-co-glycolic) Acid-Chitosan Dual Loaded Nanoparticles for Antiretroviral Nanoformulations

    PubMed Central

    Makita-Chingombe, Faithful; Kutscher, Hilliard L.; DiTursi, Sara L.; Morse, Gene D.; Maponga, Charles C.

    2016-01-01

    Poly(lactic-co-glycolic acid) (PLGA) chitosan (CS) coated nanoparticles (NPs) were loaded with two antiretrovirals (ARVs) either lamivudine (LMV) which is hydrophilic or nevirapine (NVP) which is hydrophobic or both LMV and NVP. These ARVs are of importance in resource-limited settings, where they are commonly used in human immunodeficiency virus (HIV-1) treatment due to affordability and accessibility. NPs prepared by a water-oil-water emulsion and reduced pressure solvent evaporation technique were determined to have a positive zeta potential, a capsule-like morphology, and an average hydrodynamic diameter of 240 nm. Entrapment of NVP as a single ARV had a notable increase in NP size compared to LMV alone or in combination with LMV. NPs stored at room temperature in distilled water maintained size, polydispersity (PDI), and zeta potential for one year. No changes in size, PDI, and zeta potential were observed for NPs in 10% sucrose in lyophilized or nonlyophilized states stored at 4°C and −20°C, respectively. Freezing NPs in the absence of sucrose increased NP size. Drug loading, encapsulation efficiency, and kinetic release profiles were quantified by high performance liquid chromatography (HPLC). Our novel nanoformulations have the potential to improve patient outcomes and expand drug access in resource-limited countries for the treatment of HIV-1. PMID:27190651

  7. [Positioning of lopinavir/ritonavir in antiretroviral treatment schemes].

    PubMed

    Camacho, Ángela; Rivero, Antonio

    2014-11-01

    Lopinavir/ritonavir (LPV/r) was approved for use in the treatment of human immunodeficiency virus (HIV) infection in 2001 and is the protease inhibitor that has been most widely studied in clinical trials. Despite the time interval since its approval, all the evidence accumulated in the last 14 years indicates that LPV/r continues to occupy an important position among antiretroviral drugs. Firstly, LPV/r plus 2 nucleoside/nucleotide analogs is still considered a good option for initial antiretroviral therapy (ART). Secondly, numerous studies have evaluated the efficacy and safety of new initial ART strategies based on LPV/r in dual therapy. The results obtained suggest that LPV/r plus lamivudine (3TC) or raltegravir can be as effective in initial ART as standard triple therapy and justify their consideration as alternative regimens in this scenario. Thirdly, LPV/r is a pioneer drug, as well as being the agent with the largest amount of evidence from clinical trials on simplification to monotherapy (LPV/r) or dual therapy (LPV/r + 3TC). Lastly, LPV/r is highly useful is special situations. It has a low risk of liver toxicity in patients with chronic liver disease, its use is preferred in the treatment of patients with HIV-2, and it is safe and effective in preventing vertical HIV transmission. PMID:25542874

  8. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-05-01

    (-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir sulfate, Azacitidine; Becatecarin, Belinostat, Bevacizumab, BMS-387032, BMS-690514, Bortezomib; Casopitant mesylate, Cetuximab, Choline fenofibrate, CK-1827452, Clofarabine, Conivaptan hydrochloride; Dabigatran etexilate, DADMe-Immucillin-H, Darbepoetin alfa, Darunavir, Dasatinib, DC-WT1, Decitabine, Deferasirox, Degarelix acetate, Denenicokin, Denosumab, Dienogest, Duloxetine hydrochloride; Ecogramostim, Eculizumab, Edoxaban tosilate, Elacytarabine, Elesclomol, Eltrombopag olamine, Enfuvirtide, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Etravirine; Flibanserin, Fludarabine, Fondaparinux sodium, Fosamprenavir calcium; Gefitinib, Genistein; I-131-L19-SIP, Idrabiotaparinux sodium, Imatinib mesylate, IMGN-901, Ipilimumab; Laromustine, Lenalidomide, Liposomal cisplatin, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Lopinavir/ritonavir; Maraviroc, MDV-3100, Mecasermin rinfabate, MP-470, Mycophenolic acid sodium salt; Naproxcinod, NB-002, Nesiritide, Nilotinib hydrochloride monohydrate, NK-012; Palonosetron hydrochloride, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Pitavastatin calcium, PL-3994, Plerixafor hydrochloride, Plitidepsin, PM-10450; Raltegravir potassium, Recombinant human soluble thrombomodulin, ReoT3D, RHAMM R3 peptide, Rivaroxaban, Romiplostim, Rosuvastatin calcium, Rozrolimupab; Sabarubicin hydrochloride, Salinosporamide A, Sirolimus-eluting stent, Smallpox (Vaccinia) Vaccine, Live, Sorafenib; Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Tipifarnib, Tipranavir, Trabectedin, Trifluridine/TPI; Vardenafil hydrochloride hydrate, Vinflunine, Volociximab, Vorinostat; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, Zoledronic acid monohydrate

  9. Hepatitis B Reactivation with Novel Agents in Non-Hodgkin's Lymphoma and Prevention Strategies.

    PubMed

    Ozoya, Oluwatobi O; Sokol, Lubomir; Dalia, Samir

    2016-06-28

    Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines. Non-Hodgkin's lymphoma is the most common hematological malignancy, and certain patients undergoing therapy are at increased risk of HBV reactivation. Rituximab, a monoclonal antibody, is well studied in HBV reactivation, but newer agents have been implicated as well. Here, we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation. Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin's lymphoma. Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation, and HBV reactivation rates have decreased with increased awareness. HBV reactivation is uncommon when using other novel agents. Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients. In conclusion, the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation, especially in patients treated with anti-CD20 antibody. Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. Lastly, large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation. PMID:27350944

  10. Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket.

    PubMed

    Chen, Wenmin; Zhan, Peng; Daelemans, Dirk; Yang, Jiapei; Huang, Boshi; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong

    2016-10-01

    Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7.4 nM to 9.4 nM (SI = 168-1283), superior to FDA-approved drugs of nevirapine (NVP), lamivudine (3TC) and delavirdine (DLV), and comparable to etravirine (ETV), zidovudine (AZT) and efavirenz (EFV). Additionally, compounds I-8c2 and I-8c3 showed moderate activity against NNRTI resistant strains baring mutations K103N and Y181C with EC50 values of 6.2 μM and 6.8 μM, respectively. Preliminary structure-activity relationships (SARs), reverse transcriptase inhibition efficacy and molecular modeling of selected compounds are also presented. These outcomes support our design hypothesis and demonstrate that the piperidyl group modified pyridine-typed DAPY derivatives are highly potent NNRTIs with improved water solubility. PMID:27267005

  11. Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

    PubMed

    Werayingyong, Pitsaphun; Phanuphak, Nittaya; Chokephaibulkit, Kulkunya; Tantivess, Sripen; Kullert, Nareeluk; Tosanguan, Kakanang; Butchon, Rukmanee; Voramongkol, Nipunporn; Boonsuk, Sarawut; Pilasant, Songyot; Kulpeng, Wantanee; Teerawattananon, Yot

    2015-03-01

    The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. PMID:23728769

  12. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: A review

    PubMed Central

    Sun, Hsin-Yun; Sheng, Wang-Huei; Tsai, Mao-Song; Lee, Kuan-Yeh; Chang, Sui-Yuan; Hung, Chien-Ching

    2014-01-01

    Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to the shared modes of transmission, coinfection with HBV and human immunodeficiency virus (HIV) is not uncommon. It is estimated that 10% of HIV-infected patients worldwide are coinfected with HBV. In areas where an HBV vaccination program is implemented, the HBV seroprevalence has declined significantly. In HIV/HBV-coinfected patients, HBV coinfection accelerates immunologic and clinical progression of HIV infection and increases the risk of hepatotoxicity when combination antiretroviral therapy (cART) is initiated, while HIV infection increases the risk of hepatitis events, cirrhosis, and end-stage liver disease related to chronic HBV infection. With the advances in antiviral therapy, concurrent, successful long-term suppression of HIV and HBV replication can be achieved in the cART era. To reduce the disease burden of HBV infection among HIV-infected patients, adoption of safe sex practices, avoidance of sharing needles and diluent, HBV vaccination and use of cART containing tenofovir disoproxil fumarate plus emtricitabine or lamivudine are the most effective approaches. However, due to HIV-related immunosuppression, using increased doses of HBV vaccine and novel approaches to HBV vaccination are needed to improve the immunogenicity of HBV vaccine among HIV-infected patients. PMID:25356024

  13. Hyaluronic Acid-Based Biocompatible Supramolecular Assembly for Sustained Release of Antiretroviral Drug.

    PubMed

    Song, Byeongwoon; Puskás, István; Szente, Lajos; Hildreth, James E K

    2016-09-01

    Human immunodeficiency virus (HIV) infection and its associated diseases continue to increase despite the progress in our understanding of HIV biology and the availability of a number of antiretroviral drugs. Adherence is a significant factor in the success of HIV therapy and current HIV treatment regimens require a combination of antiviral drugs to be taken at least daily for the remainder of a patient's life. A drug delivery system that allows sustained drug delivery could reduce the medical burden and costs associated with medication nonadherence. Here, we describe a novel supramolecular assembly or matrix that contains an anionic polymer hyaluronic acid, cationic polymer poly-l-lysine, and anionic oligosaccharide sulfobutylether-beta-cyclodextrin. HIV reverse transcriptase inhibitors Zidovudine and Lamivudine were successfully encapsulated into the polymer assembly in a noncovalent manner. The physicochemical properties and antiviral activity of the polymer assemblies were studied. The results of this study suggest that the supramolecular assemblies loaded with HIV drugs exert potent antiviral activity and allow sustained drug release. A novel drug delivery formulation such as the one described here could facilitate our efforts to reduce the morbidity and mortality associated with HIV infections and could be utilized in the design of therapeutic approaches for other diseases. PMID:26975245

  14. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses, which has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, providing information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abacavir sulfate; abciximab; abetimus sodium; adalimumab; aldesleukin; almotriptan; alteplase; amisulpride; amitriptyline hydrochloride; amoxicillin trihydrate; atenolol; atorvastatin calcium; atrasentan; Beclometasone dipropionate; bosentan; Captopril; ceftriaxone sodium; cerivastatin sodium; cetirizine hydrochloride; cisplatin; citalopram hydrobromide; Dalteparin sodium; darusentan; desirudin; digoxin; Efalizumab; enoxaparin sodium; ertapenem sodium; esomeprazole magnesium; estradiol; ezetimibe; Famotidine; farglitazar; fluorouracil; fluticasone propionate; fosamprenavir sodium; Glibenclamide; glucosamine sulfate; Heparin sodium; HSPPC-96; hydrochlorothiazide; Imatinib mesilate; implitapide; Lamivudine; lansoprazole; lisinopril; losartan potassium; l-Propionylcarnitine; Melagatran; metformin hydrochloride; methotrexate; methylsulfinylwarfarin; Nateglinide; norethisterone; Olmesartan medoxomil; omalizumab; omapatrilat; omeprazole; oseltamivir phosphate; oxatomide; Pantoprazole; piperacillin sodium; pravastatin sodium; Quetiapine hydrochloride; Rabeprazole sodium; raloxifene hydrochloride; ramosetron hydrochloride; ranolazine; rasburicase; reboxetine mesilate; recombinant somatropin; repaglinide; reteplase; rosiglitazone; rosiglitazone maleate; rosuvastatin calcium; Sertraline; simvastatin; sumatriptan succinate; Tazobactam sodium; tenecteplase; tibolone; tinidazole; tolterodine tartrate; troglitazone; Uniprost; Warfarin sodium; Ximelagatran. PMID:11980386

  15. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-11-01

    Abacavir sulfate/lamivudine, Adalimumab, AdCD40L, Adefovir, Adefovir dipivoxil, Ambrisentan, Amlodipine, Amlodipine besylate/olmesartan medoxomil, AN-2728, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride, Atrasentan, Azacitidine, Bevacizumab, Blinatumomab, Bortezomib, Bosentan, Carfilzomib, Caspofungin acetate, Cediranib, Cetuximab, Choriogonadotropin alfa, Clevudine, Clindamycin phosphate/benzoyl peroxide, Clofarabine, Daidzeol, Darunavir, Dasatinib, Decitabine, Deferasirox, Deforolimus, Degarelix acetate, Denenicokin, Dexlansoprazole, Duloxetine hydrochloride, Elacytarabine, Enfuvirtide, Enoxaparin, Entecavir, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Ezetimibe/simvastatin, Forodesine hydrochloride, Fosamprenavir calcium, Gefitinib, Gemtuzumab ozogamicin, Golimumab, Imatinib mesylate, Imetelstat, Insulin gl'argine, Insulin glulisine, Interferon alfa-2b XL, Ivabradine hydrochloride, Lacosamide, Lenalidomide, Lintuzumab, Liposomal adriamycin, Liposomal belotecan, Liposome-encapsulated fentanyl, Lopinavir/ritonavir, Lutropin alfa, LY-207320, Maraviroc, Mecasermin, MKC-253, MP-470, NGR-TNF, Nilotinib hydrochloride monohydrate, Ofatumumab, Olmesartan medoxomil, Omacetaxine mepesuccinate, PAN-811, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perospirone hydrochloride, PF-734200, Phentermine/topiramate, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Pregabalin, Raltegravir potassium, Ramelteon, Ranibizumab, Recombinant Bet V1, Recombinant human insulin, Regadenoson, rhITF, Romidepsin, Rosuvastatin calcium, Ruboxistaurin hydrochloride, Rufinamide, Sapropterin dihydrochloride Saracatinib, SB-73, SC-599, Seliciclib, Sirolimus-eluting stent, Sorafenib, Sunitinib malate, Tadalafil, Tanespimycin, Tapentadol hydrochloride, Tegaserod maleate, Telbivudine, Tenofovir

  16. USING PharmGKB TO TRAIN TEXT MINING APPROACHES FOR IDENTIFYING POTENTIAL GENE TARGETS FOR PHARMACOGENOMIC STUDIES

    PubMed Central

    PAKHOMOV, S.; MCINNES, B.T.; LAMBA, J.; LIU, Y.; MELTON, G.B.; GHODKE, Y.; BHISE, N.; LAMBA, V.; BIRNBAUM, A.K.

    2012-01-01

    The main objective of this study was to investigate the feasibility of using PharmGKB, a pharmacogenomic database, as a source of training data in combin