Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women

Several clinical trials have demonstrated that antiretroviral (ARV) drugs, taken as pre-exposure prophylaxis (PrEP), can prevent HIV infection(1), with the magnitude of protection ranging from -49 to 86%(2–11). While these divergent outcomes are thought to be due primarily to product adherence(12), biological factors likely contribute(13). Despite selective recruitment of higher risk participants for prevention trials, HIV risk is heterogeneous, even within higher risk groups(14–16). To determine whether this heterogeneity could influence PrEP outcomes, we undertook a post-hoc prospective analysis of the CAPRISA 004 tenofovir 1% gel trial (n=774), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine pro-inflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% CI: 7 to 80%), compared to 3% (95% CI: −104 to 54%) if genital inflammation was present. Among high gel adherers, tenofovir protection was 75% (95% CI: 25 to 92%) in women without inflammation compared to −10% (95% CI: −184 to 57%) in women with inflammation. Host immune predictors of HIV risk may modify the effectiveness of HIV prevention tools; reducing genital inflammation in women may augment HIV prevention efforts.