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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 infection1, with the magnitude of protection ranging from −49 to 86% (refs. 2,3,4,5,6,7,8,9,10,11). Although these divergent outcomes are thought to be due primarily to differences in product adherence12, biological factors likely contribute13. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups14,15,16. 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.

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Figure 1: Tenofovir efficacy in groups stratified according to level of inflammation, defined as a specified number of cytokines detected at elevated concentrations in FGT secretions (n = 774 women).


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We would like to thank W. Heneine and D. Kwon for important discussions regarding these data. The study was funded by the National Institutes of Health (5R01AI111936 to J.S.P.) and the DST-NRF Centre of Excellence in HIV Prevention at CAPRISA. The original CAPRISA 004 1% tenofovir gel trial was funded principally by the United States Agency for International Development (USAID) through FHI360 and CONRAD with additional support provided by the South African Department of Science and Technology (DST). We would like to thank all study participants and CAPRISA staff for making the CAPRISA 004 trial possible. L.R.M. is supported by a Canadian Institutes of Health Research (CIHR) New Investigator Award. L.J.L., D.A., and L.M. are funded by South African National Research Foundation (NRF) Research Career Advancement Fellowship awards.

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L.R.M., L.J.L., J.G.G.L., A.D.K., L.M., L.E.M., Q.A.K., S.S.A.K., and J.-A.S.P. designed the study. L.R.M., L.J.L., D.A., S.N., and A.S. performed the experiments. L.R.M., L.J.L., N.Y.-Z., and N.N. analyzed the data. L.R.M., L.J.L., N.Y.-Z., D.A., S.N., A.S., N.N., J.G.G.L., A.D.K., L.M., L.E.M., Q.A.K., S.S.A.K., and J.-A.S.P. wrote the manuscript.

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Correspondence to Lyle R McKinnon or Jo-Ann S Passmore.

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J.G.G.L. is named in a USA government patent titled “Inhibition of HIV Infection through Chemoprophylaxis” (US Patent no. 9,044,509 B2). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC).

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McKinnon, L., Liebenberg, L., Yende-Zuma, N. et al. Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women. Nat Med 24, 491–496 (2018).

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