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BackgroundHighly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for human immunodeficiency virus (HIV)-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STIs) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP.MethodsWe analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modeling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1.ResultsAcross 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe), STI and HIV-1 incidences were high: HIV-1 4.9, N gonorrhoeae 5.3, C trachomatis 14.5, and T vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N gonorrhoeae (r = 0.02, P = .871), C trachomatis (r = 0.49, P =

Introduction: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV‐1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. Methods: We measured the amount of dapivirine in returned rings from a placebo‐controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non‐use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time‐dependent covariate for HIV‐1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV‐1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. Results: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV‐1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV‐1 acquisition estimated 75% to 91% HIV‐1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall. Conclusions: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV‐1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long‐acting, woman‐initiated approach for discreet HIV‐1 prevention. [ABSTRACT FROM AUTHOR]