Challenges and Limitations of Current Regimens for Multidrug-Resistant HIV

Joseph Eron, MD, and Monica Gandhi, MD, MPH, describe the obstacles to treatment efficacy with the available treatment options.

Joseph Eron, MD: So, Monica, and you’ve already talked about this, but we can go over this again. What are some of the challenges or limitations of our current regimens that we’re creating for people that are highly treatment-experienced, especially those that either can’t tolerate some of our current therapies or have multidrug resistance [MDR]? Dan mentioned some drugs but they all kind of are…

Monica Gandhi, MD, MPH: I think about 4 of them. Maraviroc is in there because if we have CCR5 tropism we can use that, and we often use that for MDR-HIV. For stem cell severe, ibalizumab, and lenacapavir is coming. Then having in the background something, usually INSTIs [integrase inhibitors] and boosted PIs [protease inhibitors], even with partial activity. So all 4 of those have limitations. Ibalizumab is IV [intravenous], and it’s great that just this month we got the data that you can do a 30-second push, but it’s every 2 weeks you have to place an intravenous line. No matter what, that is a barrier. I know there’s the question about IM [intramuscular injection] ibalizumab studies, and that would great. Stem severe is BID [twice a day], we can’t get away from that. No study has ever shown QD [every day] dosing. I’m always surprised how few drug-drug interactions it has, and renal and hepatic results are fine to use fostemsavir. But no matter what, you’re working with a patient population that may have had adherence barriers because it’s BID. Then, maraviroc is actually BID too, so we have to admit that. And then, finally, lenacapavir we don’t have, but Europe does, and we’ll get it in a couple of months. That is exciting. I’m excited about a subcutaneous injection every 26 weeks to be our kind of salvage therapy as much as we can in the background. That seems easy. I’m excited about lenacapavir.

Joseph Eron, MD: Dan is going to talk a little bit about lenacapavir and its mechanism of action in a minute. I do wonder, worry is not the right word, but wonder about, I know in some of the lenacapavir studies, people have actually gone off their oral therapy. How are you going to message that, especially in someone where it’s really critically important to stay on the oral therapy, which is going to be virtually everybody right now, anyway, because that’s the only very long-acting drug we have? How are you going to message that to people?

Monica Gandhi, MD, MPH: It’s such a good question because it can not only never be used alone, nothing can really, but lenacapavir, in the CAPELLA and the CALIBRATE studies, we have seen resistance. It’s not like it’s impermeable. So it’s the same going back to the adherence tricks and messaging that we do even if there wasn’t lenacapavir on. We will schedule their 26-week visit. I imagine we’re going to provide it probably as opposed to home administration even though it can be given at home subcutaneously.

Joseph Eron, MD: Theoretically possible.

Monica Gandhi, MD, MPH: Then just really working on oral therapy. I am looking forward to a day though, maybe, if ECTG [early clinical trial group] could study cabotegravir and lenacapavir. It’s as good as we get. It’s the longest we get. I would not use rilpivirine with lenacapavir. We have too low of a genetic barrier to resistance. Can we study that combination? Wouldn’t that be something? Then, in a multidrug-resistant patient, would you feel that was enough? That we don’t know until we study it. And I’m looking forward to TAF [tenofovir alafenamide] implants someday because this is the future, very long-acting medications.

Transcript Edited for Clarity

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