BOSTON – A vaginal ring infused with the antiretroviral drug dapivirine is effective and safe for reducing HIV-1 infections in high-risk women; at least in women older than 21 who use it as intended, results of two large randomized trials suggest.
In the ASPIRE Trial, conducted from August 2012 through June 2015 in Malawi, South Africa, Uganda, and Zimbabwe, there were 71 HIV infections among 1,313 women assigned to use the dapivirine ring, compared with 97 among 1,316 women assigned to a placebo, a difference that translated into a 27% reduction in infections.
In the Ring Study, conducted in South Africa and Uganda, the drug-infused ring reduced infections in the overall population by 31%, compared with a placebo ring, reported Dr. Annalene Nel from the International Partnership for Microbicides in Paarl, South Africa.
Dr. Jared M. Baeten
“This is the first demonstration of a sustained-release approach for antiretroviral prevention, and HIV protection in this study, not surprisingly, was greater with greater adherence,” said ASPIRE lead investigator Dr. Jared M. Baeten of the University of Washington, Seattle, at a media briefing at the Conference on Retroviruses and Opportunistic Infections.
“The data from both studies show that the ring must be used consistently to achieve protection, and that protection can be achieved with consistent use,” Dr. Nel said at the briefing.
The ASPIRE results are also published online in the New England Journal of Medicine (2016 Feb 22. doi: 10.1056/NEJMoa1506110).
In both trials, the ring offered little or no significant protection for women aged 18-21. In ASPIRE, there was no benefit for the dapivirine ring in this age group, and in Ring, infections were 15% lower among younger women who received the active ring, compared with placebo.
Dr. Annalene Nel
The ASPIRE investigators noted that younger women tended to have lower objective markers of adherence, such as dapivirine levels in plasma and in used rings, suggesting that poor adherence could partly explain the lack of benefit in this age group. They also suggest that “the genital tract of women in this age group may be more susceptible to HIV-1 infection and potentially also more difficult to protect with antiretroviral prophylaxis strategies.”
Trial design
In each trial, sexually active, HIV-negative women aged 18-45 were enrolled and randomly assigned to receive a vaginal ring containing 25 mg of dapivirine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, or a placebo ring. The rings were replaced every 4 weeks. In ASPIRE, the randomization was on a 1:1 basis; in the Ring study, the randomization was 2:1, with twice as many women receiving the active ring.
Participants had monthly follow-up visits that included serologic testing, safety monitoring, and adherence counseling. Median follow-up in ASPIRE was 1.6 years. The Ring study was halted early at the recommendation of the data safety monitoring board because of a higher-than-expected incidence of HIV infections.
ASPIRE study
In addition to the overall 27% reduction in infections seen in ASPIRE, the investigators found that when they excluded data from two sites with lower rates of retention and adherence, the ring reduced infections by 37%.
A post hoc analysis showed significantly better protection for women over age 21 (P less than .001), but not for younger women (P = .45), a difference that correlated with reduced adherence.
The researchers noted that among women who acquired HIV, the rates of adverse medical events and resistance to antiretroviral agents were similar between the active ring and placebo groups.
Ring study
As of Oct. 16, 2015 – the data cutoff point for RING – there were 2,805 person-years of follow-up, and 761 women had completed 2 years of follow-up. There were a total of 133 post-randomization HIV-1 infections, 77 of which occurred among women assigned to the dapivirine ring, translating into an incidence of 4.08 per 100 person-years, and 56 of which occurred among women assigned to placebo, for an incidence of 6.10 per 100 person-years.
The overall reduction in infections in the active ring group in the Ring study relative to placebo was 31% (P = .0401). In a subgroup analysis of women over age 21, the dapivirine ring reduced infections by 37%.
The most common ring-related adverse events in this trial were abnormal uterine bleeding, pelvic discomfort and/or pain, suprapubic pain, and application site pain. Adverse-event rates, including product-related events, urogenital events, serious adverse events and death, were similar between the treatment arms.
Based on the results of the two trials, the International Partnership for Microbicides is planning an open-label extension study for the Ring cohort and submission of data for regulatory approval of the device.