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Open-label studies show high uptake of vaginal ring for HIV prevention
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BOSTON — Interim data from two phase 3b trials demonstrated high uptake and adherence of a monthly vaginal ring that slowly releases the non-nucleoside reverse transcriptase inhibitor dapivirine to prevent HIV infection in women.
Mathematical modeling analyses further showed that HIV incidence in both studies was half of what may have been expected in the absence of the ring, according to researchers.
“The data support the development of the ring as a potentially important new prevention option for women, who continue to bear the brunt of the epidemic and still lack a range of options that they can use to protect themselves,” Zeda Rosenberg, ScD, founder and CEO of International Partnership for Microbicides (IPM) — the nonprofit organization that developed the dapivirine vaginal ring — said during a press conference.
HOPE trial
The HOPE trial is an ongoing open-label extension of the phase 3 ASPIRE trial, which previously showed that the dapivirine ring was well-tolerated and reduced the incidence of HIV by approximately 27% compared with placebo, according to Jared Baeten, MD, PhD, professor of global health, medicine and epidemiology at the University of Washington in Seattle, and colleagues. The objective of the HOPE trial was to gather additional data on ring uptake and the association between adherence and protection against HIV.
“There is often a gap between phase 3 results and delivery at scale,” Baeten said during the press conference. “That can be filled by open-label studies, including open-label extensions.”
More than 1,400 women who participated in the ASPIRE trial were enrolled in the HOPE trial. The women were offered access to the dapivirine vaginal ring over a 1-year duration at 14 sites in Malawi, South Africa, Uganda and Zimbabwe. The researchers gauged adherence by measuring residual levels of dapivirine in used rings, which were returned at each study visit. A bootstrap sampling analysis was conducted to predict the impact of ring access on HIV incidence. The analysis included data from women in the placebo arm of ASPIRE who had characteristics that were similar to participants enrolled in the HOPE trial.
According to Baeten, ring uptake was high, with 92% of participants accepting the ring upon enrollment and more than 80% accepting the ring at each follow-up visit. Adherence was also high, with 89% of rings showing evidence of at least some use during the prior month. This estimate was higher than the adherence rate observed during the ASPIRE trial, Baeten said.
Altogether, 12 HIV infections in 616 person-years were observed, yielding an incidence rate of 1.9 per 100 person-years. In comparison, HIV incidence was 4.5 per 100 person-years in the placebo arm of the ASPIRE trial, according to Baeten. However, the NIH noted in a press release that the HOPE trial was not powered enough to determine maximum ring effectiveness.
“There are limitations to this analysis,” Baeten acknowledged. “There is no placebo population for HOPE, of course, because withholding access to the ring would not have been ethical. The women all previously volunteered for ASPIRE and did not acquire HIV during that time; thus, we might not have precisely estimated their HIV risk. Nevertheless, these interim results from an open-label extension trial of the dapivirine vaginal ring trial indicate high uptake and adherence, and an HIV incidence rate that is half of the expected rate.”
DREAM trial
In the DREAM trial, an ongoing and similarly designed open-label trial, Rosenberg and colleagues followed 900 women in Uganda and South Africa who were former participants of the phase 3 Ring Study. Results from that phase 3 trial had demonstrated a 30% reduction in HIV incidence among ring users compared with those who received placebo, Rosenberg said.
Using similar methods as in the HOPE trial, the researchers in the DREAM trial found that the dapivirine ring was well-tolerated and had a higher level of adherence compared with the Ring Study. Rosenberg reported that 96% of women in DREAM used the ring at least some of the time compared with 83% of women in the RING Study.
“We always thought that women would likely use the ring more once they knew the results of the phase 3 trial,” Rosenberg said. “That has been seen in early open-label studies of oral PrEP. We are seeing this here as well.”
In the interim analysis of DREAM, 11 HIV infections occurred in 623 person-years of follow up, yielding an incidence rate of 1.8 per 100 person-years. A bootstrap sampling analysis predicted an incidence rate of 3.9 per 100 person-years in the absence of the ring, resulting in a 54% reduction in HIV incidence.
“The data in very distinct, separate analyses are amazingly comparable as was seen in phase 3 trials,” Rosenberg said. “I think the consistency here is something that is quite important.”
Final results of the DREAM trial are expected to be announced in 2019. Rosenberg said the ring is currently being reviewed for approval by the European Medicines Agency. Additional regulatory applications are planned to the South African Health Products Research Agency and the FDA.
“We’re planning hopefully for success. If it is approved, we are looking at different ways of rolling the ring out. We are also developing a 3-month version of the monthly dapirivine ring as well as a 3-month dapivirine contraceptive ring in collaboration with the [Microbicide Trials Network]. We remain strongly committed to this work and remain optimistic that, if approved, the ring could help meet the urgent need for more prevention options for women.” – by Stephanie Viguers
References:
Baeten J, et al. Abstract 143LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston.
Nel A, et al. Abstract 144LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston.
Disclosures: Baeten reports serving on an advisory committee for Gilead Sciences. Rosenberg is the founder and CEO of IPM.
Perspective
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Susan Buchbinder, MD
These were promising data that were presented at CROI. We knew from the earlier efficacy trials that the dapivirine vaginal ring was associated with an estimated 30% reduction in new HIV infections. That was not a very high level of efficacy, but those earlier studies were blinded placebo-controlled trials, where women did not know if the ring worked, nor whether they were getting the active ring or a placebo. These two open-label extension studies reported at CROI were very important in evaluating the ring’s effectiveness in women who wanted the ring and knew it could provide protection. The two studies had remarkably similar results, with women opting for the vaginal ring having an HIV infection rate less than half of what it would was predicted to have been, based on data from historical controls. This substantial reduction in the risk for new HIV acquisition is good news. The effectiveness is still somewhat lower than what we have seen from some oral PrEP studies, but the effectiveness may still be higher among consistent ring users. We are waiting for data on how the ring use may correlate with the degree of protection seen.
Although the ring is undergoing regulatory review and is not currently available, we know we need strategies that women can use to protect themselves against HIV acquisition. Not all women want to take a daily pill, so a method that cuts infection rates in half could have a substantial impact on the HIV epidemic globally. Other methods are also being studied, including long-acting injectable PrEP, monoclonal antibodies and vaccines, but one approach will not be right for all women. Some women may prefer a vaginal ring over a daily pill or an injection. That is why it is so important to have multiple options. There is also interest in developing multipurpose rings that would include both an anti-HIV medication as well as a contraceptive. That would allow women to protect themselves against HIV or pregnancy, or both, in a combined ring. Giving women options for protecting themselves against HIV infection, with or without contraception, is extremely important.
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