HIV Update: CCO Official Conference Coverage of IAS 2025

Dr Daniel Kuritzkes (Harvard Medical School): It’s a great pleasure to be with all of you today. I'm going to start us off by talking about some of the presentations around HIV prevention at IAS 2025.

[00:20:26]

PURPOSE 1 and PURPOSE 2 Results in Adolescents and Young Adults: Study Designs

And we'll talk about the updates on the PURPOSE 1 and PURPOSE 2 studies. Recall that PURPOSE 1 was a randomized trial of lenacapavir, as compared to either FTC/TAF or FTC/TDF in cisgender women aged 16 to 25, as well as certain other groups. These were entirely in adolescent and young adult population.

And then PURPOSE 2 was a study in cisgender men, transgender women and others and was just a 2-arm study comparing to lenacapavir to FTC/TDF. Of course, the lenacapavir after an initial oral loading dose was given by subcutaneous injection every 6 months, whereas the FTC/TAF or FTC/TDF arms received a daily oral PrEP.

And you can see that there were more than 5000 people enrolled in PURPOSE 1 and nearly 3300 people enrolled in PURPOSE 2.

[00:21:29]

PURPOSE 1 and PURPOSE 2 Results in Adolescents and Young Adults: HIV Infections

This study shows the overall results for the trial. In the case of PURPOSE 1, which was limited to adolescents and young adults, you see that there were no new infections acquired after the start of the trial in the lenacapavir arm, and you can see somewhat more infections in the TAF/FTC vs TDF/FTC arm, not a statistically significant difference between the 2 oral arms, but obviously highly significant superiority of lenacapavir.

And then in the PURPOSE study, which really included a larger group of people, not just adolescents and young adults, you can see that there were only 2 infections acquired after the start of therapy in the lenacapavir arm. As it turns out, both of those new infections occurred in adolescents and young adults. But that was once more substantially and highly significantly lower than the 9 infections acquired among participants in the FTC/TDF arm. So these 2 studies combined demonstrate the superiority of every 6-month injectable subcutaneous lenacapavir compared to daily oral PrEP.

[00:22:47]

PURPOSE 1 and PURPOSE 2 Results in Adolescents and Young Adults: Adverse Events

Looking at the adverse events. Here, the point of this slide is to really compare the rates of adverse events in the case of PURPOSE 1 for younger participants vs older adolescents and young adults. And you can see that the rates here are really quite comparable. There were very few grade 3 or serious adverse events. And there were just a few adverse events resulting in studied drug discontinuation.

And in PURPOSE 2, where we can compare the younger group, those between 16 and 25 vs the older group, we see once again, very similar rates of adverse events. Again, a relatively small number of people discontinuing study drug due to adverse events and very few, serious or really worrisome events.

And there were injection-site reactions that were predominantly mild, and quite similar to those, reported in the larger populations, particularly the older population in the PURPOSE 2 study.

[00:24:01]

Impact of Anticipated Funding Cuts in International Aid on HIV Epidemic in Low- and Middle-income Countries

One of the real challenges we face now in the prevention world is that, with the funding cuts that have occurred due to the dissolution of USAID and cuts to PEPFAR, there really enormous concern about what this means for efforts to control the HIV epidemic in low and middle income countries.

Bowring and colleagues presented the results of a modeling study using the optimal model to estimate the impact on - on prevention and acquisition of HIV. They used data pooled from 26 lower and middle income countries, representing approximately half of people living with HIV and roughly half of all reported international aid, and a little more than half of all reported PEPFAR funding.

They used data from the Global AIDS monitoring as including international sources and PEPFAR to estimate funding reductions at the country level. They found that sub-Saharan African countries were among the most vulnerable to reductions in international funding, and that globally, national health systems are expected to prioritize treatment of people with HIV and facility-based testing. But HIV prevention is much more likely to be susceptible to budget reductions and therefore to suffer greater limitations.

They anticipate that, by the end of this decade, cuts to foreign aid would result in reductions in spending of about a quarter and a nearly 80% reduction of spending from PEPFAR. This would result in as many as 1.7 million new HIV infections attributable to the cuts to foreign aid, and perhaps as many as nearly 11 million new infections due to discontinuation of PEPFAR and the loss of support there for prevention approaches.

This, unfortunately, could translate into as many as 61,000 additional deaths due solely to the cuts in foreign aid, and potentially as many as 3 million new deaths due to the discontinuation of PEPFAR.

[00:26:32]

Key Takeaways: HIV Prevention

Key takeaways with respect to HIV prevention are that in the PURPOSE 1 and PURPOSE 2 studies, the efficacy of lenacapavir and its safety in adolescents and young adults were similar to those seen in adults. And the impact of budget cuts on the HIV epidemic was shown to be extensive in this modeling study that I just presented, with potentially dramatic increases in the numbers of HIV infections and deaths attributable to HIV, all associated with decreased foreign aid and the discontinuation of support from PEPFAR, with sub-Saharan African countries being the most vulnerable and HIV prevention services suffering the greatest impact.

[00:27:20]

ART Regimens

Let me turn this now to Professor Orkin, who will talk to us about ART regimens.

Dr Chloe Orkin (Queen Mary University of London): Thank you so much for that.

[00:27:30]

BREATHER Plus: Short-Cycle Therapy (SCT) vs Continuous ART (CT) in Adolescents Living With HIV in Sub-Saharan Africa

So the first study I'm going to talk about is, in fact, looking at short-cycle therapy vs continuous antiretroviral therapy in adolescents living with HIV in sub-Saharan Africa. And the topic of short-cycle therapy, in other words, not taking pills every day and using them for short periods of time, within a week, 4 or 5 days was a topic of the meeting because there have already been global shortages and HIV treatment programs have run out of tablets.

So the field was thinking about the study was really relevant because people were talking about how best to use a short supply of pills if that happens. So obviously that's a worst case scenario. But this study was, you know, answering an ever important question.

So this is a study looking at short-cycle therapy vs continuous treatment in adolescents in sub-Saharan Africa. And this is important because other short course treatment studies, which we have known about in the past, have generally taken place in world resource settings and are often used efavirenz. And crucially, the monitoring has been very intense, people being monitored very carefully. Whereas in this study it was a non-inferiority study in adolescents, as I've said about 3 times, who were on DTG and were undetectable for at least 12 months.

And the regimen for the short course was 5 days on/2 days off vs CT, which is continuous treatment. And although the study visits with 2-3 monthly, the viral load testing was only 6-12 monthly, so it was very scant biological monitoring. And the primary endpoint was 2 confirmed viral loads above 50 by Week 96.

And there was a noninferiority margin based on the rate of confirmed viral rebound using a safe margin, and secondary endpoints was viral load less than 50 week, 96 viral rebound safety and adherence.

[00:29:25]

BREATHER Plus: Baseline Characteristics

So the population was a median age of 16.5, predominantly female and majority acquiring HIV at around birth, or are found to be living with HIV at birth. And the median time in treatment was about 12 years.

[00:29:43]

BREATHER Plus: Confirmed Viral Rebound by Wk 96 (Primary Endpoint)

So if you look at the outcomes, what you see in the study is that noninferiority was not achieved. So short course antiretrovirals was inferior to continuous treatment. Okay. So this did not work as well as taking daily treatment. So this is a very, very important finding with the monitoring that has been done.

[00:30:05]

BREATHER Plus: Resistance Mutations in Participants With Confirmed Viral Rebound

And in terms of resistance, many of the viral loads fell below the testing threshold, and not everything amplified. But where it did amplify, you can see that 3 out of 12 on the short course —on the noncontiguous treatment had resistance vs on the continuous treatment, there were more—and there was 1 person who had 2 class resistance.

So I think, you know, it's an important study demonstrating an important point in terms of those outcomes.

[00:30:38]

IMPALA: 48-Wk Study of LA CAB + RPV in Adults With Poorly Controlled HIV in Sub-Saharan Africa

And I think the next study that was really, really important was the IMPALA study. And this study also took place in 3 sub-Saharan African countries. And it's a 48-week study evaluating long-acting cabotegravir/rilpivirine in adults.

And this study really reaches closer to the heart of what we want to know in terms of as clinicians, can we use this regimen in poorly controlled people in the past? So who was enrolled? It was over 18s in Uganda, Kenya and South Africa. And the people who enrolled had to have had a viral load greater than 1000 in the prior 2 years, despite antiretrovirals or a history of disengagement with care, or - and linked to care for more than 3 months.

And they were not on second-line treatment, and there was no pregnancy or breastfeeding at the time, and they couldn't be having HBS antigen. So essentially they were on 2 NRTIs and dolutegravir and they had to be undetectable at the time of going on to cabotegravir/rilpivirine. So there's a 3-month period of getting them undetectable.

And then they received cabotegravir/rilpivirine 2 monthly vs 2 NRTIs and DTG.

And the primary endpoint was a viral load less than 50 at Week 48 using the snapshot algorithm with some secondary endpoints around CVFs, adverse events, patient-reported outcomes. And there were also some prespecified virological failure sensitivity analyses looking at the proportion of participants with a viral load at 200, or having a single viral load greater than 1000. Because they were also wanting to understand the issue of, you know, when people stop taking their daily tablets and they have high viral loads for a period of time until they resuppress and adherence work is done, you know, what's the meaning of having this? You know, is this going to be something that's different with cabotegravir or rilpivirine?

[00:32:39]

IMPALA: Baseline Characteristics

So the baseline characteristics, they are around 40, 60% with female. And you can see that almost a third were core antibody positive. So this is an important distinguisher of the study. And around 20% had BMIs greater than 30. Had good CD4 accounts, have been on treatment about 7.5 years. And around 80% were in NNRTI exposed in the past. So that's also an important point.

[00:33:07]

IMPALA: Outcomes at Wk 48

So in terms of the primary analysis what you can see is that long-acting cabotegravir/rilpivirine was noninferior to oral ART in this population of people who were suppressed. However, in the past that had poor virological control or poor adherence. And you can see that the same findings occurred in the groups with high BMI greater than 30, cabotegravir-rilpivirine was also noninferior in this group.

They looked at some secondary endpoints and showed noninferiority in terms of viral load greater than 50 and 2 consecutive viral loads greater than 200. But when they looked at the sensitivity analysis, looking at CBF or viral load greater than 1000 copies, what they found is that actually cabotegravir-rilpivirine were superior to oral ART in this particular sensitivity analysis.

[00:33:59]

IMPALA: Characteristics of People With CVF With LA CAB + RPV

So in terms of the characteristics of people with CVF, here, it's a dense slide, which will be in the web - which will be in the downloadable slide deck. But the overarching point is that they're still determining the level of baseline resistance on proviral DNA. We didn't have all of the results, but there was some evidence of an NNRTI resistance.

You can see the viral loads of failure. In most of them, the first viral load was higher than the second. You can see that in those that did develop resistance, it was 2 class resistance, across all of the cases. But probably the most important finding is like the CARES study, these people, 4 out of 5 resuppressed on dolutegravir-based treatment and 1 resuppressed on PIs. So everyone resuppressed, but 4 of them suppressed despite having high level integrase inhibitor resistance has been shown in CARES.

[00:34:55]

IMPALA: Adverse Events

In terms of adverse events, there was nothing very surprising. Similar to other studies, no major concerns. Interestingly, no injection-site–related discontinuation at all. And there were some pregnancies. There were 2 live births both born without HIV.

And in terms of preference, very high proportions, 94% of them preferred it on long-acting treatment. And there was a statistically significant improvement in treatment satisfaction in favor of long-acting treatment.

[00:35:32]

IMPALA Subanalysis of Long-acting ART in Countries With High HBV Prevalence: Wk 48 HBV Outcomes

There was a subanalysis in the countries with high HPV prevalence. And what was interesting is that a very low proportion of people actually had vaccine-mediated immunity at baseline. Okay. Because remember I told you that nearly a third had core antibody positive. And there were no reactivations of HPV, but they did not have access to the viral load testing, HPV viral load, all the - at all the visits, whether to see there were transient viremia is that work is being done.

But there was 1 incident HPV infection in a person with unknown vaccine status. And at baseline, core antibody was negative and that person was switched to DTG/TDF/3TC and the liver enzymes improved within 3 weeks and the Hep B s-antigen became negative in 6 months.

So that was that 1 particular case. There's more work going on, on understanding whether there were transient those—you know, exactly whether the minor blips or viremias in people, you know, in terms of the reactivation work that ongoing work is happening.

[00:36:41]

Posttest 1

So the IMPALA study in adults with poorly controlled HIV in sub-Saharan Africa showed high levels of virological control and participant preference for which of the following regimens?

1. Long-acting cabotegravir/rilpivirine;
2. Dolutegravir/3TC/TDF;
3. Darunavir/ritonavir + TDF/FTC; and
4. Bictegravir/TAF/FTC.

Vote now. Okay, let's close the poll.

Okay, so 90% of you - you have said long-acting cabotegravir/rilpivirine.

[00:37:25]

Posttest 1: Rationale

And in fact, I'm pleased to say that that is the correct answer. It is, in fact, cabotegravir-rilpivirine. 94% preferred cabotegravir-rilpivirine. And 91% of participants obtained viral loads less than 50 at week 48.

[00:37:40]

Antiretroviral Pregnancy Registry: Pregnancy Outcomes Overall and With CAB Exposure

So there was also some additional data presented around cabotegravir-rilpivirine in terms of the antiretroviral pregnancy register, looking at pregnancy outcomes overall and those with CAB exposure, which is the rightmost column.

And this is a retrospective analysis - is a voluntary register, which we should all really make a huge effort to participate in and to submit to. And it's from 75 countries. You can see overall there's nearly 25,000 exposures. But in terms of CAB, there's only 42 in the context of pregnancy outcomes.

And what you can see is that 35 live births, and that those were really the focus of the analysis.

[00:38:23]

Outcomes in Pregnancy/Neonatal Period With CAB: Investigators’ Conclusions

So 35 live births. And most people were exposed to CAB in preconception, 27 were exposed in the first zero to 6 months prior to pregnancy, and 12 were exposed 6 to 12 months prior. That was the earliest exposure. And there was 1 congenital ptosis reported amongst all the live births. That was the only fetal abnormality. But there were some preterm births, some low birth weights and very low birth rates.

But the investigators concluded that the findings reflect the positive safety profile of cabotegravir that these results should be obviously interpreted with caution due to the limited number of pregnancies. And obviously, there'll be more pregnancy data coming out of the PrEP program.

[00:39:12]

Promising Investigational Drugs and Strategies

So there were some really promising and exciting investigational drugs and strategies. There was, amazingly, a new maturation in a novel HIV maturation inhibitor, a phase IIa proof-of-concept study, in people who'd never experienced antiretrovirals before, which demonstrated a statistically significant reduction in viral loads over placebo in the monotherapy period.

Then there was the PrEP study, MK-8527. And this is a monthly dosing. And this is oral monthly dosing. People at low risk of exposure, and what it showed is it was well tolerated across dosing levels showing similar safety profile to placebo. And this is an NRTTI, most drug-related adverse grade 1 or 2.

And there were 2 people who discontinued or prespecified immunological criteria with resolution within 11 weeks. And then there was a dual antiretroviral maintenance regimen, the MODERATO study in West and Central Africa demonstrating noninferiority of maintenance dual therapy with DTG/3TC or atazanavir/3TC compared to continuing 3-drug therapy.

[00:40:29]

Once-Weekly Ulonivirine + Islatravir in Virologically Suppressed Adults Living With HIV-1

So I think that comes to the next study, which is the once-weekly ulonivirine or ULO plus islatravir. And that's an NNRTI plus islatravir, the NRTTI, in virologically suppressed people with HIV-1. This is a double-blind, active-controlled, phase IIb study.

And for people that were on bictegravir/FTC and TAF and suppressed with good CD4 counts, more than 200, no treatment failure in the past, no resistance to NNRTIs and no active hep B or C. And you can see that the islatravir dose that was used in this study is not the islatravir dose that we're now using. It's 10 times the dose. So it's 20 mg.

And then you can see that there were dose finding to find the right dose of ulonivirine. And they tried 3 different doses and the comparator was continuing bictegravir/FTC and TAF.

So I'm sure you all remember that there was an FDA hold on the islatravir program due to CD4 counts and total lymphocyte declines. And this was at the dose that was subsequently changed.

However, the study is now continued with the reduced islatravir dose at 2 mg. And they're using the 200 mg of ulonivirine going forward.

[00:41:49]

Once-Weekly Ulonivirine + Islatravir: Virologic Suppression and Adverse Events

So what you can see, in terms of the once-weekly drug at Week 12 and Week 24, is that there were no confirmed virological failure events in any treatment arm. And in terms of the outcomes in terms of AEs, you can see reasonably good performance in terms of serious adverse events, a discontinuation of drug-related events.

[00:42:09]

Key Takeaways: ART Regimens

And as a result of this, this will be taken forward. This is moving forward into future studies in phase III.

So in terms of the takeaways for antiretroviral regimens in the BREATHER Plus study, the strategy of short cycle antiretrovirals was inferior to continuous daily oral therapy among adolescents taking TLD. So short cycle was not as good.

Adherence and adverse events were similar. There were major INSTI and NRTI mutations in 1 participant with confirmed CVF on the continuous treatment.

In the IMPALA study in sub-Saharan Africa, long-acting cabotegravir-rilpivirine every 2 months with noninferior daily oral DTG/3TC treatments in a cohort with prior suboptimal HIV control or adherence.

Then among 42 pregnancies with CAB exposure, generally very early, there were 35 live births associated with 1 congenital ptosis event.

And then there was phase II study switching to once-weekly islatravir and ulonivirine or continuing bictegravir/FTC and TAF, which is supporting further development of this regimen, albeit at the lower islatravir dose which is now going forward in the future.

[00:43:26]

Patient Management

So, on that note, I'm going to hand over to Dr Kuritzkes.

Dr Kuritzkes: Thank you so much for that great update. And I want to just remind the audience to please put your questions in the Q&A section of the platform. We're tabulating them and we'll - we'll collate them to be able to address them at the end of the presentation here.

So I'm going to talk now about some of the studies that relate to patient management more generally.

[00:44:00]

ACTG A5391/DO-IT Trial: Switching to DOR ± TDF vs Continuing INSTI + TAF/FTC in People With Obesity and HIV Infection

And the first of these was a study that we were involved with at my site, the Aids Clinical Trials Group A5391 study, also known as the DO-IT trial, which was a study of switching to doravirine with or without tenofovir disoproxil fumarate vs continuing an INSTI-based regimen with TAF/FTC in people with obesity and infection. This was a multi-center, open-label, randomized superiority trial with the - to test the hypothesis that switching away from an INSTI would - and to doravirine would lead to a loss of weight.

The primary outcome was the change in weight at Week 48. The study was powered to detect small differences of 5% difference between the doravirine and INSTI arms. And the study recruited participants who were adults receiving an INSTI plus TAF/FTC for at least 48 weeks and had BMIs of at least 30 kg/m².

One potential weakness in the study design is that it didn't require that people had recently gained weight because of a recent start of an INSTI-based regimen, so some people might have had a higher weight for quite some time.

And then secondary outcomes included virologic failure and safety.

[00:45:27]

ACTG A5391/DO-IT Trial: Weight Change and Safety at Wk 48

This slide shows the primary endpoints. If we look first at the top graph here, you can see the loss of weight by percentage here within arm. So we can see that for the people who changed to doravirine plus TAF, there was a loss of about a 0.5% of body weight. Those who changed to doravirine plus TDF had a greater loss of weight at 0.27% - 2.7%. And those who stayed on INSTI plus TAF actually did lose some weight interestingly enough of about 1.8%.

So all 3 arms had weight loss. And there was no significant difference in the weight change associated with switching to doravirine plus TDF or doravirine plus TAF as compared to continuing an INSTI with TAF/FTC, a surprising finding.

If we look at the pairwise comparison. So here we're looking at each doravirine arm individually as compared to the INSTI plus TAF arm, you can see that for those who switch to doravirine plus TAF that slightly favored the INSTI arm in terms of weight change but was not statistically significant.

And conversely, those who switched to doravirine-TDF had slightly greater weight loss compared to the INSTI arm, but again, not statistically significant.

Safety parameters did not show any significant changes following the switch. There was no impact on creatinine clearance, hip or lumbar bone mineral density, and no differences in virologic failure.

So the main takeaway from this study is that we really need to continue searching for other strategies to help our patients reduce weight gain and any complications associated with weight gain in people with obesity and HIV.

[00:47:34]

Posttest 2

So this brings us to the second posttest question. In the ACTG A5391/DO-IT randomized trial in virologically suppressed people with obesity, which of the following is true regarding the weight changes observed at week 48 after switching to a doravirine-based regimen, compared with remaining on an INSTI plus TAF/FTC based regimen?

1. There was significantly greater weight loss after switching to doravirine plus TDF/FTC only;
2. There was significantly greater weight loss after switching to doravirine plus TAF/FTC or doravirine plus TDF/FTC;
3. There was stable weight on both doravirine regimens vs a significant increase on continued INSTI plus TAF/FTC; or
4. There was no significant difference in weight change between the doravirine regimens and continued INSTI plus TAF/FTC.

So give you a little bit of time to ponder those choices. Okay. Why don't we close the poll? And we can see that the majority of people, nearly 80% got the correct answer. That is D.

[00:49:10]

Posttest 2: Rationale

There was no significant difference in weight gain change - in weight change between the doravirine regimens and continued INSTI/TAF/FTC. So - and again, as we showed participants in all 3 arms lost weight, although to somewhat different extents, but not significantly different.

And switching to doravirine with either formulation of tenofovir vs continuing on an INSTI/TAF/FTC regimen was not associated with a significant difference in weight change.

[00:49:42]

TECAIN: Randomized Trial of Topical Trichloroacetic Acid vs Electrocautery for AIN in People With HIV Infection

Well, let's turn now to a completely different topic. The TECAIN study was a randomized trial of topical trichloroacetic acid vs electrocautery for anal intraepithelial neoplasia in people with HIV infection.

This was a multicenter, open-label, randomized, noninferiority trial of adults with HIV infection who had clinically visible and histologically confirmed AIN. And they were randomized to treatment with either TCA or ECA. All the participants were assessed at 4 weeks and at 24 weeks after the end of treatment.

Treatment was administered at baseline and then at several time points throughout the study, unless their AIN had cleared, in which case they did not continue to receive additional treatments.

The primary endpoint was therapeutic success at a 4 week follow up, defined as complete clinical response by high resolution anoscopy with histologically confirmed resolution of AIN or - or it's regression. This was done by a noninferiority analysis.

The primary efficacy analysis that was conducted in the intention-to-treat population with sensitivity analyses done in the per protocol population. And then there were additional secondary endpoints of success at later times.

[00:51:11]

TECAIN: Therapeutic Success

So looking at the main outcomes at 4 weeks of follow up, you can see that in terms of complete clinical response with histologic clearance or downgrade, the response rate was just about 53% in the TCA arm and just under 62% in the ECA arm. And although those differences are numerically different, with a difference of just under 10%, that failed to reach - that was not a statistically significant difference.

There were similar rates of histologic clearance or downgrade, and there was a slightly higher - in the intention-to-treat population a significantly higher rate of complete clinical response in the ECA arm, as you can see there.

And if we look at the 24-week outcome, again, the differences here are now nearly spot on, 51% and 49%, respectively. So because of the differences seen here, the trichloroacetic acid arm or the TCA group did not meet the criteria for noninferiority, compared to ECA at the 4-week primary endpoint, but it was noninferior at 24 weeks.

The TCA group required significantly more interventions to achieve clinical success as compared to the ECA group. There was a similar safety in the 2 groups. Roughly two thirds of participants experienced an adverse event. There were no treatment-related serious adverse events, and only a single participant discontinued study treatment because of an adverse event, and that was in the electrocautery group.

The investigators conclude that TCA is a well-tolerated, cost-effective and simple treatment for AIN in people living with HIV, which over 24 weeks may have similar outcomes, but not - not at the earlier time point.

[00:53:26]

Key Takeaways: Patient Management

So key takeaways in terms of patient management. From the DO-IT trial in people with obesity, it showed that switching away from an INSTI/TAF regimen to a doravirine/tenofovir regimen did not result in significant change - weight change at week 48 and in the TECAIN study, the use of trichloroacetic acid for the treatment of anal intraepithelial neoplasia in people with HIV provided comparable safety to the standard of care treatment, which is electrocautery.

And it was not inferior at week 24, but it failed to meet the criteria for noninferiority at post-treatment Week 4, which was the intended primary endpoint.

[00:54:18]

Q&A

So with that, let's turn to the Q&A while you answer additional questions here. And I'm going to turn this back over to Professor Orkin to start us off on the questions.

Dr Orkin: Brilliant. So thank you so much for that. That was like - it was so well described. And I think the TECAIN study became a lot clearer to me. So if we've only had 2 questions actually in the chat and the 1 is about weight. So I'll direct that to you, Dan.

So how is weight loss explained in all arms in the DO-IT study, where weight loss measures controlled for in the DO-IT?

Dr Kuritzkes: So that's a great question. So I think it's easiest to explain in the doravirine/TDF arm, because we know that TDF is associated with - with weight loss. So even in people taking TDF as PrEP, we can see weight loss. I suspect that what happened is that this was a highly motivated population and that other measures such as reducing caloric intake, increasing activity and the like were - may have been behaviors that were adopted during the - the course of the trial. And so that there was some loss of weight across overall.

I think it's important to recall these were not people who had just started on an INSTI and were just experiencing weight gain. People had to have been on their INSTI regimen for at least - for nearly a year, but they could have had obesity for some prolonged period of time. And - and that was a bit of a compromise in how to design the study and make it practical to enroll.

And so I think there may still be differences observed if we made changes in therapy and people who are still on an upward trajectory in terms of weight gain shortly after starting an INSTI-based regimen.

Dr Orkin: Yeah. And - I - I - I think absolutely. I think - I think there's a real - a real - a real truth to the fact that, you know, if you were entering a study around, you know, trying to - to reduce weight, it is a motivator because you don't know, you know, what might happen. So I think we should never underestimate the so-called placebo effect.

So then there's a question about patients having viral loads suppressed before starting for the IMPALA study. Why can this regimen not be used to achieve suppression? Is it because of the dual therapy?

So the answer to this question is that cabotegravir-rilpivirine is licensed for people that are virally suppressed. Okay? So - but the studies that have been done so far have always have mainly been done in people in whom there are no worries about prior virological failure. There are no worries about resistance because you know, that's - that's not what the license of the drug is.

But this study goes further and it starts to answer questions about what happened if they are suppressed. But in the past, in the recent past, there have been issues with poor control or poor adherence. So it gets us closer to the population that although it's not licensed for, we really would like to use if it was - if it was able to be used safely. So I think that's the importance of that study.

And there's another question on IMPALA.

Dr Kuritzkes: I was just going to comment briefly.

Dr Orkin: Yeah, go on, Dan. Yeah.

Dr Kuritzkes: Probably that there is an ongoing study, I believe it's called the CROWN study that is addressing the - exactly the question of can we directly begin injectable therapy with long-acting CAB and rilpivirine in people who are currently viremic skipping the initial oral suppression component? And we'll have to see what the results of that trial are to know just how effective.

I don't think it's the issue of 2 drugs, because we know there are other 2 drug regimens, particularly dolutegravir/3TC that are highly effective at achieving a viral suppression in most populations.

Dr Orkin: Yeah, absolutely. So this study and also the LATITUDE study which was recently presented, is really moving towards addressing, moving closer to what the CROWN study is going to give us. But until that point, we have these 2 studies and this is the second 1, and this is the 1 that's been done in an African context. So I think that's what this adds.

And I do think the sensitivity analysis that they did is something very important, because what is found, particularly in sub-Saharan Africa, is that people sort of have small treatment holidays, stop their treatment and then they can have a high viremia, and then they have adherent support and then it goes down again.

So what they wanted to know is if someone's on 2-monthly treatment, all these events of the high viremia that then goes down with adherence, will that get better? Will there be better because they worry about, you know, high viral loads greater than 1,000 and, you know, transmission. So they were trying to understand that question. And that is an interesting aspect of the study. That's something that I haven't seen before.

There's another question about IMPALA saying that people in the oral treatment arm did quite well considering the group recruited. What extra did the investigators do? Was it this trial only recruited people who could get to the end of 3 months consistent treatment?

Okay, so what was said is that, yes, they had to do - that they weren't incentivized. So in the LATITUDE study, people were incentivized to become undetectable, and then they were given cabotegravir-rilpivirine. But in the IMPALA study, they were just given under the best possible clinic conditions 3-drug therapy with dolutegravir.

And what the - what Fiona Cresswell, who did a brilliant presentation, said when she was asked this, she was asked this and the questions, she said they tried to replicate real world conditions, the very best of their ability. But in similar to what we're seeing in the DO-IT study, if people know - know they're having intervention, things aren't always the same as they are. You know, on a study as they are in - in real life.

So I think the study itself creates an artificial situation. And, you know, senior research team and, you know, often in research studies, people get more intervention and more support. And that might be part of why - why that happened.

So those are the only questions.

Dr Kuritzkes: No, there are actually some more. We can scroll down.

Dr Orkin: Pardon? There are.

Dr Kuritzkes: Jules Levin[?] has a question about the DO-IT study. So the DO-IT study did not look at people who switched quickly within 6 or 12 months, only after starting INSTI. So does that make a difference?

So I think that's what I was trying to get at in my comment earlier, Jules. For a variety of reasons, the study focused on people who had been on an INSTI-based regimen for at least 48 weeks. So, yeah, it is certainly possible that there would be a different outcome if we looked at people who had newly acquired weight gain, due to the more recent initiation of - of a regimen.

I think part of the issue became that there were relatively fewer new starts of INSTI regimens by the time the study got going and such a large number of people on established INSTI-based therapy.

Then I have a question here for you, Chloe from Jose Miro[?], asking the issue of lymph - lymphoma and CD4 cell decline is a recurring one with islatravir. The decision is always made to reduce the dose, as is the case with the weekly low, and islatravir trial, and the side effect will likely disappear in the short term as in other studies.

The question is, do you think the total cumulative dose of islatravir over several years might still cause lymphopenia and CD4 decline?

Dr Orkin: I mean, I think it's an interesting question, a question that I can't answer because I don't know the data because we haven't seen the long-term data. But I think that - I think obviously what you're saying is that it's a dose-related effect, and that's why they reduce the dose. But what about a cumulative dose over time? And I just wonder if there's anything we can learn from other, you know, similar situations.

I mean, I think - I think the jury is out. I don't think I can give an answer to that. But I think what I can say is on the MSD program, there's, you know, very, very careful attention to monitoring. And all of the studies are being monitored. You know, and I think, I guess the participants from the original phase III studies are still being monitored. So I think, you know, we will learn more over time.

Dr Kuritzkes: Yeah, I know, I agree. I - we - we certainly learned with tenofovir that - or actually with adefovir before that the dose reduction helped. But then there was a cumulative effect. So we need time to know about time-dependent effects.

Kumar has a question. Probably I guess I can take this one on sensitivity of viruses in doravirine in the setting of prior NNRTI mutations. Doravirine is active against most of the major NNRTI mutations that would be selected by previous generation NNRTIs such as the 181C mutation for nevirapine and the 103N mutation for efavirenz, as well as several other mutations. It does select for a unique set of mutations, but by and large doravirine can be expected to have activity against viruses resistant to efavirenz and - and nevirapine, and also mostly to rilpivirine because the 138 mutation is not a major mutation for doravirine either.

I think that does bring us to the end. One more question here from - from Jules. Ah, so what is the activity of islatravir on the 184 and other nuc mutations are - are present?

I'm not aware of any data in people in vitro. Although islatravir selects for the 184V mutation, it does retain substantial activity, because it's such a potent molecule. There was an experiment done in nonhuman primates where they first treated SIV infected macaques with lamivudine to select the 184 and then administered islatravir and showed activity. But that is the extent of the data about which I'm aware.

Dr Orkin: Yeah, I mean, absolutely. The only other thing I can say is from the doravirine-islatravir studies which were presented at CROI, and which - based on those 2 studies, there was an analysis based on proviral DNA, which was presented as a poster at IAS from MSD authors.

And there were some people who had proviral DNA evidence of 184 at baseline. So I think - there is some evidence. But I think these days - that these studies are being written up as manuscripts and I think more information will be forthcoming, although you can have a look at that poster, Jules. It did describe some proviral DNA evidence from those 2 studies.

I think that is a wrap, everybody. Thank you so much for attending. It's been a real pleasure to do this with you. And I understand that it's just me standing between you and your - your wonderful - your wonderful summer break. So have a wonderful time. And we look forward to seeing you in due course.

Dr Kuritzkes: Thank you all.

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