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

Abstract

Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from -49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory 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% confidence interval (CI): 7-80%) but was 3% protective (95% CI: -104-54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25-92%) in women without inflammation compared to -10% (95% CI: -184-57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.

Figure 1

Tenofovir efficacy stratified by inflammation status, defined by the number of elevated cytokines that were detected in female genital tract secretions (n = 774) a). Those meeting the cytokine cut-off for inflammation are indicated in red boxes (efficacy estimate) and whiskers (95% confidence intervals), with those falling below this cut-off indicated in blue boxes and whiskers. Tenofovir efficacy is shown on the x-axis, with a dotted black line indicating 0% efficacy. Overall tenofovir efficacy of the participants included in this analysis is indicated by the grey box and whiskers. Efficacy was calculated as 1-incident rate ratio (IRR) multiplied by 100, as shown in Table 1. Kaplan-Meier survival plots indicating the probability of seroconversion stratified by gel adherence (< and ≥50%, panels b and c, respectively). Separate lines are indicated for participants in the tenofovir arm of the study, with (solid black) and without genital inflammation (dotted black), and the placebo arm of the study, with (solid red) and without genital inflammation (dotted red). Genital inflammation in this analysis was defined by ≥3 of 9 cytokines in the upper quartile. The number of HIV infections/the number at risk in each strata and time point are shown below each graph. All statistical tests were two-sided and unadjusted for multiple comparisons.