Title | Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Venuto CS, Mollan K, Ma Q, Daar ES, Sax PE, Fischl M, Collier AC, Smith KY, Tierney C, Morse GD |
Journal | J Antimicrob Chemother |
Volume | 69 |
Issue | 12 |
Pagination | 3300-10 |
Date Published | 2014 Dec |
ISSN | 1460-2091 |
Keywords | Adult, Anti-HIV Agents, Atazanavir Sulfate, Female, HIV Infections, Humans, Male, Metabolic Clearance Rate, Middle Aged, Oligopeptides, Plasma, Pyridines, Ritonavir, Sex Characteristics, Time Factors, Treatment Failure, Treatment Outcome |
Abstract | OBJECTIVES: It is uncertain whether HIV-1 antiretroviral exposure and clinical response varies between males and females or different race/ethnic groups. We describe ritonavir-enhanced atazanavir pharmacokinetics in relation to virological failure, safety and tolerability in treatment-naive individuals to investigate potential differences. METHODS: Plasma samples were collected from participants in AIDS Clinical Trials Group Study A5202 for measurement of antiretroviral concentrations. Individual estimates of apparent oral clearance of atazanavir (L/h) were calculated from a one-compartment model and divided into tertiles as slow (<7), middle (7 to <9; reference group) and fast (≥9). Associations between atazanavir clearance and clinical outcomes were estimated with a hazard ratio (HR) from Cox proportional hazards models. Interactions between atazanavir clearance and sex, race/ethnicity and NRTIs were investigated for each of the outcomes. RESULTS: Among 786 participants, average atazanavir clearance was slower in females (n = 131) than males (n = 655). Atazanavir clearance was associated with time to virological failure (P = 0.053) and this relationship differed significantly by sex (P = 0.003). Females in the fast atazanavir clearance group had shorter time to virological failure (HR 3.49; 95% CI 1.24-9.84) compared with the middle (reference) atazanavir clearance group. Among males, the slow atazanavir clearance group had a higher risk of virological failure (HR 2.10; 95% CI 1.16-3.77). CONCLUSIONS: Atazanavir clearance differed by sex. Females with fast clearance and males with slow clearance had increased risk of virological failure. |
DOI | 10.1093/jac/dku303 |
Alternate Journal | J. Antimicrob. Chemother. |
PubMed ID | 25159623 |
PubMed Central ID | PMC4228779 |
Grant List | AI069434 / AI / NIAID NIH HHS / United States AI069477 / AI / NIAID NIH HHS / United States AI38855 / AI / NIAID NIH HHS / United States AI38858 / AI / NIAID NIH HHS / United States AI68634 / AI / NIAID NIH HHS / United States AI68636 / AI / NIAID NIH HHS / United States P30 AI50410 / AI / NIAID NIH HHS / United States T32 NS007338 / NS / NINDS NIH HHS / United States T32 NS007338 / NS / NINDS NIH HHS / United States U01AI068636 / AI / NIAID NIH HHS / United States UL1 TR000439 / TR / NCATS NIH HHS / United States UM1 AI068634 / AI / NIAID NIH HHS / United States UM1 AI068636 / AI / NIAID NIH HHS / United States UM1 AI069412 / AI / NIAID NIH HHS / United States UM1 AI069424 / AI / NIAID NIH HHS / United States UM1 AI069477 / AI / NIAID NIH HHS / United States UM1 AI069511 / AI / NIAID NIH HHS / United States UM1 AI106701 / AI / NIAID NIH HHS / United States UM1AI106701-01 / AI / NIAID NIH HHS / United States |