Sex differences in antiretroviral therapy (ART) outcomes and in drug exposure have been reported supporting the conclusion that some ART combinations may not be as well tolerated in women compared to men. We evaluated disparities in outcomes between men and women participating in ACTG A5288, an interventional strategy trial for individuals failing 2nd-line ART in low and middle-income countries (LMIC).
Participants were assigned to cohorts based on resistance profiles and ART history: Cohort A had no LPV/r resistance, susceptibility to at least one NRTI, and stayed on their LPV/r- or ATV/r-based 2nd-line regimen; others with increasing resistance were assigned to Cohorts B, C or D and changed to a regimen that generally included DRV/r, RAL with ETR or best available NRTIs (except for those with DRV/r resistance or prior RAL exposure). The primary endpoint was virologic suppression at week 48 (VL ≤200 c/ml). In this secondary analysis, we evaluated sex differences in the primary endpoint; in confirmed virologic failure (VF: VL ≥1000 c/mL); clinical outcomes and adverse events (intent-to-treat).
Women comprised 258/545 (47%) of the study population. More women than men were assigned to Cohort A. Median follow-up was 72 weeks. Fewer women than men had virologic suppression at week 48 (table). This trend occurred in all cohorts, including in Cohort A whose participants stayed on their 2nd-line regimen (39% vs 49%) and in Cohorts B, C and D who received novel regimens (83% versus 89%). Significantly more women experienced VF, Grade 3 signs and symptoms, serious adverse events and hospitalizations, but not more frequent Grade 3+ diagnoses or laboratory abnormalities.
More women than men entered the study in cohort A, with a resistance profile suggesting they could be suppressed on their current regimen and therefore stayed on that regimen in the study. Regimens including LPV/r or ATV/r frequently failed. The more frequent occurrence of Grade 3 signs and symptoms in women suggests that tolerability issues were under recognized in women on 2nd-line therapy with demonstrated clinical consequences. More work is needed to identify determinants of drug exposure and tolerability in women in LMIC.