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Background: Exposure to tenofovir disoproxil fumarate (TDF) may cause renal toxicity. Inhibitors of TDF's apical multidrug-resistance-associated protein efflux-transporters (MRPs) in the renal proximal tubule could enhance this unwanted effect.Methods: We performed a cohort study involving patients with human immunodeficiency virus type 1 (HIV) infection. All patients had a suppressed viral load and were receiving TDF as a part of combination antiretroviral therapy. Data on mean cumulative defined daily doses (DDDs) of MRP inhibitors (NSAIDs, PDE5-i, salicylates, dipyridamole) were collected. The effects of MRP inhibitors on the estimated glomerular filtration rate (eGFR) and proximal tubular function were evaluated by generalized linear models, with adjustment for renal- and HIV-specific factors.Results: A total of 721 HIV-infected patients were included (76.3% were male; median age, 45 years; median CD4(+) T-cell count, 600 cells/mm(3)). The median duration of TDF exposure was 54 months, and the total cumulative exposure duration was 3484 patient-years. Three hundred twenty-one patients had MRP inhibitor exposure, ranging from 0.02 to 120 mean DDDs/month. Exposure to MRP inhibitors was associated with an additional mean eGFR change of -1.4 mL/min (95% confidence interval [CI], -2.9 to .1 mL/min) over 12 months in patients with ≥1 year of continuous TDF exposure. Associations were observed between MRP inhibitor exposure and eGFR declines of >10 mL/min (odds ratio [OR], 1.38; 95% CI, .97 to 1.95), or >25% (OR, 2.14; 95% CI, 1.19 to 3.85) since initiation of TDF therapy. Overall, no clinically significant associations were found between MRP inhibitor exposure and abnormal protein, glucose, or phosphate handling in the proximal tubule or with the presence of ≥2 of these markers.Conclusions: Concomitant incidental exposure to MRP inhibitors and TDF did not result in major additional TDF-related renal toxicity in HIV-infected patients. [ABSTRACT FROM AUTHOR]

The results of this large nationwide study show better virological responses to emtricitabine than to lamivudine as part of frequently used first-line combination antiretroviral regimens for therapy-naive HIV-1–infected patients.Background. Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART.Methods. This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score–adjusted models.Results. Therapy-naive HIV-1–infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11–2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25–3.52) in on-treatment analysis. Propensity score–adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61–3.42) with efavirenz and 2.01 (95% CI, 1.36–2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression.Conclusions. The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available. [ABSTRACT FROM PUBLISHER]

In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Comparative efficacy of lamivudine and emtricitabine: comparing the results of randomized trials and cohorts" by N Ford and others in the 2015 issue.

Introduction Nevirapine (NVP) induces cytochrome P450 3A4 by which rilpivirine (RPV) is metabolized. Switching NVP to RPV could result in decreased RPV exposure with subsequent virological failure and dyslipidemia because NVP is regarded as the least dyslipidemic, non-nucleoside, reverse transcriptase inhibitor. This trial evaluated the efficacy, pharmacokinetics, safety and cardiovascular risks of switching NVP to RPV. Materials and Methods Prospective open label controlled trial. HIV-1 patients with HIV-1 RNA <50 copies/mL on once daily NVP, emtricitabine/tenofovir (FTC/TDF) switched to single tablet RPV/FTC/TDF. Eligible patients on NVP, FTC/TDF were controls. Primary endpoint was week 12 HIV-1 RNA <50 copies/mL by intention to treat analysis. Secondary endpoints were week 24 HIV-1 RNA <50 copies/mL, NVP and RPV pharmacokinetics, safety and fasting lipids, Framingham risk scores (FRS) and Adult Treatment Panel III (ATP-III) lipid goals. Results Of 189 eligible patients, we included 50 RPV switchers and 139 NVP controls. Week 12 HIV-RNA was <50 copies/mL in 46/50 switchers (92.0%) which was not different from the hypothesized 90% week 12 suppression rate (p=.431). Forty-four of 50 switchers had week 24 HIV-1 RNA <50 copies/mL compared to 126/139 controls (difference: 2.6%, 95% CI −7.6% to 12.8%, p=.593). NVP plasma concentrations were below detection level in all at week 3. Mean week 1 RPV trough concentration was 0.083 mg/L and comparable to phase III trial data (p=0.747). Adverse events occurred in 36 switchers, the majority (82.0%) were grade one. Two switchers discontinued RPV for side effects. Significant changes over 24 weeks (p<0.001) were observed in switchers on total cholesterol (TC, −0.67 mmol/L, 95% CI −0.50 to 0.83), low density lipoprotein (LDL)-C (−0.36, 95% CI −0.21 to −0.51) and high density lipoprotein (HDL)-C (−0.28, 95% CI −0.20 to −0.35). The TC/HDL-C ratio increased 0.20 (95% CI 0.02 to 0.37; p=.029) and systolic blood pressure decreased 6.0 mmHg (95% CI −1.7 to −10.3; p=.007). The median FRS did not change over 24 weeks (8.4% vs. 7.7%; p=.119). More patients achieved LDL-C (+15%; p=.016) and TC (+25%; p<0.001) ATP-III treatment goals at week 24 on RPV. Conclusions A NVP to RPV switch does not influence RPV exposure and results in adequate ongoing HIV-1 suppression. RPV could be an option for patients at risk for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Introduction Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable by HIV-1 guidelines in first-line tenofovir/efavirenz (TDF/EFV) and TDF/nevirapine (NVP) combination antiretroviral therapy (cART). Data from trials on equivalence of 3TC and FTC are inconsistent. We examined the effectiveness of 3TC and FTC in the national HIV cohort in the Netherlands. Material and Methods Observational cohort study on cART naïve HIV-1 patients. Therapy was initiated as 3TC or FTC with TDF/EFV or TDF/NVP between 2002 and 2012. Patients with baseline resistance or prior cART experience were excluded. Main outcomes were Week 48 virological failure (VF) by on treatment analysis, time to HIV-RNA <400 copies/mL within 48 weeks and VF within 240 weeks after at least one HIV-RNA <400 copies/mL. Acquired resistance to reverse transcriptase was evaluated. Analyses were done by logistic regression and Cox proportional hazard models. Propensity score adjusted models and intention to treat evaluations were included as sensitivity analysis. Results A total of 4836 patients initiated 3TC/TDF/EFV ( n=546), FTC/TDF/EFV ( n=3391), 3TC/TDF/NVP ( n=207) or FTC/TDF/NVP ( n=692). Ninety-six patients were excluded for baseline resistance or prior cART experience. By Week 48, VF proportions were higher for 3TC/TDF/EFV (10.8%) compared to FTC/TDF/EFV (3.6%) and for 3TC/TDF/NVP (27.0%) compared to FTC/TDF/NVP (11.0%). The multivariable adjusted odds ratio (OR) on VF was 1.78 (95% CI 1.11-2.84; p=0.016) with 3TC/TDF/EFV compared to FTC/TDF/EFV and 2.09 (95% CI 1.25-3.52; p=0.005) with 3TC/TDF/NVP compared to FTC/TDF/NVP. Propensity score adjusted models and intention to treat analyses showed comparable results. The time to virological suppression within 48 weeks was not influenced by using 3TC or FTC in cART. If HIV-RNA <400 copies/mL was achieved on initial cART first, no differences in VF within 240 weeks were observed between 3TC and FTC with TDF/EFV ( p=0.090) or TDF/NVP ( P=0.255). Patients failing 3TC-containing cART had higher median HIV-RNA at VF compared to FTC containing cART ( p<0.001) and 89.8% had acquired resistance on 3TC compared to 81.2% on FTC. Conclusions Including FTC in cART is associated with better virological responses compared to 3TC. As cost constraints may call for the use of generic 3TC, a well-powered randomized trial to confirm the presumed equivalence of 3TC and FTC is needed. [ABSTRACT FROM AUTHOR]