In the Era of Daily PrEP, Feds May Stop Research Funding Gels, Rings, and Douches for HIV Prevention
Consider this the story of the ring and the douche.
First, the ring: It's actually a small plastic ring filled with the anti-HIV drug dapivirine that can be inserted into the vagina, and needs replacing only once a month. Thus, women and transguys don't have to ask their partners to wear a condom during sex to prevent HIV.
In two major trials of more than 4,500 African women, the ring reduced HIV infections by 27 and 31 percent overall, respectively. In the first study, it reduced infections by 61 percent among women over 25 and 56 percent among women over 21, while the other showed a reduction of 27 percent among women over 21. (Those numbers may not sound that impressive, but these were also standard "double blind" trials in which the women didn't know for sure if they were getting the drug or a placebo -- an uncertainty which can reduce participation and thus overall effectiveness rates.)
Assuming that European and African regulators approve the ring within the next few months, distribution throughout Africa could commence soon after.
Then there's the douche. In very early stages of development, it's a solution that anyone who plays the anally receptive partner during sex would use just as they would regularly douche before sex, except that it has tenofovir in it (one of two drugs in the HIV pill Truvada, which is used for pre-exposure prophylaxis, or PrEP). It would protect against HIV for a set amount of time -- not continually, as Truvada does when taken daily.
But that also means that users would not be continually exposed to the drug's possible side effects, which would be a plus.
"What's exciting," says Craig Hendrix, M.D., a Johns Hopkins professor who's one of the main researchers of the douche, "is that one to three hours after a single dose, we've been able to achieve concentrations [of tenofovir] in colon tissue cells that are up to 1,000 times higher than ... concentrations with daily oral PrEP."
A Funding Shift
And yet it's precisely because of the overwhelming success in recent years of oral PrEP -- which various large studies have found to prevent HIV by anywhere between 90 to 100 percent -- that the future of the douche and other sorts of topically applied anti-HIV agents, such as gels and dissolvable films, all loosely termed "microbicides," is suddenly up in the air, if not outright doomed.
For years, the single greatest funder of microbicide research has been the U.S. government. But recently, Dr. Carl Dieffenbach, who heads the Division of AIDS at the National Institutes of Health (NIH), declared that, with the exception of the ring, microbicide candidates long in the pipeline did not look especially promising.
Despite intense protest from microbicide activists and researchers, he announced that, starting in 2020, NIH's funding priority would be for agents that show "systemic" protectiveness -- basically meaning that provide protection in both the vagina and the rectum, as does oral Truvada. That suggests a funding greenlight for new forms of oral PrEP, as well as for currently in-development injectable PrEP, such as cabotegravir, which requires an every-other-month injection from a health provider.
But it basically means a death knell for a wide variety of gels and other insertables, which has offered the promise of numerous self-administered prevention options from which men and women at high risk for HIV could choose from -- much like the current landscape for birth control. (Some of the microbicide candidates also show the potential to have a contraceptive built in as well.)
"A lot of us are mad as wet hens, seeing this as a giant waste and failure on the part of this administration," says Anna Forbes, a longtime microbicides advocate who was at the Global Campaign for Microbicides from 2000 to 2010. (It should be noted that NIH talk of moving away from microbicide funding pre-dates the Trump administration.) "We're throwing away a chance to prevent millions of lives being lost to HIV."
Forbes is not alone among advocates who see the new direction as paternalistic, aiming to protect those at risk for HIV with something (like an injection) that must be administered from a medical point of care rather than something that the user controls. "It's saying that African women and gay men can't follow directions, so we're just going to fix it for them by giving them a shot," says Jim Pickett, of the AIDS Foundation of Chicago and the International Rectal Microbicides Advocates.
But Dieffenbach said that oral PrEP had set a very high benchmark for the efficacy of any potential HIV preventive coming down the pike. "People need to realize," he said, "that we will never be able to do studies comparing a product to anything but the standard of care, which is currently [Truvada] as a pill. If you have something that is going to be less than 95 to 99 percent effective, it's not going to make it out of the research environment."
But others argue that what appears to be low efficacy in early trials can actually reflect ambivalence on the part of trial participants because they don't know if they are getting the real drug or not.
Mitchell Warren, executive director of AVAC, an HIV vaccine advocacy group that has also advocated for microbicides, points to the difference between the IPREX and the PROUD and IPERGAY trials for oral PrEP.
In the IPREX trial, where gay men did not know if they were receiving PrEP or placebo, levels of both adherence and efficacy were so-so. In both PROUD and IPERGAY, where participants knew they were getting real medicine, adherence and efficacy rates were high.
That, says Warren, shows that early trials involving placebo don't always yield the shiniest results. "What if we'd thrown out oral PrEP for men based on the IPREX results?" he asks.
What About the Douche?
Hendrix is worried that, with NIH's new approach to funding, his rectal douche won't get the support it needs for crucial Phase II and Phase III studies by 2020 and beyond. And that's even if they can prove, as he thinks they might be able to, that douche delivery might be able to get tenofovir into the entire blood stream -- and then hence be considered "systemic" protection, which is the new thing that NIH is looking for.
"I have no assurances," he says. "I'm afraid that the NIH goalpost will move again and that they've defined microbicides in an impossible way."
But Dieffenbach says he has discussed this with Hendrix and other researchers. "There is not a switch that we're going to throw in 2020," he says. "We're not going to pull funding on a trial. That's about the most unethical thing I could do, when the study participant is giving his or her body to improve the knowledge base for humankind. Things that are ongoing will complete.
"But," he adds, "we won't start a big study at the next level unless there's good data."
And, of course, as is always the case with science, what's considered "good data" -- or at least good enough data to push forward with -- is in the eye of the beholder. Or the funder.
"We've always had to fight very hard for microbicide funding," notes Forbes. "I hope this isn't a done deal. How many times in the AIDS movement have we been told something couldn't be done?"
"We were told we couldn't lower the price of HIV drugs. Right?"