Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV‐1 acquisition: a secondary analysis from a randomized, placebo‐controlled trial

Abstract

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.

The impact of participant engagement activities in supporting dapivirine ring use among participants enrolled in the Phase III MTN-020/ASPIRE study

“…Women were randomized in a 1:1 ratio to use either a monthly silicone elastomer vaginal matrix ring containing 25 mg of dapivirine or a placebo ring containing no drug, and followed monthly for a minimum of 12 and a maximum of 33 months. Study results demonstrated a statistically signi cant reduction in HIV risk among participants assigned to the dapivirine ring by 27% in intention-to-treat analyses [3], and suggested greater risk reduction among subgroups with evidence of high adherence, exceeding 50% among individuals with consistent ring use [3,17]. Additional details regarding the study design, recruitment, and results have been published previously [3].…”

Acceptability of the Dapivirine Vaginal Ring for HIV-1 Prevention and Association with Adherence in a Phase III Trial

“…Two randomized, placebo controlled, phase III trials in healthy sexually-active women, MTN-020/ASPIRE and IPM-027/The Ring Study, demonstrated the monthly DVR was well-tolerated and reduced HIV incidence [ 4 , 5 ]. In ASPIRE, higher risk reduction was estimated with measures indicating higher adherence [ 6 ]. In earlier phase I and II trials the DVR was found to be highly acceptable [ 7 – 10 ].…”

Ask the Way From Those Who Have Walked It Before – Grandmothers’ Roles in Health-related Decision Making and HIV Pre-exposure Prophylaxis (PrEP) Use Among Pregnant and Breastfeeding Women in Africa

“…The effectiveness of these oral and vaginal PrEP strategies are driven by user adherence (12,13), which can be challenging (14)(15)(16), especially with daily dosage. As such, innovative strategies to support adherence are warranted, including in pregnant and breastfeeding women, an important population for PrEP.…”