HIV Update Webcast 1: Official Conference Coverage of AIDS 2026

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HIV Update Webcast 1: Official Conference Coverage of AIDS 2026

Initial ART

Dr. Tristan Barber (University College London):

VOGUE: Initial ART With DTG/3TC vs BIC/FTC/TAF Using a Test‑and‑Treat Strategy

So, we're going to start with the VOGUE study. You've already answered a question about this study, and we'll see if you're right as we go through the data in a little more detail.

So, VOGUE is a study looking at initial antiretroviral therapy with dolutegravir and lamivudine versus bictegravir with FTC and tenofovir alafenamide. It was a test‑and‑treat strategy. So, this means people were started on antiretroviral therapy before their baseline results were back, including their resistance test.

So, you may remember there was a study called STAT that looked at very early treatment with dolutegravir/lamivudine in just over 100 people. This is a larger study than that, and comparing to a three‑drug single‑tablet regimen that obviously we all have a lot of familiarity within terms of prescribing as well. So, it's an open‑label randomized phase IIIb noninferiority study that took place in 17 countries in North and South America, Asia, and Europe.

Participants were adults with previously untreated HIV. There were no restrictions to inclusion for anyone with a very high viral load or a low CD4 count. There were no viral load or CD4 count restrictions at all, but they did have to have no active hepatitis B infection.

People with an isolated core antibody that was positive for hepatitis B without detectable hepatitis B DNA were not excluded. So, as I said, antiretroviral therapy was initiated before genotypic resistance testing results were available. And if resistance data was available by week four, people with major INSTI, 3TC, FTC, or TAF resistance mutations were required to discontinue. And people were randomized 1:1 ‑ this is 509 participants in total ‑ to receive either of the two investigational arms.

And the primary endpoint was at week 48. There's a planned extension of the study to week 96, and the primary endpoint was an FDA Snapshot analysis of those who had a viral load of less than 50 copies at week 48, with a 10% noninferiority margin predefined.

Participants were also stratified in terms of their viral load. So, if people had a viral load above 100,000 copies or a CD4 count below 200, then this was noted. And we haven't seen those subset analyses presented yet, and I'll come on to the results shortly. But we can see that in terms of the people with a baseline HIV viral load of greater than 100,000 copies, this was half of the participants in the DTG/3TC arm and 44% in the BIC/FTC/TAF arm.

VOGUE: Wk 48 Virologic Outcomes

And these are the virologic outcomes. You can see here DTG and 3TC in red and BIC/FTC/TAF in blue. You can also see the amount of people that had no virologic data in the two bars on the right‑hand side of the first graph.

Now you can see that numerically, there were twice as many people who had a viral load above 50 copies in the DTG/3TC arm compared to the BIC/FTC/TAF arm. They were all viral loads that were above 50 copies and were less than 200 after previously reaching an HIV viral load of less than 50 copies per ml.

You can see in the graph on the right that DTG/3TC clearly met the noninferiority criteria compared to BIC/FTC/TAF. And there's also data available that shows you this reanalyzed with a viral load cut‑off of less than 200 copies. Still noninferior, but you can see numerically that the bar here moves more to the center, so there was less favoring of BIC/FTC/TAF numerically, but statistically, dolutegravir/lamivudine at the predefined endpoint of less than 50 copies per ml was noninferior to BIC/FTC/TAF in this scenario.

In terms of confirmed virologic withdrawals, there were seven in each treatment group, and no treatment‑emergent resistance was seen through week 48 in either treatment group. I think this is really important.

VOGUE: Virologic Outcomes Across Subgroups

If we look across the subgroups, the predefined subgroups, I mentioned that we hadn't seen the subgroup analyses presented really there; I was thinking about the very high viral load group. So, those who've been excluded from receiving dolutegravir/lamivudine in guidelines to date, with a cut‑off of over 500,000 copies. And those data will be presented at another meeting. But when we look here at the virologic outcomes presented according to the predefined strata ‑ so baseline viral load of less than 100,000 copies or above 100,000 copies ‑ we can see, again, very little differences across both treatment arms.

Now, this also bore up for the CD4 count cut‑off. You can see perhaps numerically a little bit ‑ Sorry. Numerically, you can see that there was a lower response in those who had a CD4 count below 200 at baseline. But this is pretty consistent across the two treatment arms at both the 50 and the 200 viral load cut‑off in addition.

The median time to virologic suppression. So, the first viral load recorded at less than 50 copies per ml was just over four weeks in both treatment arms.

VOGUE: CD4+ Cell Count Recovery, HBV Outcomes, and Weight Change

What about weight change? We have, of course, seen in the ADVANCE study in a different population, but quite considerable weight gain in people who initiated antiretroviral therapy with TAF‑based regimens. So, weight, of course, is very interesting in a study like VOGUE. We saw in the VOGUE study that CD4 count increases over 48 weeks were comparable between both treatment groups. There were no incident hepatitis B infections or hepatitis B reactivations, reassuringly, and we saw quite appreciable weight gain in both treatment arms, but it wasn't markedly different between the two treatment options. So, people gained 3.6kg. So, this is about ‑ oh, quickly does maths. This is slightly over seven pounds, I think, in the dolutegravir/lamivudine arm. And if we look in the BIC/FTC/TAF arm, people gained four kilos. So, this is about nine pounds in weight gain from baseline. So, quite appreciable weight gain in both treatment arms but not a remarkable difference between the two treatment options.

Posttest 1

So, in terms of a posttest, having been through the data for VOGUE, I'm gonna ask you to vote again. So, in this study of first‑line antiretroviral therapy using a test‑and‑treat strategy at week 48, compared with a BIC/FTC/TAF start, a dolutegravir/lamivudine start had either:

A. Inferior efficacy and more treatment‑emergent resistance

B. Noninferior efficacy, but more treatment‑emergent resistance

C. Inferior efficacy, but no treatment‑emergent resistance with either regimen, or

D. Noninferior efficacy and no treatment‑emergent resistance with either regimen

So, please vote now.

You've obviously seen this question before, so I'll just give you a couple more seconds to vote. And now we will move on.

Dr. Joseph Eron (University of North Carolina at Chapel Hill): Tristan, just to jump in, that was a beautiful presentation, a nice summary. It's kind of interesting whether we'll actually see much of a shift in what people do based on these data. I think kind of reflecting that now that we don't see as many people presenting the care less than 200, the numbers are still kind of small in that group and hard to make a really strong conclusion ‑ I think you pointed that out ‑ but it will be interesting to really see about the higher viral load group. That will be fascinating to look at, and I look forward to seeing that.

Dr. Barber: Yeah, I agree with you, Joe. I think we really need to see that group ‑ the analysis from that group, particularly if we're going to see if this data influences guidelines. And I think many people are still wedded to the idea of three‑drug therapy and people with a very high viral load. And, you know, it's quite hard to get people to change their opinion even on the basis of aggregate data like this study. So, I think we really need to see guideline change to support people to feel more comfortable. And I think seeing that analysis at over 500,000 copies at baseline will be really important.

Dr. Eron: I realize I interrupted you on your last posttest just to go over the correct results. Sorry. I'm sorry about that.

Dr. Barber: Not at all. Not at all. Really good to have some discussion.

Rationale

And I think we saw that there was a good swing to the right answer here, which was D: noninferior efficacy and no treatment‑emergent resistance with either regimen. And importantly, as I pointed out on the last slide, no hepatitis B reactivations or infections, which was really good to see.

Switch to Long‑Acting Oral or Injectable ART

Dr. Eron: Great. I'm going to take over. Thank you.

ISLEND‑1: Switch to Once‑Weekly Oral ISL/LEN From Daily Oral BIC/FTC/TAF in Adults With Virologically Suppressed HIV

So, I'm going to talk about two studies that are looking at a new combination. So, this is a once‑weekly oral tablet composed of islatravir, which is an NRTTI. Works a little bit differently than our standard NRTIs, maybe with an extra step, making it potentially more potent, and then lenacapavir, a drug we're all pretty familiar with. But this is in a pill form that can be given once a week. So, ISLEND‑1 was a switch study of this once‑weekly combination compared to continuing daily oral B/F/TAF.

These were in adults that were virologically suppressed. They had to be less than 50 for at least six months on B/F/TAF. They had no history of virologic failure and no previous islatravir/lenacapavir exposure. And it was a study of about 300 people per arm, stratified by region and by CD4 cell count less than 200, 200 to 350, and then above 350.

It's a 96‑week blinded study. So, this is a blinded switch. And then there's an open‑label extension if the study is successful. Like the study that Tristan showed you, the primary endpoint is HIV RNA above 50 copies at 48 weeks by the Snapshot analysis. And then we also got to look at the proportion suppressed at 48 weeks. And also, the change in CD4 cell count and AEs resulting in treatment discontinuation.

Some of you have been paying attention to islatravir for a while. Might remember that in earlier studies at a substantially higher dose, islatravir was associated with a decline in lymphocytes that also led to, obviously, a decline in CD4 cells. So, it was really important to see in this large study what happened to CD4 cells over time.

ISLEND‑1: Wk 48 Virologic Outcomes

So, this is one of our standard graphs that you're all very familiar with. And you can see if we look at the primary endpoint in this study, out of the 300 people that were enrolled, no participants on the islatravir arm, which is in orange, had a viral load above 50 copies at week 48, and only one participant in the B/F/TAF arm. So, obviously, very, very successful therapies of maintaining suppression.

Obviously, like many studies, there are people that don't have data within the window, but they were not virologic. rebounders.

And then suppression rates were 92, 93% in both arms. And you can see, of course, that the virological ‑ efficacy was very similar between the two treatment arms. And on the right, you can see that clearly islatravir/lenacapavir met noninferiority.

If we look at participants with no data in the window that's on the bottom right, some were discontinued because of adverse events, about the same in each arm. Some discontinued for other reasons, but their last viral load was below 50 copies, and a couple of others just didn't have any data in the window and were still on treatment.

ISLEND‑1: Immunologic, Weight, Adherence, and Safety Outcomes Through Wk 48

So, here are the kind of immunologic, weight, adherence, and safety outcomes. So, there were no discontinuations for CD4 or lymphocyte decreases. And there were similar CD4 changes and similar increases in absolute lymphocyte counts occurred throughout the 48 weeks. So, the two arms kind of ran in parallel. Body weight remained stable. There was a slight decrease in islatravir/lenacapavir and essentially stable in B/F/TAF. And again, not very small changes.

And adherence by pill count ‑ this is by pill count ‑ was slightly better, but excellent really in both groups. And a higher proportion of participants had over 90% in the islatravir/lenacapavir. There were a few ‑ remember, the denominator is 300 here ‑ a few participants that had apparently treatment‑related adverse events in this blinded study. And one participant discontinued due to the onset of new hepatitis B infection unrelated to treatment. And that participant was unvaccinated.

Posttest 2

So, this is the post‑question two for the ISLEND‑1 study. So, in this phase III randomized blinded ISLEND‑1 study that compared with daily oral therapy of B/F/TAF, so remaining on B/F/TAF or switching to once weekly oral islatravir/lenacapavir, which was the outcomes we saw?

A. Higher efficacy with islatravir/lenacapavir, but less of an increase in CD4 cells

B. Higher efficacy, and a similar increase in CD4 cells, or

C. Similar efficacy, but less of an increase in CD4 cells, or

D. Similar efficacy and similar increase in CD4 cells

So, go ahead and vote, and we'll wait a minute or two. The next study I'm gonna show you is a open‑label comparison. And we'll get to that just in a couple of ‑ couple seconds or so.

I think we've made it there. So, I'll close this and move to the next slide. But you can see that most of the people got the correct answer.

Rationale

Again, the efficacy was very, very similar. I mean, one virologic rebound above 50, and B/F/TAF none in ISL/LEN and then a similar change in CD4 cells over time. So, no concern for this potential lymphocyte toxicity was seen in this particular study, which is great.

ISLEND‑2: Switch to Once‑Weekly Oral ISL/LEN From Standard Daily Oral ART in People With Virologically Suppressed HIV

So, ISLEND‑2, very similar, except the difference here is this is a comparison of the once‑weekly islatravir/lenacapavir with standard daily oral therapy. So, the standard therapy that participants are on. This is randomized, but it's not blinded. Again, these are adults more than six months on their standard therapy. No history of virologic failure, no previous islatravir or lenacapavir exposure, and no hepatitis B. Same primary endpoint. A proportion greater than 50, a greater than or equal to 50 at week 48. And then the secondary endpoints were less than 50 change in CD4 and adverse events.

ISLEND‑2: Wk 48 Virologic Outcomes

You can again see really fantastic outcome really in both arms. Orange is islatravir/lenacapavir continued on daily standard of care, as blue, you can see there was only one rebound in the islatravir/lenacapavir arm and four in the standard of care arm. Very high continued suppression and a limited number of no data in the window.

About almost 80% switched from another INSTI regimen to islatravir/lenacapavir. And again, there was no ‑ there were no instances of islatravir or lenacapavir resistance emergence through 48 weeks.

You can see, again, noninferiority with a slight numerical favoring of islatravir/lenacapavir. And then if we look at the people not in window, AEs accounted for a small number. People discontinuing for reasons, but with a viral load less than 50 when they discontinued. A few more in islatravir/lenacapavir arm, and then finally missing data in window was also a small number. So, very successful treatment with islatravir/lenacapavir in this open‑label study.

ISLEND‑2: Immunologic, Weight, Adherence, Participant‑Reported, and Safety Outcomes Through Wk 48

Again, now are the immunologic, weight, adherence, and, in this case, patient‑reported outcomes because, obviously, the participants knew what they were receiving. There was a very small mean change in CD4 cell count and a very, very small mean change in lymphocyte count, with no difference between the two groups.

Body weight remained stable. Again, kind of minuscule changes of literally less than a pound, at least in the mean change.

And the adherence to islatravir/lenacapavir was over 99%, which is really quite remarkable. AEs leading to discontinuations were very uncommon too in ISL/LEN, and one with the standard oral therapy. That one was a person that had hyperbilirubinemia, but with a previous history of hyperbilirubinemia. There was also an acute hepatitis B infection. And on the standard of care, there was a CNS lymphoma, unfortunately, and obviously treatment‑unrelated.

Tristan, do you want to just give us your take on these, on the islatravir/lenacapavir before we move to your next set of talks?

Dr. Barber: Yeah, sure. Thanks so much. Really clearly presented. Thanks, Joe.

I was going to ask you a question actually as to which ‑ how you think we look at these two in combination, because you alluded to it, but ISLEND‑1, in a way, is not really a study that's telling us much about a once‑weekly treatment in terms of adherence, because it was placebo‑controlled, so people were taking a daily pill. ISLEND‑2, of course, perhaps gives us a little bit more information there. So, what kind of weight do you give to the two studies in terms of them being compared?

Dr. Eron: Yeah. That's a great question. You know, and others on the call may know that the blinded ‑ randomized, blinded study was published in the New England Journal. The other one was not, and I think in part because randomized and blinded is kind of our standard. It's a good way also to look at adverse events because sometimes when people switch and they get a headache a week later, they say, "Oh, I got a headache because I switched." So, I think that's a good way to look at kind of adverse events in aggregate.

On the other hand, I think the real potential benefit of once‑weekly is to see how people feel about being on once weekly. Do they forget more often because it's once a week? Or do they actually take their pills more commonly because they just have to take pills fewer times in a month or a three‑month or 48‑week cycle? So, I think the fact that 99% of participants by pill count anyway, had full adherence. I think it's pretty remarkable. And I guess people can remember to do things once a week.

Dr. Barber: No, I think, I mean, they're excellent results. And I know from talking to HIV community groups, there's a lot of enthusiasm for weekly oral treatment. I guess, certainly a concern here in the UK, but in other country settings as well. It depends on whether payers are going to reimburse some of these regimens depending on what price point they come to market at. So, I think we'll have to watch this space. But certainly, a lot of community enthusiasm from people living with HIV around longer‑acting, oral therapy.

Dr. Eron: Yeah, I totally agree. Over to you.

Dr. Barber: Thank you so much. So, I'm going to present the LATA study.

LATA: LA CAB +RPV vs Daily Oral DTG/3TC/TDF in Adolescents

LATA was a long‑acting cab/rilpivirine study versus daily oral TLD, essentially. So, dolutegravir/lamivudine and TDF in an adolescent population. So, this is an open‑label noninferiority trial in adolescents between 12 and 19 years old living in African countries of high HIV prevalence.

People had to have achieved viral suppression for at least 12 months and have been on antiretroviral therapy for at least 12 months, with no history of treatment failure. They had to be negative for hepatitis B surface antigen, and they had to weigh over 35kg.

476 adolescents were enrolled into this study. You can see 235 got long‑acting intramuscular cabotegravir/rilpivirine given every eight weeks, and 241 continued to receive standard of care. So, TDF/3TC and dolutegravir or TLD. 40% of those in the injectable arm chose an optional oral lead‑in with cab/rilpivirine.

And people have been followed up with HIV RNA testing every 24 weeks until the last participant reaches the 96‑week primary endpoint. The primary endpoint here was a confirmed viral rebound. This was defined as two consecutive HIV viral loads of greater than 50 copies through week 96. And there were secondary endpoints of confirmed viral load of greater than 200 or, in addition, greater than 1,000.

Any development of major resistance mutations at the time of the confirmed viral rebound, and also safety, pregnancy, and acceptability secondary endpoints in addition.

LATA: Wk 96 Virologic Outcomes

And these are the virologic outcomes. So, you can see in the long‑acting arm there were only two individuals who had a confirmed virologic rebound compared to 15 in the oral TLD arm. And this met the noninferiority criteria. In fact, it met the superiority criteria, although this was a noninferiority study.

In terms of confirmed virologic rebound in a per‑protocol analysis, you can see just one in the long‑acting cab/rilpivirine arm and 13 in the oral TLD arm.

In terms of FDA Snapshot endpoints, you can see those who had a viral load of less than 50 copies at week 96 was 95% in the long‑acting arm and 94% in the TLD arm.

And then if we look at the people who had a viral load of greater than 50 at the primary endpoint, just one. This is 0.4% in the injectable arm and eight individuals, or 3.3% in the TLD arm.

LATA: Resistance Mutations in Those With Confirmed Virologic Rebound

In terms of resistance mutations, there was one of the two individuals in the injectable arm did develop INSTI resistance and NNRTI resistance. In the oral TLD arm, there was one person from eight who developed NRTI resistance, and we can see that some NRTI mutations were picked up.

So, you can see the mutations listed at the bottom. Perhaps the more interesting mutations here are in the injectable arm. One out of two participants with a confirmed virologic failure developing INSTI mutations as well as NNRTI mutations in addition.

LATA: Safety and Acceptability

In terms of safety and acceptability, you can see really comparable serious and other adverse events across both arms, with no statistical differences between them. If you exclude injection site reactions, you can see there were four treatment‑related adverse events in the long‑acting injectable arm and just one in the oral TLD arm.

I think it is worth noting that seven individuals in the injectable arm did permanently discontinue treatment from that arm. Two of these reported reasons that were due to an adverse event related to antiretroviral therapy. And this compared to zero treatment discontinuations and zero, of course, related to adverse events related to antiretroviral therapy in the oral TLD arm.

In terms of injection site reactions, these were reported in 91% of people receiving long‑acting cabotegravir/rilpivirine, and mostly these were grade 1 or 2. So, very similar to what we see in clinical practice, but this time in an adolescent population. Most frequent reaction in 82% was pain, and there were no resulting discontinuations from injection site reactions. And again, as we've seen in previous trial and real‑world evidence, the incidence of these decreased over time.

94% of those getting injections said that injections made treatment a lot easier compared to daily oral medication. But actually, in 99% of both arms, there was a report that antiretroviral therapy was not a burden and did not interfere with living a normal life.

Now, I think it's worth noting that this is an important population to look at injectable therapy in. These people, almost by definition, were already quite adherent to treatment. They were undetectable, and they've been receiving oral treatment for at least 12 months.

I'll just pause there and see if Joe has any comments on that study.

Dr. Eron: Yeah. I think those of us who've lived with adolescents, part of our life as children or friends' children or relatives, adolescents are a tough population. And these are obviously very adherent adolescents. But I think to me, this is encouraging and may help those adolescents that are struggling a little bit more with adherence. And so, I'm so glad the study was done. And I think the results are remarkably good, and I think maybe allows us to feel comfortable in this ‑ in this population. So, it's another ‑ another therapy that we can feel confident in. And I think there will be adolescents across the world actually that have benefited from this particular combination.

Dr. Barber: Yeah, I agree with you. And I think, you know, obviously, as we've said, these people are very good at taking their ‑ their tablets, but actually, I think particularly as a young person not having to perhaps conceal tablets or remember to take a daily tablet may have additional benefits. I think it's really optimistic and really helpful.

Switch to Weekly ISL + ULO vs Continuing Daily BIC/FTC/TAF

Okay, I will go on to present some other data this time from a switch to weekly islatravir here. So, we've seen weekly islatravir data already, of course, from the ISLEND‑1 and ISLEND‑2 studies, but weekly islatravir this time combined with a new non‑nucleoside reverse transcriptase inhibitor, ulonivirine or ULO.

This combination was compared to individuals already with a suppressed viral load who could continue on daily oral BIC/F/TAF. It was a multicenter, randomized, open‑label phase IIb study of islatravir and ULO. As I've said, this is an investigational NNRTI with activity across HIV subtypes and with minimal changes in terms of activity when people have key NNRTI‑resistant HIV variants.

So, enrolled adults with a viral load of less than 50 copies who'd been on BIC/F/TAF for at least six months. They had to have not experienced a prior antiretroviral failure, and they had to have no known resistance mutations associated with ulonivirine resistance.

They had to have a CD4 count of greater than 200 at baseline and no active hepatitis B or hepatitis C coinfection.

So, 157 individuals entered this study. They were randomized either to stay on BIC/F/TAF or to receive islatravir 2 mg once a week with ulonivirine 200 mg also dosed once a week.

And there was a primary endpoint at week 24, although this study is continuing to week 96. You can also see that at week 48, people in the BIC/F/TAF arm will have the option of rolling over into the islatravir/ulonivirine arm as well.

You can see underneath ‑ I won't go through these individually in the interest of time, but you can see the resistance mutations that were permitted for people to be included if they had these mutations. You can also see the mutations that were excluded from inclusion in this study.

The primary endpoint here at week 24 was a viral load of greater than 50 copies, as well as overall adverse events and adverse events leading to study drug discontinuation, with secondary endpoints of safety, changes in total lymphocyte count, and changes in CD4 count as well.

Switch to Weekly Oral ISL + ULO: Wk 24 Virologic Outcomes

And these are the virologic outcomes. So, you can see in the islatravir/ULO arm, no one had a viral load of greater than 50 copies at week 24, compared to one individual in the BIC/F/TAF arm.

95% of people were suppressed in the islatravir/ULO arm, and 97.5% of people were suppressed in the BIC/F/TAF arm. And you can see a small proportion of people having no virologic data in window. And incredibly, really, no individual in the study at week 24 had a viral load of greater than 200 copies.

Switch to Weekly Oral ISL + ULO: Safety

In terms of safety, and I think we have to remember this is a stable switch study, so you would expect people that are already receiving BIC/F/TAF to perhaps have new side effects if they switch to a new drug therapy, whatever that new drug therapy is. And sure enough, you can see here that in the islatravir/ULO arm, 12.8% of participants, 10 individuals, experienced any drug‑related adverse event compared to zero individuals in the BIC/F/TAF arm.

In terms of grade 3/4 adverse events, three individuals. And actually, there were some other adverse events that occurred in the BIC/F/TAF arm, but not related to drug.

In terms of serious adverse events, again, three individuals in the islatravir/ULO arm compared to none in the BIC/F/TAF arm. And one of these individuals experienced adverse events that led to discontinuation of study treatment. And this was a grade 2 skin reaction at week 16.

In terms of grade 3/4 laboratory abnormalities, nine individuals, just over 11%, in islatravir/ULO experienced these, but they were not considered in any individual to be clinically significant. And reassuringly, again, confirming the increasing amount of safety data we see with islatravir, the mean percentage changes in total lymphocyte and CD4 cell count between baseline and week 24 were similar across both treatment arms. And there were no hepatitis B infections or hepatitis B reactivations, which was really, again, very reassuring in this study, where you have an investigational combination that doesn't offer any hepatitis B protection.

So, I'll pause there, see if Joe has any comments, and hand back to Joe to talk about long‑acting PrEP.

Dr. Eron: Yeah, there was a great question because this session, the islatravir/lenacapavir study, one of them, and this study were presented in the same session, and someone raised their hand and said, "Well, why do we need two once weekly?" And both Annie Luetkemeyer and Jürgen Rockstroh, the two presenters, really said, "Well, we need choices." And there may be limitations to one or the other, either for a specific individual or there may be availability differences by country or insurance. And I, for one, was glad to see two alternatives because, as Tristan mentioned a few minutes ago, competition might be a good thing because maybe there'll be some modulation in the price.

The final thing I'll say is that the islatravir/ULO is also being studied in treatment‑naive. It's a smaller study. It's ongoing. You can find it on clinicaltrials.gov. I'm not letting out any secrets here. And as yet, the lenacapavir ‑ islatravir single once‑weekly therapy is has not been studied. So, that's a potential differentiating factor. So, all in all, I think it's good.

We're going to move into the prevention realm now.

Long‑Acting PrEP

PURPOSE 1 and 2 OLE: Study Designs

I think probably everybody on this call is well aware of the PURPOSE 1 and PURPOSE 2 studies. Those were the two large phase III studies that led to the approval of every six‑month lenacapavir for prevention. And what we saw at the World AIDS Conference was what happened during an open‑label extension.

So, I'll just remind you about PURPOSE 1 that was in cisgender adolescent girls and young women in South Africa and Uganda. And that was almost ‑ well, 5,300, almost 5,400‑person study. That one you might recall, not only was there a lenacapavir arm, this was ‑ these were randomized, blinded arms compared to F/TAF, but there was also a comparison to F/TDF in that study. So, there were three arms in that study, in part to give us more information about F/TAF in young adolescent girls and young women. But at the end of the studies, when they were stopped based on the activity of lenacapavir, all three groups were allowed to an open‑label extension of lenacapavir.

So, what that does is it gives you just more data on safety and probably more data on activity of the lenacapavir.

And PURPOSE 2, those were for cisgender men, transgender women, transgender men, and gender nonbinary people. Again, US, Brazil, Peru, Thailand, South Africa, Argentina and Mexico. And again, people really high risk. This was a smaller study in part because there were only two arms in this study. It was lenacapavir or FTC/TDF placebo or FTC/TDF or lenacapavir placebo.

Again, the study was stopped, and both arms got to go on to this open‑label extension. And people will recall it's an every‑six‑month dosing with lenacapavir, but there are oral lenacapavir dosing on the first two days. And that's then the only oral dosing there is associated with this form of PrEP.

PURPOSE 1 OLE: HIV Incidence Through OLE Wk 52

And what you can see is here we see the primary analysis, which we've already gone through many times. This is for PURPOSE 1. You'll recall there were no infections on subcutaneous lenacapavir in PURPOSE 1 in the primary analysis. When the blinded phase was ended, that went on a little bit longer, right? Because the study was stopped and then it took a while to get the data analyzed. There was one ‑ there were, sorry, two infections that occurred in the blinded phase. And then over the 52 weeks of open‑label extension, there again were no further new acquisitions. So, basically, you're looking at essentially really thousands of young adolescent girls and young women over 4,600 person‑years of follow‑up on LEN and two infections. So, really quite remarkable on the continuous LEN.

And then if you look at the switch, there were no new infections. So, together, if you're really good at math, it's over 7,500 person‑years to two infections. Really quite remarkable.

PURPOSE 2 OLE: HIV Incidence Through OLE Wk 52

And then if we go to PURPOSE 2, these are the men who have sex with men, transgender women, transgender men, gender nonbinary people. You'll recall in the primary analysis, there were two infections. And with the subcu LEN, there was a third infection during this blinded phase through the end of the randomized, blinded phase.

And then, if we look at the open‑label extension, there was ‑ in the continuous LEN group, there was one more infection. So, a total of four infections over 4,600 person‑years. Those who switched to LEN, there were no new infections with almost another 1,000 person‑years. So, really, here an accumulation of four infections with approximately 55, almost 5,600 person‑years of follow‑up.

So, really across PURPOSE 1 and PURPOSE 2, a total cumulative acquisition of six ‑ six infections with over 10,000 ‑ well over 10,000 person‑years of follow‑up. So, really quite remarkable effectiveness.

PURPOSE 1 and 2 OLE: Safety and Adherence

In terms of safety, if we just look at the LEN switch group, really a small number of grade 3 AEs. There was less than 10%, but some serious AEs, and AEs leading to discontinuation are ‑ are in the single digits. You can see that for PURPOSE 1 and 2 in the top section of this table. The bottom section, if you look, these are the grade ‑ graded ISRs. ISRs are common, right? Over, you know, 60, 70, even ‑ even 90% of ‑ of participants have ‑ have some ISR. But grade 3 are uncommon. Again, single digits in all the groups, and those leading to discontinuation. There are some. And ‑ and on‑time injections ‑ again, this is a study people have followed very, very carefully, but on‑time injections were ‑ it was the vast majority of the time, 95% of the time.

So, in the open‑label extension, consistent with what we've seen in the past and really highly efficacious and ‑ and really very, very well tolerated.

I'm switching back to you, Tristan.

Dr. Barber: Thank you so much. I think, you know, obviously lenacapavir for prevention, Joe, is incredible. I think seeing those breakthrough infections, even, you know, one who was on time with visits had good drug levels, does make us wonder how we counsel people about receiving this drug for prevention. You know, this was a trial environment, thinking about how we counsel people in the real world.

I think what I'm starting to try and do in the UK is use some joined‑up language. We have people who say, you know, every HIV acquisition on PrEP is a failure. And I think that's stigmatizing for people who acquire HIV or people who are living with HIV. So, I'm trying to say, "Look, we've got great prevention options. They're incredibly effective. And you'll be testing regularly. So, if you're one of the unlucky people who acquire HIV, you'll be straight into HIV treatment with a normal life expectancy." And, you know, trying to use that joined‑up language rather than stigmatizing people with HIV whilst we have excellent, really effective prevention options in addition.

Dr. Eron: Yeah, that's a really good point. Really well said. Thank you for ‑ that'll make me a better doctor. Thank you.

ImPrEP CAB Brasil: High‑Sensitivity Analysis of Discordant Retrospective HIV Test Results With LA CAB PrEP

Okay, I'm going to talk about this quite complicated data quite quickly, just in the interests of time. This is the ImPrEP study from Brazil. Really, what they were trying to do here is look at the effect of cabotegravir PrEP on delayed diagnosis of HIV for those who acquire HIV whilst receiving it. We've seen lots of discussions before about the so‑called LEVI syndrome of delayed seroconversion in people that are receiving long‑acting PrEP. And this was an example of trying to look under the lid a little bit and try and find out what was going on a little better with different testing approaches.

So, HIV infection whilst on long‑acting cabotegravir PrEP is characterized by undetectable or low HIV RNA and diminished or delayed antibody responses, leading to conflicting diagnostic test results.

This was a current analysis of a prospective study to determine if clinical assays or more sensitive tests provide better evidence of HIV infection in people with discordant test results after starting LA CAB PrEP the same day. And it looked at data from public health clinics in six Brazilian cities that had enrolled 1,220 individuals who are naive to PrEP, cisgender men, transgender persons, and nonbinary people 18 to 30 who have sex with men. This was between October 23rd and October 2024.

The confirmed HIV incidence was four. This was 0.3%. There was an undiagnosed acute HIV at the time of study enrolment. This was one individual. There was an HIV acquisition 407 days following the last long‑acting CAB dose. Again, this was one individual. And then two individuals did acquire HIV with on‑time cabotegravir injections.

ImPrEP CAB Brasil: Prospective and Retrospective HIV Testing

So, you can see here they were using a rapid third‑generation antibody diagnostic test one month after enrolment and then every two months. If people were negative, they were administering the long‑acting CAB injection and storing a sample for retrospective testing. Of course, if it was reactive, they confirmed HIV infection. When they looked at the stored samples, they undertook a rapid fourth‑generation antigen‑antibody diagnostic test, a confirmatory HIV antibody differentiation assay, and an HIV RNA test, and looked for any reactive or detectable results from those combination of testing.

They also did a specialized high‑sensitivity research testing of plasma serum and buffy coats. They did an HIV‑1 RNA single‑copy assay detecting virus in plasma, right down to three copies per ml. And they also did a cell‑associated HIV‑1 DNA assay detecting integrated virus, conducting this on 1 ml of buffy coat. And you can see some of the other figures around this testing here. I won't go into those in detail, just in the interest of time.

ImPrEP CAB Brasil: Results in 14 Participants With ≥1 Reactive Retrospective HIV Test Discordant with Confirmatory Assays

So, what did they find? Well, in the 14 participants with at least one reactive retrospective HIV test discordant with the confirmatory assays, they looked at these in a bit more detail. So, four of the participants had a single reactive test result. Six had a reactive test result at greater than one time point, and there was more than one reactive test result at one time point in a further four individuals.

57% of discordant results were obtained with retrospective rapid fourth‑generation testing, and all 14 had undetectable virus by HIV RNA single‑copy assay and cell‑associated HIV DNA assay.

In terms of outcomes in the participants with discordant results, 10 continued long‑acting cabotegravir, two withdrew from the study, one was lost to follow‑up, and one switched to oral PrEP.

So, the data here suggested that there are false‑positive test results using this increased testing battery, but that the investigators said they could not rule out viral suppression or an aborted HIV infection. And so, the overall conclusion here was that rapid fourth‑generation combined antigen and antibody testing may have no advantage over rapid antibody‑only third‑generation testing.

I think this remains a little bit contentious. I think we need more work to look at how we test people for early HIV infection or acquisition when they're using long‑acting pre‑exposure prophylaxis like injectable cabotegravir.

And Joe, I will hand back to you.

OPERA Cohort: Real‑world LA CAB PrEP Use and Effectiveness Among Women

Dr. Eron: Yeah. So, I'm going to go quick because I've probably talked too much earlier. And this is looking at what people like to call real‑world. This is an observational cohort, the OPERA cohort, looking at the effectiveness of long‑acting CAB PrEP use among women in this ‑ this is a very large cohort, but only a small percentage are women.

If you look at the bottom right table, you can see that they ‑ they had 300 women who ‑ who started long‑acting CAB PrEP and ‑ and this is looking at either cisgender or transgender women. And a third of those were transgender women. And you can see that a lot of them were on Medicaid, which is, in the US, one way to have pretty quick access.

The good news is among these 315 women there were no incident infections noted in the OPERA cohort. So, that's terrific.

OPERA Cohort: LA CAB PrEP Use Among Women

On the next slide, just quickly, it just goes through kind of the cascade. So, 315 women started; about 60 were lost, I think 63 or so were lost or chose not to continue. They either lost to follow‑up or chose not to continue. Most of the 250 actually had on‑time injections, but not all. Most, but not all.

And then of those that got a second injection, another 40 chose not to go on, to continue. And again, you can see as they space out, fewer had a ‑ were on time; only 56% were on time. Of those who were not on time, most just had a short delay and didn't require a reinitiation. But 15% had a long enough delay that they required a reinitiation sequence, meaning that second shot approximately one month after the first shot.

So, again, this is ‑ this is kind of real world. Most of the injections are on time, but ‑ but there is some spacing out of on‑time injections, and just to remind you that ‑ that there were no transmissions in ‑ in this group.

OPERA Cohort: Stopping and Resumption of LA CAB PrEP

As I mentioned, 143 women stopped completely; 63 didn't finish their initiation, but many actually came back and said, "No, I think I want to try again." And then 80, after they received a maintenance injection, dropped out, but again, 20 of those, or 25%, came back to start back up. So, again, some percentage of women who stop LA CAB actually come back to start it again.

And I will ‑ I think that's the end. Oh, this final question.

Posttest 3

So, I'm hoping that ‑ this question that says: I am familiar with data from AIDS 2026 conference, and I have ideas of how to translate these data into current or future management strategies.

So, go ahead and ‑ and vote on ‑ on this. You either:

A. Strongly disagree

B. Disagree, or

C. In the middle, or

D. You agree, or

E. Strongly agree

So, go ahead.

Thank you, everyone, for your attention. And I hope you learned something. It looks like people advanced their knowledge somewhat during this hour.

Dr. Barber: I agree, thanks so much, Joe. It was great doing this with you.

Dr. Eron: Yeah. Really fun.