番茄社区

番茄社区 brought together three expert leaders for a virtual roundtable discussion on HIV news from the IDWeek annual meeting: Moderator , of the University of California San Francisco, is joined by , of the University of Virginia School of Medicine in Charlottesville, and , of the University of California San Diego School of Medicine.

This third of four exclusive episodes discusses two studies of the capsid inhibitor lenacapavir (Sunlenca), a long-acting injection recently approved by the FDA for multidrug-resistant (MDR) HIV. You can view other videos in this series here.

Following is a transcript of the discussion:

Gandhi: Going back to long-acting because now I think every study is going to bring weight into it. So this kind of is a segue into lenacapavir. There are a couple of abstracts on lenacapavir that I thought we could discuss. But one, just to talk about weight, is that now every study is going to say, what's your weight gain over time? So the CAPELLA study, there was an analysis of weight. And in the CALIBRATE studies, remember CAPELLA was the MDR HIV, and then the CALIBRATE study was that one where it was lenacapavir was looked at in the context of treatment-naive patients with different oral regimens made by the same drug company. Sometimes ones that we're probably not going to get, like BIC [bictegravir] alone, TAF/FTC [tenofovir alafenamide/emtricitabine] or BIC/TAF/FTC [Biktarvy]. So big reminder that there's BIC in here and there's TAF/FTC in here when we think about weight.

But at any rate, in the four arms of CALIBRATE, which were lenacapavir with F/TAF [tenofovir alafenamide/emtricitabine] and then lenacapavir with BIC alone -- F/TAF and then BIC alone -- versus BIC/TAF/FTC, there was pretty much a steady weight increase in all four arms, but it wasn't too much. It was over 80 weeks, 4.7 kg in every arm except the one that was [lenacapavir] with BIC alone, which again is not a combination we can get. And that was 2.6-kg weight gain over 80 weeks.

So the conclusions the investigators made are -- it's not excessive weight gain. It's kind of what you see over time anyway, and watch it, but it didn't seem to cause excessive amounts of weight gain. And also, let's just remember, lenacapavir isn't going to be approved at this point for naives. CALIBRATE was not a phase III study, it was a phase II study. So we don't have a treatment indication for naive patients with lenacapavir.

And then I think two other things, and then I'd love to ask your opinion about this with lenacapavir because I think the CAPELLA study, boy are those 72 people well studied. So it's only 72 individuals in the CAPELLA study. First we had the . Then we had , and then at of patients in the CAPELLA study. This is patients with MDR HIV, lots of drug resistance put on an optimized background regimen and the subcutaneous lenacapavir after two oral loading doses.

And at this point, out of these 72 individuals, we knew in the Lancet HIV study that nine out of 72 had developed lenacapavir mutations. But importantly, they proved that they either weren't taking the optimized background regimen or they didn't have an active background regimen. So there was kind of -- Mike Saag once said lenacapavir should never walk alone, so it should not walk alone. I think he's saying something, but it shouldn't walk alone. So I think that really proved it at 52 weeks and then at 104 weeks, we got five additional participants who developed lenacapavir mutations in their virus.

So now we have 14 out of 72 with lenacapavir mutations, which sounds terrible except for the fact that they actually counseled the participants and said, well, take your optimized background regimen. There aren't a lot of options here. Two of them out of those 14 changed the optimized background regimen. And out of those 14 that failed with lenacapavir resistance, seven re-suppressed.

And so I wanted to get your thoughts on that because I thought that was really interesting. And I think it probably indicates that again, lenacapavir has to be with something, and maybe if we work hard enough on that something, on the regimen with lenacapavir, we can get them to re-suppress.

Bamford: No, absolutely. And I think these patients didn't have other options. All of these patients had very low CD4 counts; all were detectable. I think this is what we have right now for this patient population that's highly treatment-experienced.

Gandhi: Until we can get an injectable that goes with lenacapavir.

McManus: The same thing. Yeah.

Gandhi: We all want that.

McManus: It shows that there were seven people who were really struggling with taking the oral optimized regimen. It shows that in the real world, we have patients who struggle to take these medications even when we tell them this is at this point getting to be life or death. So I think it does get to that point, Monica, where we really do need other injectables that can go with lenacapavir.

Gandhi: That's such a good point, that they couldn't take the oral in those seven who didn't re-suppress, and it makes me think that pharmaceutical companies have to discuss with each other. We just at this point don't have one company making two long-acting that will overwhelm resistance. So this means that I think we need more cooperation for our patients.

So that, and then one other lenacapavir abstract on -- and I'd be curious about your experience -- but on nodule formation. I mean there's pain, and there's injection site reactions, and then there's that nodule. In a way, the nodule is formed from that really oily, sticky, bright yellow, by the way, lenacapavir, that stays in your system and then elutes over time. So the nodules are definitely seen, and I've definitely seen these in my patients. And I don't know if, I mean, I've talked to them and it seems more notable for patients who have very low body fat, which makes sense.

Bamford: Yeah. That has been our experience. No one has discontinued, thankfully, because I think we counsel patients that this is the only option we have right now.

McManus: Yeah. I think it gets back to the drug delivery and thinking forward, how can we make this better for patients? Because we know that there are some patients who are opting not to get injectables because of these nodules or injection site reactions. And so hopefully trying to partner with different people in academics or industry and trying to think through how can we optimize the drug delivery.

Gandhi: I totally agree. Does the depot have to be that thick? Can we make it less thick? Will we get our TAF-islatravir-elvitegravir implant someday? I don't know. So we'll talk about that next time.

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