HIV Update: CCO Independent Conference Coverage of IDWeek and EACS 2025

 [00:06:08]

HIV Management Strategies

Dr Darcy Wooten (Washington University): Thank you so much, Kristen, and to CCO for inviting us to talk on some really exciting updates. And we're going to go ahead and get started talking on some updates about HIV management strategies, and then we'll focus on PrEP towards the end.

[00:06:22]

Real-world Study of Salvage Lenacapavir + OBR in Heavily Treatment-Experienced People Living With HIV

So, I wanted to start by highlighting this study, looking at the use of lenacapavir with optimized background regimen in heavily treatment-experienced people living with HIV.

This was a retrospective study done at 6 different sites throughout the United States in people who were heavily treatment-experienced and getting started on lenacapavir between 2020 and 2025. And you can see that these people really were survivors. The mean time from HIV diagnosis was 24 years.

Over half, 54%, had an HIV RNA level greater than 200, and 4 individuals actually had a higher viral load of greater than 100,000, and the mean median CD4 cell count was 271.

Now, the table on the right really demonstrates that this was quite a heavily treated group, with a significant amount of resistance to greater than 2 agents in class at the time of initiation.

You can see, not surprisingly, the most common resistance mutations were to those of NRTI and NNRTIs. But I'll also point out that 40% of individuals had INSTI resistance, and then 7% of individuals in this group had resistance to 4 of the main classes.

In terms of the number of active agents that were active at the time of LEN initiation, almost a third had 1 or fewer active agents. And then in terms of the estimated number of active agents in the optimized background regimen, about – over half had 1 or more agents. And so this is really looking at the use of lenacapavir with optimized background regimen as sort of the salvage regimen.

[00:08:17]

Real-world Study of LEN: Results

So, the results were quite reassuring among these 70 individuals. 82% of them either maintained virologic suppression or became virologically suppressed after LEN was initiated and combined with their optimized background regimen. And 89% of the individuals in this group were continued on lenacapavir.

We have pretty nice data that was followed out through almost 600 days. Now, not surprisingly, injection site reactions were noted. Most of them were minor; 27%, though, were classified as moderate, which included requiring a clinic visit.

In terms of the optimized background regimen, INSTIs were a common component, and everybody who started on optimized background regimen with LEN, who was virologically suppressed at the time of LEN initiation, continued to be suppressed. And not surprisingly, the daily ART pill burden decreased across all participants in the group, although the number of agents did not decrease because LEN was being added.

And, of course, we have all of the usual limitations that we have with observational studies, but still nonetheless, I think some nice data to support and complement the prospective data that we have on the use of lenacapavir in combination with an optimized background regimen as a treatment salvage approach.

[00:09:52]

Switch Studies in People Living With Virologically Suppressed HIV

I also wanted to highlight 2 switch studies in people living with HIV who are virologically suppressed. The first, in the sort of orange-beige color, was the EMPOWER study, looking at a switch in the opposite direction than how we may be are more commonly used to looking at some of these switches.

These were individuals. This was real-world data of individuals who are on long-acting injectable CAB/rilpivirine, and then switched over to bictegravir/FTC/TAF. And there were 33 individuals in this analysis because these were individuals who, per real world, were wanting to switch.

The primary reason that people reported switching to daily oral therapy was because of some sort of adverse effect with their injectable regimen, and this accounted for 55% of people who were switching.

Interestingly, a very small number, I think it was less than 3%, switched to daily oral therapy because of insurance or cost issues. So, that was nice, that that wasn't a significant driver here.

And what the investigators found was that after 4 weeks of switching to bictegravir/FTC/TAF, 72% were not reporting any adverse effects with their daily oral therapy. And the participants reported considerable improvement in treatment satisfaction, which is not surprising when you have people that are wanting to switch off of their injectable therapy and go to daily oral therapy. They are likely to be satisfied with that desired change.

The other switch study that I wanted to highlight is the 1 shown in blue, the PREFER-LA study. This was a real-world study looking at people switching from daily oral ART to injectable rilpivirine. And the individuals in this study were sort of—like the study—the participants in the LATITUDE trial, there were about 160 individuals, and these were people who really struggled with daily oral ART adherence. So, have those adherence challenges.

And the primary reason for wanting to switch in this study, per the participants, was self-reported suboptimal adherence. And again, because this is observational data, 97.5% of people who switched to CAB/rilpivirine, who wanted to switch, preferred this regimen and were excited to be able to switch to that regimen.

And what's really nice to see are the virologic outcomes. So 98% of people who switched to CAB/rilpivirine were virologically suppressed, less than 200, compared to at baseline. Only 89% were suppressed on their daily oral therapy.

So, again, additional data to sort of support other observational studies, as well as the LATITUDE trial. That long-acting injectable CAB/rilpivirine is a good option, especially when people struggle with adherence to daily oral ART.

And with that, I'm going to turn it over to Dr Molina to walk us through some studies on weight and metabolic outcomes.

[00:12:59]

Weight and Metabolic Outcomes in People Living With Virologically Suppressed HIV

Dr Jean-Michel Molina (University of Paris Cité): Thank you very much, Dr Wooten. And it's a pleasure to be here with you today, and to highlight some of the studies that were presented at the ART European AIDS Conference in Paris a few days ago.

And for those not able to come to Paris, I thought, you know, a couple of studies merit to be highlighted. And we're going to start with a number of studies that have looked at weight and metabolic outcomes in people suppressed with their current regimen and switching to a new option in order to try to address these issues of weight gain and metabolic outcomes.

So, the first study in blue, was sponsored by Merck. It was a study whose results were already presented at CROI earlier this year, in people switching from BIC/FTC/TAF to doravirine/islatravir. And they looked at changes in body weight and body composition at Week 48. And there was clearly no change that was significant when people switched from BIC/FTC/TAF to the doravirine/islatravir.

The second study in yellow in the middle was an ACTG trial, the DO-IT study. It was conducted in adults with obesity, and these adults were switching from an INSTI plus TAF/FTC to doravirine, and with or without TAF/FTC or TDF/FTC.

And here again, you know, it was a bit disappointing, but this switch didn't lead to changes in triglyceride cholesterol, insulin resistance, or total body fat—body fat at Week 48. And you may say, well, maybe Week 48 is a bit early. So, we'll see whether long-term data will make any, any changes to these results.

And then in pink, you had the PASO-DOBLE study. This is a non-inferiority study in people switching from a combination of ART regimen with COBI booster, efavirenz, or TDF to BIC/FTC/TAF or dolutegravir/3TC. And the results of this study were already published in the Lancet HIV earlier this year, showing noninferiority between these 2 strategies, BIC/FTC/TAF or dolutegravir/3TC. But what was presented at this conference was the body weight changes in the 2 arms, and there was a greater weight gain observed with BIC/FTC/TAF at week 96 as compared to dolutegravir/3TC.

The difference was not great. It was 1.5 kg, but still significant. And that's something to keep in mind. When you look in detail at some of the results of the study, actually, this body weight increase was also driven by people switching off tenofovir. And we know that tenofovir can induce some—you know, at least a reduction in body weight or at least keep the body weight and change. So this is also may be 1 of the explanations for these body weight gain and people switching to BIC/FTC/TAF.

So let's now move to this first posttest.

[00:16:27]

Posttest 1: A patient living with virologically suppressed HIV and obesity asks whether switching from their INSTI-based ART to a doravirine (DOR)-based regimen will help decrease their triglycerides, LDL cholesterol, and insulin resistance. You can counsel this patient that switching to DOR is likely to …

A patient living with virologically suppressed HIV and obesity asks whether switching from their INSTI-based ART to a doravirine-based regimen will help decrease their triglyceride, LDL cholesterol, and insulin resistance. And you can counsel this patient that switching to the doravirine is likely to:

1. Significantly decrease triglyceride, LDL, and insulin resistance;
2. Significantly decreased triglyceride and LDL, but not insulin resistance;
3. Significantly decrease insulin resistance, but not triglyceride or LDL;
4. Have no significant effect on triglyceride, LDL, or insulin resistance.

So you can vote.

[00:17:28]

Okay. Let's look at the correct answer. So, most of you actually ticked the right answer, 69%. And indeed, that was maybe a little bit disappointing. When you switch to these NNRTI-based regimen, unfortunately, the switch had no significant effect on triglyceride, LDL, or insulin resistance. And that was seen in the DO-IT study, also in the Merck-sponsored study. Okay.

So, let's move on now to another study. And I will hand it over to Dr Wooten again.

[00:18:18]

Phase IV CAPRI: LA CAB + RPV in People With Severe Impairment and Virologically Suppressed HIV

Dr Wooten: Thank you so much. So, I think CAB/rilpivirine is a really exciting and great option for many subgroups of patients. But we don't have data in some of these subgroups, such as individuals with advanced CKD. So, this trial, which I'm not sure if it's pronounced CAPRI or CAPRI, was a PK study looking at CAB/rilpivirine in this group that has not been largely studied with this long-acting injectable regimen. People with severe renal impairment. Stage 4. Stage  5 chronic kidney disease who were suppressed on their current ART.

So, these 12 individuals, 6 of whom were actually on hemodialysis, got started on CAB/rilpivirine. And then for the first part of the study, they did monthly administration of CAB/rilpivirine and checked levels. And then for the second half of the study, CAB/rilpivirine was administered every 2 months.

And what was great to see, although the numbers, of course, are small in this group, was that virologic suppression was maintained through week 48, as was CD4 cell count. The exception being the individuals who underwent renal transplants, who were on immunosuppressive agents post transplant. And not surprisingly, this impacted their CD4 cell count.

And similarly, kidney function was stable on this regimen. Again, with the exception of those who underwent renal transplant, of course, expectedly had improvement in renal function.

There were no significant adverse drug events. No significant drug–drug interactions, particularly with immunosuppressive regimens post-transplant, and injection site reactions, as we know, was commonly described, but overall mild.

There was 1 individual who died in the study due to an NSTEMI. This was not thought to be associated with CAB/rilpivirine, and was not unexpected with respect to the mortality rate in this group with multimorbidity.

But really, nice to see some additional data. And the PK curves looked great, whether the dosing was given monthly or every 2 months. So, some additional data that we have to have some additional confidence in using this regimen in individuals with advanced renal disease.

[00:20:32]

MORE: Mobile Delivery of LA CAB + RPV to People Living With HIV and Adherence Challenges

There was also a really interesting implementation science study that was presented at IDWeek, looking at this program called the MORE Program, Mobile Delivery of Long-Acting CAB/rilpivirine to optimize retention and engagement out of the Whitman-Walker Health Center.

So, this program overall targets individuals who struggle with adherence to ART, as well as engagement and retention in care. So, they target individuals who have elevated viral load of greater than 200, or who have not had a medical visit in the past 6 months.

And they have a variety of options that they offer to these individuals, really, kind of fulfilling the theme of meeting patients where they're at. And so what they reported on was home delivery and injection of long-acting CAB/rilpivirine, looking at acceptability, feasibility, and appropriateness per participant evaluation.

And you can see whether individuals were in the MORE Program and receiving injections at home, or they were in the MORE Program and receiving support to be able to get to clinic for care, including injections, there was a high rate of acceptability, feasibility, and appropriateness of this mobile intervention with about 67% of individuals reporting that they would be willing to receive CAB/rilpivirine injections at home. And then in terms of the numbers who actually receive these injections, 31% of this group.

And so, I think what the investigators really highlighted is that we need to have a variety of options. Receiving injectable therapy in the home is not going to be the right option for everybody if you don't want people with whom you're living to know that you are receiving antiretrovirals and/or don't have – have other reasons for maybe not wanting to receive the injections at home, then they have other mechanisms by which they can facilitate transportation to the clinic or to other places to receive these injections.

But for some people, that is going to be a good option. And so it's really having a variety of things that patients can choose from to, again, really meet people where they're at. That's going to be helpful. And this was a nice example of that.

And I'll turn it back over to Dr Molina now to talk about some updates in hepatitis B reactivation.

[00:23:02]

Low Risk of HBV Reactivation After Nucleos(t)ide Withdrawal

Dr Molina: Thank you very much. So, indeed, hepatitis B reactivation is an emerging issue in treatment of people living with HIV, especially with the new combination that we use, who lack actually, activities against HIV.

So, the first study that was presented in blue is a prospective observational cohort study conducted among 741 people in Barcelona in Spain, switching to cabotegravir/rilpivirine long-acting, which we know has no activity against HIV.

And usually, you make sure that people don't have chronic hepatitis B before switching them to this combination. And when they look at the data, they actually found no HBV reactivation, which was quite reassuring. Or no new infection after the switch, including those with isolated HBc core antibody positive.

But what we have to highlight here is that the number of those individuals who had isolated core antibody positive where there is very limited since we had only 19 individuals, or 3%. So, it's not like, so unexpected to see no HBV reactivation. And we have to be indeed very careful when we look at these data, because in that trial in particular, a significant proportion of people had no HBV markers. So, they could acquire a new HBV infection. And we have seen that, a couple of reports in other studies.

The second study is in yellow here, the Swiss HIV Cohort Study. It's a retrospective analysis of 358 people who were HBs antigen negative, HBc positive. But importantly, nearly 80% were also HBV surface antibody positive. And we know that in that case, the risk of reactivation is very limited.

And indeed, when these people were switched from tenofovir-based ART to agents without HBV activity, or with FTC or 3TC-containing ART, which we know have some activity against HBV, you could see that the level of HBV DNA reactivation was quite low. It was only 1.1% in those who switched to a regimen containing either 3TC or FTC. It was higher in those who had no HBV active ART, 5.6%.

So, overall, the rate of reactivation was low, 3.9%. There was no hepatitis—well, significant clinical hepatitis in those individuals. But remember that nearly 80% again had antibodies against HBV surface antigen.

So, I think we have to be careful. And it is still mandatory to do HBV screening before using a regimen without HBV activity. It's important to give people the opportunity to be vaccinated against HBV if they don't have any markers. And we still need to monitor people on this regimen because they still can acquire HBV infection if it is not a reactivation of a previous HBV infection.

[00:26:43]

Investigational ART Regimens

Now, we're going to switch to some of the new investigational ART regimens that were presented at the European conferences. Most of these studies were actually updates from previously presented studies. In particular, at CROI. And most of the studies I'm going to show you today are studies trying to combine long-acting agents to provide people living with HIV with convenient options.

[00:27:15]

EMBRACE: Every 4 Month IV or SC N6LS + Monthly CAB

So, the first is the EMBRACE study. That's a study that is sponsored by ViiV, assessing the combination of cabotegravir, but given monthly, not every 2 months, in combination with a broadly neutralizing antibody, N6LS, which is an antibody which has activity against the gp120 and the CD4 binding site of gp120 envelope.

And in that study, people were fully suppressed for at least 12 months under ART with no history of ART switch for virologic failure, with a high CD4 cell count above 350. No active HBV infection because, here again, this regimen has no activity against HBV. And before using these broadly neutralizing antibodies, you want to make sure that there is in vitro susceptibility to these antibodies. So this is something that was checked at baseline.

And then the participants were randomized into 3 arms. The first 2 arms with the bNAb in the first time in dark blue. The bNAb was given IV, every 4 months, plus CAB every month. In light blue, the bNAb was given subcutaneously with laronidase to make space in the subcutaneous fat. Again, every 4 months, plus CAB every month. And then you had 1 arm with oral ART.

And so the current analysis looked at the safety and tolerability of the N6LS antibody for 6 months, with patients' tolerability evaluated early and then at 4 months.

[00:29:09]

EMBRACE: Safety and Tolerability

So, I'm not going to talk about the anti-HIV results, which have been presented at CROI, with a few failures, actually, with the combination of CAB and the monoclonal antibody. But if we look now at the tolerability, the data were quite reassuring, with no serious treatment-related adverse event or discontinuation because of that.

No injection site reaction resulted in discontinuation. There were no serious or severe immune events, anaphylaxis, cytokine release syndrome, or neutropenia, and no significant lab abnormalities with either IV or subcutaneous administration of the antibody. And also, as expected, the monthly administration of CAB showed no safety issues and no tolerability issues. And you may remember that initially, CAB was given monthly in the early trials.

So, overall, the participants rated the combination of these regimens highly tolerable, and therefore, the company now is starting a phase II—part 2 of this study using the same combination, but given twice yearly. So every 6 months, with the IV administration of the N6LS bNAb, plus CAB given this time every 2 months. So, we'll see whether the results, in terms of antiviral efficacy, will be sustained with this combination.

[00:30:48]

Twice-Yearly Lenacapavir + Teropavimab + Zinlirvimab: Study Design

The other study looking at a combination with 2 bNAbs and lenacapavir was this Gilead-sponsored study assessing the combination of lenacapavir given every 6 months, plus the 2 monoclonal antibodies, broadly neutralizing antibodies, teropavimab, which is usually called TAB, and zinlirvimab, called ZAB.

And, and again, the early results of this study were presented at, at CROI. To be enrolled in the study, people had to be fully suppressed, below 50 copies, at least for a year on stable ART. Again, no HBV, infection. And susceptibility to the 2 bNAbs had to be assessed at baseline. And actually, half only, the people who screened, could be enrolled because of these criteria.

So, the participants were then randomized to receive either the IV combination of the 2 bNAbs plus subcutaneous administration of lenacapavir every 6 months, or to continue their oral baseline regimen. The primary endpoint was at Week 26. And the current analysis looked at week 52 outcome, looking at viral load and CD4 changes.

[00:32:21]

Twice-Yearly LEN + TAB + ZAB: Wk 52 Outcomes

And at week 52, what you can see in terms of viral load is that 3 individuals out of 53 in the arm combining lenacapavir plus the 2 bNAbs. So, 3 had a viral load above 50. When we had the 26-week data, only 1 patient had failed. So, we have 2 additional patients failing between week 26 and week 52.

Among these 3 individuals, 1 developed resistance to LEN, 1 resistance to ZAB, 1 had low-level viremia, so resistance could not be assessed. All of them were suppressed on oral ART with BIC/FTC/TAF.

The CD4 cell count increase was similar in both regimens. And when people were asked about their preference regarding the regimen, 76% said that they would prefer the injectable ART as compared to the daily oral ERT.

Also, it's interesting to see that the injection site reaction related to LEN were all grade 1 and 2 with no discontinuation, and that there was no infusion-related reactions reported to TAB or ZAB. So, interesting results. A few failures. So we, we need to, again, you know, conduct additional studies with this combination.

[00:33:57]

Once Weekly ISL + LEN: Study Design

An oral combination that also raised interest is the once-weekly oral combination of islatravir and lenacapavir. Again, this is a study conducted in people fully suppressed with a viral load below 50 copies per mL on BIC/FTC/TAF, no history of virologic failure, high CD4 cell count above 350, no HBV infection.

And because of earlier concern about islatravir and low impact on CD4 and lymphocyte count, people had to have a lymphocyte count above 900 to be enrolled in the study. People were then randomized to continue BIC/FTC/TAF or to switch to the combination of islatravir and lenacapavir from the start.

[00:34:24]

Once Weekly ISL + LEN: Wk 96 Outcomes

And what was interesting in that study was that no individual, actually, in those receiving this oral weekly combination of islatravir and lenacapavir, none out of 52 had a viral load above 50.

Indeed, when you have zero, you know that you need to look at the confidence interval. And the confidence interval, the higher bound was about 6%. So, but still here, no observed failure. 88% remained fully suppressed up to Week 96, which is great. And the 6 individuals for whom we didn't have any virologic data, all of them had viral load below 50 before discontinuation.

So, that's an interesting result. There was no emergent resistance but in fact, no resistance could be tested because the viral load remained below 50 copies in all individuals. And the adherence, as measured by pill count, was very high with this weekly regimen, 99.3%.

In terms of adverse events, the adverse events were all grades 1 or 2. In 19% of those who received this combination, 19% were treatment-related adverse events, and mostly dry mouth or nausea. There was no serious adverse event or any adverse event leading to study drug discontinuation, which is quite encouraging. No changes in CD4 cell count from baseline, but remember that those people were already fully suppressed at baseline. And there was no changes – significant changes from baseline in lymphocyte count, which is reassuring with this combination containing islatravir indeed.

And therefore, according to these results, the company now is studying a phase III trial, ISLEND-1 and 2, evaluating these weekly fixed-dose regimen of oral islatravir and lenacapavir.

[00:37:16]

Posttest 2: In the extension phase of a phase II trial evaluating once-weekly islatravir and lenacapavir for people with virologically suppressed HIV

 So, this is the posttest 2 question. In the extension phase of the Phase II trial, evaluating once weekly islatravir and lenacapavir for people with virologically suppressed HIV, which is the correct answer?

1. No one had a viral load above 50 copies per mL at discontinuation;
2. Several people discontinued because of CD4 T-cell decline;
3. Several people discontinued due to treatment-related adverse events;
4. Many people forgot to take the once-weekly islatravir/lenacapavir regimen.

So please vote.

[00:38:04]

And indeed, the correct answer was A. No one had a viral load below 50 copies per mL at discontinuation, and these results were good enough for the company to move to a Phase III trial now. And importantly, there was no decline in either CD4 cell count or lymphocyte count in this population with a very high adherence to the weekly regimen. So these – it's quite interesting and encouraging for people living with HIV to – in the future, maybe use this weekly oral regimen as well.

[00:38:36]

Key Takeways: Treatment

So, the key takeaway regarding the data on treatment are the following. Treatment satisfaction is usually very high after switching ART. Unfortunately, we didn't see any major changes in weight or metabolic parameters after switch to either doravirine-based regimen.

There was, though, less weight gain when you switch to DTG/3TC as compared to BIC/FTC/TAF in 1 trial, and these results have to be confirmed in additional studies.

There was a low risk of HBV reactivation when switching to ART regimen without full activity against HBV. But here again, we have to be very careful because the number of people with ability to reactivate HBV was limited. And in other studies, we've seen some reactivation in people in particular with HBs antigen. And so we have to screen out those individuals before, before moving to this regimen without HBV activity.

Mobile delivery of long-acting cabotegravir/rilpivirine is feasible and acceptable to people living with HIV. That's interesting to know. This combination is also effective and safe in those with severe renal impairment. Although the number of people that have been treated with this combination remain very low.

Interestingly, the combination of long-acting CAB or lenacapavir with the broadly neutralizing antibodies look promising, as well as the weekly oral combination of islatravir and lenacapavir. So, these are future options, which appear to be tolerable and promising in terms of efficacy. So, these are the data for treatment.

[00:40:25]

HIV Prevention Strategies

And now we're going to switch to prevention strategies.

[00:40:31]

PURPOSE 2 Persistence Subanalysis: Annual Persistence to Twice-Yearly SC LEN vs Daily Oral FTC/TDF as PrEP

And we're going to start with additional data from PURPOSE 2. This is a subanalysis looking at the persistence to twice-yearly lenacapavir or daily oral TDF/FTC as PrEP. You probably all know that the PURPOSE 2 trial, which was conducted by Gilead, was an international, double-blind, randomized Phase III trial in cisgender men, transgender women, transgender men, and gender nonbinary people aged above 60 years—16 years and up.

Previous reports have shown an HIV incidence that was significantly lower with twice-yearly lenacapavir as compared to background HIV incidence of daily oral TDF/FTC. What's important to highlight here is that the trial was double-blind.

So all people receive injections, and all people receive pills to take between injections. And the current analysis here focused on annual persistence with the 2 regimens in a random, preselected 10% of people who had at least 1 year of follow-up in the study.

[00:41:45]

PURPOSE 2 Persistence Subanalysis: Annual Persistence of PrEP

And that's important to explain in detail what is the definition of persistence in this study. So, persistence with lenacapavir was defined as receiving an injection at baseline, on-time injection at week 26, and on-time follow-up at week 52. So, only at 3 time points.

For a daily oral PrEP, persistence was defined as a DBS, dried blood spot, with tenofovir diphosphate concentration consistent with at least 4 doses per week at Week 13, 26, 39, and 52. And when you look at the annual persistence, you could see that—I was, you know, suggested in a presentation of the results. Initially, persistence was higher with lenacapavir as compared to oral TDF/FTC, 63% vs 37.3%.

And indeed, when you look at adherence to injection through Week 52 with lenacapavir, it was above 90%. But, you know, in the trial, people had to come back for the visit to receive the injections. And the adherence to oral PrEP, actually, waned from Week 8 to Week 52, from 82% to 62%. And that explains, actually, the results in terms of HIV incidence, because the adherence to daily oral PrEP was lower over time. And therefore, you know, the HIV incidence was greater.

And when you look at nonpersistence among those receiving lenacapavir, it was only 36 out of 98 people, whereas in those receiving TDF/FTC was 32 out of 51. And when you look at the reason for nonpersistence with lenacapavir arm, 21 missed their Week 26 injection, 14 missed on-time injection at Week 52, and 1 at a late injection at Week 26.

In the TDF/FTC arm, 18 has a missing DBS sample, and 14 DBS concentrations indicative of nonadherence in the prior visit.

So, I will turn it over now to Dr Wooten again for additional analysis on PURPOSE 2.

[00:44:13]

PURPOSE 2 Persistence Subanalysis: LEN PrEP Adherence and Safety Among People Who Used Substances

Dr Wooten: Thank you so much, Dr Molina. So, I'm going to present 2 additional subanalyses from PURPOSE 2. The first is looking at LEN PrEP adherence as well as safety among people who use or reported using substances.

Now, we will have results of PURPOSE 4, which is specifically looking at the use of lenacapavir for PrEP in individuals who use drugs and inject drugs. This focuses more on other types of substance use. And you can see that in the table. 40% of individuals in PURPOSE 2 reported binge drinking. 37%, any substance use. 19.9% stimulant use. A very small proportion had injection drug use in PURPOSE 2.

And what we see is really exciting, quote-unquote, "negative" results. I don't usually get excited about negative result studies, but this is 1 of those exceptions, because we see that LEN adherence was really similar between people who use the substances listed in the table, compared to those who did not.

And similarly, adherence, as well as frequency of adverse events, were quite similar across groups who used substances vs did not use substances. Again, injection site reactions were probably 1 of the more commonly reported. AEs overall relatively mild, but no difference between those who use and those who don't use substances.

Now, there was very preliminary, and I want to highlight that, very preliminary PK modeling, looking at the interaction between LEN and fentanyl. So, a little bit too early to draw significant conclusions, but so far, looks to be relatively reassuring, and no significant interactions. I suspect we will get additional updates from not only PURPOSE 2, but also PURPOSE 4, as that is underway, and we get results, and looking at that interaction or potential interaction, since that will be important for us to understand.

[00:46:24]

PURPOSE 2 Gender-Affirming Subanalysis: LEN PrEP Coadministration With Gender-Affirming Therapy

And then the other subanalysis that I wanted to present from PURPOSE 2 was 1, looking at the potential interaction between gender-affirming therapy with lenacapavir for PrEP. And again, this is great in that we had a really high proportion, 11.6%, or 253 individuals, who were receiving gender-affirming therapy.

Again, another negative study that's fun to get excited about in that there was no significant impact on LEN concentrations with any of the gender-affirming therapies that were used in the study, including estradiol, testosterone, DHT concentrations.

So, nice to know that this is not going to be a substantial issue in individuals who are receiving gender-affirming therapy. So 2 negative studies, that even though they're negative, really exciting to highlight.

And then, I will turn it over to Dr Molina to talk to us about the CLARITY study.

[00:47:27]

CLARITY: Cabotegravir vs Lenacapavir PrEP

Dr Molina: Thank you very much. So, that's an interesting study. A funny design. This is a study – it's important to mention that was sponsored by ViiV. And you will understand why in a minute. So, it's called CLARITY. And it is a study conducted among healthy adults without HIV. It's an open-label study with a crossover to compare the tolerability of cabotegravir intramuscular or lenacapavir given subcutaneously.

So, this study was conducted about adults without HIV with a BMI between 18 and 32 with no comorbidities, no substance use, 64% individuals. So, at baseline, they were randomized to receive either 1 injection of cabotegravir or 1 injection of lenacapavir.

There was a first assessment at day 8 with what's called the PIN assessment, a perception of injection questionnaire that was, you know, validated in a prior ViiV trial with cabotegravir.

Then there was a crossover, and at Day 15, the individual received another injection. So, lenacapavir if they received cabotegravir. Or cabotegravir if they receive lenacapavir, so they could experience the 2 types of injection.

And then at Day 22, another PIN assessment was made. And then, Day 29, another final assessment. And so the primary endpoint of the study was to assess participant local reaction acceptability 7 days post injection. So, at Days 8 and 22, with this questionnaire. And secondary endpoint looked at injection site reaction incidence, severity, and duration, and also the preference of the healthcare providers.

So, what to expect? Well, I said there was a ViiV-sponsored study. But nevertheless, the study was randomized with a crossover. And when you look at the proportion of patients with a local reaction rated as totally or very acceptable, you could see that the percentage was higher with cabotegravir, 69%, vs 48% with lenacapavir. And where participants were asked for their preference at day 22, after they had experienced both injections, 90% preferred cabotegravir over lenacapavir. Only 10% preferred lenacapavir.

And indeed, when you look at the frequency of injection site reaction, visible injection site reaction, it was actually more frequent with lenacapavir than with cabotegravir. And when you look at at least grade 2 injection-site reaction, 57% in those receiving lenacapavir experienced these ISR vs only 30% with cabotegravir.

Also, cabotegravir was associated with lower initial pain scores vs lenacapavir, but this score was similar than a little bit later on Day 3, 5, and 8. So, the pain was a little bit higher or greater with lenacapavir initially.

And when the healthcare providers were asked about the preference, 6 out of 7 said they preferred CAB because of fewer and less severe adverse events and less pain during injection.

So, with that, let's summarize the key takeaway for prevention. So, in PURPOSE 2, the annual persistence was higher with twice-yearly lenacapavir as compared to daily oral PrEP. But remember that this study was conducted as a double-blind study. So, people didn't know whether or not they were receiving a real drug or a placebo. And so that might have affected adherence.

We also have seen that—and that's interesting, that similar adherence and safety was seen in people who did or did not use substances. And that's reassuring. No interaction between LEN and gender-affirming hormones. And in the small CLARITY study, the local reactions were rated as totally or very acceptable by 69% of those receiving cabotegravir vs 48 of those receiving lenacapavir.

So, we need probably more studies like that or more analysis to see whether this difference is actually real. There were more frequent and visible injection-site reactions with lenacapavir as compared to cabotegravir.

And as I just said, 6 out of 7 healthcare providers preferred cabotegravir to lenacapavir due to fewer adverse events and reduced pain. But we will all agree that 7 healthcare providers is a very limited number. So, let's take now the last posttest question.

I am familiar with data from the EACS 2025 and IDWeek 2025 conferences and I plan to translate these data into current or future management strategies. Do you:

1. Strongly agree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

So you can vote.

And now we have some time for Q&As.

[00:53:11]

Questions and Answers

Dr Wooten: And maybe while people are voting, we can start with our first question from Quentin, which is a really good one. And I'll toss this to you, Dr Molina. But he's asking about whether we anticipate difficulty with adherence with oral once-weekly regimens outside of a clinical trial setting. So, I wonder what your thoughts are on that.

Dr Molina: I think that's a very relevant question. And actually, we don't really know the answer at this point. We don't have a lot of experience with a weekly regimen, actually, at this point. I think, you know, more and more people are willing to move away from a daily regimen. So, we had the option of long-acting injectable. And I think, you know, this option of weekly oral could be attractive for some individuals, maybe not everyone, because you have to remember to take your weekly regimen.

One important question is, what's the forgiveness also of this weekly regimen? And, you know, I think the forgiveness is quite good. It's – I understand quite – up to a week. So, if that's correct, that could be quite interesting. So, clearly, we need additional data, but I think that's good to have multiple options for people.

So, for those not willing to take a daily pill or having adherence issues with daily regimen, you know, I think these weekly combinations. And we have another weekly regimen we didn't talk about that is also in development. And so I think we may end up with 2 weekly oral regimens available in the near future. So, I think these are interesting options to consider.

Dr Wooten: Yeah. I agree, and I think understanding that forgiveness, as well as the genetic barrier to resistance, which ties into that, will be important. You know, we do have examples from treatment and management of other conditions of once weekly regimens, such as some of the newer regimens for treatment of latent tuberculosis, as well as once-weekly GLP-1 receptor agonists.

So, we have at least those experiences where – where we've had some degree of success. But I agree with Quentin in terms of the concern or the worry, because my patients who are on long-acting injectable rilpivirine, since they're coming into clinic to receive that, I know when they miss their injection, I know when they're late. And so I can intervene in a way that is maybe more useful and helpful compared to maybe less monitoring when people are taking weekly oral regimens or weekly regimens at home.

So, I think this is something really important to keep our eye on, and something that I think, like you mentioned, Dr Molina, really nice to have a lot of different options, meet people where they are. I have some patients who have an incredible needle phobia. So, an injection regimen, even if it's, you know, the easiest, most tolerable regimen in the world, is not going to work for them. And so it's, it's good to have other options as well.

Dr Molina: Now, clearly, I agree with you. And I think – you know, I thought there is – it's interesting to know that there are differences in the way we give cabotegravir/rilpivirine in Europe as compared to the U.S. Because you mentioned that in the U.S., and I – when I talk to my U.S. colleagues, they – they told me that people have to come to the clinic to receive their injection. That's different in Europe or in France in particular, because we can write a prescription, and the patient then goes to the nurse, a private nurse, to receive his injection.

And so we don't have to see the patient at the clinic more often than we used to do with people on oral ART. And sometimes you may feel a bit uncomfortable when you see these people only every 6 months or once a year. That – we try to do that after, you know, 1 or 2 years or 3 years on – under injectable. And, you know, it's interesting to see that these people are very well organized. They organize their life with their injection. They go to the nurse, they pick up their drug at the pharmacy, the private pharmacy. And I – I know this is something that is not yet possible in the U.S., but that's another model of, you know, using these long-acting injectables. That's true, that most people are really happy with these long-acting injectables. And people are asking, you know, would it be possible to give only once a year? That's what they are expecting us to – to give them in the – in the future.

Dr Wooten: Yeah, absolutely. I know we only have a little bit more time, but 1 question. What are your thoughts on, you know, if and when sort of bNAbs, are – are going to be sort of in clinical practice? And, and are we close to that point, or are we still a bit a ways away based on some of this data that we saw?

Dr Molina: Well, I think bNAbs, everyone is excited about bNAbs. Not only for treatment, but also maybe for prevention or for cure, remission. For treatment, I have to say, you know, the – the interest of bNAbs is to space out injection, to be able to give injection every 4 months or every 6 months. And that's what people would like to – to get, injection every 6 months, let's say.

The issue with bNAbs is first, that you have to screen people before giving them bNAbs. And, you know, that would exclude a significant proportion of people, up to 50% in some cases. So that's – so – so that means that bNAbs are not for everyone.

And then, we've seen a couple of failures with bNAbs as well. A few. But still some failures with resistance, not only to bNAbs but also to lenacapavir, because lenacapavir has a low genetic barrier to resistance. So you – you know, I think that's interesting to continue to do these studies for treatment. But, you know, if we had another drug that can be combined with lenacapavir and given every 6 months, a small molecule, I think, you know, we probably use a small molecule rather than a bNAbs for treatment – for treatment.

Dr Wooten: Yeah.

Dr Molina: But maybe bNAbs have, you know, an interest for, you know, cure strategies or remission strategies that are maybe more interesting and – that the small molecule cannot do. I don't know. What – what is your opinion about bNAbs?

Dr Wooten: I think they're exciting. And I think the idea of having a, a treatment that is every 6 months as a complete regimen it's very exciting. But I think some of these additional details and nuances that you highlighted are – are really important to sort of sort out and also to sort of do the implementation piece of this as well before they're kind of widespread.

There's a quick, rapid-fire question from Joseph, asking about the at-home long-acting injectable PrEP model. And whether blood is collected at home and then goes back to a centralized lab for monitoring tests.

The study that I presented about the at-home, it was actually for HIV treatment, but they also do PrEP. They do collect labs in the home. But I don't know, Dr Molina, if you maybe know more about the program in France and how that works.

Dr Molina: So, I wanted to say hello to Joseph, whom I know quite well. So, thank you, Joseph, for attending this webinar. And so – well, the – the nurse also, well, doesn't have to collect blood. She – she could, but the patient can go to the lab to have blood drawn and tested at a lab, and then he can go then to the nurse to receive this injection.

And now that I realize how to get access to the questions, I could see that Esteban Martinez, who was actually the PI of the PASO-DOBLE study, actually explained that maybe I've been – I misspoke about the explanation for the weight gain because that – that's true, that the weight gain that was seen when people switched to dolutegravir/3TC vs BIC/FTC/TAF. And when you see a higher weight gain in those switching to BIC/FTC/TAF.

So, you know, when they looked at independent factors, they – they had – the treatment regimen was 1 factor. And switching off tenofovir was another factor. So they were independent, both of them. So, I just want to make that clear. And I hope that Esteban, since you're watching this webinar as well, I – I correct it this way.

Dr Wooten: All right. Well, I think that we're just about at time. But I want to thank everybody for joining us. And I'll turn it back over to Kristen to close us out. But thanks, everyone, for attending. And thanks so much, Dr Molina, for all of your insights. Really great.

Dr Molina: Thank you, Dr Wooten. That was a pleasure to do this webinar with you today and with you all. Thank you for attending.

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