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What's New? Simplifying the Complex, Exploring New Approaches in HIV Care for Treatment-Experienced People

Dr. Charlotte-Paige Rollee (Orlando Immunology Center): So, hello, I'm so excited to welcome our listeners to podcast number three, entitled What's New? Simplifying the Complex: Exploring New Approaches in HIV Care for Treatment-Experienced People.

My name is Charlotte Rollee, I'm an adult infectious disease physician and the Director of Research Operations at the Orlando Immunology Center in sunny downtown Orlando, Florida. And I'm super excited to be joined today by my esteemed colleague, Dr. Paul Sax, who I will let introduce himself. 

Dr. Paul Sax (Brigham and Women's Hospital): Oh, thanks so much, Dr. Rolle. And we're going to go on a first-name basis from here on out. I'm going to force you.

All right. So my name is Dr. Paul Sax. And again, you can call me Paul. And I'm the Clinical Director of the Division of ID at Brigham and Women's and a Professor at Harvard Medical School, and delighted to be here to discuss these very exciting advances in management of treatment-experienced patients.

So I'm going to start you off by asking you, since I know you enrolled people in this study. I'm going to ask you to talk to us about the ARTISTRY-1 studies.

Dr. Rolle: Awesome. So thanks so much, Dr. Sax. And you are right, I had fun in the ARTISTRY clinical program.

So, you know, ARTISTRY-1 was really an interesting study. A lot of excitement generated around this data at CROI. And for our listeners, a reminder, this is our open-label trial that looked at switching to a combination of bictegravir and lenacapavir in people with HIV on what was considered complex antiretroviral regimens. And this study enrolled over 500 individuals and either randomized you to switch to the new combination of Bic-Len or continue on your baseline regimen.

Dr. Sax, these folks couldn't have had resistance to any of the study drugs, and they had to have been stably suppressed on their regimen for at least six months. And really, the take-home message from the data presented at CROI was, at week 48, we saw non-inferiority of bictegravir and lenacapavir compared to staying on a stable complex regimen. We saw stable immune function through week 48, and overall, the study drug was well tolerated with few discontinuations due to adverse events.

And so, again, I remember being in the room when this was presented, Dr. Sax, and I was presenting in the same session. Okay. But all the excitement was for ARTISTRY-1. You know, Chloe Orkin, she got so many questions about this data, Dr. Sax. And out of curiosity, why do you think this generated such a buzz? Is this something that we've just all been waiting for such a long time?

Dr. Sax: Well, you know, I think there are a lot of providers who have people with HIV that are taking complex regimens. Often, these regimens were arrived at years ago. So, they involve boosted protease inhibitors, multiple different drug classes.

And frankly, they also preceded the availability of high-resistance barrier integrase inhibitors, dolutegravir and bictegravir. So, I've always taken the view that those patients, really, once we had the results of studies like 2SD, and my colleague, Sabrina Koenig, and her study that she did in Haiti, once we had results of those studies showing that stable patients, even with prior NRTI resistance, could switch to bictegravir, FTC-TAF, or dolutegravir, tenofovir, FTC, or 3TC, I've always viewed those people on complex regimens as people who could switch previously, but a lot of them didn't switch. There's a reluctance to switch. But now we know from this study that there's another option, which is Bic-Len. So, I think that's important.

I do want to point out something with this study, and this is true about almost all open-label trials. If you look at the discontinuations for adverse events, it was really higher in the Bic-Len than in the stable background regimen. And that is what's commonly referred to in clinical trials as ascertainment bias, because people who are on a stable regimen, when they switch, if they have any kind of side effects at all, they're going to blame it on their new regimen.

So, I don't really think these were severe adverse events, and we have proof of that with the ARTISTRY-2 trial, and that's the one I'm going to discuss. I think this one didn't get nearly as much attention because it just compares the most commonly used oral regimen, bictegravir, FTC-TAF, to bictegravir-lenacapavir, but this was a blinded study. And in this study, you get really important information about side effects.

Yes, both regimens were really effective, but there was no difference in discontinuations due to adverse events, 2% in each arm. So, I just want to bring ARTISTRY-2 up as an important counterpart to ARTISTRY-1. I want to mention one other thing about ARTISTRY-2, and that is there was one patient in the Bic-Len arm who developed virologic failure with actually slight resistance to bictegravir.

This is the most common mutation selected, but bictegravir, people who fail at first-line or integrate first-line is 263K, and that's what emerged. I would suggest that possibly this combination, Bic-Len, is best for people who are really good at taking their regimens, and that includes all those people in complex regimens like I was talking about, but might not have quite as high a resistance barrier as people who are taking bictegravir with nucleosides.

What do you think?

Dr. Rolle: I could not agree more, Dr. Sax. As someone who's done a few open-label switch studies, you are so on the money when you talked about that what we always see if we look at any really open-label switch trial in our field, we always see that safety profile, especially early on in the trial, right, Dr. Sax? Then it seems as time goes on and people get more used to their regimen or people just relax about being in a study, we kind of see that difference in adverse events dissipate.

I have certainly personally seen that in trials that I've conducted, so thank you for mentioning that. One thing of note, Dr. Sax, about ARTISTRY-1, can you tell us a little bit about those lipid differences that we saw between Bic-Len and the stable regimen?

Dr. Sax: People coming off boosted protease inhibitors or boosted anything are going to have improvements in lipids when they switch to Bic-Len, so that's a nice thing. And I have to say, let me give you a patient anecdote. There was someone who was a study participant who came up to me, and he said, you know, this study changed my life, you know, basically I was taking gobs of pills, and I was on, you know, boosted PI and having diarrhea and my lipids were all out of whack, and I switched to this single pill, and I couldn't be happier. And that's great, that's what this regimen's for.

Dr. Rolle: Yeah, I could not be more excited for our patients who can really, really benefit from this, Dr. Sax. So, you know, speaking of single-tablet regimens that have somewhat unique resistance profiles, I want to take the opportunity to segue us into a discussion of doravirine and islatravir, and I want to remind listeners specifically of the heavily treatment-experienced protocol that enrolled multi-drug-resistant patients.

Now, some of you may remember there was a clinical hold on the initial dose of islatravir using the Dor-Isl program, and that was the 0.75 mg dose, but prior to that clinical hold, protocol 019 was open for enrollment, and they actually did manage to enroll 35 patients who did continue in the study through week 48. And I'm not sure, you know, this protocol, Dr. Sax, was actually never really presented at a congress per se, but the manuscript did come out in AIDS earlier this year, and we saw that of those 35 individuals enrolled, about 71% were suppressed at week 48. And I want to remind the audience, this trial enrolled at the same time as the CAPELLA study. My site, Dr. Sax, had both studies, and the criteria were the same. So these were people, multi-drug-resistant, previously failing a regimen, and unable to construct a suppressive regimen with currently commercially available antiretrovirals.

We saw suppression rates of 71% at that 12-month time point with, you know, generally, I will say, well-tolerated safety profile of Dor-Isl in the trial, about nine folks having drug-related adverse events. And so, you know, I think Dor-Isl, Dr. Sax, it often gets kind of forgotten when we think about our heavily treatment-experienced patients due to the premature stop of the study and the fact that it did not complete enrollment.

But how do you think about this particular combination when it comes to the HTE population, especially considering we're about to have Bic-Len available pretty soon, hopefully by the end of this year, definitely?

Dr. Sax: You know, I think the issue with Dor-Isl is that, first of all, doravirine resistance is something we do see in clinical practice, and we see it in clinical practice in people who've had extensive NNRTI exposure. And so, you know, there's this Y188L mutation, there's the 106 mutation. If you look at genotypes, you will not see 100% activity of doravirine in people with NNRTI mutations.

Certainly, it's active against K103N and Y181C, but not 100% of patients with NNRTI resistance have just those mutations. In addition, there's a suggestion that the islatravir really is not a good drug for people who harbor the M184V or I mutation, which is selected by lamivudine and emtricitabine. And if that's the case, then I would say Bic-Len is going to have a much greater utility in the highly treatment-experienced population than doravirine-islatravir.

Dr. Rolle: I totally agree, Dr. Sax, and I think that's the buzz on the streets from who I've talked to and asked that same question, but always great to have your perspective. Now, Dr. Sax, in the recent years, we have seen some exciting clinical trial data from some of our long-acting regimens that actually also hold promise for this population, given that they're not affected by many of the resistance mutations that we see prevalent in our HTE patients. Can you tell us a little bit about what's on the horizon for Len-Tab and Zab?

Dr. Sax: Yeah, Len-Tab and Zab. I got to tell you, I'm a bit of a, how do I put it, a bit of a skeptic when it comes to bNAbs for HIV therapy. And yet, when I look at the clinical trials that are going on with bNAbs, I must say this particular strategy, which is lenacapavir injectable every six months and two parenteral broadly neutralizing antibodies, teropavimab and zinlirvimab, which are Tab and Zab, and we saw very good results in Phase II.

And as a result, because of those good results, these are every six-month treatment, the thing I wanted to highlight is that a Phase III fully-powered clinical trial program is about to start, and that's very exciting. And it'll look at one population will be people taking just stable oral ART, and then it will randomize them to receive either Len-Tab-Zab or our current long-acting injectable, which is Cab-rilpivirine. So it's every six months versus every two months, but the every two months, of course, we have all this experience with, and the every six months is really investigational.

That's one of the clinical trials. And the other clinical trial is for people on stable oral ART, randomized to continue that or to switch to every six-month Len-Tab-Zab. So, two different fully-powered trials.

I'm excited for them to get started. Just since you are such a productive clinical trial site, I assume you'll be participating in those studies.

Dr. Rolle: Yes, Dr. Sax. And might I even secretly tell you, we already have a waitlist for both of those studies, because everyone's into long-acting these days, right? So as soon as we get selected, exactly, for exciting protocols like this, we start immediately telling our patients about it. And so, we have some waitlist building, and we're very, very excited about that clinical program at our site.

And so, you know, just to round us out, Dr. Sax, when I'm thinking about long-acting, I think there was one trial that was presented at CROI. It was only a poster, but it really stood out to a lot of people, and that was the use of long-acting Cab-rilpivirine in folks who are really being challenged by oral antiretrovirals, right?

And so, this was a small cohort, right, 45 participants from Taiwan, experienced folks who had viremia, okay, had viral loads of at least 200 copies, and they couldn't have had resistance to Cab-rilpivirine, and either enrolled to immediately switch to long-acting Cab-rilpivirine, or have a delayed switch in which they remained on their oral regimen until week 24, at which point they then got to switch to Cab-rilpivirine. And the study authors presented their week 24 primary endpoint, and you know, Dr. Sax, it was very, in my opinion, impressive, okay?

We saw 88% of these individuals achieve viral loads less than 200 copies, and 76% achieved viral loads less than 50 copies. And again, these were folks that were challenged by their oral regimen, unable to achieve suppression. And when I think about HTE patients, certainly when I think about my own clinic population, a lot of my HTE patients, they're suppressed, Dr. Sax, but they are on regimens that, like you commented, that anecdote you told us about, they're on regimens that they're kind of struggling with, right?

They're so used to side effects, they become a part of their life, you know? These regimens are not optimized for them, okay? It's just the best that we've got, that we're giving them based on their resistance profile.

So, this data is kind of exciting. What was your take on the SUPLA trial?

Dr. Sax: Well, you know, I thought, every CROI, there's one research study that I feel should be given an oral presentation and gets put as a poster, and this year, this was my vote. Because remember, all of the studies we've heard about in Cab-rilpivirine or in Cab-lenacapavir for people with viremia, all those studies have been cohort studies. Now, they're really not done in a prospective way. They're really descriptions of real-world evidence.

There's something much stronger about a prospective study, in particular, a prospective study with randomization, and that's this study had. And if you look at the population, it's people with true viremia. I mean, the median viral load at entry to the study was 35,000. These are people who'd been struggling to stay on oral ART for years and hadn't been able to do it. And all the, you know, exclusion was that they had no resistance to Cab-rilpivirine.

So that's actually very important. And then two other things of note about this, in addition to the better virologic results that you mentioned, I asked the investigators, I said, I said, did you have anyone fail with drug resistance? And they did not.

They had one person who had virologic failure, but the person did not have drug resistance. So, you know, even though we worry about drug resistance in Cab-rilpivirine, even in people who are suppressed at baseline, in this study, it was not that, it wasn't observed. And I'm on a site now, one of the larger cohorts of people with viremia getting Cab-rilpivirine, and this is the combined cohorts of Emory and of UCSF, they have shown only a 6% virologic failure rate with resistance, which is incredibly, incredibly uncommon.

So I think this is becoming the de facto best regimen for people with viremia because they can't take oral ART. And that's something that is not in the package label and something that's going to be addressed in the results of the CROWN study, which is fully enrolled, a larger study of Cab-rilpivirine for people with viremia. So, very exciting results.

Dr. Rolle: Absolutely, Dr. Sax, and a really good follow-up to the LATITUDE study, right? Because I think when we think about this particular population, folks that continue to have viremia and ongoing challenges with their oral regimen, this is the kind of approach that we take: an immediate switch to Cab-rilpivirine in really an effort to control someone's HIV and honestly change the trajectory of their health. And so, very, very excited to see the results of CROWN and SUPLA definitely, even though a small cohort, supporting that.

And like you said, poster presentation, but a lot of us gathered around this poster because we were very excited for these results.

Dr. Sax: As the editor of an ID journal, I was extremely interested in recruiting that trial to our fine journal of clinical infectious diseases. And I have my fingers crossed that they'll submit it.

Dr. Rolle: Dr. Sax, I think any invitation from you in that nature is one that probably is going to receive a favorable response.

Dr. Sax: Speaking of Dr. Sax and Dr. Rolle, I said at the beginning, we're going to go in first names, but you decided to ignore me. Anyway, that's what you've been, ever since I interviewed you for residency, you've been someone who's called me Dr. Sax, and that's fine. I have to just get used to it.

Dr. Rolle: I'm so glad that you're totally okay with it. Dr. Sax is probably never going to change, just an FYI. I do, Dr. Sax, want to take the opportunity to thank you for joining me for today's podcast. We covered several important recent clinical developments for heavily treatment-experienced patients. And really, Dr. Sax, I think we're approaching a horizon and a new paradigm for this population where I think viremia is going to be unacceptable for these patients. And I would argue that that's actually the case right now.

But I know for some of us, we are challenged by coming up with suppressive regimens for some patients in our practice. And we allow folks to kind of coast in this low-level viremia state because their regimens are not optimized for them. And I think with all of the data we've discussed, we've talked about some exciting oral options, we've talked about some long-acting options, we're going to come to a place pretty soon where viremia is not going to be acceptable for anyone.

And I think that that's incredibly exciting and gives me a lot of hope for the future for all of our patient populations.

Dr. Sax: Yeah, no, I completely agree. And, you know, it's very gratifying to see all of these different tools we have to really get the last group of people without virologic suppression, virologically suppressed, and to take the large group of people who are virologically suppressed and give them so many different treatment options, especially in the long-acting space.

So, allow me to just thank you for inviting me to join you on this podcast. It's been very exciting to see the very impressive career trajectory you've had since all those years ago when we first met.

Dr. Rolle: Well, I had a great start, Dr. Sax, which is sitting across from you, right? So with that said, I definitely want to take a moment to thank our listeners. I hope you were as excited as Dr. Sax and I were to review this data. And I certainly hope that you found this information useful for your clinical practice. Thank you so much.