HIV Update: CCO Independent Conference Coverage of CROI 2025

[00:17:38]

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

Let me start off by talking about some of the news related to HIV treatment. We heard an update on the CARES study, which is a study of long-acting cabotegravir and rilpivirine in a sub-Saharan African population using a public health approach. This study was initially presented a year ago by Cissy Kityo, who was the lead investigator. Actually a year ago, it had to be presented by Nick Paton when Cissy was unable to attend, but she did have the opportunity this year to present the 96-week data.

Just to quickly summarize what the study was. This took people with HIV who were on a suppressive oral regimen that included either dolutegravir, efavirenz or nevirapine, plus 2 nucleosides, and randomized them either to continue on their standard of care regimen or to receive long-acting treatment with injectable cabotegravir and rilpivirine, given every 8 weeks. And there was an optional oral lead in, but most participants didn't choose to do that.

And then they were monitored as would be standard of care in the lower and middle income country setting. And the primary end point was maintenance of viral suppression at Week 48. And then secondary endpoints were virologic failure, safety and tolerability. And as had been reported and as has been published, the primary endpoint showed that injectable long-acting CAB rilpivirine was noninferior to oral standard of care treatment at 48 weeks. And now we're looking at the Week 96 longer-term results.

[00:19:12]

          CARES: Baseline Characteristics

This slide summarizes the baseline characteristics. And just a couple of things to point out very quickly. Nearly 60% of the participants were female. About 20% were obese. Of course, the majority were of African Black race.

Most were on an INSTI at the time of screening, but three quarters had prior exposure to a non-nuc. And they retrospectively did genotyping of archival proviral DNA, finding that more than half were subtype A1. Importantly, this is the African A1 subtype, has nothing to do with a 6 subtype that was of concern in the ATLAS and FLAIR studies, and only a small number had archived rilpivirine or CAB mutations predicted to confer high level resistance, 3% and 2%, respectively after reducing the - after eliminating mutations that were considered to have been generated by host defense mechanisms during viral replication, the APOBEC-mediated mutations. And you can see how those numbers change from what had been presented previously.

[00:20:31]

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

So let's get to the results here. And you can see that at week 96, the data look almost exactly as they did at week 48, with about 97% in both groups maintaining virologic suppression. There was 1.6% and 0.8% virologic nonresponse in the long-acting vs continued oral groups, which was not statistically significantly different, well within the noninferiority margin.

And impressively more than 80% of the participants received all of their scheduled injections, and nearly all of them were on time, which is really quite an accomplishment. There were comparable rates of serious adverse events in the injectable and in the oral standard of care arm, a very few grade 3 adverse events, and again, similar in both arms. As expected, there were injection site reactions in the long-acting arm, but these were almost all grade 1 and grade 2. There was a single grade 3 ISR which did lead to treatment discontinuation.

Nevertheless, the participants who were in the injectable arm overwhelmingly expressed a preference for the long-acting therapy over their oral therapy. So the important point to take home here is that at weeks 48 and 96, virologic success with long-acting CAB and rilpivirine was non-inferior to the standard of care with oral antiretroviral therapy.

[00:22:09]

CARES: Virologic Failure at Wk 96

Looking at the 4 participants who had protocol defined confirmed virological failure in whom resistance testing could be performed, you can see that 2 of those failures occurred at Week 48, and 2 occurred subsequently. Remember, monitoring is happening only every 6 months here after the initial several weeks of the study. So we don't have the same density of monitoring as would have occurred in the ATLAS and FLAIR trials.

You can see the virus loads at virologic failure here. And then participant 1 had 2 rilpivirine resistance mutations that emerged, as well as several CAB resistance mutations. Participant 2 had 4 rilpivirine resistance mutations and one CAB mutation. No genotype was obtained in participant 3. And participant 4 had just a single mutation for low-level rilpivirine resistance and a single mutation for cabotegravir.

Notably, none of the participants who had confirmed virologic failure had obesity. The highest BMI here was just under 26, and there was no particular pattern related to either viral subtype or to preexisting rilpivirine or cabotegravir resistance associated mutations.

[00:23:37]

          Posttest 2

So let's go to the post-test. In the CARES study in Africa, using a public health approach in people with virologic suppression, when compared with oral standard of care ART, virologic success with long-acting CAB plus rilpivirine was:

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

So please vote. We'll give you some time to think about this and record your votes. All right, let's take a look and see what people thought. So three quarters of you got the correct answer. Long-acting CAB rilpivirine was non-inferior at both time points. It was never superior, nor was it ever inferior.

Let's just take a second. Beatriz, if you can come off mute for a minute. How do you think these data will impact the use of long-acting CAB rilpivirine in a country like Brazil?

Dr Beatriz Grinsztejn (STI/AIDS Clinical Research Laboratory): Thanks very much, Dan. So unfortunately, in the global South, this regimen has not been included in any guidelines. WHO guidelines will be reviewing this next week. But unfortunately, this hasn't been incorporated. And as we could see in the CARES study, the sustained results for 96 weeks and most impressively, the high level of satisfaction of our patients that were included would be really something to be taken into account. But now with the - in Brazil, we depend on the manufacturer’s price. And not only that, but also the manufacturer of rilpivirine is not doing it anymore. So we don't have any guarantees that the manufacturing of rilpivirine will - will be available for my country, for instance.

And in other countries in Africa, the uncertainties related to funding will also probably impact a lot in future perspective for a long-acting combination.

Dr Kuritzkes: Thanks for that perspective. Great study results, but very challenging for implementation and - and certainly challenging times ahead.

[00:26:23]

          Posttest 2: Rationale

All right. Well, let's continue on here. We've already discussed the answer here.

[00:26:29]

Potential Future HIV Treatments

So let's talk about some potential future HIV treatments now.

[00:26:35]

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

We saw exciting results of 2 studies of the combination of doravirine and islatravir as oral antiretroviral therapy. And these were the 48-week results. These were 2 international randomized controlled trials, phase III trials. The first was a blinded study in which participants who were on bictegravir, FTC and TAF were randomized to either continue on that regimen or switch to doravirine/islatravir.

Now, an important point here. You may recall from data presented at previous meetings that at higher doses, islatravir caused a significant reduction in total lymphocyte count, and therefore also a reduction in total CD4 cell count. There were no clinical correlates, but that was a concerning laboratory finding, and so this study made use of a much lower dose of islatravir just 0.25 mg daily.

And in the second study, the open-label study involved a switch from any current oral regimen to doravirine/islatravir. Same doses of doravirine and islatravir, and because of the variety of regimens, it could only be done as an open-label study.

Looking at the 2 results here, you see that they are really pretty much identical, between 92 and 95% or 96% of people maintain virologic suppression. The differences between the 2 regimens were not statistically a significant—as switched—I should say first, as switch studies, the primary endpoint was really the number of people who had viremia. And you can see the difference here between 1.5% and 0.6% was well within the confidence limit of the lower bound of minus 4%.

And then here again in the open-label study, once again, you see that the switch to DOR/islatravir fell well within the—actually did better than the standard of care and was within the noninferiority margin as well.

[00:28:58]

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

Going to the next slide, since there was such emphasis on the issue of safety as it related to lymphocyte count, it's important to note that in both studies, there was actually a gradual increase in the percentage of lymphocyte count and in the percent of CD4 cell count over time. These were people who had been on antiretroviral therapy for some time already, and nevertheless, they continue to see some increase in CD4 count percentages and then overall percent change in their—they had about a 5% to 10% increase in lymphocyte count, in a 10% increase in CD4 count, I should have said.

And that was true - true in both the blinded study and the open-label study. So in both of these studies, the - there was no impact of islatravir on the lymphocyte count or the CD4 count. And in both of these studies, the lymphocyte and CD4 counts looked really the same in the islatravir arm and in the control arm.

[00:30:03]

          Switch to DOR/ISL From Oral ART: Safety

Well, looking more generally at safety, one of the issues that comes up, because this regimen has no tenofovir in it, is what happens with hepatitis B. Of course, people who were known to be hep B infected were excluded. There were a couple of cases of low level viremia without antigenemia or elevated transaminases.

Two cases of acute HBV infection occurred. Both of them had been negative at baseline. This raises the question of, you know, how the potential effectiveness of tenofovir containing regimens as essentially PrEP for HBV.

And then just to summarize again, the changes in total lymphocyte and CD4 cell counts were the same across both study arms. There was no decrease at all. And then in the blinded study, there were hardly any participants who discontinued due to changes in - in their lymphocyte or CD4 count, and that was the same in the doravirine control arms.

And in the open-label study, there were no treatment discontinuations due to the changes in those parameters. Weight changes were variable at week 48. In the blinded study, where people either continued on BIC/FTC/TAF or switched to doravirine/islatravir, there was really just about a third of a kg difference. You can see that was not statistically significant.

In the open-label study, it depended on what regimen you were transitioning from if you switched to doravirine/islatravir. So if you excluded efavirenz and TDF-based regimens, both of which are known to be weight suppressing, then comparing the 2 arms, there was just a 0.2- kg—I'm sorry. There was a 0.8-kg difference, almost a kilo, but that was also not statistically significant.

And then finally, at enrollment, it's important to remember that people had been on therapy for between 3.5 to nearly 4 years, so they had been well adapted to their pretreatment, or prestudy regimens. And that may have had some impact on the changes seen as well.

[00:32:37]

          Posttest 3

So let's move to our post-test number three. Based on phase III data, when compared with continued bictegravir, FTC/TAF, or other oral ART regimens, switch to daily oral doravirine and islatravir had:

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

So again, I'll give you some time to mull over these choices and record your votes. All right. Let's take a look. Great. 80% of you got the correct answer. I will advance my slides here.

[00:33:40]

          Posttest 3: Rationale

So B is the correct choice. There was similar efficacy of the regimens in both studies, with similar changes in total lymphocyte count and in CD4 cell count.

[00:33:55]

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

We also saw interesting data on completely novel regimen that of injecting - injectable lenacapavir as - along with 2 broadly neutralizing antibodies, teropavimab and zinlirvimab, also known as TAB and ZAB, for simplicity. And these were done as switch studies in people who were virologically suppressed.

Last year we had seen some pilot data on this regimen. And so this was a more extensive, expanded phase II trial, where people who were on a suppressive regimen were randomized either to continue on that oral regimen or to receive every 6 months lenacapavir after 2 oral loading doses, together with fixed doses of TAB and ZAB. So these were not weight-based doses, but fixed doses based on PK models that suggested the doses you see here were the appropriate doses. And the antibodies were administered intravenously.

Not shown on this slide, but important to help place the results that you'll see in context, the participants had to be screened for susceptibility of their virus to the 2 antibodies because they were virologically suppressed. That had to be done based on archival DNA. That was the testing done by monogram and the - with the DNA-based entry inhibition assay. Of the 240 or so people who were screened around 40, the assay failed.

In those in whom the assay actually generated a result, half were resistant to at least one of the antibodies and excluded from the study. So challenging to find eligible participants.

The primary endpoint here was, as in other switch studies, becoming viremic at week 26 by FDA snapshot analysis and the usual secondary endpoints of safety, PK and the emergence of anti-drug antibodies.

[00:36:09]

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

This slide summarizes the results. You can see that there was just a single participant in the experimental arm who had a viral breakthrough. By week 26, nobody in the standard of care arm experienced virologic - experienced viremia. And there were 2—1 participant in each group—who had missing data at Week 26.

The participant who had virologic failure did so with detectable viremia at Week 12. That person had lenacapavir concentrations that were more than a standard deviation below the mean, which was a puzzling and may have explained in part the viremia that by Week 24, resistance to lenacapavir was detected, as well as loss of susceptibility to zinlirvimab, but susceptibility remained to teropavimab, suggesting that loss of susceptibility to just a single antibody may be sufficient to be associated with virologic failure.

That participant restarted a BIC/FTC/TAF and - and became suppressed. The most common AEs were injection related. They were mostly grade 1, and there were no serious adverse events. And you can see that between 11% and 17% developed anti-drug antibodies, but that had no effect on the PK of the antibodies, nor did it - was it associated with virologic failure.

[00:37:47]

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

The EMBRACE study is another study of a different broadly neutralizing antibody, in this case N6LS. Here it was a single antibody together with injectable cabotegravir. This study was again a switch study taking people who were suppressed on standard oral regimens and randomizing them 2 to 2 to 1, either to continue on their regimen or to get N6LS intravenously as weight-based dosing, along with monthly CAB, or to get a standard 3000 mg dose, together with a high - hyaluronidase that allowed for subcutaneous administration of the antibody and monthly cabotegravir.

The reason for monthly rather than every other month CAB is because this was an experimental regimen. And so just for maximum participant safety, the cabotegravir was dosed more frequently than we're used to doing in clinical practice. And again, the primary endpoint was viremia with the same key secondary endpoints of safety injection site reactions, and so on.

[00:39:02]

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

So here we see the primary results at week 26. 96% of the participants maintained virologic suppression in both the intravenous N6LS arm and the oral standard of care arm. There were 4% of the participants had viremia in the N6LS arm compared to none in the standard of care and 6% in the SC administration arm.

Four of the 5 participants with viremia over 50 copies met the criteria for confirmed virologic failure. There were 2 in the IV arm and 2 in the SC arm. And in the IV arm, neither one developed INSTI RAMs, but both developed resistance to N6LS. In the SC arm, 1 participant did develop INSTI RAMs, and neither developed resistance to N6LS.

As a result of this study, and I should say that there were no AEs leading to study withdrawal and injection site reactions were much less frequent with intravenous dosing than SC dosing and N6LS. As a result, it's been decided to move forward with intravenous dosing of N6LS in future studies. And so a phase III trial of this combination is anticipated.

[00:40:33]

          Pipeline: Phase IIa Proof-of Concept Studies

Two quick proof-of-concept studies to present. Exciting new data with a third generation integrase strand transfer inhibitor. This is a drug that shows in vitro activity against most dolutegravir-resistant mutants. In the study that was done in viremic participants, the maximum change in virus load through day 10 was greater than 2 logs at 50- and 300-mg doses.

All the adverse events were just grades 1 and 2 with no serious AEs. And this agent is moving forward to be developed as a long-acting injectable integrase strand transfer inhibitor. There was also a novel HIV capsid inhibitor presented. Here, the maximum reduction in virus load was between 1.8 and 2.2 logs, the highest reductions seen in the 250-mg dose. One participant did develop a capsid inhibitor mutation. And if you remember from the lenacapavir study I just presented, it's the same mutation. This is now emerging as a classic capsid inhibitor resistance mutation.

Again just grade 1 and 2 AEs. No serious AEs. And this agent is being developed as a long-acting injectable capsid inhibitor for HIV.

[00:41:58]

RIO: Effect of bNAbs on HIV Control During ART Interruption

And then lastly, let me quickly sum up by presenting the results of the RIO study. This was really presented in the HIV cure session, but it is also a novel therapy. Here the participants were people on suppressive antiretroviral therapy, and they were randomized to receive either the long-acting forms of 3BNC117 and 10-1074 or a placebo.

I remind you that the antibodies we just talked about, the TAB and ZAB are, in fact, slightly modified long-acting versions of these same antibodies. So it's very similar to what we were talking about in that lenacapavir trial.

People received a single infusion of the antibody and then underwent an ATI and were monitored closely. And then if at Week 20, in Arm A, they remained virologically suppressed, they could get a second dose of the antibody and they continue to be followed. And the primary endpoint was virologic rebound either sustained rebound above 1000 or any rebound above 100,000, as well as looking at safety and long-term viral suppression.

[00:43:26]

RIO: Viral Rebound and Safety Outcomes

The primary results show that there was no viral rebound by Week 20 in 75% of the participants who got the bNAbs vs about 9% in the placebo arm, which, given the small size of the study, didn't quite reach statistical significance, but is an impressive difference nevertheless.

The median time to rebound with the bNAbs was about 62 weeks, and among people who received the bNAbs who hadn't rebounded by Week 20, nearly 60% had no rebound even after Week 48, and a quarter of the participants remained virologically suppressed off ART at Week 72.

There were no discontinuations due to AEs, no infusion reactions, and all of those who did restart ART achieved viral suppression nearly all by week 12. One point that's missing from this slide is that the antibodies had a half-life of around 60 to 70 days, and actually half of the participants were predicted in PK modeling to have antibody concentrations above 10 micrograms per ml, which is thought to be the concentration needed to maintain suppression at day 300.

And so to me, it's not at all surprising that most of these people remain suppressed. I think they remain suppressed because they still had plenty of circulating antibody. But a lot more analysis needs to be done to dig into the mechanisms of ongoing suppression in this trial.

[00:45:06]

          Key Takeaways: Treatment

So key takeaways for this section of our webinar. The CARES study using a public health approach in Africa, a switch to long acting CAB and rilpivirine was noninferior to continued standard of care oral ART through Week 96.

In phase III studies switching to daily oral doravirine/islatravir was noninferior to continued bictegravir/FTC/TAF or other standard of care oral regimens through Week 48, with no differences in total lymphocyte or CD4 cell count changes and no decreases in those counts.

96% of participants were able to maintain suppression with a variety of investigational bNAb regimens in combination with long-acting injectable therapy, either cabotegravir or lenacapavir in phase II and phase IIb studies, and a larger, longer term studies are anticipated.

We saw potent antiviral activity with a novel investigational third generation entity and a novel investigational capsid inhibitor, both of which are going to be developed as long-acting HIV treatments.

And then lastly, three quarters of the people who received the combination of bNAbs in the RIO trial maintained virologic suppression through Week 20, and a quarter of the recipients stayed virologically suppressed off Week 72. And a lot more interesting information is going to come from that.

So it's now my pleasure to turn this over to my colleague, Dr Beatriz Grinsztejn, who will talk to us about prevention.

[00:46:44]

HIV Prevention

Dr Grinsztejn: Thank you so much, Dan, and good afternoon to you all. So let me start by presenting you the PILLAR study.

[00:46:54]

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

PILLAR is a real world, industry-led phase IV implementation trial assessing the integration of CAB LA in 17 clinics in high priority counties in the US. Despite being approved by the FDA since 2021, CAB LA rollout in the US has been very slow, and globally, the rollout is under threat during the major challenges being faced by person.

A total of 201 participants were enrolled and initiated CAB LA in the PILLAR study and the study population, as you can see, is diverse with 66% of transmen, 38% of Hispanic or Latinos, and 26% of Black. 22% of the participants had not received oral PrEP in the last 6 months prior to receiving a CAB LA injection—the first CAB LA injection demonstrating the potential for CAB LA to expand PrEP uptake.

So at month 12, 72% of participants completed all injections within the study. CAB resistance was 85% at Month 6 and 73% at month 12, higher than previously reported with oral PrEP, as we know. None of the participants acquired HIV infection through month 12 in the study, and 13% of the participants acquired an STI during the 12-month period, showing us that there was ongoing, risky exposure during study.

[00:48:37]

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

Now, I will show you some new results from HPTN 083 that were also presented at CROI. As you all know, HPTN 083 was a randomized, active controlled, double-blind efficacy study comparing CAB LA to daily oral TDF/FTC among cisgender men and transgender women who had sex with men at 43 sites in 7 countries.

The blinded phase of the study was stopped early in May 2020 for a finding of superiority of CAB LA over daily oral TDF/FTC and transitioned to an open-label extension phase thereafter. The primary results demonstrated an approximately two thirds reductions in HIV incidence in participants who were randomized to CAB compared to TDF/FTC.

This new analysis presented by Raphi Landovitz attempted to answer the question of which is the optimal ART choice when HIV is acquired in the context of CAB LA PrEP.

So this was a case series of 47 HPTN 083 participants diagnosed with HIV on or before December 1st, 2023, after receiving at least one CAB injection and having at least 30 days of follow up on ART. ART regimens were chosen locally at study sites, and the availability of genotyping results at the time of the regimen, selection was not available for these participants.

Of note, these 47 cases occurred during the blinded phase I—within 1 year after unblinding, and also included all the cases from the open-label phase of the HPTN 083. So several of these cases have not been presented before.

So in the table we can see that HIV cases were categorized according to ART regimen, INSTI-based or other. And whether or not people received a CAB LA injection in the prior 6 months. Overall, 77% were suppressed on their first ART regimen, being 71% treated with an INSTI-based regimen and 81% treated with other ART, predominantly - sorry, predominantly a darunavir based - post a darunavir-based regimen, and also a few cases on an NNRTI-based regimen.

So, for INSTI-based regimen treated cases identified within 6 months of last CAB injection, the clinical situation in which we would expect the highest frequency of INSTI resistance. And this is based on previous data from HPTN 083. We saw 83% of viral suppression.

And for INSTI regimen cases greater than 6 months from the last CAB LA injection, 67% were suppressed. So for non-INSTI regimens, 94% suppressed in those identified within 6 months of a CAB injection.

And finally, non-INSTI cases identified greater than 6 months from the last CAB injection were 60% suppressed. So based on the available data also switches from an INSTI-based regimen were safe and improved virologic outcomes.

Centralized lab testing, which was not available to sites when regimens were chosen, identified INSTI-resistance associated mutations in 9 of the 44 cases before ART initiation. Among these 9 people, 8 had received a CAB LA injection in the prior 6 months, and only 1 participant who received a CAB LA injection more than 6 months had INSTI - INSTI RAM – an INSTI RAM. So these findings are quite reassuring regarding the long tail of cabotegravir, supporting the idea that the risk of INSTI-resistance emergence during this period is small.

The data indicate that individuals at highest risk of developing INSTI resistance are those who have received a CAB LA injection within the preceding 6 months. Although this is a limited data set, but data gathered from more cases and of course, data gathered from more cases will help us elucidate the best treatment approach for individuals who acquire HIV using CAB LA for PrEP.

[00:53:44]

Potential Future HIV Prevention Therapies

So I will now move to potential future HIV prevention therapies. But first I wanted to ask then if you could comment on the HPTN 083 case series.

Dr Kuritzkes: Well, thanks so much, Beatriz. You know, I think you got it exactly right. The most interesting result to me is that it really provides reassurance around the tail that we're very unlikely to see resistance to cabotegravir emerging, despite its very long PK tail in people who acquire HIV more than 6 months after their last exposure to the drug.

So that's quite reassuring. And then I also agree that even though we saw good rates of viral suppression with an integrase inhibitor-based regimen, including in the one person who had a mutation, I believe, you know, I think the current guidance that if somebody acquires HIV after use of cabotegravir for PrEP that the best initial regimen while awaiting resistance test results or where they may not be available is to use a boosted protease inhibitor and then to sort things out later on if resistance test results do become available. Because these numbers are just a little too small to be fully reassured that you can use either bictegravir or dolutegravir in the setting of CAB failure.

Excellent. Thank you so much for your insights, Dan.

[00:55:25]

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

So now moving forward to potential HIV prevention therapy. So recognizing the many barriers that adolescents and young people face, and their preference for long-acting alternatives that can offer a more discreet and convenient option for HIV prevention. Results from the PURPOSE I study comparing age specific groups were presented.

So, as you all know, PURPOSE 1 was a phase III, multicenter, double-blind, randomized trial enrolling sexually active adolescent girls and young women who were not using PrEP in Africa and had not tested for HIV in the past 3 months. This was the first phase III HIV prevention study to include adolescents, and importantly, emancipated adolescents were permitted to provide independent consent.

So participants were randomized 2 to 1 to receive subcutaneous LEN every 26 weeks, daily oral F/TAF or daily oral F/TDF with matching customers. LEN is a first-in-class, multi-stage HIV one capsid inhibitor with high potency and a high and a long half-life, supporting twice daily injections.

So of this, 124 adolescents enrolled, 56 received LEN, 45 F/TAF and 23 F/TDF. The prespecified interim analysis was conducted when 50% of participants had completed 1 year of follow-up. So the primary analysis assessed the efficacy of LEN and F/TAF for HIV prevention by comparing HIV incidence rates against both the background incidence cohort and a negative control group receiving daily F/TDF. In addition, secondary analysis evaluated the safety of LEN in adolescent participants.

[00:57:20]

          PURPOSE 1: Efficacy, Safety and PK Outcomes

And so consistent with findings from the main cohort, there were zero HIV infections among adolescents receiving lenacapavir injections, demonstrating 100% efficacy in preventing HIV as well as in other study arms in the adolescent form. LEN was safe and well tolerated in adolescents with a safety profile that was similar to that observed in adults.

No adverse events led to treatment discontinuation in the adolescent group, and injection lab reactions and lab abnormalities were comparable between adolescents and adults.

So in regards to the PK results, plasma lenacapavir concentrations that were measured at Weeks 4, 8, 13, and 26, and then every 13 weeks were generally comparable between adolescents and adults, supporting the extrapolation of efficacy data in both groups.

In summary, the PURPOSE 1 trial generated primary analysis data that could support the early inclusion of adolescents in regulatory labeling and clinical guidelines, ultimately leading to accelerated access to LEN for these highly vulnerable groups.

[00:58:34]

          Posttest 4

So now let's move to the post-test four on PURPOSE 1. We just commented that the study evaluated LEN as PrEP for cisgender women, including adolescents aged 16 to 17 years old.

1. Some LEN discontinuations due to AEs but similar trough concentrations as adults;
2. No LEN discontinuations due to AEs and similar trough concentrations as adults;
3. Some LEN discontinuations due to AEs and lower trough levels as adults; or
4. No LEN discontinuations due to AEs but lower trough concentrations as adults.

Please vote. So excellent.

[00:59:56]

          Posttest 4: Rationale

The correct answer as you - most of you could find is option B, and we can see there were no LEN discontinuations due to AEs and trough concentrations were similar between adolescents and adults.

[01:00:11]

          Pipeline: Long-Acting PrEP

So now let's take a look at the long-acting PrEP pipeline presented at CROI 2025. First results from PK and safety of 2 novel once-yearly intramuscular formulation of LEN were presented with the aim of achieving similar concentrations to twice yearly subcutaneous LEN, which has demonstrated efficacy.

So once yearly LEN could be further addressed HIV PrEP barriers such as stigma, adherence challenges, and the need for frequent healthcare interactions.

So in this phase I study, a single dose of 5000 mg of LEN, lenacapavir was administered at two 5-mL intramuscular gluteal injections and 20 healthy adults participants received formulation one, which was formulated with 5% ethanol and 20 received the formulation 2 with 10% ethanol.

So in summary, following the administration of this one yearly intramuscular lenacapavir, median plasma concentrations exceeded those associated with efficacy in phase III studies of twice-yearly lenacapavir for PrEP for at least for 56 weeks.

Both formulations were safe and well tolerated, and injection site pain was the most reported adverse event. So there is this great potential for this new biomedical prevention with a once a year dosing interval. Next steps include the plan to investigate it as a PrEP option in - in future studies.

And in addition, as you may know, islatravir was initially intended for use as a once monthly PrEP option. However, its development for this indication was halted due to impacts on lymphocyte counts. So now a new NRTTI has emerged MK-8527 belonging to the same class. So Kapoor and all presented data on a population of macaque PK model for once monthly MK-8527-TP to inform the phase II dose selection.

So based on the results of once-monthly oral dose for MK-8527 of 6 mg or higher is expected to achieve efficacy thresholds for over 90% of the population at steady state. Phase II studies are fully enrolled and results are expected for later this year.

[01:02:50]

STI Prevention

Now changing gears to STIs.

[01:02:54]

          STOMP: Tecovirimat in Persons With Confirmed or Presumed Mpox

The STOMP study was an ACTG randomized, double-blind, placebo-controlled trial comparing weight-based tecovirimat vs placebo for 14 days for the treatment of symptomatic mpox. The STOMP study also included an open-label arm for people who were less than 18 years old, pregnant, or breastfeeding with severe immunosuppression or protocol-defined severe disease. So these people were not randomized.

The primary endpoint was time to clinical resolution with - which is all skin lesions scabbed or epithelialized, and all visible mucosal lesions healed. Secondary outcomes included, importantly pain scores and the detection of mpox virus in various comparator compartments.

So participants could also move to the open arm, if they didn't—if disease progression was seen, or severe pain on Day 5.

So of note, this study was stopped early by the DSMB based on a futility analysis. And by the time of the DSMB review, 703 participants had been enrolled with 413 randomized for presumptive mpox.

In the table, we can see that participants were enrolled approximately 8 days after symptom onset, with one-third experiencing severe pain and a similar median number of lesions and proctitis. HIV prevalence was 38% in the tecovirimat arm and 28% in the placebo arm, with prior - with same rates comparable rates of prior mpox vaccination.

[01:04:37]

          STOMP: Clinical Resolution and Other Outcomes

So in this graph, we can see how the curves from both arm overlap, placebo shown in orange and tecovirimat in blue illustrating that the time to clinical resolution was similar between both arms. So unfortunately this study was discontinued as tecovirimat did not improve time to skin lesion resolution or pain control.

These results are aligned with the PALM 007 study, a similar study but that enrolled Clade I participants in the Democratic Republic of Congo. Of note, ANRS-sponsored UNITY study also evaluating TPOXX for mpox, predominantly in South America is ongoing, and results are expected for later this year.

[01:05:26]

          Key Takeaways: HIV and STI Prevention

So moving to the key takeaways in terms of HIV prevention and STIs. We saw a high L - a high persistence on CAB LA PrEP through month 12 in high HIV epidemic priority areas in the PILLAR study. HPTN 083 data provide valuable insights into managing individuals who acquired HIV while receiving CAB LA in the study.

Notably, all participants with INSTI RAMs achieved virological suppression, highlighting important considerations for treatment strategies. In PURPOSE I, no HIV seroconversions were observed among adolescent girls aged 16 and 17, who received LEN PrEP, and in addition, PK and safety data were comparable to those seen in adult women, reinforcing the potential for this age group.

And lastly, in the STOMP study, tecovirimat did not demonstrate an improvement in time to skin lesion resolution or pain control for mpox.

[01:06:33]

          Posttest 1

So moving now to the post-test. After participating in this activity. So after participating in this activity, I am familiar with data from the CROI conference, and I plan to translate this data into current or future management strategies. Please vote now. And the options are:

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

So I'm very happy to see that the large majority agree or strongly agree, that this data - the data presented will improve their practice.

And now we have a few minutes to go to the - move to the question and answer session.

[01:07:45]

Questions and Answers

Jacqueline Meredith: Yes. Thank you so much. So please enter your questions in using the Q&A feature of the platform. But let's start off with our question from Leon[?]. Does lenacapavir have a low genetic barrier to resistance? Dr Kuritzkes, could you take this one?

Dr Kuritzkes: Sure. Well, first of all, it was really terrific hearing about all those exciting PrEP studies and - and also the STOMP study from Dr Grinsztejn. The - you know, it all depends on one's perspective. I think certainly resistance to lenacapavir has been seen in both prevention trials and in some of the - some of the treatment trials.

And actually, let me take that back. The resistance has been seen in - in several of the treatment studies. And that is similar to what we've seen with drugs like the first-generation integrase strand transfer inhibitors and efavirenz or rilpivirine. We - and is different from what we see with the boosted protease inhibitor or with the second generation integrase strand transfer inhibitors.

So compared to the - to bictegravir or dolutegravir compared to boosted PIs, it seems that you can more readily generate resistance to lenacapavir. But we did extraordinarily well with - with both efavirenz and with raltegravir, despite the fact that resistance could emerge. And so I - I think it's going to depend a lot in terms of context and how LEN is used.

From a prevention perspective, LEN has the huge advantage of not having cross-resistance to the integrase inhibitors, which are the standard of care for people who have HIV. So - and then with other forms of long-acting therapy, it will be critical to protect LEN in much the same way as we protected efavirenz or raltegravir.

Jacqueline Meredith: Excellent. Thank you. I know, Dr Kuritzkes, when we were - we're thinking about the studies to include for this rapid webinar, we talked a lot about the HIV cure studies that were presented at CROI. And we do have a question from Michael about some of the cure therapies that were presented. I don't know if you can comment on some of the preliminary results that you saw from the conference at all?

Dr Kuritzkes: I mean, there are a lot of studies. They were all very interesting. I think they're all really still quite preliminary. And I know the - the question is about the TRAILBLAZER study. I'm sorry that I don't remember off the top of my head precisely which presentation that was and don't have my program book in front of me right now.

But as a general comment, I would say that, we've seen some interesting effect on various markers. There's still really not been compelling evidence that any of the interventions is really leading to sustained virologic suppression in the absence of antiretroviral therapy. There's still a huge amount of - of work to be done in order to - to get to something resembling either a long-term remission or actual cure outside of the handful of people who've received stem cell transplants.

Jacqueline Meredith: Thank you. And then we only - we're basically up to the hour, and we just got one question from Renee[?] about the cost of these new agents. And maybe Dr Grinsztejn, you could - you could address about some of the barriers of cost to some of these new therapies and, you know, countries that might not eventually be able to afford them. And if that could also affect, you know, adherence to these therapies. So - so it was a very long question, but hopefully.

Dr Grinsztejn: Yes. No problem. Thank you. Thank you, Jacqueline. I will try. So for the CAB – CAB LA, there were licensing through the MPP and generic version is expected, but not earlier than 2027. And until now, the rollout, as I mentioned it has not been great at all. And we were counting on PEPFAR and USAID funding to properly roll out this option. And also lenacapavir that was also licensing for 6 factories have been agreed by the producer.

So we were expecting that rollout could be massive for this first from the producers, but also for the generic products that will be obtained through this licensing. And these are for countries that are contemplated in the licensing.

For countries like mine, we are having huge difficulties in incorporating CAB LA, given the very high prices that are being asked from us. So it's quite complex. It depends on the setting and the situation that we are facing of constrained resources only make us feel very insecure about the potential of this - of these agents – agents - new agents, new technologies in the most - in the areas where HIV infections is - are still growing or not under - not under control. So not at all.

Jacqueline Meredith: Thank you for answering that question. And it looks like we're 2 minutes over. So we're going to have to wrap up this webinar. I would like to thank Dr Kuritzkes and Grinsztejn for your excellent presentation, your insights on these new studies, and very informative Q&A session. And many thanks to our learners for participating in this program. Please be sure to complete the evaluation to receive credit, and you can access that link using the Resources icon here on the platform.

Thank you very much again and enjoy the rest of your day.

[END OF TRANSCRIPT]