HIV Update: Independent Conference Coverage of CROI 2026

Emerging HIV Treatments

Dr Daniel R. Kuritzkes (Harvard Medical School):

I'm going to start off by talking about emerging HIV treatments.

[00:06:06]

ARTISTRY-1 Switch to BIC/LEN From Complex ART

And the first study I'll discuss is the ARTISTRY-1 study, which was a randomized, phase III trial of switching from - to bictegravir/lenacapavir as a single tablet 2-drug regimen from complex ART, that is, people who are on multi-tablet regimens or regimens that often included a boosted protease inhibitor.

This slide shows the participant characteristics. And I'll just highlight a couple of things very briefly to note that this was an extraordinarily experienced group of people with a median HIV duration of nearly 30 years, many of whom were on regimens that included several pills a day.

[00:06:51]

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

Because this was a switch study, the primary outcome is the proportion of participants who experienced viremia greater than 50 copies per ml. And you can see on the left-hand side of the slide that these numbers are nearly identical, 0.8 and 1.1%, or 3 and 2 participants, respectively, in the BIC/LEN and complex ART group.

Looking over to the right side of the screen, you can see this easily met the noninferiority margin with a minimal difference between the arms. So from the study, one can conclude that switching to a combination of bictegravir and lenacapavir as a once-daily regimen was noninferior to continuing on complex ART in maintaining virologic suppression in this group of highly treatment-experienced people with HIV.

There were no treatment-emergent resistance mutations detected in either study arm. The CD4 counts remained stable in both groups throughout the trial. There were 3 participants in the BIC/LEN group, as you see at the bottom on the left, who had an episode of viremia, but they either resuppressed or had only low-level viremia without needing to change their assigned treatment throughout the duration of the study.

[00:08:08]

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

Not surprisingly, because many of the participants were switching from a boosted regimen to a simplified regimen, the switching to BIC/LEN was associated with an improvement in their lipids, as you can see in the table below. Switching to BIC/LEN was also associated with significant improvements in patient-reported treatment satisfaction throughout the trial, as assessed by an HIV treatment satisfaction questionnaire. Those who stayed on their complex regimen, of course, didn't really have much of a change in their satisfaction because they weren't experiencing any change in their regimen.

[00:08:48]

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

A parallel study, which was presented as a poster was the ARTISTRY-2 study, which explored switching from BIC/LEN - I'm sorry, switching to BIC/LEN from BIC/FTC/TAF. So participants who were on a regimen of BIC/FTC/TAF and virologically suppressed were randomized to either continue on that regimen or switch to the BIC/LEN regimen.

This population was somewhat younger than the previous population, only 35%, compared to about 75% were older than 55. They had pretty high median CD4 counts and had smaller number of comorbidities.

[00:09:36]

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

Looking at the outcomes, they're very similar to what we saw in the ARTISTRY-1 study, 1.3% vs 1% of participants in the BIC/LEN vs BIC/FTC/TAF arms, respectively, experienced viremia of 50 copies or greater. That meant 5 people in 1 arm and 2 in the other. And again, just as we saw in the previous study, this easily met the noninferiority margin for a switch study.

The switch - therefore, we can conclude that switching to BIC/LEN was noninferior compared to continuing on a triple drug regimen of bictegravir, FTC, and TAF.

There were 4 people in the BIC/LEN arm who had low-level viremia at Week 48, one of whom resuppressed after a change—requiring a change to a PI-containing regimen. Interestingly, 2 people in each arm were tested for resistance, and at 36 weeks, 1 person in the bictegravir/lenacapavir arm had emergence of the R263K mutation in the integrase gene, 1 of the canonical integrase inhibitor resistance-associated mutations.

To my knowledge, this is perhaps the first time we've seen an integrase inhibitor resistance mutation emerge in a bictegravir-treated patient from a - from a treatment trial.

Importantly, the CD4 cell count, weight, and BMI remained stable in both arms throughout the trial.

[00:11:16]

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

Turning now to a different regimen. This is now a combination of doravirine, a non-nucleoside RT inhibitor, and islatravir, the nucleoside reverse transcriptase translocation inhibitor vs continued BIC/FTC/TAF—I'm sorry not to continue. This is in treatment-naive individuals starting with dor/islatravir or B/F/TAF.

This was an international, double-blind, active-controlled trial, again, a noninferiority trial, but for initial therapy, not a switch study. You can see the design of the study illustrated here on the slide. And the primary endpoint was achieving viral suppression to less than 50 copies.

[00:12:10]

First-line DOR/ISL vs BIC/FTC/TAF: Baseline Characteristics

Looking very quickly at the participant characteristics. You can see there were about 270 participants per arm. They were enrolled from around the world. Although the median virus load was in the mid-50,000 range, it's important to note that a substantial proportion had high virus loads. More than a third had baseline virus loads above 100,000 copies and 10% in each arm had more than half a million copies. That will become important as we look at the - the results.

[00:12:46]

First-line DOR/ISL vs BIC/FTC/TAF: Virologic Response

Here we see that the 2 arms performed equally well, with about 92% of participants in the doravirine/islatravir arm and just under 91% in the B/F/TAF arm achieving virologic suppression and maintaining suppression through week 48. This easily established noninferiority of doravirine/islatravir regimen. There were very few virological failures, and only a handful of participants who had unavailable data at the Week 48 window.

So this study establishes similar efficacy of these 2 regimens, and the regimens were equally effective across CD4 count strata and virus load strata.

[00:13:37]

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

An interesting finding, however, was that there were 2 participants in the doravirine/islatravir arm who had very high virus loads, over a million copies, as you can see here, participant A and B, who experienced a confirmed virologic failure in the trial and in whom resistance mutations emerged.

Participant A had the emergence of the 184I mutation, which is an islatravir resistance mutation and emergence of the Y188L mutation, a doravirine resistance mutation.

Participant B, who likewise had very high virus load, had emergence again of the 184, in this case 184V mutation, the islatravir resistance mutation, and then mutations at 106 and 227, which are islat - are doravirine resistance mutations.

Curiously, the L74I mutation also emerged, not a mutation associated with resistance to islatravir. You may recall it's a resistance mutation for didanosine and for abacavir. This suggests there may have been archived resistance of - resistant viruses that were of re-emerging in this participant, and they must have been transmitted mutations, because these were people who were supposed to be getting first-line therapy. Some may have had prior treatment and not - not disclosed that information.

There were 2 serious treatment-related adverse events in the doravirine/islatravir arm. One was a hypersensitivity type reaction with eosinophilia and systemic symptoms. The second was a drug-induced liver injury that is elevated transaminases but without hyperbilirubinemia. So not meeting Hy's law.

Otherwise safety was really comparable and - with similar rates of severe adverse events and grade 3/4 adverse events, as well as adverse event-related discontinuations between the groups. And very similar CD4 cell count increases were seen in the 2 arms, and interestingly, very similar, nearly identical increases in weight were seen across both treatment arms, despite the fact that 1 arm had an integrase inhibitor and TAF and the other arm did not.

[00:16:02]

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

Turning to a switch study with doravirine/islatravir. This trial looked at participants who were suppressed on a B/F/TAF regimen, similar to what we were looking at before with the BIC/LEN study, but now they were switched to doravirine/islatravir. And so the study design is similar in concept.

Here in this study, post-baseline resistance testing was done for participants who experienced confirmed viremia above 200 copies per ml or who discontinued the study treatment with a high virus load, and you can see the secondary endpoints listed there.

[00:16:49]

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

Looking again quickly at the participant characteristics, the randomization was 2-to-1, so there were twice as many people in the doravirine/islatravir arm as in the B/F/TAF arm. And you can see they were also a fairly experienced group with about 11 years of history of having HIV and had CD4 counts in the 700 range.

[00:17:23]

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

The study showed definitively the noninferiority of switch to doravirine/islatravir as compared to continuing on bictegravir/FTC/TAF here. It's the second pair of columns on the slide that we're focused on, the proportion above 50 copies, which was 1.5% in the dora/islatravir arm and 1.2% in the B/F/TAF arm. So again, very narrow difference between the arms easily meeting the noninferiority margin.

And if we just looked at the more classic endpoints of how many people maintain virologic suppression, you can see that about 90% in both arms did so.

Importantly, there were no differences in CD4 cell count or in total lymphocyte count between the arms through week 96. I emphasized this point because earlier studies of islatravir using a higher dose had shown that islatravir could lead to lymphocytopenia and therefore reductions in CD4 count, but that was not observed in this study with the lower dose of islatravir that is now being taken forward.

[00:18:38]

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

To summarize the safety information for participants on doravirine/islatravir. There were no clinical hepatitis B reactivations observed, although there were 3 cases of low-level hepatitis B viremia. That's by HBV DNA without hepatitis B surface antigenemia, and there was no elevation of transaminases.

There were 4 cases of acute HBV infection, of both of whom—in all with—in these participants, they were negative for both hepatitis B core antibody and hepatitis B surface antibody at the time of study enrolment.

There was no difference in weight change at Week 96, as I had mentioned in the other study. There was about a 0.3 kg increase in weight in the dora/islatravir arm and a 0.4 kg increase in weight in the B/F/TAF arm.

[00:19:46]

Posttest 2

So this brings us to post-test question number 2. And actually - okay, I need to just move that so I can read it. Based on phase III data when compared with continued bictegravir/FTC/TAF, the switch to doravirine/islatravir dosed at 100 mg and 0.25 mg PO daily had:

1. Similar efficacy, but greater declines in CD4 cell counts;
2. Similar efficacy and similar changes in CD4 cell counts;
3. Superior efficacy, but greater declines in CD4 cell counts; or
4. Superior efficacy and similar changes in CD4 cell counts.

So we'll give you a moment to think through these options and record your answers. Let's see how people did. So the majority of you got the correct answer.

[00:21:00]

Posttest 2: Rationale

That is that - in this study, there were - in the - in the phase III studies doravirine/islatravir given once-daily had similar efficacy to bictegravir/FTC/TAF with similar CD4 cell count results, either similar increases in the treatment-naive study, or no real changes in the switch studies.

[00:21:29]

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

This is another study now looking at the novel combination of islatravir and lenacapavir as a once-weekly oral regimen. This too was a switch study. So starting with people who were on a suppressive oral regimen of B/F/TAF and randomized either to switch to the weekly regimen or to continue on their daily oral therapy.

The primary endpoint here - again, because this is a switch study, we're looking at the occurrence of viremia above 50 copies per ml. This primary analysis was done at week—the primary endpoint was at Week 24. The current analysis is looking at data from week 96, which was during the extension phase.

[00:22:23]

Once-Weekly ISL + LEN: Virologic Outcomes

And so here there are two switch groups, because there were the people who were randomized to switch initially and then people who switched later on in the trial. And so looking first at the early switch group, who were followed for the entire 96 weeks on the weekly regimen, all the participants who remained on islatravir and lenacapavir through week 96 maintained full suppression to less than 50 copies per ml.

There was 1 of the participants with available data. None had virus load above 50 copies per ml at week 96 or at discontinuation. Looking now at the group that switched later, that is, those initially assigned to BIC/FTC/TAF who then chose to switch to islatravir/LEN, all the participants who remained on study for an additional 48 weeks maintained viral suppression on islatravir and lenacapavir.

And as we saw in the early switch group, none of the participants with available data after - 48 weeks after the switch or at the time of discontinuation had viremia of 50 copies per ml or greater.

[00:23:38]

Key Takeaways: Treatment

So key takeaways for treatment are that the ARTISTRY-1 and 2 studies showed that switching to bictegravir/lenacapavir, given once daily, was noninferior to either continuing B/F/TAF regimen or continuing on a complex regimen through week 48, with no differences in total lymphocyte count or CD4 cell count changes.

Used as initial antiretroviral therapy, doravirine and islatravir was non-inferior to the B/F/TAF at week 48, again with no differences in total lymphocyte count or CD4 cell count changes. Switching to dora/islatravir was similar to continuing bictegravir/FTC/TAF through week 96, again with no differences in either lymphocyte or CD4 cell count.

And switching to once weekly islatravir/lenacapavir from B/F/TAF maintained high rates of virologic suppression through week 96 was well tolerated, with no clinically relevant changes in CD4 cell count or lymphocyte count through week 108, and no significant changes in body weight or BMI through week 96.

[00:24:57]

Posttest 3

So this brings us to post-test question number 3. In the ARTISTRY-2 study that evaluated a switch from B/F/TAF to bictegravir/lenacapavir, bictegravir/lenacapavir efficacy was:

1. Noninferior to bictegravir/FTC/TAF and CD4 cell counts were stable;
2. Noninferior to bictegravir/FTC/TAF and CD4 cell counts increased;
3. Superior to bictegravir/FTC/TAF and CD4 cell counts were stable; or
4. Superior to bictegravir/FTC/TAF and CD4 cell counts increased.

So we'll give you some time to ponder those options and to record your choices. Let's see how people did. Great. So every - the majority again got the right answer. I'll just advance the slide here.

[00:26:06]

Posttest 3: Rationale

Which was that, compared to B/F/TAF, switching to bictegravir/lenacapavir was non-inferior and CD4 cell counts remained stable.

[00:26:20]

HIV Prevention

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

Dr Aadia Rana (Birmingham Heersink School of Medicine): Thank you, Dr Kuritzkes.

[00:26:29]

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

So pivoting a bit from treatment to prevention, I think we have some great studies to share with you all. So the first one being the final results of the Prevenir study, which is a study out of France comparing daily vs on-demand TDF/FTC PrEP.

So this was a study that enrolled about 3,200 people in Paris - in the Paris area, mostly gay and bisexual men, I think almost 99%. And participants could choose either daily or on-demand PrEP and then also switch the strategies. And they received fourth-generation HIV testing and creatinine checks every 3 months until May 2021 and then subsequently every 6 months.

And - and so that was this - what was presented was 8-year follow-up, started in 2017. And the primary objective, just to note, was that they wanted to demonstrate that there was a greater than 15% decrease in new HIV diagnoses in men who have sex with men and transgender women from 2015 and 2016 to 2022 and 2020 - ’23 and ’24, sorry. And additional secondary objectives as listed here.

[00:27:54]

Prevenir Final Results

And so they were able to describe what happened in this cohort based on what - in classifying them as either daily use which they defined as using daily about 75% of the time or on-demand use, which was, you know, if they only used it on demand 75% of the time or switch.

And almost 40% were daily or on-demand with about a quarter on you doing the switch strategy. And overall, there was a fairly low HIV incidence across all 3 of these PrEP - PrEP groups. Daily had about an incidence of 0.6 over 1000 person-years, with on-demand slightly higher, 1.5 per 1000 person-years, and switch 0.9.

Overall, though, TDF/FTC was well tolerated, with a slightly increased risk of GI adverse events reported with on-demand vs daily PrEP.

[00:29:00]

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

The final results did demonstrate about a 33% reduction of HIV diagnoses in Paris among men who have sex with men, but only for those who were born in France during the time of the study period. There was actually no significant change overall among all men who have sex with men and transgender women, because there was a significant increase in the HIV diagnoses among foreign-born men who have sex with men who were born abroad, and among transgender women. So 73% in the first group and 95% increase in the latter.

And overall, over this time period, just to note, in this area, you know, the original primary objective was a 15% reduction and they did not achieve that. It was only about 2%. And that is despite increasing PrEP utilization overall from, you know, several hundred to - to tens of thousands of people now using PrEP. I think it was about 27,000 upwards in the Paris area.

[00:30:08]

Posttest 4

So post-test question 4. During the Prevenir study period where oral, daily or on-demand PrEP was available in Paris, HIV diagnose decreased in:

1. French-born men who have sex with men, but not those born abroad and not transgender women;
2. Transgender women and French-born men who have sex with men but not those born abroad;
3. All men who have sex with men, but not transgender women; or
4. All men who have sex with men and transgender women.

So choose - select the answer and then we will review your response.

[00:31:04]

Posttest 4: Rationale

Okay. So that's correct. The majority voted for the correct answer, that it really only decreased in French-born men who have sex with men, but not those born abroad and not among transgender women.

[00:31:16]

PURPOSE 1 and PURPOSE 2: Study Design

And so then we also had presented follow-up data from the PURPOSE 1 and PURPOSE 2 studies, which are testing the use of lenacapavir vs FTC/TAF or FTC/tenof - TDF for PrEP. As a reminder, PURPOSE 1 focused on cisgender women aged 16 to 25 and PURPOSE 2 focused on cisgender men, transgender women, transgender men and gender non-binary people.

And you can see the study designs here for PURPOSE 1 comparing all 3 groups of FTC/TAF and FTC/TDF. And PURPOSE 2 only comparing for, you know, what's approved lenacapavir vs TDF/FTC in that.

And so we did have, of course, presentation of this data in primary analysis previously. And what was presented at CROI is updated data on - at the end of the double-blind phase.

[00:32:22]

PURPOSE 1: HIV Incidence and Acquisition and Safety

And for PURPOSE 1 in the primary analysis, we did not have any HIV acquisitions reported in the lenacapavir arm. And as you can see here, at the end of the double-blind phase, there were actually two incidents of HIV acquisition reported in the lenacapavir arm and an increase from 39 to 52 in the oral/FTC/TAF arm and 16 to 25 in the FTC/TDF arm.

So overall, 77 in the oral PrEP arms and two new ones reported in the lenacapavir. They provided some details on those two in the lenacapavir arm, where participant A was diagnosed via - with HIV via standard testing just at the week - at the 52-week visit with a quantitative HIV-1 RNA of 78 copies. Did receive all of their LEN injections, and the PK concentrations were within range.

For the second participant, they had discontinued LEN for over 450 days, and then developed resistance while on oral PrEP.

[00:33:41]

PURPOSE 2: HIV Incidence and Acquisition and Safety

In PURPOSE 2, there had initially been reported two acquisitions in the lenacapavir arm and nine in the FTC/TDF arm. And there was 1 additional acquisition reported in the lenacapavir arm and 3 additional in the FTC/TDF arm.

And overall for those 3 in the lenacapavir arm, the diagnoses occurred at either week 13, 26, or 52, respectively. And in the latest case, that participant was diagnosed at week 52 with a very high viral load of over 2 million copies. It's noted that participant did receive all LEN injections on time, and PK concentrations were within range.

There were no new safety concerns reported with additional follow-up compared to the primary analysis.

[00:34:39]

PURPOSE 1 and PURPOSE 2: HIV Resistance

A little bit more detail on the resistance. So of the 5 resistance, and this is both from PURPOSE 1 and PURPOSE 2, there were 4 that were identified—of the 5 cases of infection, sorry, there were 4 cases of resistance.

There was low levels of circulating N74D, which is reported by other studies, do suggest that N74D is acquired during LEN monotherapy after acquisition. And so, as you can see, 3 of those participants did have that mutation. And then 1 participant had Q67H and K70R.

For the oral PrEP, as expected, you will see that there were 5 cases with the expected NRTI mutations, mostly M184 related but also a K65R.

[00:35:37]

Key Takeaways: Prevention

So our key takeaways. In the Prevenir study of daily or on-demand PrEP, we did find a 33% reduction focused mostly on the French-born men who have sex with men, but overall no significant change in HIV diagnosis in the population. And that was driven mostly by an increase in the HIV diagnoses among foreign-born men who have sex with men, as well as among transgender women.

And in the randomized, blinded phase of PURPOSE 1 and PURPOSE 2 updates from the initial primary analysis, we found that they presented that twice yearly subcu LEN is still highly effective for HIV prevention, with new HIV infections rare in participants receiving LEN. But LEN resistance can emerge, likely due to LEN monotherapy. And overall, LEN remained well tolerated with injection site reactions similar to those that were reported in the primary analysis results.

[00:36:41]

Investigational HIV Prevention

So now to talk about some investigational HIV prevention that were presented at CROI.

[00:36:52]

MK-8527 PrEP: Dose Selection for Phase III Trial

So MK-8527 for PrEP. So that is also a non-nucleoside - sorry, nucleoside reverse transcription translocation inhibitor, NRTTI dose selection for a phase III trial. So this is an oral, you know, goal for a monthly PrEP agent. And so in this population modelling study, they did a 5 compartment PK simulation model which was aiming to select the dose maintenance—maintaining predicted to have the concentrations higher than the preventive PK efficacy threshold of 0.15 for 1 month.

And they used the trough measurement at day 31 as the most relevant time point for efficacy maintenance. They also looked at some covariates, including sex, age, and race. And weight was identified as a - was a clearance covariate with every decrease by 10 kilogram increasing exposure by 10%.

[00:38:07]

MK-8527 PrEP: Predicted Efficacy and Dose Selection

And so, as you can see on this slide, overall they were able to demonstrate fairly fast onset of action with coverage for the entire month after the initial dose with dosing windows of 7 days. And at the higher end doses particularly at starting with 11 mg, the MK-8527 was predicted to maintain efficacy above the PK threshold in greater than 95% of participants. So the 11 mg was selected for the phase III trials.

[00:38:46]

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

Looking at this for special populations, which are certainly of interest in those who are pregnant, the MK-8527 exposure is anticipated to be 10 to 30% lower during pregnancy per investigators of assessment of similarly excreted agents, for example, TDF and FTC. But exposure levels during pregnancy are still predicted to remain effective.

And so it's anticipated that no dose adjustment - adjustment is going to be needed for those who are pregnant. And in terms of the impact on the phase III trials, though, pregnant women who are pregnant at the time of enrolment will not be eligible to enroll. If you become pregnant during the trial, you would be allowed to continue in the blinded study after reconsent.

Also for adolescents weighing greater than or equal to 35 kilograms, it was also estimated that even with the decrease in weight and increased exposure that they were expected to align in terms of adverse events with the phase II experience. And so no dose adjustment would be made for that population either.

And 16 or 7 - so adult - they will include enrolment to adolescent 16 or 17 years of age.

[00:40:16]

Early-Phase Investigational HIV Treatments

And I think I'm turning it back over to Dr Kuritzkes for early-phase investigational HIV treatments.

Dr Kuritzkes: Thanks so much, Dr Rana. So there were some really interesting studies presented about novel agents that are in much earlier stages of clinical development than the - the drugs we've been talking about thus far.

[00:40:40]

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

The first of these was the EMBRACE study. This is a study we've actually covered in previous presentations from earlier conferences, but more data are now available.

This is a study that looks at the combination of long-acting injectable cabotegravir together with a broadly neutralizing antibody, N6LS, which now has an official name, lotivibart. Lotivibart was given either intravenously or subcutaneously, along with intramuscular CAB in people who were on a suppressive antiretroviral regimen.

You can see the study design here. These participants were randomized 2-to-2-to-1 to either of the lotivibart/CAB arms, or to continue on their suppressive oral antiretroviral regimen. Because this was a switch study, the primary endpoint, again, is the occurrence of viremia greater than 50 copies/mL at 6 months, with a secondary endpoint at 12 months.

[00:41:44]

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

The data we saw at CROI were the 12-month data. And what you can see is that there were more virologic failures in the subcutaneously dosed arm of lotivibart compared to the intravenous dose arm, and the intravenous dose arm was similar to the daily oral regimen. There were no confirmed virologic fail—all these failures, I should say, really occurred in the IV arm, occurred in the initial 6 months of the study.

There were no additional virologic failures that occurred in this subsequent 6 months. There were two participants who had met the failure definition at Months 3 and 6, neither of whom showed the emergence of cabotegravir resistance mutations.

The story was somewhat different in the subcutaneous arm, which really wasn't as well tolerated. Not—and not as favored by the participants. In the subcutaneous arm, two of the 3 participants who had confirmed virologic failure did have the emergence of cabotegravir resistance mutations, which are listed for you here.

And based on these results, it's been determined that going forward, lotivibart will be dosed intravenously. But the kinetics favor is being given every 6 months. And so that will be evaluated in part two of the study. And it's important also to emphasize that there were no adverse events leading to withdrawal in the intravenous arm and no serious adverse events related to either cabotegravir or to lotivibart.

[00:43:27]

LA Injectable INSTI: GS-3242

We’ll next cover 3 novel agents for which phase I data were presented. And the first of these is a long-acting injectable integrase inhibitor being developed by Gilead. This drug currently known as GS-3242. This study looked at the phase I evaluation of this long-acting integrase inhibitor that - which was generally well tolerated and no serious safety signals were observed.

This study was done—the first part of the study was done in people without HIV given a single intramuscular dose. And you can see the very long duration of the drug in the plasma here. The dotted line shows you the concentration needed to maintain virologic activity. And you can see doses of between 400 and 2400 mg were studied.

So these results support extended dosing intervals of about every 4 months. And there are ongoing studies to see whether it's feasible to give this every 6 months.

There was also a potent antiviral activity compared to available INSTIs. And you can see here the antiviral activity of this agent achieving about a 2.5 log or just under 2.5 log reduction by day 11 and a phase - it's also notable that this drug has activity against INSTI-resistant viruses, and phase II studies are expected to begin later this year.

[00:45:11]

LA Injectable INSTI: VH4524184

Another long-acting injectable INSTI, this one being developed by ViiV, and I'll just refer to it as VH184. Similarly, phase I studies were done to look at the safety and pharmacokinetics as well as antiviral activity. Although here we're just seeing the - the PK data.

There were two different formulations that were given or studied, and they were administered either subcutaneously or intramuscularly. Formulation A shown in the top left of the graphs and then an ultra-long acting formulation, formulation B. And you can see how levels were present, extending out to 52 weeks for the 400 mg subcutaneous dose.

This agent was generally well-tolerated, with no significant safety signals. The PK profile, because of the long half-life, supports an extended interval of twice-yearly dosing, and as with the integrase inhibitor we just spoke about, this drug also has activity against INSTI-resistant viruses and is more effective in vitro against those viruses than either bictegravir or dolutegravir. And the phase IIb INNOVATE study is expected to be initiated shortly.

[00:46:42]

LA Injectable Capsid Inhibitor: VH4011499

Another novel long-acting agent is a long-acting capsid inhibitor being developed by the VH499. Here again, phase I study evaluated the safety pharmacokinetics and we’ll eventually evaluate the antiviral activity. We only saw the PK data presented here.

The study showed that, as with the other agents we've discussed, that it was generally well tolerated with no significant safety concerns. And the PK simulations based support twice yearly dosing. You can see the actual data for intramuscular or subcutaneous dosing shown in the top paragraphs, and then the simulated PK based on those data for what every 6-month dosing would look like. And the phase II CINERGY study, using either subcutaneous or intramuscular formulations, will be starting later this year as well.

[00:47:44]

Hepatitis B

So I think that brings us to the last topic, hepatitis B, which again will be covered by Dr Rana.

Dr Rana: Okay. Thank you, Dr Kuritzkes.

[00:47:56]

HBV Reactivation While on a Tenofovir-Sparing ART

So what we're going to be highlighting in this section is, I think, a concern that a lot of us have, as clinicians, when we're initiating or treating or considering switch for people who may have been exposed to hepatitis B to tenofovir or hepatitis B treatment-sparing ART. And I think this is a particular - or it can be particularly highlighted as a lot of the treatment agents that Dr Kuritzkes presented also include agents that are going to be - you know, two agents that will not have hep B treatment as part of their coverage.

So, and particularly with the long acting agents. So this is a study that was presented using the CFAR Network of Integrated Clinical Systems or the CNICS cohort, which is a cohort of, I think, about 9 academic clinics around the country. And what they did was they identified individuals who were living with HIV in this cohort who had been prescribed tenofovir-sparing regimen for at least 3 months.

And what they wanted to see if there was, you know, the rates of H - hep B, either reactivation or new hep B infection, which they defined as a new hep B surface antigen positivity, or hep B DNA greater than 10 international units.

They needed to have both the surface antigen and surface anti - antibody available in their cohort prior to the first tenofovir-sparing agent with no evidence of active hep B, so no hep B surface antigen positivity or evidence of viremia.

And as you can see, they got about almost 6,000 people as part of their cohort with the median age of 46, about 20% female sex. Most had fairly high CD4 counts, but there was a little bit - a quarter that had viral loads greater than 200 copies. They had a 20% - sorry. Yeah, 20% were on HBV inactive ART with 80% on HBV active ART.

And they were able to identify 15% who did have evidence of core antibody - of prior HPV infection with core antibody positivity, and 87% of them were also surface antibody positive. 13% were surface antibody negative, and then about 29%, I'll note also were unknown in terms of their hep B status.

[00:50:52]

HBV Reactivation Was Rare on a Tenofovir-Sparing Regimen

And so the overall conclusions from their analysis was that hep B reactivation was really rare on a tenofovir-sparing regimen. So I'll point you to the first - the first row here looking at those with prior HBV infection, those who were hep B surface antibody positive pre-switch, there were two cases of hep B either infection or reactivation. Overall, a proportion of just 0.27%.

And then when we looked at those with no prior hep B infection, we also saw some cases, both in those who were reportedly surface antibody positive at the time of the switch, as well as slightly more in those who were - 9 cases in those who were surface antibody negative. And then in those whose core antibody status was unknown. Also two, in those who were reported to have surface antibody positivity at the beginning at least and then 4 in surface antibody negativity.

So only about 0.4% overall in the cohort. And they were able to do analysis on predictors of reactivation in infection which they found were low CD4 count at the time of the switch and slight increase in those who are black and Asian race and - and - and the researchers recommended future studies needed to understand the clinical significance of the reactivation and infection. So, you know, is it a true - you know, are we concerned - we're obviously concerned about flares and liver failure and that - but, you know, what is the significance in this setting?

And then certainly as that can determine the optimal HBV monitoring strategy, particularly in - in areas that are more endemic to hep B than the US, which is - which is where this analysis came from.

[00:52:54]

Q&A

And then I think that is the last slide and we can transition to the Q&A section.

Dr Kuritzkes: Great. We have 1 question so far in the Q&A asking if we know anything about cost differences to the patient at this time. And I'm afraid we don't. First of all, I would just point out that all of the investigational regimens that we discussed remain investigational, but not yet FDA approved. And so since they're not yet approved and marketed, we don't really have any cost information. And so that makes it hard for us to be able to address, although obviously that will be an important factor.

Dr Rana, maybe I can ask you, you know, we're now seeing an amazing array of 2-drug regimens, right? We've had dolutegravir/rilpivirine, dolutegravir/lamivudine, injectable cabotegravir/rilpivirine. And now I think 3 or 4 of those studies, they've all focused on 2-drug regimens with lenacapavir or islatravir or doravirine and bictegravir. How do you choose among these now, assuming they may - they are all approved and eventually make it to clinical use?

Dr Rana: Yeah, it's - it’s a great question. I’ll - I'll say first, it's great to have choices, right? Like it's - you know, we - from - from that standpoint. And I think, you know, when we think about it, even when I'm switching now, folks, to, you know, a 2-drug or considering an initiation, the - the most - the first thing I'll always think about is, you know, sort of patient preference as well as the side effect profile. And - and particularly as it relates to our patients with comorbidities as well as drug-drug interactions. And I think that is an important thing to consider, you know, especially as our patients are - are aging and - and are on other agents.

So I think those are the 3 things that I take most into consideration. I think that the first question was good. As we all know, that there's a lot of concern about changes to things like, you know, drugs - you know, AIDS drug assistance programs and funding. So cost is certainly going to be, I think, a growing issue in selection of our agents probably more - more so going forward. And so I think that's also going to be a certain consideration in that way.

But - but I - I - I appreciate and - and applaud this trend to, for, you know, simplification of regimen. And I know our patients really appreciate it as well.

Dr Kuritzkes: Let me ask you a PrEP-related question. One of the potential advantages of a lenacapavir-based PrEP regimen is that it - up until now, it involved a drug that we rarely used as initial treatment of - of HIV. It was only used for highly treatment experienced people with HIV. And so you could say that if you nevertheless developed - acquired HIV and developed lenacapavir resistance, it wouldn't have an impact on - on, you know, the use of mainstream first-line regimens that were included, either dolutegravir or bictegravir.

Now, with all these lenacapavir regimens that we're looking at, that's no longer. Still be the case, what are your thoughts on that?

Dr Rana: Yeah, and I think that's a great point, and - and - and something that we will need to consider in terms of initiation of ART, you know, at - if they do acquire and, you know, we have the data from PURPOSE 1, PURPOSE 2 showing acquisition did happen. And you know, what - what - you know, I’m - I'm - I don't have a lot of experience with this particular, the mutation, you know, because we haven't used as much lenacapavir. So how will this - having this inner - you know, this mutation and then what do we - do we need to use a PI regimen with this?

Can - can we get away with just an integrase? I mean, it's a little up in the air, I think. What do you think?

Dr Kuritzkes: Yeah. You know, I - I think it's going to be very interesting. First of all, it's encouraging to see that even though there were now a handful of people who acquired HIV in lenacapavir resistance, acquisition and resistance were still quite rare. And it's important to keep in perspective that in the HPTN 083 and 084 studies of cabotegravir as prevention, again, although some breakthroughs were seen with resistance occurring, they were likewise quite rare.

So I - I think on a population basis, the likelihood that we would see, you know, a large number of people acquiring HIV with resistance to first-line regimens is - is low. This might be a good time to remind folks that if somebody who's been using injectable cabotegravir for PrEP does acquire HIV, the recommendation from the guidelines is to start with a boosted PI regimen, if you don't yet have results of resistance testing while awaiting resistance test results.

And then if the person has documented integrase susceptible of virus, then you can simplify therapy to - to an integrase-based regimen or something less complicated than a - than a boosted PI.

There's another question about what resources are available to bring these findings to patients who may benefit from these advances?

You know, I think, first of all, CROI makes the presentations and slides available online, albeit after a delay of a few weeks. They prioritize access to those who actually attended the conference and registered, but they will eventually be posted and available. And I think there are many programs, such as this one that are reaching out not just to providers, but also to the members of the community.

Dr Rana: That’s right.

And - and the AIDS training and evaluation centers do a great job of making sure that this information gets out to people.

Dr Rana: Exactly. And I know that most - there's centers for AIDS research will - will - will put on local presentations for their community around the country. And as Dr Kuritzkes mentioned, the AIDS education and training centers will - around the country will often do that to me, and not just for the providers who weren't able to attend CROI but certainly for community members as well. And - but - but any - any - it's a - it's a great point to - to make sure that we are getting - getting this information back to - to the population who would most benefit from it.

I think we are at the hour, Dr Kuritzkes.

Dr Kuritzkes: I think we are. This was great.

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