This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

HIV Update Podcast: Independent Conference Coverage of CROI 2026

Emerging HIV Treatments

Dr. Monica Gandhi (San Francisco General Hospital): Great. We're going to start talking about the new HIV treatments that got presented at the meeting, which were quite a bit this year and pretty exciting.

ARTISTRY-1 Switch to BIC/LEN From Complex ART

So, let's start with the ARTISTRY-1 study. So, bictegravir, of course, is an INSTI. Lenacapavir is a capsid inhibitor. And there's been a lot of interest in putting an INSTI in a capsid inhibitor together as a pretty high barrier to resistance regimen. And what ARTISTRY-1 was specifically is people who were on complex ART and got switched over to BIC/LEN, and then what happened at 48 weeks?

Now, importantly, if you look at this Phase 2, 3 trial, this was a population that was quite a bit older. So the median age was 60 years old, 77% were over 55, and also the mean duration of being on antiretroviral therapy prior to this was 28 years. So, really complex regimens, a lot of people were actually on two pills, even three pills, four pills. You can see that there was a BID or twice a day dosing, 41% of participants were on twice-a-day dosing. So it was complex ART.

But importantly, they were all suppressed. Both ARTISTRY-1 and 2, when we talk about them, are all suppressed individuals. And then they got switched over to BIC/LEN. One other point is that there was some preceding resistance, and an RTI resistance, these are again complex ART, been on ART for a long time, so lots of at least historical resistance of NNRTI resistance, NRTI resistance, and just a little bit of INSTI resistance.

ARTISTRY-1 Switch to BIC/LEN From Complex ART: HIV Outcome at 48 Wk

So, what does the results show us if you either stayed on your complex regimen or got switched to that single pill of BIC/LEN? Well, there was actually non-inferiority of bictegravir and lenacapavir compared to complex ART. And there were a few people, three participants who had low-level viremia, but they didn't need to switch on BIC/LEN, they suppressed on BIC/LEN. And so essentially it was non-inferior regimen. And then, importantly, there were no CD4 cell count changes.

Now the question would be, was this better to be on BIC/LEN? And there were a couple of outcomes that looked at - there was some improvement.

ARTISTRY-1 Switch to BIC/LEN From Complex ART: Fasting Lipids and Patient-Reported Outcomes

What I mean by that is that there was improvement in lipids when in the group that got switched to BIC/LEN versus staying on their complex ART. Now remember, complex ART is most likely, or there was a lot of boosted PIs, and so probably it was the boosted PIs, more increase in triglycerides, total cholesterol, LDL, and switching over to BIC/LEN improved those three cholesterol parameters.

And then also, if you asked participants in patient-reported outcomes if you liked the bictegravir lenacapavir, a lot of people of course, and this makes sense, would like that single pill combination instead of their complex regimens that were sometimes twice a day and lots of PIs, and it was just harder to take. So, of course, the patient satisfaction was improved with one pill once a day.

So what did ARTISTRY-1 show us? There was really good question and answer. Like the thing about CROI and the thing about any meeting is listening to the question answer. And you know, the question that was posed was why not switch to BIC/TAF/FTC? And wouldn't that have been just as okay as BIC/LEN? And I think it was important to say that there was a certain amount of NNRTI - NRTI resistance, as I said, 66% NRTI resistance, even though you can use BIC/TAF/FTC with an M184V, I wouldn't use it with lots of NRTI resistance because that's just going to set you up for a BIC resistance. And then there was a little bit of INSTI resistance, about 4%. And I wouldn't want to use BIC/TAF/FTC with that either. And lenacapavir has a high genetic barrier to resistance.

[00:09:28]

ARTISTRY-2: Switch to BIC/LEN From BIC/FTC/TAF

So, this was the main study that really looked at BIC/LEN compared to complex ART.

Now, the second big study that was presented at CROI with bictegravir and lenacapavir was the ARTISTRY-2 study. And in this case, it's the same drug company, so it's actually switching from BIC/TAF/FTC over to that single pill combination of BIC/LEN.

Now these are going to be younger patients and not as much long experience being on BIC/TAF/FTC, because that only came out in 2018. And there was though a certain amount of comorbidities in the population, as you can see here, dyslipidemia, hypertension. And then the question was, was there equal efficacy, non-inferior, result when you switched over to BIC/LEN?

[00:10:26]

ARTISTRY-2: Switch to BIC/LEN From BIC/FTC/TAF: Outcomes at 48 Wk

And so the ARTISTRY-2 data showed us that the outcomes at 48 weeks is that BIC and LEN looked pretty much equivalent, noninferior to staying on BIC/TAF/FTC, so is noninferior at 48 weeks.

Now, importantly, and I think this is important to say, no, there is no drug in the world that has an impenetrable barrier to resistance. So, there was one person in the BIC/LEN arm who had viremia and essentially developed an R263K. This person, importantly, had had dolutegravir and raltegravir experience in the past, but the fact that there was an isolated R263K, and the Mexico City data shows that R263K is probably the signature mutation of bictegravir. Even though it was phenotypically sensitive, I absolutely would not use Bictegravir with an R263K, especially one that emerged.

So, just like you're going to see in these islatravir doravirine trials later, there was one person in islatravir doravirine too, but there was emergence of one resistance mutation. So, nothing is impenetrable.

But in general, BIC/LEN looked very good compared to both complex ART and BIC/TAF/FTC. And the combination of the data from ARTISTRY-1 and ARTISTRY-2 is going to enable the drug company to file for bictegravir lenacapavir as a single-pill combination. It's going to be pretty small. The bictegravir dose is 75 mg. The lenacapavir dose it's 50 mg. It's going to be a pretty small pill. And essentially, this is going to be a drug that we can use one pill once a day, and we'll see if we switch people to that for complex ART.

First-line DOR/ISL vs BIC/FTC/TAF: Study Design

It's really a tenofovir sparing regimen, which, when we go into the next phase, is kind of the theme of the day of both these drugs, BIC/LEN doravirine islatravir, sparing of tenofovir. So I'll turn it over to Dr. Molina for the next part.

Dr. Jean-Michel Molina (Université Paris Cité): Thank you very much, Monica. And indeed, that was a great conference. We've seen a lot of new data. And this trial, doravirine islatravir versus BIC/TAF, was one of the naive study that attracted a lot of interest because that's the first time these two drug combination of doravirine islatravir was tested against the standard of care, the combination of bictegravir, FTC, and TAF.

And this was a double blind, randomized, placebo-controlled study. It was a non-inferiority study. What - it is interesting is to look at the inclusion criteria. So, people had to be antiretroviral naive viral load above 500 copies per mL, and no known resistance to doravirine or NRTIs, or no active HBV infection.

And that's - that's important to keep in mind because you are treating here naive patients. So, it was clear that people need have - to have resistance to the doravirine or NRTIs. And so, the participants were randomized 1:1 to the combination of doravirine islatravir, but with a lower dose of islatravir as compared to the one that was used in previous trials, which was associated with a decline in lymphocytes.

Here, we use the dose of 0.25 mg of islatravir instead of 0.75 mg in previous studies. With doravirine 100 mg in a single pill versus BIC/TAF at usual dose. And the primary endpoint was at week 48. The proportion of patients with a viral load below 50 copies per mL with a non-inferiority margin of 10%. We also looked at secondary endpoint in terms of viral load below 200 copies per mL, and also the changes in CD4 cell count and body weight to see whether these two drug regimen would be associated with a lower increase in body weight as compared to BIC FTAF.

First-line DOR/ISL vs BIC/FTCTAF: Baseline Characteristics

So, at baseline, the patients were pretty young. Remember that this is a naive study. And you could see that the enrolment was really worldwide with people in Latin America, North America, Africa, Europe, and Asia. Now there was quite a significant proportion of people from - who were Hispanic, you know, only 24%, 25% of women. The median CD4 was quite high, but still, 20%, 14% of the population had less than 200 CD4 T cells. And when you look at the median HIV RNA, it was in the range of 50,000 copies per mL. But you can see that nearly 35% of the population had viral load above 100,000 copies per mL, which is interesting to - to look at.

In terms of HIV subtypes, most participants had the HIV subtype B, and you know, when you look at people who had anti-HBs and HBc antibodies negative, that was nearly half of the participants.

First-line DOR/ISL vs BIC/FTCTAF: Virologic Response

Regarding the primary endpoint, which was the proportion of people with a plasma HIV RNA below 50 copies per mL, we are here at week 48, and you could see a pretty high proportion in both arms, 91.8% with doravirine islatravir and 90.6% with B/F/TAF.

So, the treatment difference is 1.2. And when you look at the lower bound of the confidence interval, you can see that it is greater than 10%. So, you can't clearly claim non-inferiority of doravirine islatravir versus the standard of care. Also, it's not going to be shown on this slide, but there was a similar increase in CD4 cell count in both study arms. What you could see here also is the few participants who had a viral load above 50 copies per mL, six with doravirine islatravir and nine with BIC FTAF.

And what is interesting here is to look at the resistance data. And for B/F/TAF, there was no resistance mutation that emerged, whether in those who had viral load of 50, only six of them in the doravirine islatravir arm, we'll see that two of them had a resistant mutation emerging. And this is going to be shown on the next slide.

First-line DOR/ISL vs BIC/FTC/TAF: Treatment-Emergent Resistance and Safety

So, we're going to look in detail at those two individuals. So, you can see that these individuals had pretty low CD4 cell count at baseline, 31 and 171. They also had a very high viral load at baseline, more than a million copies per mL. At baseline, the genotype was clearly susceptible, and you could see that at the time of discontinuation, the viral load was also quite high. And you can see the resistance mutation emerging, so in the first participant, M184I and Y188L. And in the second participant, the L74I, the V106A, M184V, and F227L. And so, these mutations are well-known mutations associated with doravirine resistance. And you could see when you look at the phenotypic susceptibility that there was a significant increase in doravirine susceptibility. So, the - these isolates were really resistant to the doravirine. And there was also an increase in islatravir phenotypic susceptibility by two to sixfold.

So, these are rare events, but they still occur. In terms of serious adverse events, we had two serious adverse events that were treatment-related in the doravirine islatravir arm. There was one DRESS syndrome and another participant who actually developed drug-induced liver injury.

And as I said, the increase in CD4 cell count were similar in both arms. What was a little bit disappointing was that the increase in body weight was similar in both treatment arms, so there was no benefit in terms of body weight with the dual combination of islatravir and the doravirine.

MK-8591A-052 Switch to DOR/ISL From BIC/FTC/TAF: Study Design

So, let's look now at other data with the same combination, but this time in people already on treatment. So, these are switch studies. This first one is also a randomized, placebo-controlled study comparing doravirine islatravir to B/F/TAF. So, participants enrolled in that study had a viral load below 50 copies per mL on B/F/TAF, with a total lymphocyte count above 650 just to make sure that, you know, we were safe in terms of potential decline in lymphocytes, which actually did not occur.

CD4 cell count above 50, no history of treatment failure, and no doravirine-resistant mutation, no active HBV infection. And so here, the endpoint looked again at the viral load. Resistance was only done in - when the virus was confirmed above 200 copies per mL. And we looked at the viral RNA above 50 copies per mL, because we are looking at the switch study, so the endpoint is how many participants had viral load that was above 50 copies per mL.

MK-8591A-052 Switch to DOR/ISL From BIC/FTC/TAF: Baseline Characteristics

So let's look at the results. And in terms of baseline characteristics of the participants here were 15 years older than in the naive study, so in the range of 48 to 47 years. Still around 20% of women. And you could see that the median time since HIV diagnosis was pretty long, 11 years - 10 to 11 years. And these participants were on BIC FTAF for a median of three years. The CD4 cell count at baseline was, as expected, quite high, nearly 700. And more than 90% of the participants at viral load above CD4 cell count above 350.

Switch to DOR/ISL From BIC/FTC/TAF: Wk 96 Virologic Outcomes (FDA Snapshot)

So, if we look now at the viral load response, so at week 96, what you need to look at is in the middle the participants who had a viral load above 50, and you could see that the randomization was 2:1. So, you had twice more participants in the doravirine islatravir arm as compared to the B/F/TAF. So, in terms of proportion of participants with a viral load above 50, it was very similar 1.5% versus 1.2%, five versus two individuals.

And you could see that the - the treatment difference and the confidence interval can show you that there was non-inferiority here in terms of the maintenance of the viral load below 50 copies per mL in those participants. As expected, the vast majority of participants in both arms maintained a viral load below 50 copies and also below 200 copies per mL, and there was no difference in terms of CD4 cell count or in total lymphocyte count. And this was reassuring. Those data, plus the data from the naive study, confirmed that using this lower dose of islatravir of 0.25 mg, there was no impact on CD4 or total lymphocyte count, and so these are quite reassuring data.

Switch to DOR/ISL From BIC/FTC/TAF: Safety

So, in terms of safety, there was in that trial, no clinical HBV reactivation. But still a few individuals had a low-level viremia regarding HBV without antigenemia or elevated transaminases. And there were also four cases of acute HBV infection, both with negative HBc antibody and HBs antibodies at baseline. So, these are acquired HBV infection because neither doravirine nor islatravir had any activity against HBV. And this is quite different from B/F/TAF.

As I said, no difference in body weight changes at week 96 and again here with a more follow-up, it's a bit disappointing to see no benefit in terms of the impact of body weight with these dual combination of doravirine and islatravir.

Once-Weekly ISL + LEN in People With Virologically Suppressed HIV: Study Design

So, the next study that we want to present is islatravir and lenacapavir. Okay. So let's remember what each of these drugs are. So, islatravir what we just talked about, was looked at as a daily combination with doravirine and the daily dose for islatravir, if you use it once a day with doravirine, is 0.25 mg a day, but you can also give islatravir once weekly. It lends itself to once-weekly dosing at a dose of 2 mL.

Now remember, islatravir was the drug that, when it was used at too high of doses, caused decreased white blood cell count, decreased CD4 cell count. So, the right dose seems to be, for once weekly dosing 2 mL a day, or for daily dosing, 0.25 mg a day. And in the once weekly formulation islatravir, the NRTTI is put with a capsid inhibitor, the only capsid inhibitor we have so far, which is lenacapavir. And the dose of lenacapavir that lends itself to once weekly dosing is 300 mg a day.

So, this particular study is a Phase 2 study, not Phase 3. Phase 2 study of looking at the combination of islatravir and lenacapavir once a week, small study 52 people, compared to BIC/TAF/FTC once a week. And these are in people who were already suppressed in this Phase 2 study.

A Phase of this Phase 2 study was looking at the 48-week time point and looking at those results. And then there was an extension phase where everyone in BIC/TAF/FTC could go over to islatravir - lenacapavir once a week. So, this is the 96-week results that was presented at CROI 2026 of that extension phase 96-week data. So, half of people are only going to be on islatravir lenacapavir for 48 weeks, half of them for 96 weeks. Now the endpoint is the FDA snapshot analysis of staying suppressed fundamentally.

So, what did the results show us?

Once-Weekly ISL + LEN: Virologic Outcomes

So, if we look at, again, kind of two groups, there's the people who were early switched to a islatravir lenacapavir. So, they got to be on islatravir lenacapavir for full 96 weeks. Their virologic suppression rate at 96 weeks was 88.5%. There was actually some data that yet hadn't gotten in window, but there were zero failures in 96 weeks. That's important to say that no one actually failed at 96 weeks, of all participants who had available data, and importantly, no resistance in any of these groups.

The second group was late switch group. So those are the ones that had to be on BIC/TAF/FTC for 48 weeks, but then they got to be on his islatravir lenacapavir after that for 48 weeks, and the virologic suppression rate there remained high at 97.8%.

And again, of all the available data, so - so anyone who wasn't in the 97.8% that 2.2, they just didn't have available data, any available data, no failures, no resistance of either islatravir and lenacapavir. So, looked good at Phase 2 data.

There are two studies. One is called ISLEND-1, one is called ISLEND-2, and these are two big Phase 3 studies of islatravir lenacapavir once weekly. And actually they are fully enrolled at this point. And the data is coming quite quickly, and they expect to present their results of islatravir lenacapavir from ISLEND-1 and ISLEND-2 at IAS in Rio this summer. And if that's true, then they will actually be able to, and if it's favorable, they'll be able to file for this once weekly pill by the end of the year.

Importantly, it is a combination pill, even though it's two different drug companies that makes them. They have put these pills together in a combination pill that's given once weekly. So, think of your patient populations as we go forward. Who's going to want once-weekly dosing? There are some people who take their GLP-1 agonist once a week, take their bisphosphonate once a week, who just can only take meds on - on Saturdays. You know, there's going to be a group that's going to want once-weekly dosing. Think about that group. Think about who you want on BIC/LEN. Switching over to from tenofovir sparing, think who want to be on is islatravir doravirine. We're going to have these three options actually, relatively soon, which is extremely exciting.

Key Takeaways: Treatment

And then, so just to sort of summarize those for ARTISTRY-1 and two. Again, looking at BIC/LEN, switching from a complex regimen looked good at 48 weeks. It's going to enable the drug company to file for BIC/LEN. Think about your patient populations.

First-line doravirine islatravir non-inferior to BIC/TAF/FTC at week 48 in a very diverse study with lots of diversity in the naive study. And the switch study also looked good at 96 weeks. And then islatravir lenacapavir from BIC/TAF/FTC Phase 2 96-week data looked good. We need the Phase 3 data that's going to be presented this summer.

HIV Prevention

Dr. Molina: Okay. Thank you, Dr. Gandhi. So, let's switch to HIV prevention. So, there were a number of studies presented on HIV prevention. Mostly updates of previously known studies.

Prevenir Final Results: Daily vs On-Demand TDF/FTC PrEP

And I will start with these French study, the PREVENIR study, which final results were presented. So, that's a cohort study that was conducted in France between 2017 and 2025. And this cohort enrolled HIV negative adults at high risk of HIV infection. With an EGFR above 50. People could use either daily or on-demand oral PrEP with TDF, FTC. Only MSM could use on-demand oral PrEP in this study. But people could choose between the two options and could switch between options during the course of the study.

So, there were two objectives in that cohort study. The first was to demonstrate, by implementing this cohort study in more than 25 sites in the Paris region, that you would have a decrease in new HIV diagnoses in men who have sex with men and transgender women in the Paris region by at least 15% between the beginning of the study and the end of the study. Also, we looked during that study at the type of PrEP regimen that was used by the participants, the retention in the study, the HIV incidence and STIs, as well as safety, tolerability, and sexual behavior.

Prevenir Final Results

Eventually, the participants were categorized in three groups, although these nearly four years of follow up in median per participants. So, there was a group of daily user on the left-hand side of this graph, who used daily PrEP for more than 75% of the follow-up, and this represented 38.4% of the population. And during the study period, their median daily use was 100%. So these are people mostly using daily PrEP. And in that group, the incidence of study discontinuation was 15%.

In the on-demand group in the middle, those who used on-demand PrEP for more than 75% of the follow up, represented also 38% of the whole population. So, they used on median 100% of on demand PrEP, and the rate of discontinuation was 17.4%.

And then there was the switch group. Those representing 23.3% of the population. The median daily use of PrEP was 50%, so there were 50% of the time using daily PrEP, 50% of the time using on-demand PrEP, on average. And they had the lowest incidence, actually, of study discontinuation of 12.8%.

Interestingly, when we look at the overall HIV incidence during the study period, it was very low, less than one per 1,000 person-years of follow-up. So, these type of incidents are those also reported with other long-acting injectable PrEP agent, whether it's lenacapavir or cabotegravir. And this incidence was similar across the different PrEP regimens that were used during the study period.

Overall, the safety was pretty good, as we know with oral TDF, FTC, except that we've seen a higher rate of gastrointestinal adverse events in those using on-demand PrEP versus those using daily PrEP.

Prevenir Final Results: Overall HIV Diagnoses From Public Health Records During Study Period

We also wanted to look at the data in the Paris region. And these are data from Public Health France. So, not coming directly from the study itself. And when you look at those data comparing two periods, so 2015, 2016 in red to 2023, 2024 in blue, you could see that overall, in all men who have sex with men and transgender women, there was only a 2% reduction in new HIV diagnoses, which was not significant.

So, this was quite disappointing. However, when you look at MSM born in France, you could see that there was a drop by 33% of the number of new diagnoses between these two periods. And as a matter of fact, most participants in the PREVENIR study were also born in France.

That means that in these PrEP studies in France, we were able to enroll mostly MSM born in France and not really MSM born abroad. And if you see in the graph, the incidence of HIV diagnoses among MSM born abroad, you could see that between the two periods, there was a 73% increase in new HIV diagnoses. And this increase was also seen among transgender women. And so, that explained why, overall, you didn't see any significant decline in new HIV diagnoses, because this decline was mostly seen in those born in France, those who actually had access and used oral PrEP.

PURPOSE 1 and PURPOSE 2: Study Designs

So, interestingly, also at the conference, we had an update on PURPOSE 1 and PURPOSE 2 studies, these large Phase 3 randomized double blind study, assessing lenacapavir - long acting lenacapavir given every six months. So, in PURPOSE 1 there was among cisgender women young cisgender women aged between 16 and 25 years who had unknown HIV status and no prior HIV testing or PrEP use in the last three months.

And in PURPOSE 2, the study was conducted among cisgender men and transgender women and transgender men and gender non-binary people, again with unknown HIV status, and who had not been on PrEP recently in the last three months.

And so you can see that the sample size was quite high. In PURPOSE 2, the participants were randomized 2:1 in either lenacapavir arm, the FTAF arm. So, it was daily FTAF or daily TDF, FTC. And in the PURPOSE 2 study, the randomization was lenacapavir versus oral TDF, FTC. And in prior reports and in the application, we have had the results of the week 52. And here they completed the analysis with the final data when they had monitored all sites, all study visits. And you will see that the results are a little bit different.

PURPOSE 1: HIV Incidence and Acquisition and Safety

If you look at PURPOSE 1 in particular, so in the primary analysis you had, and that was quite striking, zero infection in those young women with subcutaneous lenacapavir given every six months. In - at the end of the double blind phase before the open-label lenacapavir phase, we had two women who acquired HIV infection. And that was interesting to - to see that. And we will describe these two women in more detail. In the oral FTAF or oral F TDF, there were also additional cases of HIV breakthrough infections.

So, in total, we had 77 HIV infection in. If you combine the two oral PrEP arms and two in the lenacapavir arm. And so, it was interesting to see that among these two in the lenacapavir arm, one woman actually discontinued LEN before being diagnosed with HIV infection, but the other woman was actually diagnosed with HIV infection, but they she actually did not discontinue lenacapavir. And she had a pretty low viral RNA of 78 copies per mL.

PURPOSE 2: HIV Incidence and Acquisition and Safety

On the next slide, we will look at the data from PURPOSE 2, so in MSM or transgender men or women. And here again, you could see that during the primary analysis, we had two individuals who acquired HIV infection in the lenacapavir arm, and we had one additional individual at the end of the double blind phase were acquired actually also HIV infection.

Similarly, in the TDF, FTC arm, we had nine, and now we had 12. So, a couple of more HIV infection also in the TDF, FTC arm. And so, if we look at the individuals who acquired HIV infection while on lenacapavir, which was not included in the primary analysis, this was an individual who was diagnosed via standard testing at week 52 with a pretty high viral load, more than 2 million copies per mL.

And again, these participants received all lenacapavir injection on time with PK concentration, which were actually within the range of efficacy. And so, we at this point, don't quite understand how this individual could actually become infected. So, that also is a reminder that not any PrEP regimen can be 100% effective, and these rare infections can occur.

PURPOSE 1 and PURPOSE 2: HIV Resistance

On the next slide, we're going to look at the resistance which emerge either in PURPOSE 1 and PURPOSE 2. And what is important is that we had infection that also were diagnosed at baseline before lenacapavir was - was started. What you have here is the infection that occurred while participants were on lenacapavir.

So, we had, if you combine PURPOSE 1 and 2, five infections. And in these five infection resistance was emerging in four of them. So, this is important to keep in mind. This was the signature mutation for lenacapavir, which is, as you know, a monotherapy for PrEP. If you look now at the breakthrough infections that were diagnosed in the combined oral PrEP arms with FTAF of FTDF, among the 89 infections that were diagnosed, resistance was identified in only five cases. So, that tells you that the barrier for resistance is higher clearly with FTAF it is with with lenacapavir. And so, that's going to be important to look at additional data on resistance in case of breakthrough infections.

Key Takeaways: Prevention

So, the key takeaway message from the prevention study was where the following, in the PREVENIR study with daily or on-demand oral PrEP with TDF, FTC, there was a reduction in HIV diagnoses among French-born men who have sex with men, because these were the men who actually in France have access to PrEP. But there was no significant change among all MSM and transgender women because of an increase in HIV diagnoses among foreign-born MSM and transgender women who actually are underrepresented in people using oral PrEP in France right now.

If you look at the final results of the PURPOSE 1 and 2 studies during the double blind phase using twice-yearly lenacapavir, we could say that these results confirm the high effectiveness of lenacapavir for HIV prevention. New HIV infections were rare, but resistance could emerge to lenacapavir in those who had breakthrough HIV infection. Lenacapavir was well tolerated and injection site reactions were similar to those in the primary analysis results.

And with that, I'll hand it over to Dr. Gandhi to the next phase.

Investigational HIV Prevention

Dr. Gandhi: Okay. We told you about three, probably coming in the next one or two years, combination so we can use for HIV treatment. And that doravirine daily, BIC/LEN daily islatravir lenacapavir once weekly. The next part are actually investigational agents, both treatment and prevention.

MK-8527 PrEP: Dose Selection for Phase III Trial

And these will be coming in longer period of time, but they're very interesting. So the first one is an NRTTI. So remember that's what islatravir is a nucleoside reverse transcriptase translocation inhibitor. Islatravir is the one that's coming out once daily, once weekly.

And islatravir, there was another presentation, not this one, about an implant of islatravir at CROI that showed that it didn't seem to work. The implant at the end of the dosing interval against M184V virus. That's going to become important for this next part.

And - and this next part is MK-8527 seven. So what is this? This is an NRTTI. It looks like it lends itself to once-monthly dosing. And it's only going to be studied for PrEP, for pre-exposure prophylaxis. And what this was, was the actual population modelling to look at both these sort of Phase 1 trials and then one Phase 2 trial just to figure out the dose.

MK-8527 PrEP: Predicted Efficacy and Dose Selection

We really want to just say, what was the eventual dose that's going to be studied once monthly for PrEP? And that's 11 mg. You can see on that column there with 11 mg, if you look at trough and if you look at one hour post initial dose, it gave you the right concentration. So, 11mg once monthly is going to be studied in two studies, which are called EXPrESSIVE-10 and 11, that are looking at once monthly MK-8527 for PrEP.

Importantly, this is not going to maybe cover M184V viruses at the end of the dosing interval. And I just think that's important to say because we have a little bit of worry about that, but hopefully we're not going to have it be in countries with a lot of circulating M184V.

MK-8527 PrEP: Predicted Efficacy of 11 mg in Special Populations

So, this is going to be studied. The one other thing to say about once monthly MK-8527 for PrEP, it looks like even though in pregnant women the levels do go down some in the second and third trimester, that's okay. It's not going to be dose adjusted. So, you don't have to get off study if you become pregnant in the study, you just have to be re-consented.

And then adolescents, there is something about weight. The lower the weight, the higher the dose, the higher the concentration of MK-8527 and its triphosphorylated compound intracellular goes up if you have lower weight. But again, it doesn't look like dose adjustments are going to be needed. So, this the EXPrESSIVE-10 and 11 studies, there will be allowance of adolescents at least 16 and 17 year olds. And again a once a month PrEP. Let's see what the Phase 3 trials show.

Early-Phase Investigational HIV Treatments

And then what about investigational treatments?

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

One is a monoclonal - one is a broadly neutralizing antibody. So, what is this study? This was called the EMBRACE study. And it looked at cabotegravir and then a broadly neutralizing antibody called N6LS, which has been called lotivibart. And the - the question of the EMBRACE study is, N6LS given either IV or subcu with cabotegravir once a month.

Now, the cabotegravir you can see is given once a month in treatment with the N6LS being given every four months. Now remember, there's going to be an ultra-long-acting formulation of cabotegravir that's given every four months. And there is going to be an upcoming study looking at N6LS every four months with CAB every four months. But this particular study EMBRACE, looked at CAB once a month. IM with IV, N6LS every four months compared to oral subcu art.

EMBRACE: Efficacy, CVF, and Safety Outcomes at Mo 12

So, what's going to formulate and what's going to go forth is the IV formulation of N6LS. You can see that's the orange bar here. And there was a 94% virologic suppression rate in those who were on N6LS IV every four months with CAB every one month, IM. The subcu didn't work that well. So that's out. And then of course, oral standard of care art was fine.

So, this is going to move forward into the part two of the study, looking at N6LS and the PK lends itself to every six months. And that will be in part two of the study. And then there's going to be another study of N6LS every four months, IV with CAB every four months, ultra long acting formulation.

LA Injectable INSTI: GS-3242

Okay. What's the next drug to - to be on the alert for? The next one is an INSTI. It's long acting. It's called GS-3242. And all we got from CROI were actually three studies. One was an oral abstract shown here, and then there was actually two posters, one’s called 490 and the other one's 521. I would encourage you to look at those posters of GS-3242 as well.

Now what this INSTI does is it looks like it can have pretty long efficacy at - at every four month dosing. And it's a single intramuscular dose. And you can see that it does drop the viral load in people with HIV. Strong antiviral activity, drops the viral load quickly, just like an INSTI does.

And it looks like the PK is going to lend itself to every six months. Why is that important? It's made by the same drug company that makes lenacapavir. Lenacapavir is every six months, so likely GS-3242 is going to be able to be extended every six months and be given with a ultimately tested with lenacapavir every six months.

Importantly, if you look at Poster 521, you can see that 3242 does have activity against some INSTI mutations, at least in vitro. For example, N155, Q92, E92Q and also Q148 and even R263.

LA Injectable INSTI: VH4524184

So, what about the other two in experimental agents that we're going to be on the lookout for? The next one is also a long acting INSTI. It's called VH184. And the presentation in the oral session that you can see down below just looked at its safety, PK, and antiviral, but both in an IM and a subcutaneous formulation. And this this is not being tested every four months. Right off the bat, it looks like it will enable every six-month dosing. So an INSTI every six months. Maybe you can put it with lenacapavir. Maybe you can put it with a new capsid inhibitor that the same drug companies producing, which is VH-499, which we'll talk about next.

So VH184, one thing to remember, and there's a poster on this is that it looks like it also works against INSTI mutations. We had seen this data before. So VH184 may work against dolutegravir-resistant mutations, which could be very intriguing to have kind of this, now, we're in the third generation of integrase inhibitors. So VH184, every six months, IM subcu it's going to be studied in a Phase IIb and EVADE study.

LA Injectable Capsid Inhibitor: VH4011499

And what's the final drug to remember? It's called VH-499. This is going to be the next capsid inhibitor that's developed. We only have lenacapavir so far. And this was a Phase 1 study that looked at, again, either subcu or IM of this new capsid inhibitor. It lends itself to every six-month administration. It's made by the same drug company that makes VH184. So, VH 184 and VH-499 will eventually be studied every six months for treatment, and it will move on to its Phase IIb study, studied, which is a synergy study in 2026.

Q&A

So, those are the four new drugs that we need to look out for, N6LS, VH184 VH-499 and GS-3242. And now we want to answer your questions. Thank you so much for your attention.

Dr. Straube-West: Thank you, Dr. Gandhi and Dr. Molina. We do have some questions in our queue for - from our audience. So, if you would like to discuss, how often do you see HIV after surgery or post-transfusion in adults and kids after skin grafting on both patient types post op?

Dr. Gandhi: You know, I would just say not seen this at all because of the, you know, so the - the blood supply is really, really safe at this point. So, I've never seen a seroconversion after these kind of procedures. What about you, Jean-Michel?

Dr. Molina: Well, that's the same now you know. This is now something we - we see anymore. You know, we've seen a lot of people becoming HIV infected after blood transfusion, but that was back to the 80s, 1980s. So since then, you know - the blood now is being tested in France, at least not only for antibodies against HIV, but also for RNA against HIV. So, we - every single blood donation is tested for antibody and HIV RNA.

And so, I think with that, it's a costly strategy, but it makes the blood transfusion very safe. But I can understand that it's not possible everywhere. And so in some countries that might happen that you may get HIV infection through blood transfusion if the blood bank is not secured or tested.

Dr. Gandhi: Though you know, it does bring up the idea of PrEP in transfusions and in those who use drugs and inject drugs. And I would say that at this point we have pretty good evidence, at least for oral PrEP, that - that works in transfusion. Well, at least in persons who inject drugs from the original Bangkok TFE study.

Dr. Molina: Right. And there is, as you know, another study with lenacapavir that is being implemented also in IV drug users. So, that's going to be also interesting to demonstrate that lenacapavir would also be able to prevent HIV acquisition in HIV - in IV drug users as well. So we don't have the results yet, but this is probably something we will learn at ACE [? 00:59:27] 2026, potentially.

Dr. Gandhi: You know, since we have a minute and I don't see another question in there, I wanted to bring up hepatitis B because I thought it was a good time to do so. There was a lot of talk at this meeting, Jean-Michel, about hepatitis B reactivation, the question of that with tenofovir sparing regimens. Because not only is long-acting ART with CAB tenofovir sparing, LEN CAB is tenofovir sparing, but so are all these new combinations that we just talked about. Islatravir doravirine, BIC/LEN, islatravir lenacapavir once a week. They all don't have hepatitis B activity.

So, what do you think about, you know, there was a maybe just mentioned verbally the SINEX study that looked at hepatitis B in the context of tenofovir sparing regimens.

Dr. Molina: Right. In that very large study, actually, the incidence of breakthrough HBV infection was very low, in fact. And so, this is probably a rare event, but I think still we have to be careful when we start these, you know, tenofovir sparing regimen, especially if there is no activity against HBV if you don't have any 3TC or FTC in your regimen.

I think it is probably worth checking the HBV serology and to see whether these people might be able to reactivate HBV. And, you know, this is - again, this was a rare event. We've seen also that in people using the combination of injectable cabotegravir and rilpivirine, a few people who were able either to reactivate or to acquire HBV.

So, I think if the person doesn't have any antibodies against HBs or HBc, then, you know, we should probably provide vaccination in these individuals. In the others, I think we probably need to be a bit careful and especially if we don't have any idea about their DNA for HBV before starting ART, maybe that's something that would need to be checked. Although again, we haven't seen you know, clinical or clinical reactivation really in those individuals. But they were mild reactivation with mild increase in ALTs.

Dr. Gandhi: But I agree with you that the message of this entire, you know, we - we saw applause at the microphone when people said we should be vaccinating people for hepatitis B everywhere. I think that was one of the biggest messages. And the other is not to use tenofovir sparing regimens and those with hepatitis B surface antigen positivity, which really means that you want to screen everyone for hepatitis B surface antigen at the beginning.

And if you’re core antibody and surface antibody negative - core antibody positive surface antibody negative vaccinate, and if you're core antibody positive surface antibody positive, you're good. And if you're core antibody positive, it's fine. Like use the tenofovir sparing regimen, but watch people.

Dr. Molina: It can be tricky with hepatitis B, and I think you're, you know - as you said, eventually these are rare events, but when they occur, it can be a bit shocking for - for the people because they do not expect that. And we should tell them that, you know, they don't have any protection against HBV, yes, they should be vaccinated.

Dr. Gandhi: And then one thing is, because this is a good question, that Dr. Kaplan Lewis asked is, would you not even consider long-acting CAB, and those who refuse hepatitis B vaccination. I would say that there was another message that came out that if you are only going to take HIV therapy by long-acting, then go ahead and do it.

And I will say that we had a focus group at the [inaudible 01:03:18] meeting where people said, okay, if you refuse to know for a year and you have hepatitis B, but you have an opportunity to get your HIV treated, then treat your HIV. So, I don't think that we would like say absolutely no, you cannot have long-acting CAB, but we'd really support that getting hep B vaccine.

And then I think we could just end with this final question by Dr. Nagori, which I think is a really good one, which is the lenacapavir resistance, because you know, there is this worry that if you roll out, LEN, that we're going to get, with prevention, we're going to get resistance and we won't be able to use it for treatment.

I'd like your thoughts, Jean-Michel, but I will say one thing, that boy, the - the genetic barrier to resistance to LEN is probably higher than we thought. And there was a lot of pretty pictures at this CROI about the capsid and the capsid inhibitor and how strongly lenacapavir binds there. And - and I think it's just a higher genetic barrier than we thought, which is a good thing.

Dr. Molina: Well, you know, I think, you know, the - the talk on capsid inhibitor was fantastic at CROI - that was one of the highlights of the conference. Indeed. Regarding lenacapavir resistance, I think, you know, we don't know yet the full picture. And I think lenacapavir is being, you know, used for prevention and also for treatment. I think, although in the data that you presented so far, there was limited evidence of resistance emerging in those being HIV infected and treated with lenacapavir based regimen, let's say.

I think this is also something we need to keep monitoring, because we don't want to jeopardize the use lenacapavir prevention. This is such a great prevention strategy. Soon being able to be used only once a year intramuscularly. So, I think we should make sure that lenacapavir would work. Indeed, this is only monotherapy.

And, you know, I think we've seen that in the rare cases of breakthrough HIV infection in those who use lenacapavir. You know, of course, we focus on the rare events. And, you know, I mentioned the individual who had breakthrough HIV infection despite on-time injection with lenacapavir and pretty good actually PK concentration in plasma.

So, we don't fully understand why these individuals acquire HIV. We can only say this is rare. But in case of HIV infection on lenacapavir, you're bound to see resistance. And resistance with pretty high plasma RNA level, which is different from what we've seen with cabotegravir. So, it seems that we don't have the LEVI syndrome we've seen with cabotegravir with lenacapavir. You have time to - to show that data. But they were presented also at the conference because in both PURPOSE 1 and PURPOSE 2, there were a few individuals who were infected at baseline and still received lenacapavir, and when they looked at the viral load at baseline, they found that people were already infected, although they didn't have any antibodies against HIV. In these individuals, also there was emergence of resistance to lenacapavir in at least 50% of those people. So, that means that no drug is perfect.

Dr. Gandhi: Yeah, no drug is perfect. Yeah. That's the message, I think. Yeah.

Dr. Molina: But we - we're going to see resistance.

Dr. Gandhi: Never use monotherapy.

Dr. Molina: Yeah. So-

Dr. Gandhi: Thank you so much.

Dr. Molina: You're very welcome.