“You [advocates] push us as hard as you can. It’s your job, and you’re always mad,” said Carl Dieffenbach, Director of NIH’s Division of AIDS (DAIDS), who oversees a global HIV/AIDS research portfolio of more than US$1 billion. “And we’re always failing but in the end, there’s success. Keep pushing.”
Success is no joke. A few of us advocates gathered with Dr. Dieffenbach in a hotel lobby in Paris, ahead of IAS 2017 in July, to discuss the future of HIV prevention research. We all acknowledged, almost giddily, the “Golden Age of HIV Prevention” we currently inhabit: two vaccine efficacy trials—one enrolling, the other about to begin; two antibody trials; injectable PrEP moving into efficacy studies; the potential addition of the vaginal ring alongside oral pills for PrEP; and, of course, the large-scale rollout of VMMC and treatment, which are starting to bring down HIV incidence in some places.
But there’s still plenty to get “mad” about. As it does every seven years, DAIDS is reviewing the structures it has in place for HIV clinical trial research networks focused on different candidate products. It’s evolved several times over the past two decades. The structure as it is now includes the following prevention-focused networks—HVTN, HPTN, MTN and IMPAACT—along with the ACTG. The current funding for these networks has three more years to run, but the network recompetition process is already underway to determine the focus and structure for HIV research from 2021 through 2027.
Below are some of Dr. Dieffenbach’s rather intentionally provocative ideas, which will for sure get varying degrees of attention, praise and criticism. But, like the DAIDS boss says, he likes it. Indeed, he wants the community to weigh in. It’s not merely for the sake of box ticking that DAIDS is soliciting feedback, he said; there’s a stated desire to get a sense of the community’s unbiased aspirations—as opposed to opinions of those with a horse in the race or their own research agenda.
But, as Dr. Dieffenbach reminded us, decisions will get made through the filter of science. He can’t change the laws of physics to bring miracle products through the research pipeline. Here are some of his musings about specific research candidates—challenges and promises, and the questions they may raise for the next clinical trial research network structure.
Vaginal rings and things
Over the past 10 years, the Microbicide Trials Network (MTN), along with the International Partnership for Microbicides has helped provide information on how women use vaginal rings and gels, as well as oral PrEP, and how these products work when used consistently or irregularly. IPM has submitted an application for regulatory approval of the dapivirine vaginal ring while, as Dr. Dieffenbach noted, vaginal tenofovir gel has been shelved: “Gels have failed. They were given the college try to the tune of US$1 billion. Women have run away from gels. The social behavioral side failed,” he said. “We need to listen to community.”
The DAIDS leader also pointed out the emerging data showing a higher rate of rectal sex in women than originally perceived, which could confound any vaginal protection offered by the ring. This is a challenge for any research network, regardless of future structural network configurations.
In the meantime, according to Dr. Dieffenbach, the licensing of the vaginal ring will be a good incentive for industry to take on next-generation products. For example, “The NuvaRing for birth control is off patent soon. Can it add ARVs?” he asked. “The ring studies are done; NIH will not go further but companies can,” he said. (See Dr. Dieffenbach’s most recent blog, Positioning Topical HIV Prevention for the Future.)
The MTN 033 study will show how well a rectal dapivirine gel permeates the colon—comparing rectal administration via vaginal applicator and a coital simulation device (dildo). The tricky part is getting the right balance of volume and concentration, according to Dr. Dieffenbach. He warns a smaller volume may be more acceptable, but this would require higher drug concentrations, which could lead to irritation and higher risk. Likewise, he “worries about a suppository, which could burn the crap out of the rectum.” His concerns belittle a robust rectal microbicide research pipeline, boasting seven experimental drugs, four formulations—including douches and inserts—and eight different studies. (For more, check out a recent IRMA webinar, We’re On Our Way: Moving forward on the rectal road – new drugs, formulations and modes of delivery.). However, the outstanding scientific questions, according to Dr. Dieffenbach, “do not need an entire network devoted to it.”
Such a stirring statement raises several questions: If there is no MTN, what will happen to the pipeline, the expertise and the hundreds of millions of dollars spent? Will DAIDS not pursue its first phase III trial even after the phase II MTN 017 study results in 2016 showed the gel to be safe and well tolerated? In the era of oral PrEP, do people not need an alternative, on-demand, non-systemic, non-committal way to protect themselves?
Injectables and implants
The HIV Prevention Trials Network (HPTN) has two major trials of the injectable ARV cabotegravir, one underway and the other close to launch. Given the buzz around less-adherence-dependent methods, it’s almost certain the next trials network will have infrastructure for testing other long-acting systemic PrEP methods.
These networks won’t be able to evaluate how an injection would be delivered in the real world though. “[Delivering] injections will require a change in infrastructure, away from pills in the clinic—for both treatment and prevention,” said Dr. Dieffenbach. “But NIH is terrible at implementation research,” he continued. “We need to partner with health departments.” Dr. Dieffenbach also anticipates future research into removable implants that might last 6–12 months.
DAIDS: Coming attractions
Results from an array of trials will shape DAIDS’ next steps. These include: HPTN 083 and 084, HVTN 703/HPTN 081, HVTN 704/HPTN 085, HVTN 702 and 705; and MTN 034/IPM 045. At minimum, the networks would have to be able to follow up on these vaccine, antibody-mediated prevention, long-acting PrEP and ring trials.
Dr. Dieffenbach suggested we look at the three-year time horizon when the current funding period will end. By then, we’ll have results from efficacy trials in the most at-risk populations including young women in eastern and southern Africa as well as young black gay men in the US. (To hear the DAIDS director speak about the future prevention landscape, listen to AVAC’s Px Pulse interview with him.)
“We’ll have completed the vaccine trials and the VRCO1 [antibody-mediated prevention] study,” he said. “We’ll need to look at how to mix a semi-working vaccine with combination prevention in 2021–2027. Where there are successes, there’s a need to discontinue,” he explained. All this to say that in the next round of funding, DAIDS is looking at collapsing the current networks into just three—focusing on treatment, non-vaccine prevention and vaccines, explained Dr. Dieffenbach in a recent blog and AVAC webinar.
Now, if any of this leaves you enthused, scratching your head, or even upset, DAIDS wants to hear from you. It is currently accepting public comments and questions online through November 30, so now is your chance!