Women account for an increasing proportion of patients with HIV

Sex and gender

Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial.

Women account for an increasing proportion of patients with HIV-1 but remain underrepresented in antiretroviral clinical trials. The objective of the analysis was to evaluate sex-based differences in efficacy and adverse events in treatment-experienced, HIV-positive women and men receiving darunavir-ritonavir therapy over 48 weeks. This was a multicentre, open-label, phase 3b study designed to enrol a high proportion of women, with sample size determined on the basis of a noninferiority design with a maximum allowable difference of 15% in virologic response favouring men. The study was conducted across 65 sites in the United States, Puerto Rico, and Canada. 287 women and 142 men were enrolled into the trial. Patients received darunavir-ritonavir, 600/100 mg twice daily, plus an investigator-selected optimized background regimen. Virologic response (HIV RNA <50>A higher proportion of women discontinued treatment than men (32.8% vs. 23.2%; P = 0.042); more women than men discontinued treatment for reasons other than virologic failure. Response rates in women and men at week 48 were 50.9% and 58.5%, respectively (intention-to-treat TLOVR), and 73.0% and 73.5%, respectively (TLOVR censored for patients who withdrew for reasons other than virologic failure). The absolute difference in response, based on logistic regression and adjusted for baseline log(10) viral load and CD4(+) cell count, was -9.6 percentage points (95% CI, -19.9 to 0.7 percentage points; P = 0.067) for intention-to-treat TLOVR and -3.9 percentage points (CI, -13.9 to 6.0 percentage points; P = 0.438) for TLOVR population that censored patients who withdrew for reasons other than virologic failure. Adverse events were similar between the sexes. The most common grade 2 to 4 adverse events that were considered at least possibly treatment related in women and men were nausea (5.2% and 2.8%, respectively), diarrhoea (4.5% and 4.9%, respectively), and rash (2.1% and 2.8%, respectively). A limitation of the study is that baseline characteristics differed between sexes. Non-significant, sex-based differences in response were found during the 48-week study; however, these differences were probably due to higher discontinuation rates in women, suggesting that additional efforts are needed to retain women in clinical trials.

Editors’ note: This study was designed as a non-inferiority trial, meaning a trial that is intended to determine that the effect of a new treatment is not worse than that of an active control by more than a specified margin. In this case, the researchers wanted to know whether women’s response to the treatment regimen was more than 15% different than that of men’s, measured by viral load responses. Each site could enrol a man only after they had enrolled three women. The treatment response in men and women was not significantly different but the study did highlight the challenges of retaining women in clinical trials: almost a third of women discontinued treatment compared to 23% of men. The GRACE trial (Gender, Race and Clinical Experience) did note a slightly higher exposure to darunavir (20%) and ritonavir (70%) in women compared to men at week 4 suggesting sex-based differences in pharmacokinetics – a finding deserving of further exploration. This applies to these agents as well as to other fixed dose combinations that are used for both men and women.