A flexible vaginal ring loaded with the HIV antiretroviral dapivirine has been hailed as an exciting new HIV prevention option, particularly for women in sub-Saharan Africa who say the insertable vaginal ring is easier to use and more discreet than existing HIV prevention methods.
Yet in several large research trials, the ring has not matched the effectiveness of more well-established HIV prevention tools like condoms and oral pre-exposure prophylaxis (PrEP), which have demonstrated an 80% to 99% reduction in HIV acquisition risk when used correctly.
The most recent of these studies, called HOPE, found that the ring reduced women's risk of acquiring HIV by about 30%, according to data presented at the 10th International AIDS Society Conference on HIV Science in Mexico City.
Last month, a similar open-label study called DREAM found a 63% reduction in HIV risk. Previously, two randomized, phase 3 trials that HOPE and DREAM were based upon found that HIV infection risk was reduced by about 56%.
Collectively, these studies seem to demonstrate what many HIV prevention experts have suspected for a long time: The dapivirine ring cuts a woman's risk of HIV infection in half. But will that be enough to merit regulatory approval?
We'll soon find out. The International Partnership for Microbicides, the organization that makes the ring, has already applied for approval under a special program called Article 58 under the European Medicines Agency (EMA). This program will allow the EMA to collaborate with the World Health Organization to offer a recommendation for the ring's use in low- and middle-income countries.
The group is slated to make its decision within the next few months.
"The question is: Will they get a positive opinion?" said Mitchell Warren, executive director of AVAC. "Clearly, the product is modestly effective. I wish it were higher."
Dázon Dixon Diallo, D.H.L., M.P.H., isn't confident that regulators will approve the dapivirine ring this time around -- but she hopes they do.
"It doesn't matter what this current study says. What matters is that there is a proof of concept that the ring is an option," said Dixon Diallo, who is the founder and president of SisterLove.
"Women were excited about the ring. This is something that works for them," she said. "The more options we have, the more likely we are to increase women's engagement."
A majority of the women involved in the HOPE study said they would use the dapivirine ring as an HIV prevention option, even if it can't promise 100% protection.
"This is the data," said Carl Dieffenbach, Ph.D., director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. "We need to stand by it. We need to accept it and deal with it and figure out next steps."
Those next steps likely include further studies to investigate why adherence and efficacy differed between different age groups, with older women more likely to see an HIV protection benefit.
But Dixon Diallo argues that those next steps should take place after the ring's approval. Once the drug-device combo is approved and widely available, implementation scientists can continue to study the circumstances in which the ring works best, she said.
It's not unusual for HIV prevention trials to show modest efficacy at first, noted Dieffenbach. In fact, early studies of oral PrEP such as the iPREX trial showed an average risk reduction of about 44%. Later, investigators analyzed blood samples from participants and figured out that the drug worked extremely well among trial participants who took PrEP consistently; adherence was indicated by trace levels of drug in their blood.
The ring studies may be subject to the same phenomenon, said Dieffenbach, though he said it's unlikely the dapivirine ring will ever yield protection in the 80% to 90% range, akin to the levels seen with oral PrEP.
The HOPE Study Results
HOPE was an extension study launched on the back of ASPIRE, a Phase 3 trial that randomly assigned participants to use the active ring or a placebo ring. After ASPIRE ended, investigators circled back with HIV-negative women who had been involved in the trial and asked them if they would be willing to participate in HOPE. Those who enrolled were given a choice of whether or not they wanted to use the active dapivirine ring (there was no placebo group).
A total of 1,456 women enrolled across 14 sites in Malawi, South Africa, Uganda, and Zimbabwe. During the first three months of the study, women visited the clinic each month to get a replacement ring. After that, they visited every three months to get a supply of three rings -- an effort to mimic the way the ring would be offered in clinics if it is eventually approved.
Women's ages ranged from 20 to 49 years old, and about 12% of study participants were under 25. At their first visit, 92% of the women accepted the vaginal ring, though some participants declined to take the ring with them during subsequent clinic visits, with the acceptance rate dropping to 79% over the next several months.
Excluding women who became pregnant or became HIV positive, 73% of women accepted the ring for all 12 months of follow-up. Of the women who accepted the ring and returned the devices to the clinic, about 86% appear to have used the ring for some period of time, although it's not clear if they used it consistently.
The uptake and use of the ring was higher in HOPE than it was in ASPIRE, indicating that pre-existing familiarity with the ring encouraged more women to use it. None of the serious adverse events reported in the study were related to the study drug. As well, there were no birth defects observed among 70 pregnancies during the study.
The primary objective of the HOPE study was to determine adherence and safety of the ring in an approximation of a real-world setting. The secondary objective was to measure HIV incidence and antiretroviral resistance.
By the end of the one-year study, 35 women were HIV positive, meaning that for every 100 women followed over the course of an entire year, 2.7 of them became HIV positive. Women were also offered HIV prevention counseling in addition to the dapivirine ring.
Because there was no placebo group, researchers drew from the placebo arm of the ASPIRE trial and estimated that HIV incidence rate without the dapivirine ring would have been about 4.4%.
From there, they estimated that the ring created a 39% reduction in HIV risk. Dieffenbach noted that although study authors were careful in their analysis, the 39% estimate should be interpreted cautiously, because it was derived without a true placebo arm.
And, although adherence in HOPE appeared to be higher than in ASPIRE, it is still not clear whether or not women used the rings exactly as prescribed. Investigators measured adherence by checking whether the dapivirine had been released from the returned rings, which would only happen if it was inserted into the vagina.
"What we know is that a significant number of the rings were used, but that doesn't mean a significant number of the women consistently used the rings. We don't want to conflate those two statements," said Dieffenbach.
"The study still needs to finish data that will look at the level of consistent ring use in individual women," he added. "I will be very curious to see in subgroup analysis if there's a group of women that have high use that [the ring] gave 50% to 60% efficacy. That data needs to be developed."
In both HOPE and ASPIRE, the ring appeared to work better in women who were older than 21 years old, with investigators hypothesizing that older women may be more likely to leave the rings in place.
"We've tried hard to increase the adherence of this, and I think that we obviously need to do much better," said Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
"There is no easy answer," Fauci said.
Even with questions left unanswered about the vaginal dapivirine ring, many experts are hoping that the prevention tool will be more widely accessible soon.
"Women urgently need more options for HIV prevention that fit into their lives," said the HOPE study's lead author, Jared Baeten, M.D., Ph.D., professor of global health, medicine and epidemiology at the University of Washington, according to a press release.
"We need all these partially protective methods, because there is never going to be one method that is perfect, scientifically, at 100%," said Warren.