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A Phase III Trial of the Dapivirine Vaginal Ring for HIV-1 Prevention in Women
Jared M. Baeten1; Thesla Palanee-Phillips2; Elizabeth R. Brown3; Katie Schwartz4; Lydia E. Soto-Torres5; Annalene Nel6; Zeda Rosenberg7; Ian McGowan8; Sharon L. Hillier9; for the MTN-020/ASPIRE Study Team
1Univ of Washington, Seattle, WA, USA;2Wits Reproductive Hlth and HIV Inst, Johannesburg, South Africa;3SCHARP, Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA;4FHI 360, Durham, NC, USA;5NIAID, NIH, Bethesda, MD, USA;6Intl Partnership for Microbicides, Paarl, South Africa;7International Partnership for Microbicides, Silver Spring, MD, USA;8Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA;9Magee-Womens Hosp of the Univ of Pittsburgh Med Cntr, Pittsburgh, PA, USA
Antiretroviral medications used as prophlaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1). However, in clinical trials among African women, HIV-1 incidence was not reduced because of low adherence to daily- or coitally-prescribed antiretroviral-containing pills and vaginal gels. Sustained drug-delivery products, including antiretroviral-containing vaginal rings, may improve adherence and provide protection against HIV-1 with lower systemic antiretroviral exposure.
We conducted a randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, among women aged 18-45 years in Malawi, South Africa, Uganda, and Zimbabwe. Dapivirine concentrations in plasma were measured in quarterly-collected samples; levels >95 pg/mL, a concentration nearly always achieved with >8 hours of use, were used to define adherence. Thus, plasma dapivirine could exclude those who were non-adherent but could potentially overestimate adherence if a ring was inserted only several hours before a visit.
A total of 2629 women enrolled. Their median age was 26 years, median follow-up was 1.6 years, and women attended 91% of expected monthly visits. Among women assigned to the active dapivirine vaginal ring arm, approximately 80% had dapivirine detected in plasma. A total of 168 post-randomization HIV-1 infections occurred: 71 among those assigned the dapivirine vaginal ring (incidence 3.3 per 100 person-years) and 97 among those assigned the placebo ring (incidence 4.5 per 100 person-years). Compared to those assigned placebo, women assigned the dapivirine ring had a 27% (95% CI 1 to 46, p=0.046) relative reduction in HIV-1 incidence overall, a 37% (95% CI 12 to 56, p=0.007) reduction in an analysis excluding data from two sites with lower retention and adherence, and a 56% (95% CI 31 to 71, p=0.0003) reduction in an as-randomized analysis among women older than 21 years of age. Adherence was lower in women aged 18-21 compared to women older than 21. The rate of adverse medical events was similar between study arms.
A monthly dapivirine vaginal ring was safe and effective for HIV-1 prevention in African women. This multi-country study is the first to demonstrate HIV-1 protection for a sustained-release approach for delivery of an antiretroviral for HIV-1 prevention. HIV-1 protection was greater in as-randomized subgroups with evidence of better adherence to ring use.