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

Abstract

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.

Keywords: abacavir; atazanavir; efavirenz; sex; tenofovir.

Figure 1.

Time to virologic failure (A), safety (B), and tolerability (C) endpoints by sex. Abbreviations: ABC/3TC, abacabir/lamivudine; ATV/r, atazanavir/ritonavir; EFV, efavirenz; TDF/FTC, tenofovir/emtricitabine.

Figure 2.

Treatment and sex comparisons for virologic failure, safety, and tolerability endpoints. A, Subjects on abacavir and lamivudine (ABC/3TC), comparing atazanavir (ATV) vs efavirenz (EFV). B, Subjects on ABC/3TC, comparing women vs men. C, Subjects on tenofovir and emtricitabine (TDF/FTC), comparing ATV vs EFV. D, Subjects on TDF/FTC, comparing women vs men. Univariate analysis (u) stratified by screening human immunodeficiency virus type 1 (HIV-1) RNA, and based on all available data for the covariate. Multivariable (m) analyses were adjusted for race/ethnicity (white, black, Hispanic), intravenous drug use, HIV-1 drug resistance genotype screening, age quartiles, CD4 cell count (4 categories), HIV-1 RNA level (4 categories), history of AIDS-defining event, and hepatitis B or C. Multivariable analysis excluded participants of “other” race/ethnicity due to small numbers. P value: likelihood ratio test, for main effect in “overall” results, and interaction tests otherwise. All models are stratified by screening HIV-1 RNA group (<100 000 or ≥100 000 copies/mL); univariate and multivariable adjusted estimates are based on interaction model; treatment effects by sex and sex associations by treatment are derived from the same model. Abbreviations: ABC/3TC, abacabir; lamivudine; ATV/r, atazanavir/ritonavir; CI, confidence interval; EFV, efavirenz; HR, hazard ratio; TDF/FTC, tenofovir/emtricitabine.