Background: Tenofovir (TFV) gel is a vaginal microbicide that has recently been shown to prevent 39% of male-to-female sexual transmission of HIV. In contrast, some earlier microbicides enhanced HIV transmission by disrupting the vaginal epithelial barrier, and/or inducing inflammatory cytokine responses and recruiting target cells for HIV infection. These studies have highlighted the need for a better understanding of immune events in the genital tract that are associated with susceptibility to HIV infection and to identify biomarkers of efficacy and safety of potential microbicides. In this study, we investigated the effect of TFV gel use on cervicovaginal lavage (CVL) cytokine concentrations in trial participants, and signatures of enhanced susceptibility to HIV infection in women who became infected.

Methods:  HIV-uninfected South African women (n = 889) were enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial and randomized to use either placebo or 1% TFV gel. Prior to unblinding, Luminex was used to measure the concentrations of 20 cytokines in pre- and post-infection CVL from 35 women who became HIV-infected and from 40 women who remained HIV-uninfected and were frequent gel users and high adherers to the study dosing strategy. Mann-Whitney U and Wilcoxon Signed Rank tests were used for unmatched and matched comparisons, respectively. Logistic regression was used to control for gel use. p values were adjusted for multiple comparisons using a false discovery rate step-down procedure.

Results:  CVL cytokine concentrations did not differ between TFV and placebo gel users. Women who became infected with HIV did not have increased cytokine levels during early infection relative to pre-infection. However, women who became HIV-infected had significantly higher concentrations of inflammatory IL-1β, IL-6, IL-7, TNF-α, MIP-1α, MIP-1β, and GM-CSF before infection relative to women who remained uninfected, with 1 log₁₀ pg/mL increases in the levels of each of these cytokines associated with 35 to 153% greater risk of HIV infection.

Conclusions:  TFV gel use was not associated with changes in genital tract cytokine concentrations. Women who became HIV-infected had higher levels of inflammation in the genital tract prior to HIV infection compared to women who remained uninfected. These findings suggest that high levels of genital tract inflammation may facilitate breakthrough infections and that enhancing the efficacy of TFV gel may require augmentation with an anti-inflammatory agent.