HIV Update: CCO Independent Conference Coverage of CROI 2025

[00:19:42]

HIV Treatment

Dr Joseph Eron (University of North Carolina, Chapel Hill School of Medicine): Hi, everyone. I'm going to start our discussion of HIV treatment. It was an incredibly exciting conference with a tremendous amount of new science of all different levels. So let's focus on HIV treatment.

[00:20:03]

CARES: LA CAB + RPV in a Sub-Saharan African Population Using a Public Health Approach

The first study is going to be the CARES study. People may remember that this was presented a year ago and then published in the New England Journal. This is looking at the combination of long-acting cabotegravir and rilpivirine in Sub-Saharan Africa. So this is the first large study looking at long-acting therapy in that Sub-Saharan setting.

And it was a randomized study, so people came in on oral therapy, they had to be suppressed, and they couldn't have hepatitis B, and no history of treatment failure. And then they were randomized to go on to CAB rilpivirine. They could choose the oral lead in or stay on their oral therapy.

And while there was some increased monitoring for safety at the beginning, it was basically a public health approach every 24 weeks. The primary endpoint was the proportion of people - participants less than 50 at 48 weeks, which we thou - saw. And that was clearly a noninferior result. And then at this meeting, we got to see the 96-week result. And you might remember people were asking, "Well, it worked over the short term, what about over longer term?" So that's it's - that's what we're going to talk about here.

[00:21:20]

CARES: Baseline Characteristics

Here are the - the - the data on the baseline characteristics. I just want to just point out a couple of things. First is that it was 58% female. Second is that there was prior NNRTI exposure, but most people were on an integrase inhibitor at screening. So most people were - were probably on TLD at screening.

One really important point has to do with the resistance mutations. When we first heard about this a year ago, there was a really high proportion of intermediate and high-level resistance that was reported for both rilpivirine and cabotegravir. It's important that these are done on proviral DNA, so they weren't available at baseline. It's proviral DNA, that is not a very precise assay.

And also what happens is when you do PCR, there are errors that are made, and it turns out that the first resistance testing didn't account for these errors. So the actual proportion of people entering the study that had intermediate or high level resistance to rilpivirine was actually only 3%. And intermediate or high level resistance to cabotegravir was only 2%. So it was very low.

So again, this isn't really important, and I don't use proviral DNA in my practice. What was surprising a year ago was, wow, this really worked despite all this resistance, and there really just was a lot less resistance than we thought. So I think that's the important message here.

[00:23:07]

CARES: Virologic Efficacy, Injection Timing, Safety, Tolerability, and Treatment Satisfaction at Wk 96

What's amazing, and these are the results, are that 81% of all the participants received all their scheduled injections, and they were—97% were administered on time. The follow-up was incredible in both arms, and what you can see is there's absolutely no difference in terms of proportion suppressed.

And then the primary endpoint is the proportion above 50. So that's on the left. And you can see that CAB rilpivirine remained noninferior. There were very few participants that had viral loads above - HIV RNA levels above 50 at 96 weeks. And then there were very few people with no virologic data. So this was a really terrific - terrifically done study.

[00:24:01]

CARES: Virologic Failure at Wk 96

And then in the next slide, we can just look at the virologic failure at 96 weeks. So there were 4 people. And you can see that most of them had, you know, measurable virologic failure at, you know, 8000 and 44,000, 700, and then 200 and then 16,000 copies.

And what you see is that at baseline, 2 of the 4 had these kind of low level rilpivirine mutations. In other words, they don't add a lot of weight till rilpivirine resistance. And none of them, not a single one, had a high BMI. So the virologic failure weight was 1.6%, so between 1% and 2%, which we know happens with CAB rilpivirine. But overall, the success rate and the acceptance of the therapy and the follow-up by the participants was fantastic.

[00:25:15]

Posttest 2

So we're going to go into our posttest question. So in the CARES study, again, using a public health approach in people who entered with virologic suppression with - when compared to oral standard of care ART, CAB LA was:

1. Noninferior at 48 weeks, but superior at 96;
2. Superior at 48, but noninferior at 96;
3. Noninferior at both 48 and 96 weeks; or
4. Superior at both 48 and 96 weeks.

So go ahead and vote, take your time. Go over what - what I just said and - and we will wait a few seconds.

Terrific. Okay. So 74% of you were - were listening, and - and that's the correct answer, noninferior at both 48 and 96 week in this large public health approach study.

So let me turn it over to Dr Gandhi, and she'll continue our HIV treatment discussion.

Dr Monica Gandhi (University of California, San Francisco): Yes, just trying to - okay, there we go. So thank you.

[00:26:36]

Potential Future HIV Treatments

So next I'm going to present the - some potential future HIV treatments. Unlike cabotegravir and rilpivirine, none of these are yet approved.

[00:26:46]

Switch to DOR/ISL From Oral ART: Efficacy Results of Blinded and Open-Label Studies at Wk 48

So the first was—actually there are 2 studies summarized here, and these are Merck sponsors—the company-sponsored studies of doravirine/islatravir. Remember doravirine is a second-generation NNRTI, islatravir is an NRTTI transcription translocation inhibitor. And the design of these 2 studies were to take people who are already suppressed on whatever they were on.

One study was BIC/TAF/FTC, and they had been on that regimen for a median of 3 years, completely suppressed, switching over to doravirine/islatravir, and the second study was switching over from a variety of oral ART regimen, in which they were virologically suppressed.

The dose importantly was doravirine 100 mg, which is standard, and islatravir 0.2 mg a day, which had been calculated kind of as being a dose that should be safe, because remember we had some concerns about islatravir causing white blood cell count and lymphocyte decreases at higher doses.

Okay. So you can see the results of both of these studies, 513 and 551 individuals, respectively. And there were high rates of maintenance of virologic suppression switching over to doravirine/islatravir in both studies. So lots of questions came up in the question and answer for these studies about, okay, but what about weight? Why would I even want to switch doravirine/islatravir?

Second question was, did you exclude people who had had a history of M184Vs? Because in vitro data would show that you can't use islatravir with M184Vs. And some of those questions were answered in the question and answer period as summarized in this next slide.

[00:28:26]

Switch to DOR/ISL from Oral ART: Total Lymphocyte and CD4+ Cell Counts

So one thing is that when looking at the total lymphocytes and CD4 cell counts, the orange is the old therapy, the blue is doravirine/islatravir, and these lines superimpose on top of each other. There were no decreases in total lymphocyte and CD4 count, with the islatravir-based regimen, but also there was kind of expected increases when you keep on being on suppressive antiretroviral therapy.

So didn't look like this dose of islatravir was of concern for CD4 cell counts and total lymphocyte counts, 0.25 a day.

[00:29:03]

Switch to DOR/ISL From Oral ART: Safety

What about some other questions? Weight? And I want to address the M184V, and I also want to say something about clinical hepatitis B reactivation. So doravirine/islatravir, neither one will have any impact on hepatitis B treatment. Of course, BIC/TAF/FTC would treat—TAF/FTC would treat hepatitis B.

So there were no clinical hepatitis B reactivations going to doravirine and islatravir, but there were 3 cases of low-level viremia, no hepatitis B surface antigen conversion, elevated transaminases, but kind of this low level hepatitis B viremia.

And then 2 cases of acute hepatitis B infection, which of course TAF/FTC would be protective, as actually shown in another study. I'm sorry that there's a cat there. And so that is important to keep in mind with all these regimens that do not treat hepatitis B.

Also, we already talked about the CD4 cell and lymphocyte count in the blue box here. But what about weight? So several things occurred. Everyone was interested in weight, and there were a lot of questions afterwards about weight.

Now, the thing is that the people who were in the study of BIC/TAF/FTC that switched over to doravirine/islatravir, the damage had been done, meaning they had been on 3 years of BIC/TAF/FTC, and indeed whatever weight gain they were likely to have on that regimen had been achieved and there was not weight loss of doravirine/islatravir. And what the study investigator would say is, you know, that weight has already been gained and it's very hard to lose weight, and we're not going to see this in a switch study. So that's true. We did not see weight loss going to doravirine/islatravir.

And then in the open label study, and this was the one where you switched over from whatever regimen someone was on, those who had been on efavirenz and TDF containing regimens had the expected loss of suppression of weight, meaning weight gain occurred when they went over to doravirine/islatravir, but that's because they lost the weight suppressive effects of efavirenz/TDF. And that is true in every study, those 2 agents do keep the weight down.

So I think that this weight question will not be answered by these 2 studies. I think it could be answered by the naive studies. Take people who are naive, randomize them to doravirine/islatravir vs BIC/TAF/FTC, or any other regimen. And those naive studies will not be - they're in process, but they will not be available for at least a year or more. So let's look at the weight closely there.

And then the 184V, we cannot say from these studies, because they excluded people with a history of 184V, if islatravir is going to work on that. Again, in vitro it doesn't look like it works on M184V, but in vitro is different than in vivo.

[00:32:00]

Posttest 3

So this leads to the next question for you. Based on phase III data, when compared with continued BIC/TAF/FTC or other oral ART regimens switched to daily oral doravirine/islatravir had:

1. Similar efficacy but greater declines in total lymphocyte counts;
2. Similar efficacy and similar changes in total lymphocyte counts;
3. Superior efficacy but greater declines in total lymphocyte counts; or
4. Superior efficacy and similar changes in total lymphocyte counts.

And please vote. And I think the results will be shown in the next slide. So 83% of you got, which is exactly correct. They really were exactly the same in terms of efficacy and similar changes in total lymphocyte count, 83%, so great job.

[00:33:04]

Lenacapavir, Teropavimab, and Zinlirvimab for People Living With Virologically Suppressed HIV

Okay. Let's go on to several other, again, investigational therapies, not yet available, may not become available. We'll see. So this is a study that was essentially a combination of lenacapavir, which is given subcutaneously, capsid inhibitor, every 6 months, combined with IV infusions of 2 bNAbs, one is TAB, one is ZAB. They're investigational bNAbs.

And the study design was that—it's a very small study, either staying on oral baseline regimen vs getting that LEN once, you know, just once at 26 weeks and then again at 52 weeks—the subcutaneous injection along with those 2 IV infusions.

Now, the primary endpoint was looking at 26 weeks of whether there was any failures or not, essentially. FDA snapshot means if you go off regimen, you're still in the arm that you are intention to treat essentially.

[00:34:09]

Lenacapavir, Teropavimab, and Zinlirvimab: Efficacy, Virologic Response, and Safety Outcomes at Wk 26

So this was the result of this small study. So 53 people in the LEN + TAB + ZAB arm, 27 in baseline ART, everyone in baseline ART did great, all had less than 50. Almost everyone did great in the LEN + TAB + ZAB arm, but there was one confirmed virologic failure above 50 copies/mL.

Now, there was a lot of questions asked about this particular participant that virologically failed in the question and answer period. Because why did they fail? Seems really powerful and anything to do with ZAB/TAB susceptibility, or also LEN concentrations. And indeed we did get the answer that that particular individual had really low lenacapavir concentrations. Don't know why, no association of BMI with lenacapavir concentrations to our knowledge, and this person had a normal BMI, maybe something to do with their host self and their pharmacogenetics, but they had low concentrations, probably the reason for the failure and actually developed resistance to lenacapavir with a specific mutation.

These mutations look like thymidine analog mutations, but it's a 67 change in the capsid gag gene. And also loss of ZAB susceptibility in that individual. So really that LEN having low lenacapavir concentrations is what led to that failure.

Now, whether this will go forward or not is going to on drug companies desires to have it go forward, because they have to make the product.

[00:35:42]

EMBRACE: IV or SC N6LS + CAB for People Living With Virologically Suppressed HIV

And then I want to tell you about one other study and we'll end and discuss, which is with a bNAb. This is specifically a bNAb that is called N6LS, and it's investigational as well, and it's combined with cabotegravir. The same innovator company makes both of these drugs.

So if you're going to combine it with cabotegravir, you have to think about how often it's given. Cabotegravir can be given every month and - at 400 mg and it actually can be given at 600 mg every other month.

Now, the dose that was chosen in this study was cabotegravir every month, given with one arm being the NX - N6LS every 4 months by an IV infusion, and then there was also a small arm with subcutaneous every 4 months of the bNAb formulation, vs oral standard of care ART and the same primary endpoint.

[00:36:39]

EMBRACE: Efficacy, CVF, and Safety Outcomes at Mo 6

So the results are shown in this next slide. And in the EMBRACE study, let's just say that the subcutaneous N6LS dose didn't do as well and it's gone. That's not what's going to go forward. What's going to be looked at is the IV formulation of the bNAb, which is 96% in terms of giving efficacy.

And importantly, 4 out of 5 participants did fail meet confirmed virologic failure criteria with more than one. Two of them is in the SubQ arm. That's not going forward. But let's look at the IV arm. Neither had INSTI RAMs, to begin with, and both had levels of the bNAb that were supposedly above the IC90 of the virus. So don't know why those 2 individuals failed. And then injection site reactions, of course, would be more with a subcutaneous injection.

So what's going to be looked at, and this is going forth, is the IV formulation every 6 months with long-acting CAB. Please remember the long-acting CAB was given every month. I think that would be nice if they could give it less often.

[00:37:38]

Pipeline: Phase IIa Proof-of Concept Studies

Okay. And then 2 final studies. These are both pipeline products. So I just want to say that these are very small studies. The VH-184 product, VH-184 was a 22-person study, and it was a phase II study. And it was just asking this particular integrase inhibitor, which is supposedly a third-generation integrase inhibitor, and what I mean by that is that there was data presented in Munich, that this particular INSTI works against dolutegravir resistant mutants, at least in vitro. That'd be nice as we - if we destabilize, unfortunately, dolutegravir resistance worldwide with - with what's happening in the world.

So if VH-184, the question was just that simple, when you first study a product monotherapy and people living with HIV, this was given on 1, 4, and 7 days. And then did you get that expected decrease in HIV RNA in that period of monotherapy? And indeed that did happen.

And the expected decrease was the same as what was seen with dolutegravir. So it's an INSTI, and it drops the HIV RNA quickly. So that's VH-184.

VH-499 is an HIV capsid inhibitor. Now, you'd want to put a capsid inhibitor with a - with a long-term integrase inhibitor. One thing I should say is that both these formulations look like they're going to be able to go into long-acting formulations as injectables, but these were, of course, just studied as oral.

So if the PK—that favors injectables in the future, that'd be great. And this particular VH-499, still same thing, the expected decrease in HIV RNA that you'd see with monotherapy in these early phase studies. One participant though did have a emergent capsid inhibitor RAM, and it was a very small study. So we have to watch that VH-499.

[00:39:26]

RIO: Effect of bNAbs on HIV Control During ART Interruption

Okay. So we are going to end this section with another comment on bNAbs in the context of cure. And my colleague, Dr Eron is going to present the RIO study.

Dr Eron: Yeah. Hi. I'm trying to make my video appear but doesn't want to. It's unhappy. So oh, now you get - I'm going to stop clicking. So the RIO study, it's really important. This is not a treatment study. This is actually a cure study to try to see whether giving people these long-acting bNAbs, broadly neutralizing antibodies. It turns out these are the same antibodies that were given in the study Monica just showed you, that they haven't been modified by the industry partner, but they are structurally the same antibodies.

And the goal here was to see if giving antibodies and stopping therapy would result in prolonged suppression. And - and there was a placebo arm. The nice thing about this placebo arm is that if people rebounded, they could then get the antibodies, but they didn't really talk about that arm.

What they were really looking at is that active arm, Arm A here. And these people were treated either early or with a high CD4, so with a reasonable - reasonably strong immune system, and they were - they did look just to make sure that they weren't resistant to the 10-1074, which is the ZAB in the other study, which has a kind of low genetic barrier to resistance.

And what they were interested in is, could people stay off therapy after getting the IV antibodies, and what proportion could stay off by 20 weeks? So again, only focusing on Arm A, not on the - whoops, maybe my - too much caffeine, and I'm hitting the button twice.

[00:41:33]

RIO: Viral Rebound and Safety Outcomes

So on the active arm, there were no viral rebounds by 20 weeks after ART interruption. So that again, 75% of people who received the bNAbs did not rebound. And 8%, which were 2 people on placebo, did not rebound. And obviously that strongly favors the bNAbs. There were some rebounders on the bNAbs, and some of them had developed resistance.

People who stayed suppressed were allowed to then get a second injection of the antibodies. And really what was the most interesting thing is, again, in the treatment arm, arm A, you can see 7 of 29 participants or 24% remained virologically suppressed 72 weeks off ART. So that's potentially very exciting. What was the mechanism? Were these people that were super sensitive to the antibodies and this is still an antibody effect, or did giving these antibodies change something about these individuals, allowing them to stay suppressed?

And there were a couple of very interesting posters at the meeting suggesting that perhaps there was an expansion of their HIV specific T cells that might be contributing to this control.

So this is not a treatment study, this is a cure study. And I think what we can say is something happened that led to prolonged suppression in about a quarter of these individuals, and now we need to find out, well, what did happen? And that will be at a next conference, I'm sure.

[00:43:20]

Key Takeaways: Treatment

So there's some really key takeaways here. Monica, what did you think about the CARES study?

Dr Gandhi: Oh, there we go. Okay. I wanted to say that I was really excited by the CARES study. I don't know. For a variety of reasons, I just thought at 96 weeks we wouldn't have as high of levels of virologic suppression as of 48 weeks. Really high levels. People stayed on it, people liked it. There was quality of life surveys, people preferred long-acting.

We do need access to these regimens in low and middle-income countries, but I - I thought it was great. And, you know, the other thing I want to just say about resistance is I personally don't do HIV DNA genotyping at Ward 86 and nor do I allow anyone to do it for a variety of reasons, we're a low income clinic, but - but I certainly don't think it's relevant for low and middle-income countries. We're barely trying to get our HIV RNA when needed with failures.

Dr Eron: Yeah, totally agree. I totally agree. And I do think there's a lot of excitement about long-acting. The study you presented, you know, that 1 person that rebounded who got lenacapavir and the 2 really very interesting. Certainly one of the advantages, you know, people like to be on the people who join the study. So that's selected. You know, we have several - actually, they're all women at our site for some reason, who are on this long-acting 6 monthly study, and they are thrilled to not take their medicines, and they don't mind the infusions.

But there was a lot of discussion about whether that's really practical, should we really do it? What about the risk of resistance? So I think that's still an open question.

Dr Gandhi: Yeah, I mean the combination of IV and IM, or IV and SubQ, I'm not sure is going to be as practical going forward with these austerity kind of times. But I do like the idea of IM, and we're going to get into this later when we talk about HIV prevention over subcutaneous formulations, and I think that's part of the reason N6LS, SubQ got dropped, and we're going to talk later about LEN IM, because I'm kind of excited about that.

Dr Eron: Yep. Yeah, terrific. So, and then I mentioned the RIO study. I think what we now need to know is what happened, and we don't know. It looked good, and we just have to find out. So I think we should keep going. And Monica, I believe it's you.

[00:45:42]

HIV Prevention

Dr Gandhi: Yes. So I'm going to just start us off with 2 studies about HIV prevention, and then we'll go into more studies on prevention.

[00:45:50]

PILLAR: LA CAB PrEP Integration in High HIV Epidemic Priority Areas in the US

So one is the PILLAR study. Now, if we think about long-acting cabotegravir-based PrEP, this is really every 2 months, given at a 600-mg dose, and has been approved in this country since 2021 for pre-exposure prophylaxis. But we haven't had the rollout, I think that we would've hoped.

And now we’re - this was a specific study that looked at HIV - high HIV epidemic priority areas in the US. So we do need PrEP. No administration should ever cut PrEP at the CDC, so rumors are flying but should not happen. Of course, PrEP is really important. And this was specifically an HIV epidemic priority areas, which was these priority areas were defined in the first Trump administration as End the HIV epidemic hike - high priority counties.

So it was a phase IV trial looking at integration of long-acting cabotegravir in 17 clinics. And 22 participants had not received oral PrEP 6 months prior. That already tells you something, high risk individuals, high risk counties, and somehow, you know, hadn't gotten an oral PrEP. And it was a population, 201 people, 6% transgender men, but 94% men who obsessed with men, diverse, 26% Black.

And at month 12, by the time you got there, 72% of people had completed all the injections. Now that's only 6 injections a year. That's the nice thing about CAB. And there was zero acquisitions in this 12-month study. So I think that's very exciting, because people were still getting STIs. So that means there was still ongoing sexual activity that could be perceived as high-risk to get STIs, but no HIV acquisitions, very powerful, real-world study in high priority areas of the power of cabotegravir.

[00:47:42]

HPTN 083: HIV Treatment After HIV Acquisition While Receiving LA CAB PrEP

And then one other study about cabotegravir specifically. So remember the HPTN 083 study was the original study that looked at CAB as prevention in men who have sex with men and transgender women. And lots have been—we've been trying out—the group has really been trying to look at people who broke through CAB, seroconverted, and what are those risk factors for acquiring HIV when you're receiving long-acting CAB.

So this was a case series of participants who had received at least 1 dose of long-acting CAB and had those breakthroughs. And, you know, seroconverted essentially. And - and specifically, the investigators or the local clinicians would choose what the participant would be put on for their ART once they seroconverted on CAB.

And importantly, the people who seroconverted somehow those who got INSTI RAMs, and I just want to focus on that particular population, 9 people seroconverted with a resistance mutation, which you'd worry about because of course INSTIs are first-line therapy in this country. Of those 9, 8 out of 9 had received long-acting CAB for less than 6 months. So is it something that they had brewing infection? What do we know about this less than 6 month, you know, proclivity to develop INSTI RAMs? And we don't know.

But I will say that interestingly, as you would expect of those participants, only one was put on an INSTI-based ART because they had INSTI RAMs, and they actually did okay. But the others were put on non - alternatives to INSTI ART and that would really be PI-based therapy.

So think about that 6-month mark, what does that mean? More frequent follow-up during the 6 months doing HIV RNA testing instead of rapid testing in the first 6 months. Think about that as a critical time, I would say.

[00:49:47

Potential Future HIV Prevention Therapies

And I'll move to - for Joe to present the next slides.

[00:49:51]

PURPOSE 1: LEN in Cisgender Adolescent Girls Aged 16-17 Yr and Women Aged 18-25 Yr

Dr Eron: Yep. So we're talking about potential future therapies. We're going to talk really briefly, I think, about lenacapavir in - in young - well, adolescent girls, 16 to 17 in PURPOSE 2. LEN is a future therapy, though we do know that PDUFA date is in June in terms of when the FDA is supposed to provide us with information on approval.

I think everybody knows PURPOSE 1 was done in cisgender women and girls in Africa, and it was a comparison of lenacapavir with FTC/TAF and FTC/TDF. But what they did, which this team should be congratulated, they did enroll girls 16 to 17, and while the numbers were small, you can see them on this slide, 56 girls received lenacapavir, 45 received FTC/TAF, and 23 received FTC/TDF. But I think it's really important that they did this.

[00:50:58]

PURPOSE 1: Efficacy, Safety and PK Outcomes

And of course people know the results of - of PURPOSE 1. There were no infections in the lenacapavir arm while there were multiple infections in both FTC/TAF and FTC/TDF arms. But in the adolescents, again, numbers were small, they didn't see any infections in any of the 3 different arms.

Now, the person years are very short, 42, 33, and 18-person years. So I don't know that we have a lot of information. But we do know that none of the girls discontinued. So no discontinuations among the adolescents due to adverse events, which is great, because there are injection site reactions, as everybody knows.

And then importantly, that LEN plasma trough concentrations were very similar between these adolescent girls and these young adult women. And you can see the median trough concentrate - concentrations at the bottom there. So again, no LEN discontinuations due to AEs and - and - and very similar trough concentration. So again, congratulating the study team for - for doing this work.

[00:52:19]

Posttest 4

So here's our posttest question number four. In PURPOSE 1, the study evaluated LEN as pre-exposure prophylaxis for cisgender women, and they also included adolescents aged 16 to 17, which we just talked about. So what happened?

1. There were some LEN discontinuations due to AEs in these young girls, but similar trough concentrations;
2. There were no LEN discontinuations due to AEs and similar cross - trough concentrations in the girls as compared to the adults; choice three
3. Some LEN discontinuations due to AEs and lower trough concentrations; and then finally,
4. No discontinuations due to AEs but lower trough concentrations.

So - so go ahead and vote. Okay, let's see those results. Monica does better than I do. This makes me sad. The - most of the people got the correct answer. There were no LEN discontinuations in the girls due to AEs, and they had similar trough concentrations as adults. So - so in this case, choice B was the correct answer.

[00:53:48]

Pipeline: Long-Acting PrEP

So we're moving on one more time to Monica. Oh, I'm sorry. We're staying with Joe. There were 2 other presentations. One is long-acting lenacapavir. So this was once yearly.

Now, these were big doses, these were intramuscular doses, 5000 mg, so 2 5-mL doses of 500 mg/mL. But what they showed was that persistent high LEN concentrations over an entire year, so actually greater than you see with subcutaneous LEN in PURPOSE 1 and PURPOSE 2. And so they probably will be able to use a lower dose, somewhat lower dose when they go forward.

And while this was a small PK study, the IM LEN was safe and well tolerated, and there were ISRs but they improved with ice pretreatment, and - and there were no nodules observed. Obviously intramuscular, it might be hard to observe those nodules. And then we saw that—I think everyone knows that islatravir was going to be a once monthly PrEP. It was going to be studied as once monthly PrEP, but that was stopped because of the lymphocytes that - impact that Monica talked about.

But there is a new NRTTI, so the same class as islatravir. This is MK-8527, and this looks like it will be able to be given at once monthly and keep levels above the threshold. This is from a population study in MCACS, and I know that the phase III study of this medication for once-monthly PrEP are being planned.

So that's my completion. And now I think I go over to Monica.

Dr Gandhi: Yes. Keep on doing that thing where you press the video, and it's not working. So I may just proceed and then I'll get to that video as soon as I can to get me on. Oh, there we go. Okay. So tecovirimat.

[00:56:02]

STOMP: Tecovirimat in Persons With Confirmed or Presumed Mpox

So this is the final study we're going to present, and then we're going to hear from you for your questions. So we do randomized trials for a reason, and that's actually why the ACTG was, of which Joe was the chair, this was the right thing to do, right? We do randomized trials because - just because we think something works in vitro or tecovirimat as a medication for smallpox that had been proved on not clinical data but virological plausibility.

We need to see if tecovirimat as a medication works for mpox. And so this was a randomized-controlled trial called the A5418 or STOMP study. And it was a randomized double-blind, placebo-controlled study and randomized people to either getting placebo or tecovirimat if they presented with mpox in this country.

Now, please remember the PALM 007 study had—we already had the results of those by the time that we saw this presentation at CROI last week. The PALM 007 study was a study of tecovirimat for mpox, mainly Clade I in the Democratic Republic of Congo, which showed no resolution, no improvement of symptoms, clinical symptoms when given as early as possible, tecovirimat in Clade I mpox in DRC.

So this was a study design that asked the same question, could you get more hasten time to clinical resolution as the primary endpoint, or was there at least better pain scores or even the viral detection of the mpox virus, or patient-reported outcome? Those were the secondary endpoints if you randomized to tecovirimat vs placebo in those who presented with mpox during our global outbreak, which is ongoing.

So the tecovirimat, there were 232 individuals; placebo, there was 112. And importantly, there wasn't big differences, at least in how they first presented. Meaning the - the - the groups in randomized studies to be expected had similar rates of, for example, severe pain, median number of lesions, proctitis, 38% in the tecovirimat group though had HIV and a fewer percentage in the placebo group. And importantly, not a difference in prior smallpox vaccination, which should provide some protection.

[00:58:25]

STOMP: Clinical Resolution and Other Outcomes

And what the results showed, and this study was actually stopped early because of futility analysis, that this study did not show improvement, clinical resolution with tecovirimat vs placebo in that primary outcome or any of the secondary outcomes.

And importantly, those curves look exactly the same. And the hazard ratio adjusted was 0.98 in terms of symptom duration, number of lesions. So it didn't improve anything.

Now, tecovirimat—again, now we have 2 big studies, Clade I, this would mostly be Clade II showing that tecovirimat is not at least useful here, maybe a little bit higher viral clearance. And it is - there's one more study ongoing of tecovirimat, which would be in pregnant women, which is to - to ask the question, if you maybe have higher rates of viral clearance, could you reduce transmission to the fetus?

But in general, this and the PALM 007 study has left us without a clinically viable treatment for mpox. And that's why we had to do studies and we have to accept the results of our studies.

So that's where we are with tecovirimat for Mpox. As we go into, you know, sort of ongoing transmission of Mpox, we really need to get everyone vaccinated who is at risk for Mpox.

[00:59:52]

Key Takeaways: HIV and STI Prevention

So the key takeaways of this second section of the presentation is that CAB works, totally works in high epidemic priority areas, and people stayed on it, and they liked it, and there was zero HIV seroconversions. If you get an INSTI RAM on each - on an INSTI, people tend to use after that PI-based therapy, but we—that makes sense.

And then the PURPOSE 1 also looks - continues to look good, but also specifically among those younger girls, adolescent girls, and then STOMP, tecovirimat is not for Mpox, not for treatment.

So anything that you want to say about any of these studies, Joe? I mean, one thing I do want to say as I kind of alluded to this to begin with, but when you presented those new formulations, those 2 new formulations of lenacapavir, there were exactly zero nodules that developed of course with intramuscular lenacapavir because nodules happen with a subcutaneous formulation. In fact, there's quite a bit of concern that that subcutaneous formulation really almost has such a high rate of nodule formulation. Totally makes sense. I think it's the deeper formulation under the skin and then it alludes over time. But whether that's acceptable, completely acceptable to people, and I do like the IM idea since CAB and ril are IM.

Dr Eron: Yep. No, I don't really have anything to add. I do think that, you know, there was a question about whether tecovirimat would work in people that were more immunocompromised. I don't see any evidence for that.

I think one of the biggest challenge with mpox is that people don't show up when they first get symptoms. Because, oh, it could be herpes, it could be nothing, you know, and they - they - they show up at, you know, 5 days, 7 days, 8 days when the pain starts to get. And I think it's pretty clear that tecovirimat alone doesn't work in that situation, whether you're in, you know, East Africa or whether you're in East LA, it just doesn't matter. It doesn't work.

Dr Gandhi: Exactly. And we have to accept that. I mean, that's why it was good to do this study. I'm positive you got criticism like, oh, let's just—CDC's has given it compassionate use.

Dr Eron: I can tell you that as being part of the team, there was a lot of criticism about how could you - and - and we did - actually people that had facial lesions near their eye, people that had persistent terrible pain, they were allowed to go to open label, and there was no difference between the 2 arms.

And there was actually a - there was a separate arm for people that had these - these kind of severe symptoms at the beginning, and they got open label also. But there was no difference between progression to that more severe - the severe lesions between the 2 arms. So I think it just doesn't work in the setting that we can manage to use it right now.

So we have a bunch of questions. They're kind of exciting. The first one is about this proviral - oh, we have to ask the question.

Dr Gandhi: I think we should discuss this, because there's 2 questions on this.

Dr Eron: Okay. Yeah, I guess we have to ask a posttest question first.

Dr Gandhi: Oh, okay. Yes.

[01:03:16]

Posttest 1

Dr Eron: So after participating in this activity - this is a question for all our listeners or watchers - I am familiar with data from the CROI conference and I plan to translate these data into current or future management strategies. So now we're asking you the question after we've presented to you. So…

1. Strongly disagree;
2. Disagree;
3. Neither agree or disagree;
4. Agree; or
5. Strongly agree.

So we're going to count to 10 while you vote, and then we'll get to the questions. Okay. Now, let's see. Well, people said agree and strongly agree, so that's pretty good. 83% said agree or strongly agree. So that - that's good. Thanks to Monica.

[01:04:10]

Questions and Answers

Dr Gandhi: So before we get to that HIV RNA, I just want to answer one question really quick. The intramuscular formulation on lenacapavir that you asked was given in the buttocks. So the same place as CAB and LEN are given in the gluteal muscle. So that's where they were given.

So yeah, maybe we can talk a little bit about your practice with HIV DNA testing even prior to switching to CAB LEN if - sorry, CAB rilpivirine if you are - if the patient is virologically suppressed.

Dr Eron: Yeah, I'll just say, so my practice, a couple things. One is I try to take as good an antiretroviral history as possible, and you can't always do that, but I try to take as good. And then, you know, I think you need to weigh all the different factors, right? Because you know, unfortunately that some people who do everything right might have virologic rebound. So - so you really - and that's really hard to communicate, because we all, like, minimize risk and - and hope for the best, like that's why we all play a lottery, and - because we all think we might win, right?

And - so we don't think bad things are going to happen to us. It'd be hard to live that way. But - but I don't do proviral DNA testing. Is there a situation where I would consider it? I suppose if someone felt very, very strongly about it, and - and I knew that they had passed previous NNRTI failure, I might consider it in that setting, but I haven't done it. So Monica, and I know you don't - you don't do it. Have you ever done it in this setting?

Dr Gandhi: But I'll tell you why. I mean we have - we have some kind of reasoning behind it. So one is that we use it in a lot of people with viremia as we've presented before. So of course then we - we can get the HIV RNA genotyping. If we use it in someone with virologic suppression, we do - makes the fellows sometimes do this, but very deep dive on their historical genotypes and we use that information.

Third is that we've seen the Owen Clinic at UCSD does do standardly, HIV DNA when they're virologically suppressed and switch over. But we haven't seen a change in practice as a result of the data, at least they've presented.

And then fourth, we had a fellow do a really deep dive on concordance between HIV DNA genotyping and HIV RNA genotyping. And they're not very concordant, partially because what's in the HIV DNA may not be transcript - transcriptionally active. These may be latent proviruses that are actually not replicating. There's lots of reasons to think that, that what's in the DNA may not reflect what's in the RNA.

And all those 4 reasons, put together along with the fact that we're a low-income clinic, have made us not standardly do proviral DNA testing before switching to CAB and LEN. But - one thing I do want to say, because just this also can be knocked off quickly in terms of the question is with lenacapavir in - in - Shivan[?] asked 2 times 5 mL sounds like a large volume, I agree. But they did say - I mean, number one, it's easier to do that large volume in the IM space by SubQ 3 mL. They're each 1.5 mL. When you give 927 mg of lenacapavir SC, I can just tell you from experience even 1.5 mL in a SC space is a lot.

So as Joe said, those were high levels. They got, like, super therapeutic lenacapavir concentrations with the IM dose once yearly. So I think they're going to bring down that dose, and I don't think they're going to need 5 mL. I think they're going to need less.

And then - and then, do you want to comment on, there's a question here, Joe, about - about in RIO, were those L...

Dr Eron: Yeah, they were LS antibody.

Dr Gandhi: Yeah. Right version. Okay.

Dr Eron: Yeah, and - and - and - and, you know, they don't have, you know, the - the end of their follow up. But most people after, you know, 120 weeks actually did eventually rebound, so - so - but they were the - the LS antibodies.

And then it's interesting, I saw the question about the CD4. They didn't actually show a CD4 curve. I - I went back to the presentation while Monica was talking, and they - what they did say is no one restarted due to their CD4 criteria. So no one had that drop to CD4, less than 350 confirmed that required a restart, but - but they actually didn't show those data. So I don't - I don't know.

I mean, Sarah Fidler may have said those words, but at least in the slides that I now have, they - they - they didn't actually show that. So - so I'm assuming they remain stable, but I don't know.

And then the other quick question is about where can we read about long-acting LEN? The publication actually came out the same day as the presentation

Dr Gandhi: Lancet HIV. Yeah.

Dr Eron: Yeah. Which I can't remember is Lancet - it's Lancet HIV. So you can actually read the whole study.

Dr Gandhi: It came out, like, the day, the minute that they - they presented. Yeah.

Dr Eron: Yeah. The - the minute they presented it. So that's good.

Dr Gandhi: I love your opinion on Jules's[?] question. I have to say, where do I see doravirine/islatravir? I'm kind of interested in it. I'm interested in it for 2 reasons. I am interested in it possibly because of the weight. And again, we don't know yet. I just know that I have a lot of women in my practice and I've truly seen the weight gain with BIC and TAF. So I'm interested in seeing the naive studies and what's going to happen with weight.

And then, you know, you sparing tenofovir, renal, metabolic, bone, I mean there's just no tenofovir in there. And that's kind of a good thing as we get older. So I think it’s - it could have a role in older people, but I want to wait for the naive data.

Dr Eron: Yeah, I think the other role, Jules, and everyone actually, not just Jules, is that I think there is a pretty convincing signal that the second generation and then our integrase do have some impact on glucose control. I - I think there - the - the data are, you know, imperfect and they're observational, but they - I think there is an association between bictegravir and dolutegravir on - on - on risk of diabetes. That is - doesn't seem to be totally dependent on the weight change.

I am very - like, I don't think TAF has any impact on weight personally, but that's my own opinion. And I do think that we don't understand why people gain a lot of weight, but we do know when doravirine/islatravir was given at the higher dose of islatravir, at least over the short term, there was the same weight gain that was seen with B/F/TAF and that you can see on clinicaltrials.gov.

But that was short term and it didn't break it down by women, people who are overweight. So there is something going on in some people. So I think those are the reasons that - that I might consider doravirine/islatravir - I think we have to make sure, you know, the very long-term follow-up, make sure that CD4 and lymphocyte counts are okay, but that's what I think.

Dr Gandhi: And then I would like to - to comment on the DoxyPEP, because we didn't have time to put it in these studies, but Cassandra is asking. There was 2 good ones, I thought, the lots are little - lots of good posters too, but 2 orals is, one was on a study called PRIDOX from Spain, which was real world use of doxy-PEP. So super real world, no study at all and looked great. I mean, really decreased chlamydia and - and syphilis rates as you would expect in that mostly MSM study.

And then there was a kind of follow up of the San Francisco ecologic data presented by Hyman Scott and continues to like our STD rates in our city are really much lower than they were and what we would've expected without DoxyPEP, at least ecologically.

And then I'd love to end with this just final question, because I know we're running out of time, because we're actually going to propose this for ACTG symposium, but the hepatitis B along with hepatitis group, but this - we have to keep in mind this hepatitis B - having a hepatitis B core antibody, if you're switching the long-acting, because like we said before, CAB ril isn't going to cover hep B; LEN CAB isn't going to cover hep B; islatravir/doravirine is not going to cover hep B, and islatravir/lenacapavir once weekly is not going to cover hep B.

And so I think that we need to do a deep dive on all the data, because there were 3 posters at CROI 2025, one from Spain that I thought was really good, that looked at this question. If you had hepatitis B core antibody and you switched over to CAB ril, did you get, for example, HIV DNA - sorry, hepatitis B DNA replication, did you lose your surface antibody?

And - and - and at least in the Spain study, no, there was - I mean they only went out to 48 weeks. They had to go long. No, they went out in 96 weeks, and didn't see re-quiescence of hep B. But I think we had to put all that data together. I would say this is something that our large CAB ril program we look at really closely. We vaccinate, you know, as we're contemplating CAB ril. We think if they have core antibody, we follow them more closely because we know we're not covering for hepatitis B, we don't prophylactically start.

Dr Eron: But Monica, if someone has surface antibody, I definitely give those people CAB. I mean, so that they've had -

Dr Gandhi: Yes. Yeah.

Dr Eron: If they have surface antibody, maybe I'd be a little bit more careful about it. But I think - and - because, you know, no - no hepatologist treats someone that's core positive surface antibody positive, who doesn't have HIV. So I mean, the concern might be someone with a very low CD4 cell count, obviously if you're going to get chemotherapy or you're going to get a – a rituximab or - or - you know, there is some risk of reactivating if you're surface antibody positive. But that group, I wouldn't worry about. The core antibody positive who are surface antibody negative, those are the people I think to worry about. And that's my opinion.

Dr Gandhi: I think that this is one final question I want to answer. By the way, we all need to advocate for everything that's happening. And I - I would say that's very true of HIV prevention. And you're going to see all the rumors are all hitting the news right now. We've got to advocate for HIV prevention division at the CDC.

The thing that Jeffrey Kirshner[?] asks is really important. I did ask the company that makes lenacapavir and apparently it's just humming along with lenacapavir at the FDA. That seems to be one of the 3 federal agencies under DHHS. It seems to be working and seems to be going well. And yes, they are expecting a june-teenth, a June 19th approval date for lenacapavir. Not seeing the same for CDC -

Dr Eron: I don't think what happens in the world will - will affect that approval. It might affect our ability to roll it out.

Dr Gandhi: Yes. Fair enough.

Dr Eron: Yeah. But yeah, I totally agree.

Dr Gandhi: So advocate everyone, do is - do all your work to advocate with our Congress people.

Dr Eron: Yeah, absolutely.

Jacqueline Meredith: Well, thank you both for such a great presentation and really informative question and answer. And thanks to our learners for joining in and participating. Please be sure to fill out the evaluation to receive credit. And also, I know there has been questions asked about access to the slides, and they will be available in a few weeks for you to download, along with additional studies from CROI 2025.

Dr Eron: Great. Thank you.

Jacqueline Meredith: Well, thank you. Have a great day.

Dr Eron: Super.

[END OF TRANSCRIPT]