More than 300 members of the Microbicide Trials Network (MTN) were gathered in a hotel conference room in Rockville, Maryland, earlier this month and, somewhat unexpectedly, the assembled scientists had something to celebrate. On March 13, four days after the National Institutes of Health (NIH) convened a stakeholder meeting of African women, researchers, advocates and statisticians, it announced that it would indeed fund follow-up studies to the ASPIRE dapivirine (TMC120) antiretroviral ring trial.
The results of ASPIRE and its sister trial, The Ring Study, were released during CROI 2016 at the end of February. Then, this month the NIH held its meeting. When Sharon Hillier, Ph.D., one of ASPIRE's principal investigators, announced the results to MTN staff, "people literally cheered -- they just stood up and cheered," she said.
That's because, after many attempts and several disappointing trial results, this was one of the few microbicide trials -- and one of the fewer designed specifically for women -- to move on to open-label extension trials and potentially lead to availability for those women who need HIV prevention most.
"Everyone is so anxious to take this next step, to see -- can we realize the promise we think we have [with the ring]? And can we build on this to do even better?" she said. "No one is happy with 27% [overall effectiveness rate]. And we think we can do better than 27%."
ASPIRE and HOPE
When ASPIRE's results came out at CROI 2016 last month for the dapivirine ring, the 27% reduction in HIV acquisition sounded modest to say the least.
But, when researchers parsed the data further, they discovered that efficacy went up with a woman's age. For women aged 21 and under, the ring provided no benefit. For women 21 to 25, effectiveness shot up to 56%. For women older than that, the rate was 61%.
That 61% was the foundation for moving forward with additional studies, said Anthony Fauci, M.D., director of the NIH's National Institute of Allergy and Infectious Disease.
"Everyone went in to the [NIH] meeting saying, 'We need to first examine the data -- is there really a pathway forward?'" he said. "It's clear there is, even though it's confusing when you look at the data. Twenty-seven percent is rather weak, but when you break it down by women older than 25 and women younger than 21, the 61 percent effectiveness is good enough to move forward. That's as good as circumcision in some respects."
Specifically, the NIH funded two follow up studies. One, ASPIRE's open-label extension trial, named HOPE, will seek to recreate the first study, but with some twists. Each of the 2,629 women in Malawi, South Africa, Zimbabwe and Uganda who participated in the original trial will be offered the dapivirine ring. The hope, said Fauci, is that if women know that they are getting a ring with active drug in it and that it's been proven to reduce HIV acquisition, then more women will use the ring, which may change overall protection rates. It's happened before.
However, the study will also tackle adherence another way: by asking the women to once again consent to the study, but this time also asking them candidly whether they're participating in the study because they really want to reduce their risk for HIV, or whether the study is the only way for them to get regular sexual and reproductive health care.
"By re-consenting them, we're saying, 'We get it,'" he said. "'So tell you what: Sign up for the study, but be honest, tell us if you have any intention or not of using the ring.' So then they'll be able to separate out the people who are really using it from those who aren't."
Study participants who say they don't intend to use the ring will still receive health care, but their intention not to adhere will be factored into results.
Then, the study will check in with participants every month for three months, changing out the ring and checking how much less dapivirine is in it after 30 days than when it was distributed -- a sign that participants have actually used it. The idea is to remove the incentive to lie to get health care and use drug levels to test for adherence.
Finally, the study will have a divided design: In those first three months, participants will come to the clinic every month to get a new ring. For the second three months, participants will be given a pack of three rings and be instructed to change the ring out themselves. Then, participants will be asked to bring back the rings, and total drug depletion will be measured.
"It's clever," Fauci said. "It will give [researchers] a chance to compare a clinical trial setting, where [women] are seen every month, versus a real-world setting, where we give them three rings. The bottom line is to figure out what role adherence plays in efficacy and what are the motives to participate."
Dazon Dixon Diallo, president and founder of SisterLove, Inc., and convener of the U.S. Women and PrEP (Pre-Exposure Prophylaxis) Working Group, was at the NIH meeting and described it as a robust discussion of both the science and women's reproductive health needs.
Unlike the VOICE trial, which was designed to test the ability of combination tenofovir/emtricitabine (Truvada) to prevent HIV in women, but was stopped early due to lack of adherence, there was no effort to blame participants for not using the drug. The question was, "How do we design these trials in a way that does not design it to fit the research, but is also meant to fit into women's lives?"
"It was not about blaming them," Dixon Diallo said. "It was really looking at the full implications of a large clinical trial like this, and how nimble can it be to really understand and shift as needed to make sure that the trial itself is fitting into women's lives in such a way that makes them want to be more adherent and to participate."
In particular, she pointed to the comment of one 18-year-old participant, who had asked the ages of the counselors who worked with women during the trials. The implication, said Dixon Diallo, was that mixing peer support and relatable staff could improve social connections and change how younger women, especially, perceive the trials.
For her part, Hillier said that the NIH's decision to fund the studies was not just a win for ASPIRE, but also for the technology in general, which will receive follow up separately in The Ring Study.
"With these two positive results in two separate studies, if [the NIH] didn't move forward, it was really closing the book on this kind of research," Hillier said. But now, she said, everyone on the team is excited about next steps. "We're feeling like we have a ton of work to do, but we're really excited we get to do it."
|What a Young Woman Wants|
When the NIH announced its funding of HOPE, it also announced funding for another trial, one meant to ask a different question: Why did the dapivirine ring show no effectiveness in women under 21, the group of women at highest risk for HIV?
It could be that younger women weren't using the ring. But it could also be that there's something biologically different about young women that makes the dapivirine ring ineffective. So MTN-035, also funded by the NIH this month, will seek to determine if it's preference or biology.
The 18-month study will be divided into three sections. For the first six months, women will get to choose either tenofovir/emtricitabine pills or the dapivirine ring for HIV protection. For the next six months, they will switch. Then, at the end of the year, they will be asked which method they prefer -- "or neither, obviously," Hillier added.
At the same time, when women attend their monthly clinic visits, researchers will take biological samples -- vaginal fluid samples, for instance, or swabs -- to study the immune cells in the vagina and other biomarkers of HIV risk. That data will be broken down further into very young women aged 16 to 17 and women 18 to 21, to assess whether biological markers and efficacy differ by prevention type.
"So we're trying to give women a sense of agency," said Hillier, "that they're going to be empowered to select what works for them."