“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.
‘Adherence is key’
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.”