HIV Update Podcast: Official Conference Coverage of AIDS 2026

Dr. Chloe Orkin (Queen Mary University of London): Hello, everybody. And it's wonderful to be here with our wonderful local co-chair of the conference, Professor Claudia Cortes. I'm going to start by talking about initial treatment.

VOGUE: Initial ART With DTG/3TC vs BIC/FTC/TAF Using a Test-and-Treat Strategy
And I'm going to start with the VOGUE study. And that is looking at something really interesting, which is starting people on first-line therapy, people who are treatment-naive with dolutegravir/3TC compared with bictegravir/FTC and TAF. So it was a test-and-treat strategy. And it was an open-label study, randomized in 17 countries across South America, Asia and Europe. And they did do a stratification by viral load and CD4 count.

So it was people who'd never had treatment and with no restrictions on viral load and on CD4 count who didn't have hepatitis B. And the interesting thing about the study is that the clinicians did not have access to resistance tests when they started people on treatment. They only got the test four weeks later. So people were randomized to dolutegravir/3TC or bictegravir/FTC and TAF. And the primary endpoint was HIV viral load less than 50 copies at week 48 by FDA's snapshot analysis.

I think it's a good idea to pause here and tell you who the participants were because this is a really important consideration. So the median age was 33, and around 84% were white and 84% were cisgender males. Another very important characteristic is that nearly half of the people had viral loads greater than 100,000 copies when they started. And 15% had very, very high viral loads greater than 500,000. So this is quite an unusual study in that respect.

VOGUE: Week 48 Virologic Outcomes
So if we go forward and have a look at the virological outcomes, what we see is that for dolutegravir/3TC in orange, 89% was suppressed versus 92% with bictegravir/FTC and TAF. And that this means that it was non-inferior. Dolutegravir/3TC was non-inferior to bictegravir/FTC and TAF.

And actually, for those people who did fall into the category of viral load greater than 50 in the snapshot analysis, they were predominantly people with viral loads less than 200 who then re-suppressed. So there was some confirmed virological withdrawals, seven in each treatment group, and no treatment-emergent resistance through week 48. So non-inferior efficacy for dolutegravir/3TC against bictegravir/FTC and TAF with no treatment-emergent resistance.

VOGUE: Virologic Outcomes Across Subgroups
If we look at the viral load outcomes, I've told you that we had lots of people with high viral loads. And what you can see is that there were similar outcomes, regardless of whether your viral load was greater than 100,000 copies or less than 100,000 copies. And also regardless of the CD4 count.

One of the other questions that the study addressed was the median time to virological suppression. They wanted to know if it would take longer. And what they found is that it was 4.1 weeks in both treatment groups. So it worked the same in terms of time to suppression. And it also showed that the odds of virological suppression with dolutegravir/3TC were 23% higher than virological suppression on bictegravir/FTC and TAF.

VOGUE: CD4+ Cell Count Recovery, HBV Outcomes, and Weight Change
In terms of CD4 count recovery, HBV outcomes and weight change, there was nothing different about them. There were no incident HBV infections or reactivations. And CD4 counts changes were similar and weight was very, very similar.

Switch to Long-Acting Oral or Injectable ART
So now we're going to look at switching to long-acting, oral or injectable treatment. And yes, that is right. I said long-acting oral. So the studies that I'm going to present, the next two studies are really exciting because it's our first-ever weekly oral therapy in the field of HIV. And there were two studies, okay.

ISLEND-1: Switch to Once-Weekly Oral ISL/LEN From Daily Oral BIC/FTC/TAF in Adults With Virologically Suppressed HIV
Study one is called ISLEND-1. And this was a randomized double-blind controlled study. And it took place in about 11 countries. And it was for people who are virally suppressed for at least six months on bictegravir/FTC and TAF with no virological failure and no resistance or hep B infection.

Around 300 people were dozed with ISL/LEN. And or alternatively, they got bictegravir/FTC and TAF. And it was placebo-controlled. The primary endpoint was viral load greater than 50 at week 48 by FDA snapshot.

I'm going to go back there. And I'm going to tell you about the participants once again, because I do think this is really important. So the median age for this study was 49. And about 15% of people were over the age of 65. Unfortunately, only around 20% were female. That is assigned female at birth.

ISLEND-1: Week 48 Virologic Outcomes
So if we look at the results, again, you don't have to be a statistician to see that it was non-inferior. You can see that ISL/LEN in orange was non-inferior to bictegravir/FTC and TAF. Biological efficacy was similar. And there was no emergent Islatravir or Lenacapavir resistance in the people who had viral load throughout the study. And you can see that in terms of Islatravir and Lenacapavir in orange, you can see that there was no resistance.

So if we look at the reasons for no data in the window, discontinuations due to adverse events was six in ISL/LEN and four in BIC/FTC/TAF. And you can see very similar missingness levels of data.

ISLEND-1: Immunologic, Weight, Adherence, and Safety Outcomes Through Week 48
If we look at immunological weight, adherence and safety outcomes, there were no discontinuations for CD4 lymphocyte count decreases. Very similar findings in terms of the CD4 count numbers and similar findings in terms of absolute lymphocyte counts. Body weight remains stable. The median change was minus 0.8 with ISL/LEN and 0.1 with bictegravir/FTC and TAF.

Now, interestingly, the adherence was really high. It was nearly 99% for ISL/LEN versus 95.8% with BIC/FTC/TAF. And there was a high proportion with more than 90% adherence on ISL/LEN than BIC/FTC/TAF. Now, I can't explain this because it was placebo-controlled. If we look at the people who had treatment-related discontinuations, it was myalgia and arthralgia, macular papillary rash, and brain fog. And one person discontinued due to onset of grade 2 hepatitis B unrelated to treatment, and this person was not vaccinated.

ISLEND-2: Switch to Once-Weekly Oral ISL/LEN From Standard Daily Oral ART in People With Virologically Suppressed HIV
So I'm going to move to the ISLEND-2 study, and this was the sister study to ISLEND-1, and it was looking at switching to weekly oral ISL/LEN from standard daily oral therapy, in people that were virologically suppressed. And it was the similar inclusions, and a similar primary endpoint.

In terms of the study itself, this was done in 12 countries. The median age was 52. There were more people that were assigned female at birth in the study, there were 33%, and 40% were white, so more people from diverse backgrounds. And most people switched from integrase inhibitors, but about 15% switched from NNRTIs and about 8% switched away from PIs, so the majority were integrase inhibitors switches.

ISLEND-2: Week 48 Virologic Outcomes
So if we look at the outcomes, once again, you don't need to be a statistician to see that ISL/LEN was non-inferior to daily oral therapy. And as I've previously alluded to, 78% in the ISL/LEN arms switched away from INSTIs, and there was no resistance.

So if we take a look at reasons why people discontinued and people had no data in the window, you can see that the discontinuations for other reasons were very slightly higher in ISL/LEN, but the rest of the data was very similar.

ISLEND-2: Immunologic, Weight, Adherence, Participant-Reported, and Safety Outcomes Through Week 48
And you can see that there was also no discontinuations for CD4 lymphocyte reasons, the mean changes were very, very similar. Similarly, body weight remained stable with a mean change of 0.1 versus minus 0.3, and the adherence was very high.

Now, one thing that this study was able to evaluate that they couldn't evaluate in the ISLEND-1 study is that because it was open-label, they were able to ask about satisfaction. And in this study, 78% of participants were more or much more satisfied with ISL/LEN than standard daily oral therapy, so they preferred ISL/LEN, and 63.7% said that they found the weekly pill less of a burden than the daily pills. And you can see that the adverse events leading to discontinuation are mentioned on the slide.

LATA: LA CAB + RPV vs Daily Oral DTG/3TC/TDF in Adolescents
So the next study I'm going to talk about is also very, very interesting and exciting study in my opinion. And this is the LATA study. So it's long-acting cabotegravir/rilpivirine eight-weekly versus daily oral dolutegravir/3TC/TDF in adolescents and was conducted in four sub-Saharan African countries.

And the participants, let me tell you more about the participants. So the median age was 16. It was 98% of people acquired HIV vertically in the study; 54% were female. And almost all of them switched away from a dolutegravir-based regimen, but more than 80% had previously had NNRTIs. So this is a really important fact because it means that there was some previous exposure to NNRTIs. So the primary endpoint of the study was confirmed virological failure through week 96. So we're going to look at the primary endpoint here.

Now, why do I think this study is so interesting? I think it's so interesting because it's the only randomized study to evaluate adolescents. We've previously seen the MOCHA study, which is a one-armed study for adolescents, but we haven't seen a comparator.

LATA: Week 96 Virologic Outcomes
So if we go forward now, what we see is very similar findings in terms of testing for non-inferiority. So really similar findings for non-inferiority, which was actually the primary endpoints to see if non-inferiority was achieved. But when they tested for superiority, they showed that cabotegravir/rilpivirine wasn't just non-inferior, it also met the criteria for superiority. And you can see that this happened according to the confirmed virological rebound protocol as well. And in the FDA snapshot, you can see that they were very similar. So this study actually showed superiority, which is a really very important finding in this population of adolescents. So as we know, it's a real struggle for adolescents to take treatment.

LATA: Resistance Mutations in Those With Confirmed Virologic Rebound
So in terms of resistance, there were two people who had detectable viremia, and one of them in the cabotegravir/rilpivirine arm ended up with resistance to INSTIs and NNRTIs. And there was one person who didn't end up with that because they just discontinued. And then on the oral dolutegravir/3TC arm, interestingly, there were also people who had resistance, but this was to NRTI and NNRTI.

LATA: Safety and Acceptability
In terms of safety and acceptability, we can see that safety was very similar. No significant findings. Interestingly, there were no discontinuations due to ISRs. They had ISRs, they were mainly grade one and two, as we know, and they decreased over time. But in terms of acceptability, 94% said injections made treatment a lot easier and that it made treatment not a burden and that no longer interfered with their normal lives. So this is a really resounding and massive success.

Switch to Weekly ISL + ULO vs Continuing Daily BIC/FTC/TAF
The next study is switching to another weekly oral therapy study. This is switching to ISL and ULO, okay? So versus continuing bictegravir/FTC and TAF. So it's Islatravir plus ulonivirine. And this is a, again, it's an open-label study, but it's a phase 2B study, so it's much smaller. And in phase 2B studies, they're almost exclusively young white men, and we saw that in the study.

So ULO, in case you're thinking, what on earth is ULO, used to be known as MK-8507. It's an NNRTI with activity across subtypes and minimal fold changes against NNRTI-resistant variants. So people who'd been undetectable for six months on BIC/FTC/TAF with no prior virological failure or resistance to NNRTIs or ULO, and good CD4 counts were randomized to see if it's Islatravir and ULO versus bictegravir/FTC and TAF. And once again, it was open-labeled. And this is week 24 was the primary endpoint. So we're going to have a look at that.

Switch to Weekly Oral ISL + ULO: Week 24 Virologic Outcomes
So what we see here is very similar findings in terms of people with viral loads greater than 50. Very similar outcomes in terms of less than 50. And in terms of discontinuations, the discontinuations due to other reasons were not virological. And there was no one with a viral load greater than 200. So very exciting.

Switch to Weekly Oral ISL + ULO: Safety
In terms of drug-related adverse events, again, when you switch study and open-label switch, you will always see more drug-related events in the investigational arm. We did see a few more events, but only one that led to discontinuation. And the other important point is that the mean percentage change in lymphocyte count and CD4 count between baseline and week 24, very similar across the treatment arms, and there were no new infections or reactivations for hep B.

So with no further ado, I'm going to hand over to the wonderful local host and co-chair of the meeting, and my colleague and friend Claudia Cortes.

Long-Acting PrEP
Dr. Claudia Cortes (Centre for HIV AIDS Integral Research): Hi. Hi, hello, everybody. Good morning, good afternoon, good evening, depends where in the world you are. It's a pleasure to be here with my close friend, Chloe Orkin. So now we're going to move to PrEP, and we're going to move to long-acting PrEP, and see how it's changing PrEP around the world for the ones who got access to that. So we're going to talk about it. And the next one.

PURPOSE 1 and 2 OLE: Study Designs
Okay, so here we have PURPOSE 1 and PURPOSE 2, open-label extension. And you know that PURPOSE 1 was only in women from 16 to 25 years old that lives in South Africa and Uganda.

And now we're going to see the open-label extension of this group, plus the PURPOSE 2 participants that are cisgender men, transgender women, transgender men, and non-binary people, that of course are in HIV unknown status from Latin America, several countries, Brazil, Argentina, Mexico, Peru, United States, Thailand, and South Africa. So it's very diverse in terms of ethnicity.

PURPOSE 1 OLE: HIV Incidence Through OLE Week 52
So here you can see that after this longer follow-up, we can see there are some very, very few patients that are acquiring HIV. You can see in the primary analysis of this combination, we're looking to PURPOSE 1 first. We have this more than 2,000 patients with zero HIV new acquisition.

And now we are to the end of the randomized-blended phase, and there was two acquisitions. At the very beginning, the results were fantastic, 100% of effectivity, but now we have two, but still very, very low cases. And again, as Chloe says, when you don't need to be a statistician to see the difference between using cabotegravir and these two other combination oral combination. And then if we go to the open-label extension, 52 weeks, no new HIV acquisition during the open-label extension for the Lenacapavir branch.

PURPOSE 2 OLE: HIV Incidence Through OLE Week 52
So we can see here in the PURPOSE 2, remember these men, cisgender men, transgender men,  transgender women from all around the world. And you can see here a new case acquisition in the first primary analysis, two cases against nine cases in the oral FTC/TDF.

When we finish the end, or when the investigators finish the end-randomized-blended phase, only one more case plus three more cases. And in the open-label extension, one HIV acquisition occurring, despite this on-time Lenacapavir injection and plasma concentration that were in the expected range. So that means that the person received the injection when they were supposed to receive it. And the HIV was diagnosed at week 39 with this capsid mutation that was detected, Q67H.

The cumulative HIV acquisition across PURPOSE 1 and PURPOSE 2 through the open-label extension of week 52 is six cases.

PURPOSE 1 and 2 OLE: Safety and Adherence
And injection site reaction, less than 1% of the people participate in deciding to stop the medication because of the injection site reactions. So how was the adherence of this treatment? On-time maintenance injection. Very, very high. So have a very good acceptability.

Safety is consistent with long-term lenacapavir exposure and on-time injection adherence  acceptability remains very, very high even after a year of using this combination.

OPERA Cohort: Real-world LA CAB PrEP Use and Effectiveness Among Women
So the next study is the OPERA cohort. This is a real-world long-acting cabotegravir PrEP use, and we're going to look at women in this particular cohort.

So this is a large US database that get together information and electronic health records that includes almost 86,000 people who are receiving PrEP.

Different kind of PrEP because the study was analyzed depending of the date, and when long-acting was available, and for use in United States was later. So most of the patients were using oral PrEP, as you can see here, 5,000 against 300. So 5,330 women who initiate PrEP during this period, 80% received FTC/TDF, and 14% received FTC/TAF, and 6% only received long-acting cabotegravir because as I already mentioned, cabotegravir was approved later.

So the median follow-up in here was 13 months, so a little bit more than a year, with an interquartile range of eight to 19 months, and the STIs among women receiving long-acting cabotegravir PrEP was 18%. So the incident HIV infection women here was zero and why this is important because always, and I teach all my students all the time, the difference between a clinical study, that everything is controlled. There is a lot of people doing the follow-up against real-world data and in real world data here, you can see in this follow-up, there was zero cases, zero infections or incident HIV infections.

OPERA Cohort: LA CAB PrEP Use Among Women
So among 1,193 maintenance injection, 88% were on time. So, was very good adherence.

OPERA Cohort: Stopping and Resumption of LA CAB PrEP
30% of women who stopped long-acting PrEP resumed the injection.

Questions and Answers
So now we're going to move to the question and answers. I'm going to call back my colleague, Chloe.

Dr. Orkin: Hi, I'm back. And the question is, any regards about DDI for LEN and ISL for TB treatment. Yeah, so I think what I would say here is we know that there are some interactions in terms of LEN potentially with TB therapy.

This is sort of CYP3A4 issues. So I think that is an important consideration and we obviously we need more studies to assess this, but this is definitely an important consideration. ISL all less so, but LEN, yes.

I have a question for you, Chloe.

Dr. Orkin: Yeah, go for it.

Dr. Cortes: In VOGUE, you mentioned that it was, the results were independent of the viral load, even with high viral loads, 100,000. What happened to half a million? There were half a million or no, I'm not sure.

Dr. Orkin: Yeah, there were people in 0.5 million, and I'm trying to remember whether they actually presented people. The cuts that I've seen that I remember seeing were above 100,000 copies. I didn't see the data cut according to whether they were taking greater than 500,000 copies.

It was 15% of people. So it would be a relatively small group, but I think it's a really important group because if you think about other treatment-naive studies, there are very, very few individuals with high viral loads, particularly above 500,000 copies.

So I think the greater than 500,000 would be interesting, but I think for now I'll have to settle with 100,000 and wait for a sensitivity analysis.

So someone's commented that for both situations, either PrEP or treatment using these great news is really depends on access. And totally agree. And before we started, we were thinking about what the biggest take-home from the conference was. And I said, weekly oral therapy, and Claudia said access.

Dr. Cortes: For me, it's incredible that in a study that were run in Latin America, we still have difficulties to get, or in several countries start difficulties to get long-acting PrEP. But yes, that's part of what we're living. That's why I truly think that my second-best news from the IAS conference was long-acting oral because it's cheaper to manufacture it. So at the end, if the big studies demonstrate that effectiveness is going to be a great idea because it's going to be easier to implement oral, long-acting oral than long-acting injectables.

Dr. Cortes: About one of the studies that you present that was striking me, the LATA study that was done in very young people. It's striking to me that they prefer intramuscular injections over taking pills. I don't know, intramuscular injection, usually people don't like them a lot. They're painful. But they prefer that to taking pills every single day. So we need to offer that. We need to have that so people can choose from a broad menu what they want, what they prefer.

Dr. Orkin: Yeah, I think it's so important. And I think that I've seen it with LEN in the PURPOSE study that we're doing in the European PURPOSE 5 study. And of course I've seen it with CAB as treatment that we make the wrong assumption that people don't want to take pills, they don't want to take treatment, they don't want to take PrEP because they're not taking them.

But when you offer them something they actually want, people that have never been willing to take PrEP stepped forward for the PURPOSE 5 study, people we've never been able to convince. They know they needed the PrEP, but when we offered them something they're willing to take, they took it. And it's the same with these adolescents, okay? We think they're just chaotic adolescents, but in reality, they knew they needed to take this. So I think it's really, really interesting.

So, okay, so now we've got, given the access issues noted, what is the takeaway to reduce transmission between treatment and prevention? Who should be prioritized for the limited available PrEP LEN? I mean, I mean, Tyler, I don't know if you want to comment, but if you think about, you know, Lloyd Mulenga's talk, and he was talking about, you know, the constraints in Zambia and how the Zambian government have dealt with things he identified as the most critical, the antiretroviral supply for people who are already on treatment and people who need to start treatment. And that is a huge factor in terms of treatment and prevention. So he identified that as critical and then prevention is moderate.

So I guess you can think about it in different ways, but when I listened as an audience member, I found that very, I found that powerful and not easy, very difficult to read that, but I understood why he said that. I don't know, Claudia, do you want to say anything on that?

Dr. Cortes: It's difficult to choose between both options. It depends where in the world you are also, and what kind of people you want to make prevention. Today, I believe prevention is our biggest tool. Of course, we need to complete the 95, 95, 95 of treatment, of hopefully 100% in all the different areas.

But today we have a tool that it's Lenacapavir that it's so easy twice a year, subcutaneously, and it's affordable if you get all the support from WHO or PAHO, the pharma companies, and that make for a very specific group for women that usually very difficult to negotiate condoms or they suffer intimate partner violence, or they cannot take care of themselves. They can go twice a year to protect themselves from HIV with this simple injection. So if I have to put my dollar somewhere, I will go there in areas with very high prevalence.

Dr. Orkin: But yeah, but I think, Moses, you raise a very important point that with limited funding, terrible choices are being made between whether to keep funding up for treatment or PrEP. And these are terrible choices, which no one should have to make. And it's very hard to come down on an answer.

So that's the last question. And it's been lovely to engage with the audience. And thank you for those really interesting and thoughtful questions. And of course, it's been wonderful to engage with you, Claudia. I think anyone who hasn't listened to Claudia's opening speech has certainly listened to it. It was a wonderful piece of advocacy and truly a remarkable contribution to the meeting.