HIV Update: CCO Official Conference Coverage of IAS 2025

So let's talk a little bit about what is new around HIV prevention.

[00:13:17]

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

Now, youth aged 15 to 24 account for approximately 28% of the 1.3 million new HIV infections each year. So this is an important group where we need prevention and obviously better prevention tools than we currently have.

The PURPOSE trial is a trial you are familiar with because results have been published before, which looks at lenacapavir, a capsid inhibitor for prevention subcutaneously every 6 months. And that was a randomized, placebo-controlled trial compared to either FTC/TAF or FTC/TDF and each corresponding with placebo.

And this included cisgender women in PURPOSE 1, aged 60 to 25. So a very young group of individuals, sexually active with cisgender men and more than 1 vaginal intercourse within the last 3 months but not being pregnant. Unknown HIV status. No prior HIV testing or PrEP/PEP use in the last 3 months.

And PURPOSE 2 enrolled cisgender men, transgender women, transgender men and gender nonbinary people with unknown HIV status aged above 16 years, again being sexually active with more than 1 partner.

So this is a great study to sort of assess the efficacy of this new PrEP modality, the subcutaneous injection every 6 months overall PrEP, which we already have available.

[00:14:36]

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

And what you can see in the overall results from the PURPOSE 1 and PURPOSE 2 study in adolescents and young adults, you can see that there were zero infections in the lenacapavir arm in PURPOSE 1, whereas the background HIV incidence was very similar to what was seen in new infections in the individuals who were randomized to F/TAF or F/TDF, with 39 and 16 infections, respectively.

And then you can see that in PURPOSE 2, the background HIV incidence was pretty similar to what we saw in PURPOSE 1, but there was more efficacy with the oral regimen with only 9 infections, and then there were only 2 infections in the lenacapavir arm.

Now, if we break that down to the particular youth participants, there were zero infections in PURPOSE 1. And the 2 infections that occurred in PURPOSE 2 occurred in very young individuals.

[00:15:28]

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

Now, if you look at the results with regard to adverse events, and you can see here how the breakdown was by age. So in PURPOSE 1, what the researchers did was look at those who were aged less than 18 years, but above 16. That was a small group of 56 when compared to the large group of those who were above 18, 2084. And then in PURPOSE 2, it was individuals below 25 years of age, which was 752, and then those above 25 years, which was 1431. So big groups of individuals are here.

And when you look at the low-grade events—adverse events that are the serious adverse events, you can see that the numbers very much seem similar between the younger individuals and the older individuals. And also, if you look at study discontinuation because of adverse events, you can see that it was zero in the small group of individuals less than 18 years and was comparable to that in the ones above 18, and the same is true for PURPOSE 2.

So I think what this really highlights is that the overall tolerability was very good. Injection-site reaction in youth were predominantly mild and aligned with those reported in the broader PURPOSE 1 and 2 study populations. So really, I think offering a very, very promising tool for HIV prevention in very young aged sexually active individuals.

[00:16:46]

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

Now, 1 of the biggest topics at the conference, and we have to raise that is really the discussion about what is the impact of anticipated funding cuts and international aid on the HIV epidemic in low and middle-income countries. And there were really a whole range of different presentations on that.

We picked this one because this is a very nice modeling study. It used the optimal HIV models to estimate the impact of funding cuts and try to include 26 low/middle-income countries, which represent almost half of the people living with HIV globally. Of note, of those 26 countries that also include 3 of the 5 sub-Saharan countries which account for the most patients living or most individuals living with HIV, which was South Africa, Kenya and Mozambique.

They have - represent 49% of all report international aid and 54% of all reported PEPFAR funding. The Global AIDS Monitoring data was used to estimate the funding reductions of the country level. And - and obviously in these countries with a very high prevalence of HIV, these countries are most vulnerable to reductions international funding, but this is the most part the funding has gone to these countries. So it's quite clear this is going to be an issue, and probably HIV prevention and testing services are even more reliant on international funding, and that's more susceptible to budget reductions. And they were also at this conference presentation to focus only on the impact of the prevention impact.

Now, if you look at the anticipated impact by 2030. Remember, that's the year we're also going to look at the 95 UNAIDS goals. You can see that there is an expected cut to foreign aid, which is from all kinds of different countries, including Netherlands, Germany and UK. There will be a reduction of 24% that leads to additional at least 71,000 new HIV infections, and additional deaths will be 5000.

And then if you add these cuts with the discontinuation of the PEPFAR program, that would increase to additional HIV infections of at least 4,400,000, up to potentially even 10,800,000 new HIV infections and a very high number of additional deaths, ranging between 770,000 to 2,900,000. And that's clearly something we're all worried about, because all the success which has been made with the excess treatment, the good efficacy and safety of the regimens we currently have, plus the now available improved PrEP and prevention services are obviously at stake if these cuts all take place as envisioned.

[00:19:30]

Key Takeaways: HIV Prevention

So in summary, I think the key takeaways from HIV prevention are, in the PURPOSE 1 and PURPOSE 2 trials is that the lenacapavir efficacy and safety in adolescents and young adults was similar to that seen in adults.

The impact of budget cuts on the HIV epidemic was shown to be extensive in modeling studies, with dramatic increases in HIV infections and deaths associated with decreased foreign aid and discontinuation of PEPFAR.

Sub-Saharan African countries clearly remain among the most vulnerable countries with regard to these funding cuts. And HIV prevention services will be most impacted.

And with that, I think I'll hand over to wonderful Eric to walk us through some of the highlights from these studies on ART regimens.

[00:20:10]

ART Regimens

Dr Eric Daar (David Geffen School of Medicine at UCLA): Thanks, Jürgen. That was terrific. And Jürgen will be back to join us on non-HIV treatment-related management issues after this section. So it's a pleasure to be here and have the opportunity to talk to all of you and share what we thought were some of the key studies related to antiretroviral therapy from the meeting.

[00:20:32]

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

So let me go ahead and get started. Obviously, the last presentation was quite sobering and is a big challenge for all of us, regardless of where we're living and dealing with potential cuts in the future.

One strategy to address issues related to cuts would be to somehow manage people with less drug. And we've looked at this in the past, looking at the concept of perhaps less than daily oral therapy. This is separate from long-acting treatment issues. Can we get away with less than 7 pills a week?

And there have been some studies in the past that suggested promise. And at this meeting there was a meta-analysis and a variety of studies looking at different strategies of perhaps 4 on/2 off, 3 on/4 off.

And then there was this study, BREATHER Plus in adolescents living with HIV in sub-Saharan Africa that was using basically weekends off, 5 on/2 off of antiretroviral therapy. And they called this short-cycle therapy as opposed to continued antiretroviral therapy.

So this was a multicenter, open-label, randomized, noninferiority trial conducted between 2022 and 2025 that enrolled adolescents 12 to 19 years of age on therapy for at least a year and on dolutegravir. Tenofovir/3TC for more than a year, no prior treatment failure, which is always important in these kinds of studies. And HIV RNA of less than 50 for at least the last 12 months.

And it randomized 470 individuals to stay on their current therapy or go to this so-called short psychotherapy with regular follow-ups. And the primary endpoint was a confirmed viral rebound, so defined as 2 consecutive RNAs are greater than 50 by Week 96.

And the 9—noninferiority margin ended up being at 8%, and they had secondary endpoints of RNAs of less than 50 at Week 96. Viral rebound without confirmed viral failure, safety and adverse events.

[00:22:49]

BREATHER Plus: Baseline Characteristics

So these were the baseline characteristics of this population, again adolescents. So the median age was 16.5 years. A little more than half were female at birth. The majority, not surprising based on the age, were HIV acquisition via vertical transmission. And the median time on therapy was quite long. And although there were minimal requirements, these people had been on therapy on median of almost 12 years.

And time on dolutegravir, the median time was over about 2.5 years. So this is a highly experienced population, but again without a history of virologic failure in the past.

[00:23:32]

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

These were the confirmed viral rebound at 96-week primary endpoint, looking at a 99% and 95% confidence interval. You can see looking at the 99% confidence interval, there were 23 viral rebounds, or 10% in the short cycle therapy vs about half as many, 11 at 5% and those who continued their antiretroviral therapy.

So the rate of confirmed virologic rebound at 96 weeks in this investigation arm did not meet criteria for noninferiority to the continued antiretrovirals and was actually found to be inferior. So this has not been seen consistently amongst other related studies in adults. But in this one clearly not noninferior and inferior, raising concerns about this kind of strategy in this population.

Needless to say, anytime we do a study like this, it's very important to understand what the consequences are of failure as well as the differences.

[00:24:44]

BREATHER Plus: Resistance Mutations in Participants With Confirmed Viral Rebound

So here's the data looking at resistance mutations in the participants with confirmed viral rebound. There was data available for 12 of the 23 with confirmed rebound and short cycle therapy. And 6 of the 11 had data available in the continuous by 96 weeks.

Major INSTI and new mutations was present in just a single person with confirmed viral rebound. And it was actually in the continued antiretroviral therapy arm. There was some non-nuc resistance seen in the short cycle therapy. And they further described the data in the short psychotherapy, there were 9 individuals who switched to continuous therapy after confirmed viral rebound, all of whom were reported to have resuppressed, and there were 10 of the 14 who chose to stay on the short cycle therapy, who also resuppressed with 4 not doing so.

So while clear inferiority, the majority of people ended up doing well, some of whom even stayed on their short cycle therapy.

[00:25:56]

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

A second trial that I wanted to talk about, I think is highly relevant for a very specific patient population, and that specifically are those who have poorly controlled HIV. This study reminded me a bit of the LATITUDE trial that was conducted and recently reported, looking at whether we can use long-acting CAB/rilpivirine to help people who have difficulty adhering with their oral regimen.

As everybody knows, the long-acting CAB/rilpivirine registration trials looked at people who were stably suppressed on antiretroviral therapy. And there's emerging interest and data, mostly noncontrolled data showing that people who have difficulties adhering with their oral therapy, who are put on long-acting regimens, may be very successful. And this could be an option.

What the LATITUDE study and really this one attempted to do was look at people in this case in sub-Saharan Africa. It was a multicenter, open-label, noninferiority phase IIIb trial. So it was adults in Uganda, Kenya and South Africa who had viral loads of greater than 1000 in the prior 2 years, despite being on therapy, a history of loss to follow up for at least 4 weeks or more, or unlinked to HIV care for more than 3 months, not receiving second-line antiretroviral therapy, not pregnant or breastfeeding. And because its long-acting therapy with a hep B active drug, they couldn't have hep B surface antigen positivity.

So the goal here was to take these individuals who were having challenges in engaging in care and taking therapy, who were at low risk for resistance and no hep B, and to put them on 2 nucs plus dolutegravir. And if they achieved an RNA of less than 200 for 3 months or more at the end of this screening period, they were then randomized to either continue the 2 nucs plus dolutegravir or to go on long-acting cabotegravir-rilpivirine every 8 weeks.

And the primary endpoint was the proportion of individuals with RNAs of less than 50 at 48 weeks, and then a variety of secondary endpoints, such as RNAs of greater than 50, confirmed virologic failure, adverse events, and patient-reported outcomes.

In the prespecified virologic failure sensitivity analysis, where the individuals with confirmed failure at greater than 200, or a single RNA of greater than 1000.

[00:28:42]

IMPALA: Baseline Characteristics

Here are the baseline characteristics. The median age was 40. You can see more than half were cis female. And overwhelming majority based on where this study was conducted were Black Africans. There were about a third who were hep B or antibody positive. Remember, we excluded the people who were surface antigen positive in this trial. BMIs of greater than 30, a potential risk factor for failing long-acting CAB/rilpivirine, so in about 20%.

Median CD4s were good. Median duration of therapy was quite prolonged at over 7 years. In prior AIDS-defining condition at present, in about a quarter. And prior non-nuc experience was quite common, so they were experienced with non-nucs at some point.

[00:29:28]

IMPALA: Outcomes at Wk 48

Here are the data, the outcomes at 48 weeks. For the primary analysis, you can see about 90% in both groups clearly meeting the noninferiority for the 2—and the response rates were very good, including in the BMI patients of greater than 30 kg/m². From a secondary endpoint, again, overall the outcomes were fairly similar.

So it appeared that in this study, the strategy of taking people who are having difficulty adhering to a therapy in South Africa, getting them suppressed on dolutegravir-based regimen and switching them on continuous therapy was quite effective.

[00:30:12]

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

There were 5 individuals with confirmed virologic failure on long-acting cabotegravir/rilpivirine. Forgive the fact that this slide is dense, but what it really is trying to do is to give you a sense as to who these key people were, even though the failure rate was small. You can see that the subtype, there were a couple of A1s. You may recall that initially it was thought that people - it was said A1, A6 were at higher risk for failure. I think more recent data suggests this was really the A6 people, not the A1.

Baseline resistance was seen using archived resistance testing in a subset of individuals in which the data was available. And then non-nuc resistance, including the so-called resistance prediction, you can see. It was thought that there would be high level resistance in the 4 individuals for which resistance testing data was available.

And then as far as INSTIs, again, 4 individuals had data available, all of whom had predicted high level cabotegravir resistance. So again, relatively small number of failures. The people who failed often failed with integrase and integrase resistance. But importantly - and we're seeing more and more of this kind of data. It's what happens to these people who fail. It turns out that when these people who failed were switched to a new regimen, 4 of the 5—5 of the 5 all suppressed.

And interestingly, despite INSTI resistance, mostly high-level CAB resistance, you can see that the use of tenofovir/lamivudine/dolutegravir in 4 of the 5 individuals was associated with viral suppression of less than 50 copies/mL.

Now, again, the numbers are small. We can't assume this would be the case for everybody failing long-acting CAB/rilpivirine. And the follow up was relatively short, a median of about 35 weeks. But at least it is promising data that for the subset that failed, they may still be able to be treated with a relatively simple, easy to take regimen.

[00:32:28]

IMPALA: Adverse Events

From an adverse events perspective, if you don't look at injection-site reactions, which obviously occurred more often in those who were randomized long-acting CAB/rilpivirine, overall adverse events were quite similar across the groups.

There were injection-site reactions, but few or none who stopped because of injection-site reactions. Pregnancies did occur in 6 of the long-acting CAB/rilpivirine. Again, the follow-up data are limited with 4 elective terminations. And of the 266 participants who switched, when they did a survey to ask them about their satisfaction, they found that it was significantly higher on the long-acting CAB/rilpivirine vs those who - their oral regimen that they were on before being randomized to the long-acting regimen.

[00:33:16]

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

Here's a subanalysis of people who had hepatitis B infection. This is an important question that comes up whenever we look to switch people to a regimen that doesn't have hep B activity. So they looked at the people from the IMPALA study, and they looked at their hep B serologies. And you can see that those who were on the dolutegravir with 2 nucs vs long-acting CAB, about a similar number were hep C antibody—I'm sorry, hepatitis B core antibody negative. Surface antigen was positive, but these people were excluded.

And there was a subset of individuals who were core antibody and surface antibody positive, about 80 in each arm. There were no people reported that were lone core antibody that I'm aware of. And they look to see what the risk was in these individuals of either developing incident hep B infection or for having evidence of reactivation of hepatitis B.

And if you looked at ALT elevations at greater than 3 times the upper limit of normal, it was relatively rare and more common in the dolutegravir to nuc. If you look at reactivation B in the lower line, there was no evidence of reactivation in either study arm. There was a single incident infection in the long-acting CAB/rilpivirine. And again, people who are on tenofovir probably have some protection if they're not immune from incident infection. But there was the 1 case.

And this is the data from the 1 individual. The vaccination status was unknown. You can see their initial serologies for hepatitis B were all negative and then became core antibody and surface antigen positive. They did have an increase in transaminases. And when they started dolutegravir with TDF/3TC, their LFTs improved within weeks and their surface antigen became negative in 6 months.

[00:35:22]

Posttest 1

So a post-test question. The IMPALA study in adults with poorly controlled HIV in sub-Saharan Africa showed high levels of virologic control and participants preference for which of the following regimen?

1. Long-acting CAB/rilpivirine;
2. Dolutegravir/3TC/TDF;
3. Darunavir/ritonavir plus TDF/FTC; or
4. Bictegravir/TAF/FTC.

Go ahead and vote.

So a whopping 87% of you are correct that the level of satisfaction was highest in the long-acting cabotegravir/rilpivirine.

[00:36:22]

Posttest 1: Rationale

94% preferred that over the oral regimen that they were on prior to enrolling in the study.

[00:36:32]

Antiretroviral Pregnancy Registry: Pregnancy Outcomes Overall and With CAB Exposure

As far as registry looking at cabotegravir exposure and pregnancies, the pregnant outcomes in a retrospective analysis of voluntary registrants from 75 countries, they list in the middle column the actual exposure between 1989 and 2025 of over 24,000 exposures, and looks at some outcomes to give some baseline numbers.

And then they have those who had CAB exposures through July of 2024. And the numbers are very small. There was a total of 42. Fetal outcomes were available in 43. They were twins, 1 set. And you can see overall it seemed to be a little difference. But again importantly, small numbers.

[00:37:22]

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

In the 42 pregnancies with CAB reported to be in the registry, 35 live births, most individuals were exposed to CAB preconception, but 27 were exposed at zero to 6 months prior, with 12 6 to 12 months, so the majority fell into that category of exposure prior to conception. One congenital defect, congenital ptosis, was the only one reported amongst the live births.

The investigators concluded that the findings reflect positive safety profile of CAB but importantly emphasized that they have to be interpreted with caution due to the small numbers of pregnancies.

[00:38:08]

Promising Investigational Drugs and Strategies

I'm going to quickly talk about some promising investigational drugs just to touch on them, because they are important parts, I think, of the future of treatment. The first 1 is this HRF-10071. This is a maturation inhibitor that works at the late stage of GAG process. It inhibits - demonstrated statistically significant reduction in RNA vs placebo over 14 weeks. They basically looked at 14 days of monotherapy comparing placebo to 20, 30, 40 and 80 mg, 6 for each arm.

So a small proof of principle study, everybody who started had an RNA of greater than 5,000. And the viral load reductions ranged from about 1 to 1.8 log 10 copies/mL. They did note that amongst the small number of individuals included in this pilot monotherapy study, there were 3 who had emergent resistance to the maturation inhibitor, very similar to what has been seen with other maturation inhibitors.

Another promising drug is MK-8527. More importantly, this has a long half-life so that it can be dosed monthly. This was a phase IIa study of 6 oral monthly doses of this drug in individuals who are at low risk of HIV exposure, all HIV and infected, and it was well tolerated across the doses and showed similar safety profile to placebo. And this had about a 100 individuals per study arm with placebo vs 3, 6 and 12 mg. So again, very promising safety profile. And it is now moving forward with future studies for PrEP in phase III trials of the so-called EXPrESSIVE 10 and 11 studies that are projected to open later this year as a possible oral monthly PrEP agent.

And then finally dual ART maintenance regimen. This was a study that was looking at a switch in stably suppressed individuals who are from West and Central Africa. It was looking at noninferiority of maintenance, dolutegravir/3TC or atazanavir/ritonavir/3TC compared to continuing a TDF/3TC or efavirenz/TDF/3TC or dolutegravir-based study. This had 160 individuals per study arm. And overall, they found that there were similar rates of virologic suppression in the 95-plus range in all 3 study arms. So continuing their regimen vs switching to these novel 2-drug regimens.

The safety profile more or less favored 2 drugs over 3 in most cases. But 1 notable observation was that weight increased more in those who stopped the TDF part of the regimen and went to 2 drugs vs those who continued. Again, what the clinical relevance of this weight gain is we don't know. And how much of this is related to the new regimen vs stopping TDF, which may mitigate weight gain [inaudible] healthy people and stable therapy again remains to be seen.

[00:41:59]

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

And then the last study I'm going to talk about is another novel agent, a novel NNRTI that has pharmacokinetics that are supportive of weekly therapy. This is a so-called ulonivirine—sorry, ulonevi-nivirine. I always struggle with NNRTIs names. It was a double-blind, active control study, about 35 individuals per arm in people who are stably suppressed for 6 months on bictegravir/TAF/FTC.

No virologic failure in the past. Virologic resistance was not observed previously to NNRTIs, no active hep B or C infection. And you can see they were dosed at 20 mg of islatravir, the nucleoside reverse transcriptase translocation inhibitor that hopefully you're all familiar with, which also has a long half-life vs the ULO at 100, 200 and 400 mg a week vs bictegravir/TAF/FTC.

As you all are aware, the islatravir development was stalled because of an affect lymphocytes and CD4 lymphocytes until they found the right dose. And this was a study that was conducted some time ago before all this information was available. And although virologic efficacy is promising, the study was halted about 8 months after full enrollment because of documented decrease of about 10% to 20% in CD4 lymphocyte counts.

They did note that those numbers returned to normal upon discontinuing the islatravir, and there's good modeling data to suggest that this kind of a combination regimen as a weekly oral therapy could be done with safety using a lower dose of islatravir 2 mg per week, and that they can move forward with the ULO at 200 mg a week as well.

So there's phase IIb study that's underway that we'll be looking at this novel 2-drug weekly oral therapy.

[00:44:12]

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

As far as virologic suppression and adverse events, as I mentioned, the virologic suppression was very good at 12 and 24 weeks. And there were no confirmed failures in any of the treatment arms and from an adverse event perspective. Again, the numbers are relatively small, but no obvious concerns were observed other than the documented change in lymphocytes and CD4s, which will hopefully be overcome by just a simple lowering of the dose of islatravir, which has been seen in other trials.

[00:44:47]

Key Takeaways: ART Regimens

So the key takeaways in the BREATHER Plus study, the strategy of short cycle therapy was inferior to continuous daily oral ART in adults taking TLD. Adherence and adverse events - I didn't mention, but the adherence part was similar between the treatment arms, so it didn't appear to be driven by that.

Major INSTI and nuc mutations were detected in 1 individual with confirmed failure. In the IMPALA study, long-acting CAB/rilpivirine every 2 months was not inferior to daily oral dolutegravir-based regimen in an African cohort with prior suboptimal HIV control. And then among 42 pregnancies with CAB exposure, mostly preconception, most were - 35 were reported with only a single birth defect.

And then finally the phase II study of switching to once-weekly islatravir ULO very low vs continuing BIC/FTC/TAF supports further development with the lower dose of 2 mg per week of islatravir.

[00:45:51]

Patient Management

So with that, I will thank you all, and I will hand it back over to Jürgen to talk about patient management.

Dr Rockstroh: Thank you, Eric. That was really great. We're going to now talk about a few trials which are important with regard to patient management.

[00:46:05]

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

And 1 thing I think where everyone has to deal with in clinic is obviously the issue of individuals presenting with increased weight gain under antiviral therapy. We all know there's a return to health phenomenon. We started therapy. But even in people who switch regimens, we've seen weight gain. And so it's always been a discussion, what is the contributing part of antiretrovirals, in particular the context of integrase and TAF-based regimens.

And this ACTG trial I think is a very good one because it addresses an important question, namely, if we switch someone to doravirine plus/minus TDF vs continuing an integrase plus TAF/FTC in people with a high BMI and HIV, could that potentially be a strategy and have an impact on further weight gain or the course of weight altogether.

So this multicenter, open-label, randomized superiority trial really looked at individuals who received an integrase TAF/FTC regimen for more than 48 weeks with a stable HIV RNA suppression and BMI equal to or above 30 kg per square meter include 145 individuals. The permitted integrase inhibitors were bictegravir/dolutegravir/raltegravir, so no boosted raltegravir in there.

And they were randomized either to switch doravirine/TAF/FTC, switch doravirine/TDF/FTC or continue the integrase with TAF/TC. And the primary outcome was weight change at Week 48, and the study was powered at 5% to treatment differences between the arms and the secondary outcomes for virological failure and safety.

[00:47:36]

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

And the amazing result of this study was that in all 3 arms, the researchers noted weight loss with no significant difference in weight change associated with switching to doravirine/TDF or doravirine/TAF vs continuing the integrase/TAF/FTC.

Now you can see numerically there are a little bit of differences. So it was minus 2.73 kg—so it was a little bit different in the TDF arm. And you would think that TDF, at least in some of the studies, in particular placebo controlled PrEP trials or HPV trials, had some weight suppressive effects. It's a little higher, but there was no statistically significant difference.

The safety parameters also did not change significantly following the switch, and there was no impact on ground clearance on bone mineral density or virological failure. So obviously we will still need other strategies to reduce weight gain and associated complications in people who develop increased weight gain living with HIV.

[00:48:43]

Posttest 2

Now this brings us to the post test question 2. In the ACTG 5391/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 doravirine-based regimen compared with remaining on INSTI plus TAF/FTC based regimen.

1. Significantly greater weight gain loss after switching to doravirine/TDF/FTC only;
2. Significantly greater weight loss after switching to doravirine/TAF/FTC or doravirine/TDF/FTC;
3. Stable weight on both doravirine regimens vs a significant increase on continued integrase plus TAF/FTC; or
4. No significant difference in weight change between doravirine regimens and continued INSTI/TAF/FTC.

Please vote now.

Right. If you can close the vote. Perfect. So 77% got it right. No significant difference in weight change between the arms in this particular trial.

[00:49:57]

Posttest 2: Rationale

And so the correct answer was D. And the rationale is that in the DO-IT trial all treatment arms lost weight. So switching doravirine/TDF or doravirine plus TAF vs continuing integrase plus TAF/FTC was not associated with a significant difference in weight change.

[00:50:17]

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

The last thing I want to present is the TECAIN study. This is a study which was done in Germany. And it sort of dealt with the question that people living with HIV are very well known to have a strong increased risk for human papillomavirus associated cancer, and therefore screening by guidelines is recommended for anal intraepithelial neoplasia as well as treatment.

And this study was trying to look at what is the better intervention. So it was the randomized trial looking at topical trichloroacetic acid vs electrocautery for AIN in people who live with HIV.

Now the topical trichloroacetic acid is something which these people who do dermatology know is something which is commonly used for treatment of warts. It's more easier to apply and to control. And so - and also much cheaper. And the other intervention is a little bit more difficult.

So this is a clinically, I think, quite relevant question that there have not been many randomized trials addressing different approaches for treatment of AIN in people living with HIV.

So individuals who were adults lived with HIV and had clinical, visible, and histologically confirmed inter-anal AIN. And I can tell you that from the trial we participated in, that was not so easy because a lot of people were screened. And that took quite some time, actually 5 years to get all the patients into the trials. That did take some time to find all these individuals with AINs, and then they were randomized 1-to-1 for the 2 different interventions.

All patients were assessed at Week 4 follow-up and 24 weeks follow-up after end of treatment. Treatments administered at baseline at Week 4, 8, and 12 unless AIN cleared.

The primary endpoint was therapeutic success at Week 4 follow-up defined as clinical complete remission by high resolution endoscopy with histologically confirmed AIN resolution or regression.

[00:52:21]

TECAIN: Therapeutic Success

And if you look at the overall outcomes, you can see that the TCA group did not meet criteria for noninferiority. So there was a difference of 52% complete clinical remission with histological clearance or downgrade of only 52% in the TCA arm vs 61.7% in TCA. So that did not reach noninferiority, as you can see here.

But when you look at the 24-week follow-up, then you can see that the amount that achieved remission was 50.8% vs 48.7% for the 2 methods. And that was then met the criteria for noninferiority. So at Week 24 that was the same outcome.

Safety was similar for TCA vs ECA, 64 vs 65% experienced. Any adverse event with no treatment-related SAEs and only 1 discontinuation due to AEs in the ECA group.

So the overall conclusion of that trial was that TCA is a well tolerated, cost-effective, and simple treatment option for AIN and the people living with HIV.

[00:53:28]

Key Takeaways: Patient Management

So just to quickly summarize this part of patient management. The DO-IT trial in people with obesity show that switching to doravirine plus/minus TDF vs continuing integrase TAF/FTC did not result in significant weight change at Week 48, which means we will still have to look at other strategies for weight loss in individuals who have issues with that.

In the TECAIN study, the use of trichloroacetic acid for treatment of AIN in people with HIV provided comparable efficacy to the standard of care treatment with electrocautery.

[00:54:02]

Posttest 3

All right. And with that, I think we can open the - sorry. I think we're going to come to the Q&A session. Or we're going to take the post-test question first.

[00:54:17]

Posttest 3

Kimberly Miller: Yeah. If you could just answer the post-test number 3. I'm familiar with data from the IAS 2025 conference. I plan to translate these data into current or future management strategies. We'll just give it about 10 more seconds to make sure everybody has a chance to answer. And then we can move on to the Q&A, doc.

Dr Rockstroh: Perfect. Right. Looks like a lot of people are going to use the data. Perfect.

[00:54:59]

Q&A

Dr Daar: So again, let me start with the - on the question and answer. Let me start by thanking 1 of our listeners for paying close attention, because I clearly must have misspoken. For the MK-8527, the monthly novel drug, it is a nucleoside reverse transcriptase translocation inhibitor, NRTTI, not an NNRTI. So forgive me if I misspoke, but that's a really important point.

So it's like islatravir only with the potential for monthly dosing. And it looks like early on no effect on lymphocytes and CD4 cells. Yeah.

Dr Rockstroh: I think the particular thing about this translocation inhibitors that they have this long half-life. The islatravir was not further developed for PrEP because of the lymphocyte issue. But this is sort of the follow-up substance with hopefully no lymphocyte toxicity. Great.

Dr Daar: Jürgen, can I ask you a quick question before we go into the - delve into the is - with - you know, with your expertise in HIV and hepatitis B, and you know, the discussion in these studies about long-acting therapies that don't include hep B active drugs. And this would apply to other regimens that don't include hep C active drugs in our core antibody positive surface antigen negative individuals. What are you - what are you doing with these kinds of people? What are your cautionary notes?

Dr Rockstroh: Yeah, I think that that's the most complicated question. You really nailed it. Because several studies have already looked at that quite carefully. And what they see is that in individuals who only have anti-HBCs, only core antibodies as the signs of a past infection, but have lost their anti-HBS, and that is something we find quite commonly in people living with HIV. Around a third of the individuals who had passed hepatitis B infection have that serologic finding that they have only anti-HBC. So it's a common finding.

And if you switch them to a regimen without a tenofovir component, there have been cases reported of very low level HPV DNA premium. This was not associated with the flare of transaminase. So you can detect, I don't know, 60 or 55 copies.

And the question is what does that mean? You haven't seen any of the appearance of HBS antigen. We have not seen clinically relevant hepatitis. But still something is obviously different than before. And if you measure, you can potentially find something. So I think that is a worry. And that has sort of led to prompt people to say that we may need more vigorous hepatitis B monitoring individuals for anti-HBC only positive.

I would say though nevertheless, because no case of hepatic decompensation or clinically relevant events have been described at this point would not preclude using long-acting strongly, which is that in the setting of a sole anti-HBC positive issue.

I think the other question obviously is what is with those who are completely negative? Because in every trial this is just 1 more trial. And there have been other trials in the last 2 years just because of all the 2 DR regiments which are now under development with cases of acute hepatitis C. So if you are completely negative and you are not having tenofovir, which has a kind of a PrEP function for hepatitis B, you may acquire acute hepatitis B in an individual who already probably has sexually acquired HIV.

So I think we really have to reinforce the importance of vaccination for hepatitis B. I think that's just very important.

Dr Daar: That probably applies to the core antibody lone cores as well, right, to immunize them.

Dr Rockstroh: Yeah. That has been discussed a little bit controversially. So there have been sometimes the question of do you really need that? Because the immune system had obviously responded to hepatitis B, clear the HBS antigen infection is no longer. There's only at anti-HBC and you really need anti-HBS.

I would say if you don't have relevant reactivation, probably not. But we do know that individuals for example they have only anti HBC and let's say they would stop taking their HIV medicine and the CD4 count would drop below 200, and actually they can - they can reemerge and get HBS antigen. So in the setting of severe immune suppression, don't forget that anyone who ever had hepatitis B. And that's the reason why if you treat someone for lymphoma, you should screen for hepatitis B because if they have core antibodies, they can potentially - even if they have anti-HBS lose that in the setting of immunosuppression and develop HBS antigen replication again then have hepatic failure.

All right. So there's 1 question around the PURPOSE studies. You noted more infections in the PURPOSE studies in the oral vs the subcutaneous regimen. You know, why is it possible that adherence issues and inconsistently taking the oral medication could have created that resistance?

And I think you're absolutely right, Steven. That is the reason. We know from many oral PrEP studies, particularly in females from Africa, that oral PrEP was always difficult. There always have been adherence challenges. And in particular in the PURPOSE 1, which is a very large study, you can see where there was absolutely no difference, significantly – no significant difference between background HIV incidence and oral PrEP, that really adherence was the main driver of that.

Interestingly, if you just look at those who were able to adhere and take oral PrEP, you also have no infections.

So yes, oral PrEP is efficacious, but you have to take it, or you have to have a tenofovir exposure.

Dr Daar: And I think we learned a lot of how important the concept of using that counterfactual placebo control, looking at incident infections within the community as our comparator, because of the limitations of looking at oral PrEP regimens as a comparator knowing that adherence is so problematic.

Dr Rockstroh: Yeah. And I thought it was also great that they did RNA screening. So in between screening and baseline, they already found, I think 6 or 7 fresh infections just telling you that this was the right population to study, but also reminding us that even when you put someone on, it could already be that someone got infected. So that's an important thing to remember.

There's 1 question on the PEPFAR funding. I think that's a very important point Christopher raises here that PEPFAR funding was restored last week in the updated budget. So there has been some turnaround, which I think is at least promising. I think it still has to pass the last chamber, I think, to get approval.

And what I want to highlight, though, in this modeling study, it did not only look at potential PEPFAR cuts, but also on international funding aids. So this would go also for other countries like the Netherlands, where differences in the government and their willingness to submit to the Global Fund have changed. So - so I think it's important to remember that any change, whether it comes program A or B, can lead to dramatic consequences. And I think it's kind of nice to do this modeling work to sort of remind us of how important these programs are.

Dr Daar: We have a question. It's a great question talking about IMPALA, but maybe they're saying OPERA study. But regardless, the conclusion that people who have difficulties with adherence going on long-acting cabotegravir-rilpivirine didn't lead to increased suppression, but compared to ongoing oral therapy, but was more popular.

I think it really depends a lot on the patient population, how difficult and challenge they are with adherence. So I think if you have a population that's otherwise doing reasonably well and they're able to commit to therapy, and being in a study often helps. Yeah, you may get similar outcomes by continuing them on oral vs switch.

The LATITUDE study, the thing that was so telling about that. It was a very high risk population, all of whom were viremic at the time they came into the study, and were struggling with oral therapy. And that study was stopped prematurely because they actually had better rates of continued suppression. And those who were initially incentivized to get suppressed on oral therapy, who were then randomized to either stay on their oral therapy or switched to injectables, the long-acting injectables did significantly better than those who were forced to continue on oral therapy.

So it really depends on the population. I think increasingly the people who choose to be in these studies seem to be very - looked quite favorably at their satisfaction with long-acting CAB/rilpivirine. Again, those are the people who choose to be in these studies. But as far as the actual benefit in a high-risk population, it's going to be in part driven probably by the patient population.

Dr Rockstroh: Were you part of the DO-IT trial, of the ACTG trial?

Dr Daar: Yes.

Dr Rockstroh: There's 1 question here from Terrace[?] is, is in that trial, did the investigators educate participants about diet or weight control? Which I think is a great question. Because since there was weight loss in all arms, you wonder whether there was sort of a nutritional advice given.

Dr Daar: Yeah, it's a great question. I should know the answer. And off the top of my head, I'm not sure I do. But regardless, you know, anytime somebody comes into a trial, for a specific problem, that just being in the trial is going to impact the outcome to a certain extent, which is why it's so important to have control groups.

Dr Rockstroh: Yeah. Well - and I think, you know, in general, if you go into a trial with the question, is this going to lead to a weight loss? You're going to talk more and think about weight and what you can do. And you are in a controlled setting. So I think that per se may have a potential impact.

Dr Daar: And you're - you're by definition motivated to impact that outcome because that's why you're in the study.

Dr Rockstroh: The – and Terrace also asked please review current recommended regimens using only 2 antiretrovirals for people living with HIV. Which ones are highly promising?

Dr Daar: Interesting. You know, boy, there's a - there's a list. There are less for first-line therapy than there are for switch studies. And, you know, the ones that we have for first-line is really dolutegravir and 3TC is the main one for people starting first-line. There are others in development, but it's early stages.

For switch, we have dolutegravir 3TC, dolutegravir-rilpivirine for sure. We have data with boosted PIs. I think what's most exciting thinking about the future and what's most promising, although it's still fairly early days, is a long-acting therapy, particularly oral therapy. And we have a couple of regimens like lenacapavir-based therapy with islatravir. There's a novel INSTI that was looking at lenacapavir for weekly therapy as well. That - that particular study is at least on hold for now because of an effect on lymphocytes again and CD4 cells that they're trying to sort out.

So I think, you know, we have several combination 2-drug regimens available now that may have advantages for select individuals. And then we have some in the future particularly I think the long-acting oral therapy that would be potentially exciting. But it's a - it's a ways off.

Those are what come to mind. Jürgen, others that come to your mind?

Dr Rockstroh: Yeah, I - I think of dolutegravir and doravirine, for example, something you already have available, but because of the retained activity of doravirine in the K103 mutation, for example, you can actually use some of the, you know, historic individuals who had, you know, a boosted PI and 1 - NNRTI already had some resistant field this and that and have a 3-drug class resistance where you still have options if you haven't already developed the integrase resistance.

And then there's bictegravir-lenacapavir in an oral formulation for those with complex regimens who may be on a booster that's being studied currently in phase III. So I think there - there's really a whole - whole new group of - of regimens coming our way in the - particularly also in the switch scenario.

All right. All right. I think we're – see was like 1 question on the TECAIN study, where the individuals in the TECAIN study who did not cleared at 4 weeks retreated. Yes, that's because there were other steps of treatment. And at Week 8 and 12 and they were reassessed. So that they - yes, they did continue to become treated.

Jule’s[?] right. In DO-IT, they did not look to switching to doravirine quickly within 6 months or 1 year. Switching to AM[?].

In DO-IT, they did not look to switching doravirine quickly within 6, so they were suppressed for quite a while. That's true. But I think that makes some sense.

And then there's 1 question from Central Europe where there is no access to long-acting agents. So we would like to have, do you know what is the reason?

Well I think at least I know it's - it's - it’s very well accepted in Czechoslovakia, which is not so far away from Slovenia. So I think just a question of getting these drugs registered, reimbursed and then - but I think with the greater implementation of that and more and more countries, I would I'm pretty positive that that's also going to happen in Slovenia, hopefully soon. But I have no clear answer because we don't know what companies plans are for these countries.