Charlotte-Paige Rolle, MD, MPH
Hi, everyone. Welcome to all of our listeners. We're so excited that you've joined us for this post-CROI update on what's new and heavily treatment experienced patients. By way of introduction, my name is Charlotte Rolle. I'm an adult infectious disease physician and the research director down at the Orlando Immunology Center. And I am so stoked and excited today to be joined by my good colleague that I Usually referred to as Doctor O., and I'm gonna let him introduce himself.

Onyema Ogbuagu, MD, FACP, FIDSA
Hello, everyone. We're super excited that you joined us for this podcast today. So I'm Onyema Ogbuagu. I'm a professor of medicine and pharmacology at Yale School of Medicine. I also direct the Antivirals and Vaccines Research Program, kind of rebranded from HIV Clinical Trials Program. And I think probably the thing I'm most proud of is I continue to provide clinical care to people with HIV and manage some of the most complex cases of HIV and associated comorbidities.

Charlotte-Paige Rolle, MD, MPH
So that is why I'm so excited to be here with Dr. O, right? Because even though we both do all of this research, we both still take care of patients. And I'm with you, Dr. O, a lot of my clinic is actually composed of heavily treatment experienced patients with complicated resistance that I've had the joy of coming up with suppressive regimens for. So, you know, just to start and maybe our readers can relate to this, heavily treatment experienced patients still make up about 3 to 10% of people living with HIV here in North America. Actually, it's about 3% in North America and 5 to 10% in Europe. And you know, Dr. O, I always find this so fascinating because when I talk to providers in the community, they tell me, hey, Dr. Rolle, I don't have these patients. These patients are so rare. I cannot find them in my practice, but yet they're making up 3% of our patient population here. I'm wondering, does that reflect the breakdown in your clinical practice, do you see more or less of that defined as HTE?

Onyema Ogbuagu, MD, FACP, FIDSA
So 2 reasons, at least for my practice, right? So one is I think academic centres or tertiary centres tend to be referral centres for very, very challenging cases. So we tend to get lots of calls from community providers around some of these cases. And we also tend to have a lot more access to things like PK assessments, resistance testing, and just that information gathering, right, that's required to make an informed decision about treating individuals. Of course, we do clinical trials like you do, Charlotte, right? So we do clinical trials, and I think we're also a pipeline for referrals for complex cases.

Charlotte-Paige Rolle, MD, MPH
So it sounds like you probably, you're like me, your clinic population is a little bit more skewed to having a more significant proportion of HTE patients. And so that's really exciting. And you know, the definitions, Dr. O, of what is an HTE patient has really been, I feel like evolving over the past you know, a few years. You know, you and I both do research. So we have that classic definition of HTE in our mind or multi-drug resistant, a patient that has resistance to at least one drug from three different classes. But I don't know. I feel like that definition is becoming more fluid and more evolving. So what is the typical HTE patient in your practise look like?

Onyema Ogbuagu, MD, FACP, FIDSA
So I think you asked an important question. I agree with the confusion around the definitions. And I think for each of the individual agents that have been approved for HTE patients, we also see differences in the definitions in the clinical trials. But I think you bring up a really important point, Charlotte. You know, I prefer to think of this in terms of the people, right, who have multi-drug resistant HIV, and they tend to cluster around certain kinds of individuals. So people who've had HIV for a very long period of time, and I think it reflects that sequential exposure to classes of drugs as they evolved in drug development, right? You remember some time we did one NRTI for HIV treatment, right? That was like late 80s, and then we did 2 NRTIs, 3 NRTIs, so some people have grew resistant for no fault of their own. It wasn't even an adherence issue, is the fact that we hadn't even figured out the right cocktail, and then when we got the PIs, they were hard to take and tolerate by people, right? It's only truly when we had the era of NNRTIs also had class, you know, things like, you know, neurologic and psychiatric side effects and all that, right? But I think it's truly only when we got to the integrases, right, that people began to really enjoy virologic suppression with meds they could actually take and tolerate. So there are people who've gone through that evolution and have acquired multi-drug resistance over time. But let's not forget our disadvantaged populations, people with social determinants of health challenges, people with psychosocial challenges that interfere with the ability to take a pill every day.

And there's unique demographics. I find that quite a few of my paediatric to adult transitions also, who have very different stories, right? There's two groups there. There are those who are born to HIV positive mothers, where they may not even have been full disclosure around what they were taking meds for. And then you have young adolescents who, like any other adolescents, have no concept of what it is to take a daily treatment for a chronic lifelong illness. And of course, you know, adherence, right? So I think those are the humans, right, behind heavily treatment experienced patients. And the reality is those of us that are providers remember these individuals, right? Because those are the ones that we work really hard to try to give the best clinical outcome, which is virologic suppression and CD4 recovery.

Charlotte-Paige Rolle, MD, MPH
Yeah, absolutely. I'm with you, Dr. O. I can see all of my HTE patients clearly in my brain with their smiling faces. And you so beautifully walked us through the different treatment eras. And it really is an honour and a privilege to practise in today's treatment era where we have a number of new innovative options that we're able to offer to this population to achieve and maintain suppression. So Dr. O, why don't we just jump right into the CROI 2026 data? And I'm going to invite you to educate us a little bit on what new did we learn about lenacapavir.

Onyema Ogbuagu, MD, FACP, FIDSA
Yeah, Charlotte, there's three, you know, posters or presentations I wanted to highlight and just, you know, give a top line of what I take from them. So one was interesting, right? So one was from Ward 86, right? And Ward 86 is, you know, kind of like this epitome of how HIV care can be delivered innovatively, right? And, you know, it's a good example of really innovative use of long-acting ART.
So here they looked specifically at a group of people who with HIV who were using a lenacapavir. So they had around 50 participants in that study. 

Interestingly, though, you know, 44% of people in that group actually had viral loads less than 50. So again, really reminding us, even though this may be considered off-label use of lenacapavir, but this was the clinic's effort to try to address the unmet needs for people who are either not experiencing biologic suppression or even for those who are suppressed, who had challenges with using oral therapy. I mean, the results are just really astounding: 44% viral suppression at start, 100%, like 100% biologic suppression one year in. I think this just, again, showcases like the power of injectables. Again, it's not just lenacapavir.It's also companion, and they were smart with, you know, again, there was about 70% that had NNRTI resistance, so they recognised when, you know, rilpivirine long-acting wasn't a good partner there, and I think that's just an excellent example of the power of long-acting injectables for those who need them.

The second one I want to highlight shamelessly was a study that I presented. And this one was looking at just the real world user of lenacapavir, right? So we all know that the Capella study, which was a registrational study for lenacapavir had roughly about 72 patients. Everybody says it's a small N, but Charlotte, like you rightly said, right? The numbers in a good way are dwindling in almost every region and territory, because we just have more tools to treat people successful.

So real world outcomes really help. So we looked at HealthVarity and HealthVarity is this huge database that has like over 360,000 people with HIV and looked at lenacapavir use from 2023 to mid 2025. Again, we find in this study that about 36% had viral loads less than 50, again, showing that providers are using this in the real world for people who may be struggling with adherence challenges to oral therapies who may have been virologically suppressed. And then you start to see common threads in the virologic suppression rates: 36% at baseline, 67% one year in achieving viral loads less than 50. Again, just remarkable.

They also looked at tolerability here, and they saw that discontinuations were roughly about 14%. Again, like many of these kinds of studies based on EMRs, the reasons for discontinuation were not clear, but again, showcasing in the power of lenacapavir for people who were highly treatment experienced. One fourth of whom had three class resistance, 10% of whom had four class resistance, great virologic suppression rates in that cohort. And I would argue that even when you did a little more lax definition of virologic suppression with a viral less than 200, that number was even as close to 90%, which is just amazing.

And the last study I want to mention, which interestingly, again, was a poster which was just right beside mine. So it's great that we have, you know, the data from the US. And now this was data from France. And France also initially had used lenacapavir nationwide as part of an early access program. But I think at some point, they also had access to early access to the drug as well in clinical practice. And so they pulled data from about 19 practices. And again, they brought in people who the approval for lenacapavir for those in multi-drug resistance who could not achieve suppressed viral loads on oral ART. But again, we see here again, 55.8%, about 56% had viral loads less than 50 copies. Lots of drug resistance, about 55% also had three class or more resistance. Again, deploying LEN into this group, they found viral logic suppression rates really remarkable. So at the end of this month 12 period,
they found about 85% having viral loads less than 50. And when you use viral loads less than 200, there was about 97.3% who had achieved virologic suppression. Again, thinking about the people who were in this study, like many of the other studies, you know, there were high rates of people who had adherence challenges, about 35%, 43% were unemployed, 22% had mental health challenges, etc. So again, I think just robust evidence from these three data that I presented as just the power of long-acting injectables and the ability to result in great treatment outcomes for people with HIV.

So, Charlotte, what do you think about anything I just said?

Charlotte-Paige Rolle, MD, MPH
No, Dr. O, I think you hit the nail on the head. I think that we are now in an era where we have the ability to kind of take a step back and actually really ask ourselves, like, what is regimen optimization for the individual patient sitting in front of you? And I want to go back to one of the key points you kept making, which was that, you know, 30 to over 50 percent of folks in these cohorts were suppressed at baseline, which actually technically means that in the real world, providers are using the drug off label, not necessarily to achieve suppression, but rather to maintain suppression. What do you think about that?

Onyema Ogbuagu, MD, FACP, FIDSA
Yeah, there's two points I'm going to make, right? So the problem is, you know, for people who do not have drug resistance, right, we have long-acting agents like cabotegravir and rilpivirine. But for those who are heavily treatment experienced, who may have INSTI or NRTI resistance or even both, that's not an option, right? And so, again, it shows the need providers have or the unmet need for an all injectable regimen for heavily treatment experienced patients, especially those who may have adherence challenges. The other thing I want to highlight is in the lenacapavir drug label beyond multidrug resistant HIV, there's also in the label allowance to use it in cases of intolerance of other available agents as well as where there are safety concerns.

Charlotte-Paige Rolle, MD, MPH
Absolutely, Dr. O. And I definitely want to remind our listeners that that allowance is in label for lenacapavir, but it's actually also in the allowance for fostemsavir label as well. You know, so a lot of these HTE agents do allow you to use these agents for regimen optimization for suppression that is not necessarily related to resistance. And I think that that is a very important point. So speaking of fully long-acting regimens, let's kind of transition a little bit. Let me share some data with you about one of the fully long-acting regimens that was presented at CROI, which was the pop PK data from the dual regimen of cabotegravir and lenacapavir.

And you know, I bring this up, Dr. O, because I'm really curious to know what you think about CAB/LEN, how are you using it, and what you thought about this pop PK study from CROI. So there was actually a multi-center cross-sectional study from France, you know, and also small, 41 people enrolled. And it basically looked at the PK profile of 41 people receiving the dual combination of cabotegravir with lenacapavir. And what they saw was at month 6, 6% did actually not achieve the target cabotegravir levels. And what are those? That's four times the protein adjusted IC90. That's typically what we use, right? 31% of folks in that study did not actually achieve the target LEN levels at month 6, which was defined as four times the inhibitory quotient for LEN. And so, you know, the authors kind of concluded that maybe Dr. O, there may have been some issues with, you know, inadequate absorption of the oral LEN dose and the fact that we may really need to be critically evaluating that oral LEN dose, how our patients are taking that, making sure that they're taking that appropriately, and maybe even considering some therapeutic drug monitoring to make sure people are actually getting the target levels from that oral load.

But it's fascinating, right? Because very often we just give these agents and we just expect that people are achieving the target drug levels. But here we have this data from a real world cohort that showed us that 30% of people actually didn't have target LEN levels at month 6. What do you think about that, Dr. O? That made me stop and really kind of take a step back and think about that.

Onyema Ogbuagu, MD, FACP, FIDSA
Yeah, I saw that picture as well. I want to preface this though. You know, again, some of those drug targets are really designed to be a very high bar, right? Like, again, you really want to have four times what it needs to inhibit, so I just want to be clear that some of those targets are kind of a high bar, right, for ARVs. But that said, we have seen from even clinical trials and data trying to explain some failures along that in therapy be tied to pharmacokinetics, right? So, I've seen one study that showed rilpivirine exposures. There's even another study that showed cabotegravir exposures where so there was failure, so that again goes to show that we still have a lot to learn.

I think one thing the field is doing that we may need to rethink at some point, including with the injectables, are using fixed dose combinations for everyone, right? I mean, it could be that, you know, people who have higher BMIs, et cetera, as we're seeing some of our other drugs in the pipeline, that sometimes even weights and BMIs can be a determinant of drug exposures. And of course, that determines clinical outcomes now.

This study didn't tell us about the clinical outcomes, right? So we don't have those correlations. So it's again, just trying to make sense of PK in the absence of clinical data. One last point I want to make, though, again, I think from the patient experience, I think both my studies and this study, you know, we're all looking for fully long acting regimens to treat our patients. And we unfortunately have combinations that are a bit of mix and match and asynchronous with their dosing frequencies. And that again, just to show again that need for us to have regimens that have similar, you know, pharmacokinetic profiles, we can dose at the same time, etc. Anyone who's ever giving any injection will know that there issues sometimes with injection technique, the depth of injection, the plane of injection, the backflow of injections, and all those can influence PK as well.

Charlotte-Paige Rolle, MD, MPH
Awesome, Dr. O, thank you so much for that. And speaking of fully long-acting regimens and data sets that look at that, we did get an update from the PROMISE US study, which is this observational registry study whose real objective is to look at the long-term efficacy and durability of ibalizumab containing regimens compared to non-ibalizumab containing regimens and heavily treatment experienced patients. And we saw a data set that included about 167 patients, but is now giving us an update from the PROMISE registry, looking at data all the way out to two years.

Dr. O, and this particular data set really focused on what were the suppression rates and CD4 related outcomes at month 12 and 24 in both of those cohorts, which by the way are actually matched for disease severity in terms of baseline viral load and agents in the background regimen.

And what we basically saw were similar suppression rates through month 24 and similar CD4 related outcomes in both the ibalizumab containing cohort and the non-IBA containing cohort. And that is despite the fact that folks in the ibalizumab containing cohort had more advanced disease at baseline even after matching, right? Those folks had significantly lower baseline CD4 T cell counts. And so I participated in the PROMISE study. We do use a fair bit of ibalizumab here in my clinical practice because we, again, do take care of a significant number of heavily treatment experienced patients. And so I was happy to see this sort of long-term data because it really does highlight not only virologic efficacy, but durability, right? That is an important concept in our field. There's always an ask and a request for longer term data. And I think PROMISE US is not even finished yet, Dr. O. So we're probably going to see even more long term outcome data from this registry, but that was particularly exciting to me just because I use this agent a lot in my patients.

And then the final study that I definitely want to highlight is the data from the Prestigio registry, which is one of our oldest, longest term cohorts of HTE patients. Dr. O, these were 255 folks with four class resistance and we were looking at 7 year outcomes. Like that's incredible, 7-year outcomes from over 200 HDE patients presented recently at CROI. And what they did was they basically told us about the virologic and immunologic outcomes from that registry all the way out through seven years after patients entered the registry. And what we primarily saw was that viral suppression increased from year one post-registry initiation to year 7, from 72 to 85% virally suppressed. The proportions with CD4 T cell count greater than 500 also increased one year post-initiation all the way out to year 7. Those proportions went from 57 to 67%, and we saw similar increases in CD4 to CD8 ratio.

Now, what was interesting, Dr. O, was that the authors commented that the regimen compositions had significantly changed over time, and that's not surprising, right? We've kind of alluded to that and discussed that a little bit. They commented that they observed decreased protease inhibitor use, decreased use of first generation INSTIs, and more fostemsavir, more lenacapavir, and perhaps inclusion of those two agents may be contributing to those improved clinical outcomes. And I would argue, Dr. O, that these guys are probably right. Those 2 agents probably really are contributing because we know that both of those agents in their registrational studies have demonstrated durable efficacy with significant CD4 recovery. So, you know, with all of that new data,that we just reviewed, Dr. O. What do you think this means for our HTE patients and what their options may be on the horizon?

Onyema Ogbuagu, MD, FACP, FIDSA
Yeah, Charlotte, I mean, I mean, this is all good news, right? I mean, this shows that we figured out a way, even with, in some cases, imperfect tools, to be able to deliver best outcome for patients, right? Again, I think as new classes have emerged, for example, like lenacapavir, or we have new drugs within a class that have a differentiated resistance profile from antecedent agents, right? We're seeing that again, you know, we just have this opportunity to put things together to improve patient outcomes. So, and honestly, the pipeline is robust again, with still drugs from either more classes or again, with differentiated resistance pathways. So I think it only gets better from here. In fact, it gets so better, I think the clinical relevance or four class drug resistance to the four historical classes will mean less and less over time. And we're already seeing that we're able to suppress a lot of these guys in clinical practise such that these long acting are in some cases acting for maintenance of suppression, not even achieving suppression. Again, I think some gaps that do exist are, again, trying to find things that match together with dosing frequency. So, for example, one study I'm heavily involved in is looking at Len with bNabs that are dosed every six months. Clearly, there's a need for long-acting injectable synchronised dosing. I'm impressed with the logistics. I think the fact that different contexts have found a way to deploy these long-acting injectables, and Charlotte, you're being modest, right?

So you had done a series of LEN and ibalizumab. And I think almost half of the people in ibalizumab were getting home injections, right, of ibalizumab. And I think in the PROMISE US study, you showed that people were on drug for 24 months, which means they got 48 injections. So I mean, kudos to the field. I think, again, we're just finding innovative ways to get these drugs out and achieve a great outcome. So future is robust, we're doing great, and I think it'll only be brighter.

Charlotte-Paige Rolle, MD, MPH
Yeah, I totally agree with you, Dr. O. I think with all the options that we have available right now, you know, what I want our listeners to come away with is the fact that complacency with viremia in this population is honestly becoming unacceptable, right? Do you remember when we used to let these folks live below 200 and we used to be super happy, especially if they had a stable CD4 T cell count. That is just no longer acceptable.

Like we have ways, innovative ways to get people suppressed that may not even require the use of an oral agent if that's what the patient prefers. We've seen that time and time again now. And so you know, I want to encourage all of our listeners, like, know the goal for every patient now in 2026 really should be viral suppression. And if you don't know how to go about doing that, you can phone a friend. You can talk to myself, you know, shoot me an e-mail, reach out to a referral center. You know, we have, excuse me, clinical research studies that sometimes focus on these populations. Definitely don't be shy about reaching out to someone who may be more familiar with the use of these agents to get your patients access to the options that they may need. So, you know, with that said, I want to wrap us up by thanking Dr. O for joining me on this podcast. I really enjoyed chatting with you about what was new at CROI. I enjoyed seeing you in Denver as well. And hopefully our listeners found this information useful for their clinical practice.