HIV Update: Independent Conference Coverage of CROI 2026

Dr Chloe Orkin (Queen Mary University of London, and Barts Health NHS Trust):

[00:06:09]

ARTISTRY-1 Switch to BIC/LEN From Complex ART

So I'm looking really forward to talking with you about emerging treatments. So I'm going to start with a study which I think is very exciting, which is the ARTISTRY-1 study in which people who are taking complex regimens switched to receive the first ever single tablet regimen containing BIC/LEN, which is a daily treatment.

This was a large-scale study in people who had a complex regimen, and that meant they were taking pills twice a day, or taking multiple pills a day, or needing injectable pills, or using at least 3 ART classes. And what you can see is this was a very elderly population, the oldest population that's been seen in a registrational study.

Their median age was 60, and they'd been on treatment for a median of 28 years. So these people were really, really experienced. And you can see that a third of people were taking more than 4 pills a day. And lots of people were taking BID therapy, and there was a lot of resistance. So the reason for being on a complex regimen was resistance in 81% of the total population. And you can see that there was resistance in the left-hand panel in - to a number of different classes. So it's a very, you know, unique population.

[00:07:28]

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

Despite this, you can see that BIC/LEN was non-inferior to maintaining a complex antiretroviral regimen. There were only 3 participants with detectable viral load greater than 50 in the BIC/LEN arm, and none of them required a change to their regimen. There was no emergent resistance on this drug or on the comparator. Actually and BIC/LEN was non-inferior, as I've said, but also very importantly, the CD4 count remained stable in both participants - in both - in both arms. So there was no problems with CD4 count.

[00:08:02]

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

So now we look at lipids and patient-reported outcomes, something that was very important in this population, in whom very high proportions were living with multiple comorbidities. The lipids improved, and this was largely driven by withdrawing the protease inhibitor. And also there were statistically significant improvements in treatment satisfaction measured by the HIV task questionnaire at all of the time points. So in summary, it was non-inferior with no resistance, improvements in lipids, and improvements in satisfaction. And there was no - no significant safety concerns.

[00:08:46]

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

So then there was the ARTISTRY-2 study. So this was a double-blinded study switching people to BIC/LEN from bictegravir, FTC, and TAF. And this was a slightly younger population. Median was around, you know, sort of late 40s and with the good CD4 counts. And you can see that a fairly high proportion did actually have some comorbidities, but much less than in the ARTISTRY-1 study. And, you know, a fair number had actually more than 1 comorbidity.

[00:09:14]

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

So in this study, what you see is that BIC/LEN, which is in orange again, non-inferior to bictegravir, FTC and TAF, there were 4 people in the BIC/LEN arm who had low-level viremia, and there was 1 person who resuppression after switching to a PI-containing regimen. There was 1 person in the BIC/LEN arm who had an isolated R263K integrase substitution, which remains acceptable and wasn't present on a proviral DNA at baseline. CD4 count, weight, and BMI remained stable in both arms throughout the trial. You couldn't really tell between the weight differences, so it was very, almost identical.

[00:09:59]

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

So then we saw a very interesting study, which was presented by Jürgen Rockstroh wonderfully. And this was a first-line study looking at doravirine/islatravir 2-drug therapy and single tablet vs bictegravir, FTC, and TAF. And it was a double blind, active, controlled, randomized study comparing DOR/ISL plus placebo vs B/F/TAF plus placebo.

[00:10:25]

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

And this again was a very interesting population. But before I look in more detail at the population, what I will tell you is that there was really good enrolment across the world. You can see very, very good enrolment on the right across the different regions, and also very high completion rate of the study. The participants were young and predominantly male, 75% were male. And in terms of the CD4 count sort of between 50% and - 15%, and 20% had CD4 counts less than 200. But a very, very high proportion of participants had viral loads greater than 100,000 copies, much higher than in any of the other studies that we've seen of this ilk. And even 10% had people with viral loads greater than 500,000 copies. And you can see it was mainly clade B virus, but there were some non-B viruses included. And in terms of the anti-HSV, HBc negative, you can see that about half were negative to both.

[00:11:26]

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

So here's the outcome. You can see that DOR/ISL vs B/F/TAF was non-inferior very strong result from both drugs. And there were some people who discontinued due to lack of efficacy. There were 4 in the DOR/ISL arm vs 2 in the B/F/TAF study. The treatment groups were very well balanced. And interestingly also similar efficacy across the baseline CD4 count and viral load strata. So no differences based on CD4 count and viral load strata. They did a very careful sensitivity - sensitivity analysis across multiple subpopulations and found no differences.

[00:12:06]

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

So what they did find is that of those 4 people who had detectable viral loads in the DOR/ISL arm, there were 2 people who developed treatment-emergent resistance to DOR/ISL. And interestingly, there were some similarities between these people. Both of them started off with CD4 counts less than 200, and their initial viral loads were close. One was over 2 million, and one was nearly 2 million. So these are really unusual cases. Apparently, there were about 14 people who had very, very high viral loads, you know, above a million. And these were 2 of them.

And you can see that in 1 person the drug levels were - were not adequate. And you can see in both people there were mutations at baseline. But in 1 person, they suppressed and then developed [inaudible] in 1 person, they didn't really suppress. And in both cases, they ended up with M184 substitutions and also some NNRTI mutations. Additionally, there were 2 people who had serious treatment adverse events in the DOR/ISL arm.

One was a DRESS at eosinophilia plus a systemic syndrome, and the other one was a drug-induced liver injury, which did not meet hy's law for raised bilirubin. In other respects, the safety was comparable, and importantly, the CD4 count once again was stable, and the weight was, you know, almost identical, the changes it was like 3.5 vs 3.9 kilos, so it was very, very similar.

[00:13:39]

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

So then they looked at the week 96 data for the switch study. This was the blinded switch study from DOR/ISL - to DOR/ISL from B/F/TAF. Once again, this was a double-blinded study. And we've heard the 48-week results last year at CROI, and now we're hearing the update at week 96.

[00:14:01]

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

So all that's - so what's new is the extended duration. And this population is, you know, typical switch study population aged around 50 and being diagnosed around 11 years. And they started off with a good CD4 count.

[00:14:19]

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

And in terms of the update from last year, what you can see is that very similar outcomes, not non-inferior between DOR/ISL and B/F/TAF. No difference again in CD4 count or T lymphocytes throughout week 96. There were some discontinuations due to lack of efficacy, there were 2 in DOR/ISL vs 9 in B/F/TAF. And then there was some other reasons for discontinuation in DOR/ISL vs none in B/F/TAF.

[00:14:52]

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

And importantly for individuals on DOR/ISL there was nobody that met the criteria for HBV reactivation. So the actual criterion for an HBV reactivation, according to AASLD, is a viral load HBV DNA greater than 1000. But there were some very low-level viremias that occurred with no antigenemia, nor were there any elevated transaminases. There were 4 new cases of acute HBV. Both had negative HBC antibodies and HBS antibodies at baseline. So there was no differences in weight change at Week 96. And then you can see, once again, very tiny differences in weight. At Week 96, almost you know, infinitesimal, barely visible to the naked eye.

[00:15:44]

Posttest Question 1

So let's have a post-test question. Based on the phase 3 data, when compared with - with continued B/F/TAF switch to DOR/ISL 100 vs 0.25 once daily had

A. Similar efficacy but greater decline in CD4 count;

B. Similar efficacy and similar changes in CD4 count - CD4 count;

C. Superior efficacy, but greater declines; or

D. Superior efficacy, and similar changes in CD4 cell counts;

Vote now. Okay. Let's have a look at the poll. Yeah. And we can see that the audience has got it very right. So it's similar efficacy when switching to DOR/ISL from B/F/TAF and similar changes in CD4 counts.

[00:16:53]

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

So now there's a really interesting study. The new kid on the block in terms of long-acting regimens is, of course, the weekly oral therapy. And they're calling this LAO, long-acting orals. And this is - is ISL+LEN, so islatravir plus lenacapavir in people with virally suppressed people with viral suppression. Now, this, unlike the other studies, is a Phase 2 study, so it's much smaller. So it was for people that were virally suppressed, and they were randomized to receive ISL 2 ml plus LEN 300 weekly or B/F/TAF. And then they moved into an extension phase. And the primary endpoint was, as ever, a viral load greater than 50 according to the snapshot window.

[00:17:40]

Once-Weekly ISL + LEN: Virologic Outcomes

So here are the outcomes. So the early switch group who spent 96 weeks on ISL+LEN, so the weekly oral, you can see the suppression was 88.5%. And then the late switch group, who at week 48 went on to switch to at ISL+LEN week 48, you can see 97.8% were undetectable. However, it's important to say that all participants in the early switch group who remained on ISL+LEN through the end of the study, through week 96, were undetectable. And of the participants where there was data available, none had viral loads greater than 50.

I think what - the point of this is that it's an FDA snapshot, which means that only viral loads that are taken within that snapshot window, 2 weeks before and 2 weeks after are included in the analysis. And as you can see, there's quite a few people, relatively speaking, who didn't have viral loads in the analysis. And then when you look at the late switch group, all participants who remained on study after week 48 were undetectable. And of participants with available data, none had viral loads greater than 50 or - or at discontinuation. So promising results.

[00:18:54]

Key Takeaways: Treatment

So the key takeaways for treatment are that both ARTISTRY 1 and 2 showed that switching - to switching to BIC/LEN was non-inferior to continuing either the complex regimen or B/F/TAF through week 48, with no differences in total lymphocyte count or CD4 counts. Using DOR/ISL first line was non-inferior to B/F/TAF at week 48, with no differences in lymphocytes or CD4 count changes. However, there were 2 additional resistance cases in people who started with exceptionally high viral loads. And there was also these 2 unusual, serious adverse events. One was a DRESS syndrome, and one was a raised LFTs. Switching to oral DOR/ISL was similar to continuing baseline B/F/TAF through week 96. No differences in total lymphocyte or CD4 cell count. And in the weekly, this was the Phase 2 study, small numbers showing high rates of success for those that switched early and those that switched later, again with no concerns around lymphocyte count or changes in body weight.

[00:20:02]

Posttest Question 3

So here's another posttest question. In the ARTISTRY-2 study that was the switch from complex treatment, sorry, switched from B/F/TAF. So this was - the ARTISTRY-2 study evaluated switching from B/F/TAF to - to BIC/LEN what we saw - the - the options are did we see that B/F/TAF BIC/LEN was

A. Non-inferior to B/F/TAF and CD4 counts were stable; was it

B. Non-inferior to B/F/TAF and CD4 counts increased; was it

C. Superior to B/F/TAF and CD4 counts were stable; or was it;

D. Superior to B/F/TAF and CD4 counts increased;

Once again, in the ARTISTRY-2 study, which was looking at switching from B/F/TAF to BIC/LEN, we're looking at the BIC/LEN efficacy, and those are the options. Vote now. Okay. Let's have the answer. Great. So what we see here is a very high percentage of the audience got it right. That's absolutely correct.

[00:21:17]

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

We're going to move to prevention. And I'm going to cover a fantastic talk given by Jean-Michel Molina himself, and he was covering the PREVENIR study. And this is looking at daily vs on demand, TDF, FTC and PrEP. And it's a famous study and I'm sure you've heard about it. But basically participants could choose daily or on demand PrEP, and they could also switch between strategies and then they would be monitored according to various monitoring tests, including STI tests. You can see the dosing was 2:1:1 for on demand. And they were trying to see if they could make a difference epidemiologically and then decrease the new diagnoses in Paris between 2015 and 2024. So it's a massively ambitious, you know, plan. And they wanted to decrease it by 15%.

[00:22:10]

Prevenir Final Results

So what they did in this at this point, they've been going for a long time is they looked at differences in the PrEP dosing strategy, daily on demand, and switch. So most people use it a daily and on demand. But there were some people who chose to switch. And the discontinuations were actually lowest in those who switched between modalities. And that's what we tend to see. That choice is good when it comes to PrEP or anything in life, but especially in PrEP.

So there was low incidence overall and across PrEP use, and daily PrEP had the lowest rate on demand had the highest 1.4, and switch had 0.9, but none of these were statistically significant. These were numerical differences. Only TDF/FTC was well tolerated, and it was the highest number of GI events was actually in the on-demand group.

[00:23:00]

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

So here's the real findings that the overall diagnosis from a public health perspective showed that there was a 33% reduction in HIV diagnoses in Paris among men who have sex with men who were born in France. And this is because 99% of the people in the study were MSM, and 85% were born in France. So in those people who were in the study, they did super well, and there was a reduction in diagnoses. However, there was no changes in the people who were MSM born abroad. And also, you could see in fact, there was an increase of 73% and also an increase in transgender women, a massive increase. So what this shows is that, you know, these people were not being reached by PrEP, and that's why they weren't being helped by PrEP. So access and reaching populations is critical.

[00:23:54]

Posttest Question 4

So here's the PREVENIR study period, where oral daily or demand PrEP was available in Paris, HIV diagnoses decreased in

A. French-born men who have sex with men, but not those born abroad, and not transgender women; or

B. Transgender women in French-born men who have sex with men, but not those born abroad; or

C. All men who have sex with men, but not transgender women; or

D. All men who have sex with men and transgender women;

Vote now. Okay, let's see the result. And very high proportion of the audience got it right. It was the French-born men who have sex with men who improved. And now I'm going to hand it over to my wonderful colleague Dr Daar, and-

[00:24:55]

PURPOSE 1 and PURPOSE 2: Study Designs

Dr Eric Daar (David Geffen School of Medicine at UCLA): Great. Thanks, Chloe. Thanks so much for getting us started. That was a terrific overview. Now I'm going to touch on some additional studies related to prevention, including new drugs in development, and then finish up with some investigational agents and a little bit on comorbid conditions. But let's start with the I'm sure well-known to all of you, PURPOSE 1 and PURPOSE 2 studies. These were the 2 large registrational trials that led to the approval of lenacapavir given subcutaneously every 6 months as pre-exposure prophylaxis. And again, I think this is probably familiar to all. PURPOSE 1 is outlined here at the top. This was in cisgender women. And then PURPOSE 2. And the study designs were quite similar.

There was also this counterfactual placebo group, where they basically looked at what the predicted incidence of infection would be in the communities in which the study was conducted, and that was the primary endpoint. The difference in PURPOSE 1 and 2 was in the cisgender women group, they added the FTC/TAF because, as you know, FTC/TAF from the discover trial is FDA approved and approved in guidelines for MSM transgender women, but hadn't been studied in cis women, so it was added as a third arm in this study. And as you know, the Data Safety Monitoring Board reviewed these trials and recommended that both of them be stopped early because highly efficacious.

[00:26:32]

PURPOSE 1: HIV Incidence and Acquisition and Safety

Intervention. So this was PURPOSE 1, looking at additional incidents and acquisition, and safety. So we have the primary analysis, and then we have the data from continued follow-up at the end of the double blind phase. And you can see that the overall HIV incidence, as you probably recall, during the primary analysis in the cisgender women was zero, where it was higher, although still low, but considerably higher in the oral regimen arms. There were zero cases of HIV acquisition, and the original report was 100% efficacy at the time of the primary analysis, which is absolutely unheard of.

At the end of the double blind phase, there were 2 HIV acquisitions. Although the overall incident per 100 person-years remained extremely small. In the oral PrEP, it was considerably higher there, 77 overall, compared to the 2. And of the 2 that acquired HIV in the lenacapavir arm, 1 was diagnosed through routine testing at week 52 with a low level RNA had received all of their lenacapavir injections, and the PK concentrations were within range, so it couldn't be explained based on poor adherence or missed doses. And in the other participant had discontinued Len for over a year and developed resistance while on oral PrEP. So again, some continued follow-up. Extraordinary efficacy.

[00:28:07]

PURPOSE 2: HIV Incidence and Acquisition and Safety

And here is some additional data in PURPOSE 2. Again, the primary analysis you may recall not 100% efficacy, but over 95% with only 2 HIV acquisitions during the primary analysis, with 9 in the oral FTC, TDF group. So again, a low incidence for sure, but not as low as with lenacapavir. And at the end of the double blind phase, there was an additional infection in the LEN group. And there were 3 additional infections in the oral FTC TDF.

For the incident infections in LEN, the 3 total—2 during the early part and 1 later—the diagnosis occurred at 13, 26, and 52 weeks. As far as the late case, the diagnosis was through standard testing and was notable for having an extremely high viral load of over 2 million. Participants received all len injections on time, and PK concentrations were within range, so again, not easily explained.

And good news, no additional safety concerns. So this is now available. Obviously, there will continue to be some access issues, but it is certainly FDA-approved as a highly effective every 6-month dose. And this additional data contributes more information for people who are looking at this as a potential strategy for prevention.

[00:29:36]

PURPOSE 1 and PURPOSE 2: HIV Resistance

Now, there were some people with incident infection. One of the big questions and all of these trials is what do we see in those "who fail PrEP" with regards to resistance? As you may recall from PURPOSE 1 and 2, there were a total of 5 HIV infections, and resistance was identified in 4 of the cases. And you can see that in the table 4 and PURPOSE 1, 2, and PURPOSE 2. And you can see 4 of the 5 had evidence of resistance in the constant, and 3 of them was this N74D, a known mutation associated with lenacapavir resistance.

In contrast, if you look at a much larger number of people who experienced incident infections on oral therapy, this would include FTC, TAF, and FTC, TDF in the cis women vs FTC, FTC, TDF in the men. So most of these were associated with suboptimal adherence. And of the 89, there were only a handful of 5 that actually had evidence of resistance. And they had resistance with what you'd expect, FTC resistance, the 184V or I, and 1 also had the K64R.

[00:30:54]

Key Takeaways: Prevention

So the takeaways from the trials that we talked about, the large PREVINIR and then the PURPOSE 1 and 2 in PREVINIR a study of on-demand oral FTC, TDF PrEP. There was 33% reduction of HIV diagnoses amongst the French-born men who had sex with men. There was no significant change among all men or those who had sex with all - men who had sex with men and transgender women, because of the increased diagnosis observed amongst the foreign-born population in this trial.

As far as the PURPOSE 1 and PURPOSE 2 twice-yearly subcutaneous lenacapavir, new infections occurred, but were rare amongst participants on lenacapavir. It was likely to be associated with exposure to LEN monotherapy at the time of infection, with a frequency amongst the small number infected of acquiring lenacapavir-associated resistance mutations.

[00:31:53]

MK-8527 PrEP: Dose Selection for Phase III Trial

Now, let's talk about 1 investigational HIV prevention agent that's in advanced stages of development. This is MK-8527. This is a nucleoside reverse transcriptase translocation inhibitor, like islatravir, that Chloe talked about in the context of treatment. The characteristics of these drugs are that they tend to be very potent and have long half-lives. And that's certainly the case with 8527. Now they were looking at dose selection for a Phase 3 trial in this study. So they did modelling of the pharmacokinetics to try to look at levels and triphosphate PK from a variety of studies that were done.

They looked at 5 compartment PK simulation models aiming to select a dose that maintained triphosphate concentrations higher than that that was thought to be needed for preventive PK efficacy for at least a month thinking about monthly dosing. They looked at Ctrough at day 31 as a relevant time point to assure efficacy and maintaining sufficient levels to prevent infection out to 30 days.

They didn't find covariates such as sex, age, and race, and then weight was identified as a clearance covariate. So these are the characteristics listed on the right. There were 408 participants in these various trials that had pharmacokinetic analysis. A very small number 37, were individuals with HIV infection.

[00:33:29]

MK-8527 PrEP: Predicted Efficacy and Dose Selection

And here is an example of what they saw when they looked at the data from the trials that assessed all of these doses 6, 7, 8, 9, 10, 11, and 12 mg per month. And they looked across the board, looking at PK and where you saw levels that were above those thought to be needed to be protective. So you have the 1-hour post initial dose. Most of them did well. The dark purple is the highest level of efficacy, greater than 95% of the participants.

The C-trough at Day 31 obviously critically important if thinking about monthly therapy. You can see really the optimal you saw was amongst 11th and 12th at the greater than 95% of participants. They also looked at the Ctrough at day 38, which is thought to be important because not everybody gets to their treatment all the time. And you want to have a window. So this would allow for a window of 7 days if they were late in taking their therapy.

And you can see that again at 11 and 12 mg doses, you see adequate 1 hour post initial dose. You see adequate Ctroughs post initial dose and steady state, and at 11 and 12mg you see adequate levels even at 38 days. And that's what led to the 11 mg dose being selected for the Phase 3 trials. And those Phase 3 trials are actively underway in this expressive 10 and expressive 11 study.

[00:35:08]

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

They looked at the pharmacokinetics amongst important populations that might benefit from such therapy example, pregnant people, and they found that the overall levels in the triphosphate exposure was anticipated to be 10% to 30% lower in pregnancy, but similar excreted agents - assessment of similarly excreted agents. This wasn't a surprise. The question was, would the exposure be sufficient to overcome that reduction? And it did appear to be the case, and that there would be no dose adjustment needed for pregnant people. And then adolescents who were greater than 35 kg and other population in need of new PrEP options. They found there was a relationship between weight and exposure, but at 11 mg the exposure was likely to be adequate.

[00:36:03]

Early-Phase Investigational HIV Treatments

Now, let's talk a little about early-phase investigational treatments. So shifting from prevention to treatment. Chloe showed a lot of the data for novel combination therapies and agents that are moving forward in clinical trials.

[00:36:16]

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

There were several more that are worth commenting on. One of them came out of this EMBRACE trial. We had previously seen some of the early data, and this was an attempt to look at a broadly neutralizing monoclonal antibody, this so-called N6, that had been modified by the LS modification and FC segment of the antibody that prolongs the half-life. And this is lotivibart. And it was looked at as both IV or subcutaneously, along with CAB for people living with virologically suppressed HIV.

So a multicenter, randomized, open-label trial. This was a phase 2B trial. So again, smaller numbers of individuals in the different arms. And you can see that 1 arm looked at IV QM month 60 mg/kg, along with CAB given IMQ month. Another 1 looked at the broadly neutralizing antibody at a dose of 3000 mg plus this human hyaluronidase pH 20 to allow for it to be administered subcutaneously every 4 months, with again CAB on a monthly basis vs oral standard of care. So these were adults, 18 to 70 years old. HIV RNA is less than 50. 12 months prior to screening, no history of switch for virologic failure. CD4 is of over 350 on a stable regimen.

The other really important characteristic in this trial, and likely to be the case in all of our trials moving forward, that are thinking about broadly neutralizing antibodies as a therapeutic is that the baseline virus needs to be demonstrated to be phenotypically susceptible. So they screened 350 individuals for this trial with these inclusion criteria in almost 200 of them, they were actually unable to assess sensitivity, or they were ineligible. 70% of them because of assay failure.

So they simply couldn't determine 1 way or the other about susceptibility. And about a third of the individuals actually didn't have susceptible virus. So it's going to be for a select population. But for those who are susceptible, they looked at this study with the primary endpoint of a viral load of greater than 50 at 6 months by FDA snapshot, and then secondary endpoints.

[00:38:47]

EMBRACE: Efficacy, CVF and Safety Outcomes at MO 12

So here are the results overall. Looking at IV in orange subcu and purple, and oral and grey. Overall, the proportion of individuals with viral loads of less than or greater than 50 was relatively low across the different groups. And then there were some for which there was no data. So there were no confirmed virologic failures in the IV group between months 6 and 12.

Two met confirmed virologic failure in Month 3 and 6, both without CAB rams. The - the monoclonal antibody subcu group 3 participants met confirmed virologic failure. CAB resistance was seen 2 of the 3. And then in the IV every 6 months is going to be looked at in the part II phase of this study.

In thinking about how to move this forward as a long-acting combination regimen. The other important thing, where there were no adverse events leading to withdrawal in the IV arm, no serious adverse events related to CAB or the monoclonal. Injection site reactions, obviously, and not surprisingly, were less frequent in those who received at IV vs subcu.

[00:40:08]

LA Injectable INSTI: GS-3242

What about other potential long-acting options? This was data looking at a Phase 1 evaluation, mostly of pharmacokinetics and antiviral activity for this long-acting injectable entity GS-3242. So this was generally well tolerated without any serious safety events after a single IM dose. You can look at the pharmacokinetics on the top right figure, showing these were in weeks of follow-up that for the 3 higher doses, all of them at 6 months, were well above the level that is predicted to be required to maintain virologic suppression. And then you can see the antiviral activity in the lower panel. So clearly a potent agent, but even more importantly, one for which there is very slow clearance after intramuscular injection. And this was looking at approximately every 4 months. But the data suggests that they may be able to even look at this as an every 6-month option. So again, in development and would be a major and important advance in long-acting options.

[00:41:21]

LA Injectable INSTI: VH452481

Here's another long-acting INSTI: VH4524184. Another Phase I evaluation of a long-acting INSTI, looking again at PK and antiviral activity. This is really focusing on a standard formulation as well as an ultra-long-acting formulation. And you can see the pre-K profiles again, showing very high levels. Out to 4 and 6 months with most of the doses tested. And then they did the simulated concentrations of the standard and the ultra-long-acting version. If we focus attention on the lower-

Dr Orkin: Has Dr Daar frozen for everybody or just for me?

Dr Straube-West: He froze for everyone. He froze for everybody.

Dr Orkin: Okay, so I think what we're just saying is that the PK profile supports extended interval dosing. And also has some activity against INSTI-resistant viruses compared to BIC. And there's a Phase IIb study starting imminently.

[00:42:34]

LA Injectable Capsid Inhibitor: VH4011499

And then the next drug is the long-acting injectable capsid inhibitor VH-499. And - and this is just really trying to understand the Phase 1 study is just understanding the safety, the PK, and the antiviral activity. And what was found in this study, which was the drug was injected both IM and subcutaneously to try and see which would work better. That it was well tolerated, with no significant safety concerns in either - in either way of administering, and the PK simulation support twice yearly dosing. So potentially really, really long-acting. And the Phase 2 synergy study for both SC and IM formulations are expected to begin in 2026 because both of them looked promising.

[00:43:24]

HBV Reactivation While on a Tenofovir-Sparing ART

So in terms of hepatitis B, while we're waiting for Dr Daar, I'll just keep going. We all know that HBV reactivation is on a tenofovir-sparing regimen is an increasingly big issue as our pipeline and our reality moves increasingly towards 2-drug therapy. So this was a very large retrospective cohort study of adults in the CFAR network in the CNIC, and looking at the cohort was adults living with HIV on tenofovir sparing regimen for more than 3 months. And the primary outcome was to look for reactivation or new HBV infection.

So this is defined as a new S antigen or HBV DNA greater than 10. So inclusion criteria they were looking at people who had both S antigens and antibodies available prior to the first TDF sparing antiretroviral with no evidence of active HBV. And they were analyzed using logistic regression. And you can see here are the demographic characteristics the majority of people had viral loads greater than 200.

And you can see that most people had HBV active ART with XTC, so although they were without TDF, some of them still had XTC in their regimen, which of course is some protection against HBV or has some activity against HBV, but 20% had nothing. So prior - prior infection core antibodies, you can see that, that 15% had core antibodies. And of those, you can see 87% also had S antibodies, and 13% didn't.

And then there was the no prior infections, core antibodies negative. And then you can see that some people had antibodies, so those people would have been vaccinated. 60% had vaccinated. And then there were some people with an unknown status who just had antibodies. And that was 60% approximately. So what this shows eventually, after all of these categories. And all the analysis essentially is that HBV, I'm not going to go through every number, but effectively HBV reactivation or infection occurred in only 0.4% of the cohort. But bearing in mind this was the cohort which 80% had XTC.

So that's probably not an insignificant factor. The strongest predictors of HBV reactivation or infection were low CD4 count at the time of switch, and also in Black and Asian people. Future studies clearly are needed to understand the clinical significance of HBV reactivation or infection, and to determine the optimal HBV monitoring strategy. So I think they did - there were quite a lot of limitations that were presented, including the fact that they couldn't quite - things weren't entirely well timed. The ALTs were not always done at the right time. They may have missed - there may have been reactivations that were missed because there was no sort of relationship between the testing. It was, you know, it was a cohort study. So there was some element of - of messiness to the data. But it's a very big and very helpful study, and I was very glad that it was presented.

So I'm going to move to the Q&A. We've got Dr Daar back. Fantastic. Eric, I did actually complete the presentation. I'm not quite sure when you rejoined. But we're at the Q&A now, and there was - I don't know if you wanted to say anything else other than I don't know if you heard me summarizing the reactivation. I don't know if you wanted to say anything else about it, but Eric. No. Okay, so we have a question which was really about DOR/ISL vs B/F/TAF, and the question is, should we slowly stop implying that second gen entities and TAF is associated with weight gain? So I think - I think my answer is probably quite quickly, and we should stop implying.

[00:47:33]

Posttest Question 1

I think that it's - I think what we can definitely say is that based on these studies, there was absolutely no difference with the 2-drug therapies, either BIC/LEN or with - either with BIC/LEN or with DOR/ISL. No difference whatsoever. So I think, you know, obviously, at the meeting, there were other presentations. We heard more data from the PASO-DOBLE from the study that's led by Esteban Martinez. It's a wonderful study. It's a crossover study B/F/TAF vs DTG/3TC and then switching around. And they have found some differences, particularly in people with a higher degrees of weight gain.

But I think, you know, these studies switching people to - to drugs have shown no difference. And additionally, the first-line therapy study DOR/ISL vs B/F/TAF was very similar. So I do in essence, agree with your point. So then we have another question. Did any of the ARTISTRY studies include people with M184V? Did they do retrospective proviral DNA testing? What can we expect? Okay.

So let's take that as a question. So yes. So the ARTISTRY, the B/F/TAF study, they had to be sensitive to all of the components of B/F/TAF. But for the complex regimen, they had a very large proportion of NRTI resistance. Nearly 70% had NRTI resistance. And the ARTISTRY study was a switch to BIC/LEN, not DOR/ISL. And in that study, there was a lot of resistance to NRTIs, to PIs, to NNRTIs.

And despite this, the drug did very well, there would definitely have been M184V, but BIC and LEN are not related to 184. So this letermovir [? 00:49:28] has a common pathway with 184. But the big length ARTISTRY studies contained BIC/LEN, not DOR/ISL. So then there's a question about what we can expect on efficacy of DOR/ISL in the context of M184V. So it is a widespread mutation. But it's not a mutation that persists very long. So it often reverts back to wild type. So, the question is in the context of it being archived in proviral DNA, would that be important? Would it be important immediately? Would it be important if it was there for more than 5 years? I think this is a, you know - a question that we don't know the answers to.

One of the questions that was asked is, did they do retrospective proviral DNA testing for the ARTISTRY studies? Well, they - they did. They knew that there was a lot of M184V and other NRTI resistance already based on the baseline resistance tests. So then we have LEVI syndrome. Was LEVI syndrome observed with breakthrough HIV on the lenacapavir PrEP? So the answer to - in terms of the discussions that happened after the presentation, there was discussion saying that there was no evidence of LEVI syndrome.

What happened is that in the - in the PURPOSE 1 study, there were the 2 cases, 2 acquisitions, and the 1 acquisition was somebody who was offline for, you know, more than 400 days and was on FTDF at the time that they acquired HIV and that they had NRT mutations. But then there was another person who, after about 13 weeks with adequate levels, acquired HIV. And what happened is that week 13, there was an isolated, very low-level viral load of about 37 or 40.

And then 13 weeks later, about all the antibodies were test - all the antigen antibodies, the rapid, and also the antigen antibody fourth generation were all negative. And then they did it again 13 weeks later. And then once again, the viral load was low, but the antigen antibody tests were positive. So I think what we can say is that it was at low levels. There was a low-level viremia without accompanying antigen and antibody tests being positive on the first - at the first time point, and then another low-level viremia with positive antigens. So the answer from Gilead is there was no LEVI syndrome. And that's the information that I can give you about how the viral loads and the antigen antibodies looked. Eric, are you back?

Dr Daar: I am, and I am very sorry. I somehow I got kicked out and was having trouble getting back in, so I apologize.

Dr Orkin: No problem, Eric - no problem, Eric.

Dr Daar: I think - I think I missed all the fun.

Dr Orkin: You might have missed a little bit of the fun, but I'm - I'm having it on behalf of both of us. Then there is a question about metabolics at CROI. So they're asking about REPRIEVE. Do you want to give a little summary about reprieve, Eric, or do you want-

Dr Daar: Yeah - yeah - yeah, I'll give it a shot, and then you can perhaps weigh in as well there. You know, obviously, REPRIEVE has been an incredibly rich study. For those who don't recall, that was the large randomized controlled trial of over 7000 relatively low-risk for cardiovascular event HIV infected individuals, most of whom are suppressed. And that was a 1:1 trial looking at pitavastatin vs placebo.

And again, it was a very low-risk group. The LDL was 100, about less than 5% cardiovascular risk, and it demonstrated the 35% reduction in cardiovascular events. So that was all great news. It changed practice guidelines and has really been impactful to the field. And they've been, I think, on the order of almost 100 publications now that have come out of that study, that expanded what it's looking at.

And a couple of the things from the meeting that jumped out at me was that there was another attempt to look at the relationship between inflammatory markers, particularly those that have been associated with cardiovascular events like IL-6 and pitavastatin use, to try to better understand what was the factor or the key factors associated with pitavastatins efficacy. The hope was that some of it would be related to reductions in inflammation, and not just reductions in LDL.

A previous analysis, I think, suggested that it wasn't all LDL, but of a lot of it probably was. And I think that the more recent study was similar. The other things that jumped out, the other 2 things that jumped out at me from REPRIEVE, and again, Chloe, welcome you to weigh in afterwards is one was looking at incident hypertension. This has been an ongoing issue as to whether there may be certain therapeutics that are more commonly associated with hypertension, and indeed in REPRIEVE. Again, there are always issues because they're not designed to look specifically at this question most of the time. There did seem to be an association between second-generation integrase inhibitor use within the REPRIEVE cohort and incident hypertension. Why and what we do with it is an open question, other than obviously monitoring people for hypertension and treating it when appropriate.

And then the third one was a look at steatosis and whether pitavastatin would reduce steatosis in a population of patients with evidence of non-alcoholic fatty liver disease, a MAFLD. And - and basically, the bottom line is it did not and - and that is consistent with some other studies. Those are the 3 that jumped out at me. Chloe comments on those or others that you thought were interesting?

Dr Orkin: I mean, I found - I think you couldn't have summed it up better in my view. I mean, I think the hypertension is really interesting. And I think the mechanism is also interesting, but I think the hypertension reductions, it is important and I think - I think it feels to me like statins should be put in the water, whether you can find the how they work or not.

I think the reality is this is really important. And I think the study, as you say, it just keeps on giving in terms of, you know, the depth and the richness of breadth of what it provides. And I think, you know, we just have to keep, you know - keep reading and keep understanding and, you know, keep trying to learn from, you know, what it's provided. But I haven't got anything else particularly to add. There's a question on - oh, sorry.

Dr Daar: No, I was going to ask you, Chloe, also, you know, 1 of the things we had so many great large, random or large and small randomized controlled trials. I don't know if you already talked about this, but we always out of these study - out of these meetings, we always hear about a lot of observational data, of real-world use of some of these newer drugs or key drugs that we're using. And one - the long-acting therapies, this tends to be a really important question is - it's great in the clinical trials, what happens in real use?

Dr Orkin: Yeah. So in the last 4 minutes, because we probably have to stop at 6. Just to say that there were some CAB rilpivirine real world evidence. The largest of the cohorts is the upper cohort for treatment, and they had about 4,500 people on treatment who were virally suppressed at the start. And then they had about 500 who were not, but those that are not are barely detectable. The median is about 120, so we can't really consider them to be very detectable.

But the - the VF rate is very low. It's like around 1%. And there's no difference with BMI. And that's maintained across, and it was approximately 16 months of follow-up. So that was positive. I think 1 thing that caught my eye is the EBONI study. And this is like a Phase 4 hybrid implementation effectiveness study using CAB as PrEP in Black women and in the US - and in the US, although Black women account for about 60% of new HIV incidences, but by the end of Year 1 on PrEP, only 20% remain on PrEP.

So it's a population that, you know, is really important population for us to try and reach. CAB was rolled out in this population. And interestingly in the study at 6 months, 76% remained on CAB. But at a year, 56% remain on CAB. It was very acceptable. It was very feasible. It was very, you know, did very highly on acceptability, and many people would recommend it.

So I think it was 3 times more successful than oral PrEP. And that is a huge outcome. That's hugely important. And then they reported data. There was data from the opera cohort, there was opera from the cohort, and there was another American big US cohort with the name that I can't remember if I've never heard of, but all of the cohorts, my impression is that it's, you know, PrEP delivered in the - in the real world, in inverted commas, is messier than in trials. The monitoring is worse. Everything is worse. The STI testing but despite this, it's going well. It's going really well. And it continues to go well, we saw that last year at CROI, and it keeps going well. So I would say that, you know, despite the messiness of real life, it's going well, the rollout of CAB.

So I think that's probably all we have time for. It's been really great to be with you all. And it's really great to do this with you, Eric. And please feel free to go online for more coverage. There's lots - lots to be seen in the capsule summaries and podcasts, and all the other on-demand webcasts for you to see. And thanks for attending.

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