A "whisper" of drug. No side effects. About 61% effectiveness in preventing HIV in women over 25. A proof of concept.
That's the good news out of the ASPIRE trial, a study of 2,629 women in Malawi, South Africa, Uganda and Zimbabwe who used an investigational vaginal ring loaded with the antiretroviral drug dapivirine (TMC120). The results were unveiled on the first day of CROI 2016, at a press conference where the mood was decidedly not optimistic. Instead, questions were doubtful about the program's ability to cut women's HIV rates.
One reporter asked both ASPIRE lead author Jared Baeten, M.D., Ph.D., and Annalene Nel, M.D., Ph.D., lead author of the companion "Ring Study," "I've heard both of you express that the results are encouraging. I'm confused as to why."
After all, the ring's overall effectiveness rate -- 27% -- doesn't sound like anything to get excited about.
"We shouldn't underestimate," responded Nel, "that a 30% reduction in a community where we see up to 8% incidence can still have a significant impact."
Baeten, whose results from ASPIRE were released by the New England Journal of Medicine in conjunction with the press conference, took a different tack. He invited people to "harken back to sitting in this room four or five years ago." That's when initial results of the iPrEx study of tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) were released. As you might recall, he told the audience, those results weren't the greater-than-90% effectiveness now attributed to the study. Those numbers came only in 2014 from an open-label extension trial.
Back in 2011, when the initial iPrEx results came out, the initial efficacy rate was 44%. Not so different, he said, from what he presented on Monday.
"Here today, we have statistics that show that this ring significantly reduces HIV incidence in women, a population where we've had flat results in the past," he said. "Now we need to understand what best-case scenario use is and the HIV protection provided by it. We also need to figure out who are the populations who will use the ring, and who are populations that might use the pill but not the ring."
ASPIRE in Context
Worldwide, more than 50% of people living with HIV are cisgender women. It's unclear how many transgender men, who may also have vaginal sex, have HIV. In the U.S., the Centers for Disease Control and Prevention estimate that about 460,000 cisgender women could benefit from PrEP, nearly as many as gay and bisexual men.
And tenofovir/emtricitabine, the combination drug currently approved for PrEP by the U.S. Food and Drug Administration, though effective, has a spotty history among cisgender women.
For one thing, the drugs concentrate more in the digestive tract than in the vagina. This means that results of studies such as IPERGAY, the French study of gay and bisexual men that found that taking the pill just four days a week provided protective concentrations of tenofovir/emtricitabine, don't apply to women. While no specific study has been done to determine how often women would need to take tenofovir/emtricitabine to create protective levels for vaginal sex, conventional wisdom is that women should take it every day to achieve results similar to men who take the drugs four days a week.
For another thing, those studies that have tried to ascertain tenofovir/emtricitabine's effectiveness in women have been met, largely, with non-adherence from study participants. Thus far, results from PrEP trials on women have only shown effectiveness when women are partnered with men who they know have HIV. The Partners PrEP study showed that PrEP is effective in women when they take it. But two other PrEP studies that sought to test tenofovir/emtricitabine's -- or at least tenofovir's -- effectiveness against HIV in cisgender women were stopped early because adherence was so low that it was clear the results would be irrelevant. That led some to say, as researcher Judy Auerbach noted nearly two years ago, that PrEP doesn't work in women. At the time, she called that a bad rap.
The Ring Study and ASPIRE sought to answer the question of whether women would use an HIV-prevention method that was designed just for them -- and whether it would be effective.
What researchers have found, so far, is that some women will use the ring, and that the likelihood went up as women aged.
Among 2,629 women between ages 18 and 45, only 71 women acquired HIV in the dapivirine group, while 97 acquired HIV in the placebo group. This means that, overall, the ring had an effectiveness rate of 27%.
However, for women under 21, no statistical protection from HIV via the ring was found. For women 21 to 25, effectiveness shot up to 56%. For women over 25, the ring was 61% effective.
By measuring blood plasma and the amount of dapivirine left in the ring at monthly check-ins, researchers were able to ascertain whether women used the ring during the month. But specificity -- that is, how often they used it -- is difficult to judge, said Baeten. That's because dapivirine reaches effective levels after just eight hours of wear.
"So drug levels can look exactly the same [in blood plasma levels] whether you've used it for a full month or whether you put it in the night before," said Baeten.
He did add, however, that the Ring Study found that the lower the amount of drug left in the ring at the end of the month, the greater the HIV protection -- that is, the more you use it, the more protected you may be.
"This is the first demonstration of an antiretroviral preventing HIV in women," he said. "And that HIV prevention was greater with greater adherence."
Similarities to iPrEx
The analogy to iPrEx, which had an overall effectiveness rate 44% based on initial results, seems apt.
When you stratify the results by age, iPrEx participants aged 25 and under on tenofovir/emtricitabine had a 33% protection rate. For gay and bisexual men and transgender women over age 25, the protective effect was higher: 59%.
"If we hadn't been able to prove [in follow-up analyses] that Truvada use raised the effectiveness over 90%, and then that in people who used it every day there have been no infections, iPrEx wouldn't have been significant," Robert Grant, M.D., M.P.H., lead author on the iPrEx study, said. "With rings, we can't seem to get above 50%, and that's a problem," he added.
|Comparison of Initial Results for iPrEx and ASPIRE|
|Initial results released||2011||2016|
|< 21 years old||Not calculated||No effect|
|21-25 years old||33% (< 25 years old)||56%|
|> 25 years old||59%||61%|
|Potential side effects||Bone mineral density/kidney function||None|
|Protects||Whole body||Vaginal sex|
The Future of the Program
Baeten has been through all this before. As the lead author of the Partners PrEP study, he said he's sat at the same table, in the same room, and fielded the same questions from some of the same reporters about tenofovir/emtricitabine.
"All the questions being raised right now [about the ring studies] are good and right and quite similar, in fact, to the questions that tenofovir PrEP faced," he said. "They are questions of what this means, when will it be available, what is good enough, how can this work in practice. We had all those exact same questions for tenofovir PrEP, and there was a long period of true uncertainty about tenofovir PrEP."
It wasn't until two to three years after initial results came out -- with the results of the iPrEx open-label extension, in which participants knew that PrEP would work if they took it, and they took it in real-world settings -- that we got the confirmation of greater-than-90% effectiveness.
"We need those open-label extensions to know if we can do even better," he said.
Whether the ring studies will get that chance will depend, largely, on what happens at meetings at the National Institutes of Health (NIH), the study's primary funder, next month.
That's when, according to an NIH press release, the organization will convene a panel of experts to "determine next steps for research on the dapivirine ring."
This makes sense, said NIH's Gina Brown, M.D., an ob-gyn and medical officer at the NIH's Office of AIDS Research. Her focus is on HIV, women and microbicides.
"Any of the results affect the future of this kind of a program," said Brown. "For these study results, like those for iPrEx, we'll have to drill down to get more specific about adherence and effectiveness. These things are more complicated than just blood levels. I think over the next several months, we'll have additional information that will influence positive or negative decision-making on this."
|Vaginal Rings Are Not PrEP: Understanding Microbicides|
Rings are not next-generation PrEP. In fact, they are not PrEP at all.
Instead, vaginal rings -- as well as films, gels and microfilaments, all under development -- are so-called microbicides. That means that the drug is applied directly to the area one wishes to protect. For instance, Baeten said that levels of dapivirine reach more than 1,000 times the level needed to block HIV in the vagina, but only a tiny fragment of that seeps into the blood.
Sharon Hillier, Ph.D., the microbiologist who led the ASPIRE program from the University of Pittsburgh, sat in her office overlooking the city's downtown area in January, held up the opaque, white ring and said it emits "just a whisper" of drug.
That means, said Baeten, that potential side effects such as the bone-mineral density loss and kidney trouble possible with use of tenofovir/emtricitabine PrEP aren't a problem with the ring.
"The drug concentrates right where exposure happens," said Baeten. "That means the potential for side effects is really low."
In fact, he said, when they tested liver and kidney function in ASPIRE participants, they saw no differences between those receiving the drug and those on placebo.
The drawback of microbicides, of course, is that they only protect from one kind of HIV risk. That's why Grant said he's not a big fan of the ring. Protecting only the vagina leaves women at risk for HIV if they have anal sex.
"I don't want to say that any method is not useful," he said. "But if I had a woman in my practice who wanted to use the ring, I would also put her on Truvada."