Editor's note: Fred Hutch News Service reporter Mary Engel and photographer Robert Hood are in Durban, South Africa, covering the news from the 21st International AIDS Conference.
The ring is lightweight, flexible, affordable and innocuous looking. It can be worn — and forgotten about — for four weeks at a time. And when used correctly, it can protect women against HIV.
New analyses released Monday from a large, Phase 3 clinical trial conducted in several African countries further bolster the study’s previous findings that the vaginal ring, laced with an antiviral drug known as dapivirine, can effectively protect women from HIV infection.
The research study, called ASPIRE, enrolled 2,629 sexually active, HIV-negative women in South Africa, Zimbabwe, Malawi and Uganda. The women were asked to use either the dapivirine ring or a placebo ring, changed every 28 days; the researchers followed them for one or more years with follow-up visits every month. The study’s initial results, published in February in the New England Journal of Medicine, showed that the antiviral ring worked to protect against HIV — if it’s used correctly.
The women who used the dapivirine ring had, overall, a 27 percent reduction in HIV infection. But there were already hints in that first study that many women weren’t using the ring consistently, and that those who used it more reliably were better protected against the virus.
“In our study we actually started very early on testing adherence, because we knew adherence had been an issue in earlier HIV prevention studies,” said Dr. Elizabeth Brown, a statistician at Fred Hutchinson Cancer Research Center and the Microbicide Trials Network, or MTN, an international HIV/AIDS clinical trials network funded by the National Institutes of Health. Brown led the new analyses of the ASPIRE data and will present her findings Tuesday at The International AIDS Conference, or AIDS 2016, in Durban, South Africa.
“So we had some objective measure of adherence in every participant in the study,” she said.
In the ASPIRE study, led by University of Washington vice chair of global health Dr. Jared Baeten, women visited clinic sites monthly to receive a new ring and turn in their previous month’s ring. ASPIRE researchers then tested both the levels of drug present in the women’s blood and the amount left in the used (or not-so-used) ring. More than 12,000 returned rings were tested.
The dapivirine rings were developed by the nonprofit International Partnership for Microbicides, or IPM, and contain 25 mg of the HIV-fighting drug. If used consistently during the entire 28-day period, about 4 mg of that drug should have been released through the vaginal tissues into the woman’s bloodstream. In two different analyses, Brown and her team looked at women whose ring-drug-levels indicated that at least 3 mg or at least 1.5 mg of the dapivirine had made it into their systems. In those datasets, women had a 65 or 56 percent reduction in HIV infection risk, respectively, compared to women who’d received the placebo ring.
Brown then developed a statistical model to take into account times when women were not able to come to follow-up visits exactly on time, as the study allowed off-schedule visits if needed. The researchers were thus able to stratify levels of adherence from those who didn’t use the ring at all to those who used it nearly perfectly. In these analyses, women who used the ring most consistently reduced their risk of HIV infection by either 75 or 92 percent, depending on the analysis.
It wasn’t that many women in the study just didn’t use the ring at all, Brown said. It’s more that they had stages of consistent and inconsistent use. The researchers don’t fully understand all the reasons behind the inconsistent use, but scientists from MTN and IPM will be conducting behavioral studies to further understand the barriers to consistent use and how they might be overcome.
Dr. Zeda Rosenberg, founder and chief executive officer of IPM, noted in an interview that adherence is often lower in a clinical trial than it would be for an already-approved product precisely because researchers tell trial participants that the method being tested may not be entirely safe or effective.
“In a trial, every month a woman is told, ‘We don’t know if it’s safe and we don’t know if it works,’” she said. In some cases, women may join a trial for other benefits, such as the health care and social support that comes with it, with little incentive to actually use the product.
The new analyses add to the body of evidence that the dapivirine ring may be highly protective against HIV when used consistently. They provide a better understanding of what perfect use looks like so that clinicians will be able to tell women, “If you use the ring all the time, you can get this much protection,” Rosenberg said.
MTN researchers also announced the launch of an extension study to ASPIRE, known as HOPE, at the AIDS 2016 conference Monday. Since the ring’s safety and efficacy are now well understood, HOPE is what’s known as open-label study — all women will have access to the dapivirine ring, if they want to use it, and no placebo will be used. The first HOPE study site opened Monday in Durban; the study will be open to all women who participated in ASPIRE and is expected to conclude by early 2018.
“The results are extremely encouraging as we move forward with new studies,” said Baeten, who will also lead the HOPE study, at a press briefing Monday in Durban. “Adherence is key to HIV prevention.”
The ring already is on the pathway for licensure based on the overall data and several smaller supporting studies. IPM conducted a similar study, known as The Ring Study, in parallel to ASPIRE in order to accelerate the licensure application process. (Typically, at least two Phase 3 efficacy trials are needed to move a product to regulatory approval.) IPM plans to submit the application to regulators in mid-2017; a decision could come by 2018.
In a few months, a longer-acting ring that could be used for three months will be tested in new studies. The cost of the original, one-month-use model will be about $7 per ring, although donor support could bring the price down to about $2.50, Rosenberg said.
There are also plans in the works to test a three-month ring, also made by IPM, that combines the antiviral drug with hormonal birth control, Brown said, which would likely make the product even more popular among women. And, as with birth control, it’s important to offer women different options for HIV prevention.
“We like to have several methods because many people prefer different methods for birth control and I think the same is true for HIV prevention,” she said.
Truvada, a daily antiretroviral pill, is an approved and effective method of prevention for women and men, Brown said, but the dapivirine ring may be an appealing alternative for some women — they won’t have to remember to take a pill every day and it can be used discretely.
Options like the dapivirine ring in all its formulations and the daily Truvada pill are desperately needed in sub-Saharan Africa, where nearly 60 percent of HIV-infected adults are women, according to the MTN.
“Maximizing the ring’s potential means doing all we can to effectively support women to use it consistently,” Rosenberg said. “We need to continue research to overcome the barriers for use by women who face the highest rate of infection in the world.”
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.