Evaluation of Efficacy, Safety, Pharmacokinetics, and Adherence in HIV-1—Infected, Antiretroviral-Naïve Patients Treated with Ritonavir-Boosted Atazanavir Plus Fixed-Dose Tenofovir DF/Emtricitabine Given Once Daily
ABSTRACT Evaluate efficacy, safety, tolerability, pharmacokinetics, adherence, and treatment satisfaction of atazanavir/ritonavir (ATV/r) 300 mg/100mg and tenofovir DF/emtricitabine (TDF/FTC) 300 mg/200mg once daily in antiretroviral-naïve HIV-infected patients.
Single-arm, open-label, multicenter 48-week study.
100 patients were evaluated; 17 patients discontinued early including 6 for adverse events. There were 2 deaths (multi-organ failure, lactic acidosis). At 48 weeks, 81% achieved HIV-1 RNA <50 copies/mL (ITT, M=F). No K65R or ATV/r associated mutations emerged; M184V developed in one patient. Median CD4 increase was 217 cells/mm3. The most common adverse events (> or = 10%) were diarrhea, nausea, scleral icterus, fatigue, upper respiratory tract infection, headache, and vomiting. Grade 4 hyperbilirubinemia occurred in 5%. Median increases at 48 weeks in total cholesterol, HDL, LDL, and triglycerides were 11, 3, 2, and 5 mg/dL, respectively. Two patients had confirmed graded increases in serum creatinine (one grade 1, one grade 2). Median (IQR) creatinine clearance change from baseline at 48 weeks was -7 (-19, 2) mL/min. Geometric mean (95% CI) ATV trough concentrations exceeded suggested therapeutic range. At 48 weeks, 92% of patients reported complete adherence by 1-week recall and 90% reported being "very satisfied" with the regimen.
ATV/r+TDF/FTC was safe, well tolerated, and convenient for patients. Larger comparative trials are ongoing.
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) integrase inhibitors belong to a novel class of antiretroviral drugs with high potency and better tolerability. Elvitegravir (EVG) is the second integrase inhibitor approved by the US Food and Drug Administration when administered in combination with a novel pharmacoenhancer, cobicistat (COBI), and two nucleoside/nucleotide reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). This combination of drugs (EVG/COBI/FTC/TDF) developed and marketed by Gilead Sciences Inc. (Foster City, CA, USA) as STRIBILD(®), is the first integrase inhibitor-based single-tablet regimen administered once-daily. In the USA, it has been approved for use in antiretroviral treatment-naïve HIV-1 patients with estimated creatinine clearance of >70 mL/min. The Department of Health and Human Services has approved EVG/COBI/FTC/TDF as one of preferred first-line regimens for HIV-1 treatment. In Europe, the European Medicines Agency has approved STRIBILD in treatment-naïve patients as well as in patients having no resistant mutation to any of the antiviral agents contained in STRIBILD. Its availability as a fixed-dose combination and once-daily dosage makes the adherence highly likely. However, it also discounts the possibility of dosage adjustment if needed.HIV/AIDS - Research and Palliative Care 01/2014; 6:81-90. DOI:10.2147/HIV.S39178
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ABSTRACT: Introduction Despite antiretroviral (ARV) therapy reducing renal disease in human immunodeficiency virus overall, there is concern that certain ARVs, particularly tenofovir disoproxil fumarate (TDF) with or without a boosted protease inhibitor (PI), may reduce renal function over time. It is not known whether effects seen with PI-based regimens are independent, result from interactions with TDF coadministration, or are artefactual owing to inhibition of renal tubular creatinine transport by ritonavir or cobicistat pharmacoenhancement. The aim of this review was to conduct a systematic review of studies, weighted toward high-quality evidence, examining changes in renal function over time with PI-based regimens. Methods PubMed, Embase, and Medline databases and conference abstracts were searched using pre-defined terms for English language articles, published up to and including August 12, 2013, describing changes in renal function over time with PI-based regimens. All available randomized controlled trials (RCTs) were selected; however, to reduce bias, only observational studies recruiting from more than one center and analyzing data from more than 1,000 patients were included. Evidence was qualitatively evaluated according to levels established by the Oxford Centre for Evidence-Based Medicine (OCEBM). Results A total of 2,322 articles were retrieved by the initial search. Of these, 37 were selected for full review, comprising 24 RCTs (OCEBM Level 1 evidence: 4 reports of fully double-blinded or blinded with respect to the PI component). The remaining 20 RCTs and 13 observational studies qualified as OCEBM Level 2 evidence. Level 1 evidence showed initial but non-progressive increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate (eGFR), suggesting an effect on renal tubular transport of creatinine. Level 2 evidence suggested that atazanavir and lopinavir especially in combination with TDF were associated with non-progressive reductions in eGFR over time, with a decreased risk for the development of chronic kidney disease (CKD) on cessation and without the development of advanced CKD or end-stage renal disease (ESRD); whether these reductions were independent or associated with interactions with coadministered TDF could not be established with certainty. Data on darunavir were insufficient to draw any conclusions. The principal limitation of the reviewed studies was the lack of standardization of creatinine measurements in virtually all studies and the lack of corroborative data on changes in proteinuria or other indices of renal function. Discussion In this review, there was little evidence for progressive changes in eGFR, or the development of advanced CKD, or ESRD with lopinavir or atazanavir. Further long-term studies, employing a wide range of validated renal function assessments, are required to fully evaluate potential association of PIs with CKD.01/2015; 4(1). DOI:10.1007/s40121-014-0056-4
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ABSTRACT: Atazanavir (Reyataz(®) ) is an important member of the HIV protease inhibitor class. Because of the complexity of its chemical structure, metabolite identification and structural elucidation face serious challenges. So far, only seven non-conjugated metabolites in human plasma have been reported, and their structural elucidation is not complete, especially for the major metabolites produced by oxidations. To probe the exact sites of metabolism and to elucidate the relationship among in vivo metabolites of atazanavir, we designed and performed two sets of experiments. The first set of experiments was to determine atazanavir metabolites in human plasma by LC-MS, from which more than a dozen metabolites were discovered, including seven new ones that have not been reported. The second set involved deuterium labeling on potential metabolic sites to generate D-atazanavir analogs. D-atazanavir analogs were dosed to human in parallel with atazanavir. Metabolites of D-atazanavir were identified by the same LC-MS method, and the results were compared with those of atazanavir. A metabolite structure can be readily elucidated by comparing the results of the analogs and the pathway by which the metabolite is formed can be proposed with confidence. Experimental results demonstrated that oxidation is the most common metabolic pathway of atazanavir, resulting in the formation of six metabolites of monooxidation (M1, M2, M7, M8, M13, and M14) and four of dioxidation (M15, M16, M17, and M18). The second metabolic pathway is hydrolysis, and the third is N-dealkylation. Metabolites produced by hydrolysis include M3, M4, and M19. Metabolites formed by N-dealkylation are M5, M6a, and M6b. Copyright © 2013 John Wiley & Sons, Ltd.Journal of Mass Spectrometry 09/2013; 48(9):1019-31. DOI:10.1002/jms.3247 · 2.71 Impact Factor