Myron Cohen, MD, of the University of North Carolina, has been working on HIV since it was called Gay-related Immunodeficiency Syndrome. In 2011, the landmark trial he led, HIV Prevention Trials Network (HPTN) 052, found that treating someone for HIV with standard combination antiretroviral therapy (ART) could eliminate their ability to pass on the virus. Today, he is involved in HIV prevention trials, including one on broadly neutralizing antibodies (bNAbs) and another on injectable HIV prevention drugs.
Univadis asked Cohen to sit down with us to explain what the International AIDS Society 2019 Conference on HIV Science tells us about where HIV treatment and prevention are heading.
This interview has been edited for clarity and length.
UNIVADIS: You have been known to say that every 10 years, there's a shakeup [in HIV drug development]. Describe that.
DR. COHEN: If you look at the history of the treatment of HIV, we start out recognizing a viral infection in the mid-80s, '84, and there's no treatment. It's a kind of a terrible, uniformly fatal infection, no antiviral treatment. By '89, we have our first antiviral, [zidovudine] AZT, but it's clearly not enough. By 1996, we recognize that we need triple-drug treatment to have excellent viral suppressant, but there's a lot of pills involved.
Fast-forward 10 years, and the best of the combinations are combined to a single [pill]. It’s a huge deal because it simplifies treatment, and it's so much better tolerated. That’s 2006. By 2016, 2015, 2014, we have integrase inhibitors and the dolutegravir rollout. We're still with kind of triple-drug therapy but with better agents.
Now, in 2019, we're seeing another shift, a big shift, and we're seeing 2 kinds of things going on in this shift.
One is the notion that 2 drugs is enough. It’s going to be cheaper and perhaps simpler and better tolerated. Then we're going to attempt to deliver the drug a different way, through long-acting injections or implants or reservoirs or microneedle patches.
UNIVADIS: Talk about the 2-drug regimens.
DR. COHEN: We're pretty confident that the combination of rilpivirine and cabotegravir is going to be approved as a 2-drug injectable long-acting treatment regimen. Ultimately [injections will] become every 8 weeks.
[The 2-drug regimen of dolutegravir and] lamivudine… Lamivudine is a very well-tolerated drug, and dolutegravir is a very potent integrase inhibitor.
Merck’s doravirine/MK-8591 [MSD’s investigational drug islatravir] seems to have successful suppression of viremia [in a small pilot study], which is attractive. It's another 2-drug regimen.
So, we just see this evolution to 2-drug regimens. It's a movement, and that movement's not going to go away.
UNIVADIS: Do you think the 2-drug regimens will be useful for people who have a tough time adhering?
DR. COHEN: It's still a pill, right? The obvious person to benefit from the long-acting injectable agent is the person who's demonstrated that they can't be adherent to a pill for whatever reason.
UNIVADIS: Are bNAbs being developed for treatment?
DR. COHEN: Sanofi's [trispecific broadly neutralizing antibody] has gone into humans with suppressed viremia.
UNIVADIS: We were talking about the new capsid inhibitor. Can you talk about that?
DR. COHEN: It's Gilead [GS-6207, delivered subcutaneously, which presented phase 1b data at IAS]. These are drugs that are in the early development. It’s unknown where it's going, but it's exciting because of the pharmacology and the unique mechanism action.
UNIVADIS: What about the pipeline for prevention?
DR. COHEN: We start out, rightly, recognizing that we need to understand the magnitude by which antiviral therapy reduces transmission. That becomes extremely robust, with zero transmission events when people are properly treated, whatever their sexual behaviors. That's probably not sufficient [to end the epidemic], so we see now what's referred to as a status-neutral approach [to treatment and prevention]: Anyone who comes in to be tested either can be treated if they're infected, with excellent treatment, or they become eligible for all kinds of interventions to prevent acquisition of HIV, including the use of an antiviral agent.
[Gilead’s tenofovir disoproxil fumarate/emtricitabine, Truvada, TDF/FTC] is the first agent we had. It turned out to be a remarkably great agent and extremely powerful intervention, but it turns out it's hard for many people to take 1 pill a day, especially some of the people at greatest risk. I can tell you right now that HPTN is looking for alternative ways to get better uptake and adherence to TDF/FTC. So, we're not done with TDF/FTC.
The first thing that is probably forthcoming is TAF [tenofovir alafenamide] instead of TDF because, for an otherwise healthy person, there's fewer side effects.
But taking a pill when you're HIV-negative appears to have substantial stigma associated with it. So, delivering antivirals for prevention that are given infrequently, in more private settings, is where the field is heading. This mostly focuses on either pills or injections or implants or microneedle patches or infusions of antibodies or subcutaneous delivery of antibodies.
[MSD’s islatravir] as an implant is intriguing. MSD is good at implants. They've got a lot of experience with [the contraceptive implant] NEXPLANON. The chemists were able to successfully integrate the agent into a matrix, where it's leaching out of a matrix, which is another very effective feature of that drug. And it takes very little drug to provide antiviral levels for a long period of time. Now, the correlates of how much drug you need to prevent infection are, of course, not known. So it's a long regulatory pathway.
UNIVADIS: What other prevention approaches are you excited about?
DR. COHEN: We haven't talked about bNAbs yet. bNAbs are going to be in direct competition, in a good way, with ARVs [antiretrovirals] — otherwise you'd just use an ARV. If bNAbs pan out, it'll be 2 or 3 bNAbs or a bNAb that's a multitargeted bNAb, like Sanofi's bNAb, that'll offer prevention from HIV for months. Then Michel Nussenzweig's antibodies [3BNC117 and 10-1074] are pretty far downstream in terms of demonstrating the potential to serve as a PrEP combination.
UNIVADIS: It sounds like what you’re saying is that the ARVs are so good now that the bar is high for bNAbs.
DR. COHEN: For a bNAb combination to make a contribution, it's going to have to last a long time, be very well-tolerated, be administered in a way that's acceptable, and be cheap enough to compete with ARVs, especially long-acting ARVs. Let's assume cabotegravir long-acting [an injectable ARV on which Cohen is working] works. That's going to last for at least 8 weeks. The benefit will extend probably beyond 8 weeks, at some level.
So the bNAbs are going to have to last that long or longer and be comparable in their preventive effect.
UNIVADIS: Other thoughts on prevention?
[Researchers] in the treatment community, they take a person with HIV infection, and they develop the drug because they can suppress viremia. If the drug does not suppress viremia, they kill the program, right?
DR. COHEN: It's over.
But for people working in prevention, whether it's vaccine or nonvaccine prevention, it's much harder because we don't have a metric like that. We have to go a long time in a very complicated and ethically challenging space to prove that a drug prevents HIV infection. So, we first do it in animals, and then we try to do it in humans. But we know the animals are not always truthful [in terms of research in animals translating to humans], especially in vaccines.
So these are real experiments, you know? They're not for the fainthearted.