Long-Acting Prevention and Treatment of HIV: CROI 2022 Part 1

At the virtual Conference on Retroviruses and Opportunistic Infections (CROI), researchers presented multiple abstracts that could change prevention and treatment strategies for HIV.

MedPage Today brought together three expert leaders in their field -- moderator Monica Gandhi, MD, MPH, of the University of California San Francisco, Carlos del Rio, MD, of Emory University in Atlanta, and Renee Heffron, MD, of the University of Washington in Seattle -- for a virtual roundtable discussion on cabotegravir-rilpivirine (Cabenuva), the first long-acting injectable HIV treatment, which was FDA approved last year, as well as new phase IIa data on the safety and efficacy of islatravir for pre-exposure prophylaxis (PrEP). This is the first of four exclusive episodes.

Following is a transcript of their remarks:

Gandhi: Welcome to the roundup of CROI 2022. I want to introduce my co-panelists here, Dr. Carlos del Rio, who is a professor of infectious disease at Emory, and Renee Heffron, who is a professor of infectious disease at University of Washington. And we all work in the clinical space for HIV, so we're going to try to tell you about the more clinically relevant abstracts from CROI 2022, which was very fast-moving and very virtual, and we'll include some of the symposium ideas that came about in the second week of CROI.

So I want to actually start out with long-acting treatment and prevention, Carlos and Renee, and specifically mention that Chloe Orkin gave an amazing plenary on this whole topic. But we'll maybe start with HPTN 083 with Dr. del Rio, to tell us about the results.

del Rio: Yeah, thank you, Monica, and pleasure being with you. As you say, Chloe Orkin gave a tremendous plenary that people should watch because really a new era is starting with antiretroviral therapy with long-acting agents, both in treatment and prevention.

For prevention, we have HPTN 083 and HPTN 084. In 083, the interim results were already published in the New England Journal of Medicine and showed that injectable cabotegravir was actually superior to tenofovir-FTC [fumarate–emtricitabine] in the prevention of HIV infection among men who have sex with men and transgender women. HPTN 084 shows similar results in cisgender women. That study conducted in Africa has yet to be published, so I'm not going to talk about that study.

What we heard at CROI is an update in HPTN 083, and again just to remind people, in this study people were given blinded cabotegravir plus placebo or FTC plus injectable placebo. So, it was a double-blind study. And after an oral induction, people were then switched to the injectable. And people were followed for approximately 3 years. And then after follow-up, after the results were made available, then we went into an open-label study.

In the original paper published in the New England Journal of Medicine, there had been a total of 11 infections in the cabotegravir arm and 31 infections in the tenofovir-FTC arm. At this presentation at CROI, Raphael Landovitz, who is the PI of this study, presented data now with the 13 additional infections on the cabotegravir arm.

And there's still superiority. There are more infections on the tenofovir-FTC arm. But I think what's really interesting is what happens with those infections, some of which occur in people who had been over 6 months after having had cabotegravir. And those breakthrough infections really are very, very fascinating because they really showed us some of the challenges that we're going to have with this drug.

In other words, the administration of cabotegravir in people that got infection suppresses viral replication and delayed antibody production. So there's really a failure of antibody antigen tests to detect infection. And, in fact, some people are saying, well you need to do viral load monitoring, you need to do viral load testing. And I just wonder whether this is even scalable -- forget about globally, just here in the U.S. -- I've just not seen how we're going to do that.

And then the other thing is to see what happens when they did, sort of, deep single genome sequencing analysis in which they were able to detect the presence of cabotegravir of INSTI [integrase strand-transfer inhibitor]-resistant mutations in six of seven participants who were first detected with serum samples with viral loads less than 500. And, again, emphasizing how difficult the challenges are that we're going to have in detecting infection in people that receive cabotegravir. But, also, I want to make sure that people don't get discouraged and still realize that cabotegravir is an incredible option for prevention of HIV infection.

Gandhi: I agree that I thought that Sue Eshleman's point that you may have to screen people with RNA at every 2 months, and then she said at the end that doesn't actually look like it's going to be feasible. I mean, Renee, I turn to you, do you think that's going to be feasible for cabotegravir every 2 months? Or we're just going to have to rely on its superiority and hope that we do well?

Heffron: Yeah, I think we're going to see, the World Health Organization is trying to figure out what to put in their guidelines, and that will be very important for countries that are lower-resource to figure out how to do it. Because it is clearly a very powerful tool.

And Deborah Donnell gave a talk also showing the kind of modeling work that they've done against a contemporaneous placebo arm in other trials, because the 083 and 084 trials were using an active comparator. And it does have very high efficacy, I don't think there's any question about that. And so trying to figure out what to do about the potential for undetected infections is going to be really important and a challenge. And it's going to come back again to this balance of, we need to be able to implement and use this product, and what's the cost of missing a few infections in people who are newly infected and are not zero positive on the antibody antigen tests.

del Rio: You know, Renee, I think that's really critical. The benefit of preventing HIV infection is going to have a cost. And that cost is going to be some people who have developed resistance. But for the same reason that we don't stop giving antiretroviral therapy just because of the risk of resistance, this is going to be one of the issues that we're going to have to deal with. And I can tell you this is not only an issue in Africa, I think this is an issue even for most of us in the United States. I don't think viral load monitoring is feasible or affordable for most places.

Gandhi: Let alone, you're not going to change your management, you're not going to not give them that injection, even if you draw an HIV RNA that day. So, whether we do pooled RNA, whether we just do adherence counseling, whether we wait until we see it later, I think this is going to be really important.

And I think that then relates to islatravir and maybe, Renee, you can tell us the updates on islatravir -- not even just from the meeting, because there was some stuff on it from the meeting -- but just in general what's going on with islatravir. Because this was hailed for both prevention and treatment, possibly put with other agents for treatment.

Heffron: Sure. So, islatravir is a new drug that's being tested as both a PrEP medication and also an HIV treatment medication. It's in the form of long-acting oral tablets. And so there were a couple of nice abstracts at CROI with data from the phase IIa study, which is a safety study of islatravir used as PrEP in both a 16-mg monthly tablet, and also a 120-mg tablet compared to placebo. And the primary safety data for those trials presented, I think, last year, have paved the way for this to move into a phase III efficacy study, multiple phase III efficacy trials, in different populations globally.

And I'll talk about that in a minute, but just to give you an update on the data that were presented from 016, which is the safety protocol, the phase IIa. There were two abstracts. The first one was by Dr. Craig Hendrix, looking at different compartments and really looking at the pharmacokinetics of islatravir in people and looking in both systemic levels and also local levels, so in PBMCs [peripheral blood mononuclear cells], in rectal tissue, and in cervical tissue and vaginal tissue, and then in rectal cells.

And the good news from this was that there's not a lot of difference. And so you actually probably can use the easier-to-collect, the systemic levels, as a surrogate for the tissue exposures. And then, not surprisingly, something taken orally does have an impact and does show up in all of these compartments in all of these places, which is good news.

Then, the other study, the first author is Pippa Macdonald, that was looking at metabolic changes and renal changes after using both doses compared to placebo. And, again, it looks very safe in terms of, there was no measurable change in weight or BMI, or also in renal function. And so that also looks safe.

The presenters were really clear also to mention that the U.S. FDA has put a clinical hold on the current phase III trials of islatravir for PrEP. And that's a full clinical hold. And so what I can say about that is that both trial teams working on those studies are working hard to look at the available data from the small amount of people who were enrolled in those phase III trials. They were stopped because of the potential for reductions in lymphocyte counts, and so to look at the recovery of lymphocytes, which they can get from people and are continuing to follow trial participants.

And then also to conduct some mechanistic studies to try and understand what might be happening. And then also some modeling studies to try and look at the potential for lower doses to not have this impact on lymphocytes, but still to remain potentially protective against HIV infection.

And so all of that is happening in the background, led by the developer Merck, to try and come off clinical hold and be able to move this product to its next chapter and see how that would go.

Gandhi: Great.

Watch episode two of this discussion: Long-Acting Prevention and Treatment of HIV: CROI 2022 Part 2

Watch episode three of this discussion: Second-Line Dolutegravir for HIV Favorable to Other Boosted PIs

Watch episode four of this discussion: Third 'Cured' HIV Patient Headlines CROI 2022

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