Seventy-five percent: That's how much HIV protection women might be able to expect from a flexible, silicone ring loaded with the antiretroviral medicine dapivirine when they put it in their vaginas and leave it there.
This news comes from a data sub-analysis of the ASPIRE clinical trial, presented at AIDS 2016 in Durban, South Africa. It's also an important step in sussing out the difference between adherence -- that is, using the ring as directed -- and the power of dapivirine, an investigational medicine, in protecting the body against HIV.
"'Encouraging' is very much the right word," Jared Baeten, M.D., Ph.D., lead investigator of the ASPIRE trial and professor at the University of Washington School of Public Health, said of the sub-analysis. "We have seen in the prevention field and especially in the antiretroviral prevention field that adherence is so important. The data from ASPIRE suggest that enough drug is getting out of the ring and into the right places in the body to provide significant HIV protection."
Efficacy versus Adherence
To understand the importance of the data, first imagine a vagina at rest.
"It's the same as the gastrointestinal tract: It expands for some purpose, in this case, childbirth or intercourse," said Laura Ensign, Ph.D., assistant professor at the Center for Nanomedicine at the Johns Hopkins Medical Institutions Wilmer Eye Institute. Ensign studies nanotechnology that could protect women from HIV and isn't connected to the ASPIRE trial or the data released at AIDS2016. "[The rest] of the time, it's folded in. It's not a cylinder," she said.
That's important because it's into those small vaginal folds that topical HIV prevention drugs, called microbicides, must squeeze in order to provide protection from HIV and other sexually transmitted infections. And that, said Ensign, can be difficult.
"With rings, like with nanotechnology, it's a question of how far the drug diffuses before it's taken up by the cell," she said.
Watch: Vaginal Ring Is Safe and Effective in Preventing HIV
Researchers from The Ring Study, a trial parallel to ASPIRE that tested the same dapivirine ring in African women, have studied the distribution of dapivirine in the vagina, said Baeten.
However, there's another issue in understanding microbicide efficacy. Since microbicides, including dapivirine, are applied right to the spot where HIV might enter, they also don't concentrate heavily in the blood. That's good for patients: Lower levels of medicine in the blood mean fewer side effects. In the initial results from ASPIRE, released in February at CROI 2016, side effects were negligible.
But testing blood concentrations of medicine is how researchers studying HIV prevention drugs such as oral tenofovir/emtricitabine (Truvada) confirm participants' self-reported adherence: The more drugs found in the blood, the more pills were taken. Yet, it's not as simple with microbicides. Dapivirine, for instance, reaches its maximum blood concentrations after eight hours of use.
"When it comes to blood concentrations [of dapivirine], it can reflect either that she's worn it for part of the last day" or for 30 days, Baeten said, "[Eight hours] would look exactly the same as if she used it every day."
So when Baeten and colleagues presented the initial ASPIRE results at CROI, showing an overall effectiveness of 27%, it was hard to know whether that meant women weren't using the ring or whether the medicine itself wasn't effective against the virus. Data released at CROI did show that women who returned dapivirine rings with almost no drug leeched from them saw almost no protection -- and that the ring conferred about 61% effectiveness in women over 25. But the question lingered: What's the relationship between adherence and effectiveness?
Trial Design versus Trial Reality
So before AIDS2016, Elizabeth R. Brown, Sc.D., the statistician for the Microbicides Trials Network and ASPIRE, started parsing adherence levels. For this, Baeten said, they had hard evidence.
"We have another measure of adherence" besides self-reports and blood concentration levels of dapivirine, said Baeten, and that is "the ring itself."
This is because each ring comes loaded, initially, with about 25 mg of dapivirine. When used consistently for four weeks -- the length of time between each scheduled lab visit -- the body would be expected to absorb 4 mg of dapivirine. And, because after each month of the ASPIRE trial the participants returned the previous month's rings and picked up new ones, ASPIRE researchers had all the rings from each month of the study -- all with different levels of drug left in them.
"Toward the end of the study, we started analyzing all these rings, testing them to see what was left in them," he said. "That's what this new data [released at AIDS2016] is based on -- these residual amounts of drug in the ring."
So here's what they did: First, all the data for all the rings was entered into the computer. Then, Brown took this data and created two cutoffs: one for rings with more than 23.5 mg of dapivirine remaining and one for rings with 22 mg remaining.
If a ring had 23.5 mg of dapivirine left, it meant that only 1.5 mg was absorbed into the body, said Baeten. Remember, 4 mg missing from a ring would indicate full adherence. So rings with 1.5 mg missing and 3 mg missing, respectively, showed low- and medium-to-high adherence, said Baeten.
"We picked 23.5 mg while the study was ongoing because we knew that women who hardly used the ring at all should have more than 23.5 mg remaining," he said. "It was a good identifier of non-adherence."
What they found was that women who used the ring at least some of the time -- as opposed to women who never used it -- were 56% protected against HIV compared with women who received a placebo. Women who used it more than that had 65% protection.
"Those were the two," said Baeten. "But as we were analyzing the data, we realized that it didn't tell the whole story."
The whole story, it turns out, has more to do with real life versus study protocols than high adherence versus low adherence. Women were supposed to come back four weeks to the day after they'd been issued a ring, and the first analysis crunched the numbers under that assumption. But that's not how the women actually behaved. Women would come back a week earlier or a week later, depending on their schedules. And, as life goes, sometimes women came in as late as six weeks after receiving their rings.
So, Brown went back and look up how long each ring had been dispensed, from three to six weeks. She looked at how much dapivirine remained in each ring and calculated adherence from there. Then she added in HIV acquisition for each woman, estimating time of infection.
The picture started to change.
"We know what nonadherence looks like," said Baeten. "Let's see what low, medium and high looks like."
What they found was that, like the no-adherence group, the low-adherence group received no protection from the ring. But those women who wore the ring consistently and the longest also received the highest levels of protection -- 75% or more.
Promise and HOPE
The sub-analysis was met with encouragement, including from Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH).
"[These results] are telling us something very important," Fauci said. "They are telling us that adherence has everything to do with whether the ring works or not."
Fauci said that the next step is to study whether adherence improves effectiveness in real-life trials -- exactly like the study getting underway in Africa.
The HIV Open-Label Prevention Extension or HOPE study was funded by NIH in March and began in July. The study will give every participant a ring loaded with dapivirine, eliminating the placebo group of the ASPIRE trial. It will also offer participants the chance to switch between the ring and oral Truvada to see which they prefer and which is most effective. And the study will pay special attention to effectiveness in women under 21, the group in Sub-Saharan Africa hardest hit by HIV and least adherent to the ring.
The data presented at AIDS2016 is still a sub-analysis of initial results -- not, Baeten said, the gold standard of research, which is a double-blind, randomized and placebo-controlled trial. If any of the data were wrong or if any of the assumptions behind the model were wrong, it could mean that the analysis was wrong, too. But for now there is a strong suggestion that greater adherence makes the ring work better -- something that researchers can now take back to the women starting the HOPE trial.
"It's perfect timing," said Baeten.