Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, hosted by Dr. Eileen Scully and Dr. Christopher Hoffmann, both HIV specialists at Johns Hopkins, who explore quandaries in adult HIV care. Each case discussion includes
medical history and diagnoses, challenges in care and treatment, and key evidence and guidelines
that inform clinical decision making.

Cases are presented as a composite from the hosts’ clinical practice, with all identifying details removed to protect the privacy of patients. Case discussions are for informational purposes only and not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use only, not an endorsement.

Dr. Eileen Scully:
Welcome to Viremic, a podcast where we discuss all things HIV. I’m Dr. Eileen Scully, coming to you from Johns Hopkins in Baltimore. Today, I am super excited to welcome my mentor, colleague, and friend, Dr. Paul Sax, to the podcast.

Before we begin, just a reminder to please share this episode if you like it with a colleague, and follow us wherever you listen to podcasts. We’d love to hear what you think. Please leave a comment or send an email to us at viremicpodcast@jh.edu, and we are definitely open to suggestions for future topics.

To get started, let me introduce our guest. Dr. Paul Sax is the Clinical Director of the Division of Infectious Diseases at the Brigham and Women’s Hospital in Boston and is the Bruce A. and Robert L. Beale Endowed Chair in Infectious Disease and a Professor of Medicine at Harvard Medical School. He’s one of the most trusted voices in infectious diseases, communicating through beautiful writing in multiple formats—through blog posts from the New England Journal of Medicine, via a Substack, and through social media. He has mentored generations of HIV fellows through training, specifically in the care of people living with HIV, including me. He’s also led guideline-driving research in antiretroviral therapy and cost effectiveness.

Before we get started with our discussion today, Paul, you’ve been a cherished teacher for so many. I was wondering if you had any thoughts specifically for people who are listening and who are considering a career in infectious disease. What do you love about your job and why would someone choose it today?

Dr. Paul Sax:
That’s a great question, Eileen, and I want to thank you for inviting me on and for those kind words.

One of the great things about what we do is that it’s never boring—changes all the time. There’s always progress; there’s always mysteries. And I have to say, on Sunday evening, when I prepare for our Monday morning case conference, I have this excited feeling that the next day is going to be interesting. To be able to say that your job is never boring is a real gift.

So, for people who have interest in an ID, I strongly encourage it, and I would defend it to the last days of my life.

Eileen:
Well, hopefully that won’t be necessary, but I totally agree. It’s super fun and always exciting.

Let’s turn to the task for today. Outside of his many credentials I’ve already mentioned, one of the most amazing things about Paul is his ability to make incisive observations about new data and his fearlessness in taking a stance. This makes something that could be just a dry conference review into something more provocative and entertaining.

So, with that background, our charge for today is to review CROI 2026, which was in Denver in late February. To those of our listeners who don’t have what I would consider to be the tremendous luck and privilege of attending CROI, Paul, can you describe what the meeting is like and the purpose?

Paul:
CROI is our best HIV meeting. It’s relatively small. When I say relatively small, it has about 3,000 people, which may sound like a lot, but if you compare that, for example, to a cardiology conference, it really is small.

In addition, it’s multidisciplinary, so, it brings together investigators who do clinical research, investigators who do translational research, investigators who do implementation and public health research, and clinicians. All of those people together in one meeting makes for a really exciting chemistry. In my opinion, for those of us who do HIV care and HIV research, CROI is the best meeting.

Now, it is frequently in cold locations in the wintertime. It’s been in Boston, it’s been in Montreal, it’s been in Chicago, it’s been in Denver. But this year, Denver was unseasonably warm and next year, it will be in San Diego, California. So, I hope people will consider coming. It really is a wonderful meeting.

Eileen:
I will always remember my very first CROI, which was while I was the HIV fellow. It’s one of the perks of that position, although it was in Boston and it was quite cold.

So let’s dive in. We’ll start by talking about some treatment studies, and I thought we should start with things that are already available. How we make choices of which things to use for each patient always becomes important.

Let’s start with Abstract 530 (Chan, NY, et al. Week-24 Outcomes of Long-Acting Injectable ART in People With HIV and Suboptimal Viral Suppression). The presenters discuss the use of cabotegravir/rilpivirine (CAB/RPV) in people who have non-suppressed HIV, so not the FDA-approved indication for CAB/RPV, which is in a switch of treatment in someone who is already suppressed [not] in the case of someone who has viremia.

Paul, do you want to talk a little bit about what the abstract showed?
[Note: Throughout the transcript, all citations of “abstracts” are referring to the Conference on Retroviruses and Opportunistic Infections (CROI), 2026; February 22-25, 2026; Denver, Colorado]

Paul:
Yeah; the reason I highlighted this one in my review, and by the way, please do go to voices.nejm.org, which is the new home of my infectious disease blog. In my review, I chose this study, even though it’s pretty small, because it’s the first prospective comparative study looking at CAB/RPV in this population of people with viremia. And it’s real viremia; it’s not just the people who have a viral load that’s detectable between 50 and 200. They did the study in Taiwan, and they had 4 hospitals. The population had a median viral load that was like 35,000. So, this is the real deal. I use the term with a little trepidation, but these are people with hardcore challenges in medication adherence. We’ve been hearing about managing them with CAB/RPV for a while, but we haven’t actually had any prospective comparative studies.

So, it’s a small study. It’s only 45 adults. They’re randomized to immediate long-acting CAB/RPV or to delay it for 24 weeks and continue best possible oral therapy. The results were quite striking. Despite the small sample size, viral suppression was significantly better in the CAB/RPV group—88% versus 55% in continued oral ART. The investigators that we spoke to were actually surprised that people in the oral arm did so well, but it shows that just by enrolling in a study, you can actually improve outcomes.

I also asked were there any virologic failures with resistance, and encouragingly, even though this is a study of CAB/RPV in people who struggle with adherence, they had one virologic failure, but they had nobody who developed resistance. I think these are the best data we have that this is the optimal approach for people who really struggle with non-adherence, and you’ve done everything you can to get them to take oral ART, and they simply can’t do it. This is very compelling data.

Eileen:
I totally agree, Paul. I think, with the narrow approval of CAB/RPV for switch, there’s 2 levels of question—one is will it work when the viral load is high? And the other is when do you employ something that has not been studied, even if you think it will work? In this case, it had not been studied in a registrational trial as an initiation therapy, and I think that gives everyone some level of pause. But the other thing that goes on in the background is partially [that] we’re not sure of the risks of long-acting injectables, and we’re fearful about failure of the regimen.

Once it’s an injectable therapy, I think that the failure ends up feeling more like it’s something we’re doing. It’s not that the patient is going home and opting not to take the medication. It’s that we’ve given them something and then we can’t maintain it over time. We talk about this a lot in conference when we talk about our challenging cases. There are just some patients who can tell us with their long-standing inability to suppress their viral load that they simply cannot take oral medications, and sometimes you just have to listen to what people are telling you.

Paul:
Mm-hmm.

Eileen:
The patients in this trial, they had to have had an HIV diagnosis for at least a year. They had to have sustained viral non-suppression, and as you mentioned, they did have robust viral loads. The interquartile range went all the way up to 200,000, so it’s a good challenge of whether the therapy actually works. It does seem to work, even in people who are viremic, and it supports the use in that case where someone has told you for many years (not saying it with their words) despite attempts and ability to get suppression, that oral medications are just not going to work for them.

Paul:
I completely agree. In the setting of our having cohort data from several clinics this works pretty well. It’s not the same thing as a prospective comparative trial, but at CROI, Abstract number 529 (Spinelli, M. et al, Virologic Outcomes After LA ART Initiation With and Without Viremia in 2 Large US Clinic Cohorts) looked at the Grady Hospital and the UCSF Ward 86 experience and combined the two. They looked at 1,000 people starting CAB/RPV with suppression and 299 starting with viremia. Despite the fact that there was lots of social determinants of health that were unfavorable, 96% got virally suppressed with a median time to suppression of 4 weeks. It did find a slightly higher failure rate among the people with viremia at baseline, but it was still only 6%, so 6 % versus 1%. I got to tell you, when we modeled this, we modeled a much higher rate of failure among people with viremia at baseline. So, I look forward to seeing this pivotal CROWN study (ClinicalTrials.gov ID NCT06694805). The CROWN study is the larger controlled trial comparing CAB/RPV to oral therapy that is being funded and run by the manufacturers of CAB/RPV. That’s fully enrolled, so I don’t think it’ll be long before we have results. It’s being enrolled in study sites in the United States and in Spain.

Eileen:
I think that point you’re making is excellent, and it does surface one of the things that’s been a challenge in infectious diseases over the last few years, which is this elevation of the randomized controlled trial as the only possible way to get usable data, with always the parachute counterfactual of “you don’t need a randomized trial of whether or not you need a parachute if you’re jumping out of a plane.”

Paul:
[laughs]

Eileen:
I think some people would have argued we were in that position with the cohort data from early adopters like Ward 86 on use of CAB/RPV in individuals who have non-suppressed viral loads, but it is nice to have an RCT, and I’m sure that we are all hopeful that the CROWN study will show, and pretty confident actually, that it will show similar efficacy.

Paul:
Yeah, and it’ll lead to change in the package label. I think that’s the primary reason for the companies doing it because once it’s in the package insert, you’re much more likely to get insurance coverage for it. So yeah, we’ll see.

Eileen:
Now, since we’re talking about CAB/RPV, let’s also talk a little bit about the data that came out at the meeting about that regimen and potentially other regimens that are nuc-sparing and lack a hepatitis B active component. There, we’re referring to tenofovir.

Initially, this was one of the big considerations. It is one of the things that you’re taught to look for as you think about making a transition away from a tenofovir-containing regimen. I think there was at least one presentation that suggested that we probably didn’t do that great of a job about that at the beginning. I’m referring to Abstract 593 (Dieterich, DT et al., HIV-HBV Coinfection and Long-Acting Cabotegravir + Rilpivirine in the US: HBV and HIV Outcomes), which was from the OPERA cohort. In this study, they looked at routine clinical data from the electronic health records in this OPERA database, which is 101 clinics in U.S. states and territories that represents about 14% of the people living with HIV in the United States. They included people who were greater than or equal to 18 years and started CAB/RPV between January of 2021 through December of 2024. They were looking at how frequently people were checked for hepatitis B—either having hepatitis B immunity and prior infection, active hepatitis B, or hepatitis B infection without demonstration of immunity.

That is sorted out through the combination of antibody positivity. So not to belabor the hepatitis B serologies, which are a bit complex, but if you have surface antibody positivity, you have a higher level of immunity to hepatitis B and are likely to control it if you have it or to be immune to it if you are challenged with it and have never been challenged with it before. You can get hepatitis B surface antibody from either vaccination or infection that you have controlled. Isolated core antibody is interpreted generally to mean that you have hepatitis B, but you don’t have a high titer of surface antibody, so your immunity status is a little bit less secure. And then hepatitis B surface antigen positivity or DNA positivity is interpreted as active infection, meaning you don’t have control of that and you do have evidence of the virus itself.

So from the OPERA cohort data, it was pretty remarkable how infrequently people had their hepatitis B status checked prior to a switch to CAB/RPV. It was notable that in those who were classified as having active hepatitis B at the time of switch, meaning they had evidence of surface antigen positivity or hepatitis B DNA, there was a reasonable rate of experiencing hepatitis B reactivation, which they defined as a substantial increase in one of those measures of hepatitis B activity. That overall suggested that, at least at the beginning, we weren’t doing a great job with monitoring this, but it turned out that the rates of reactivation in those with a surface antibody positive or even that isolated core, which is considered a little bit less protected, were really very low and that the people we need to think about the most are those who actually have evidence of active hepatitis B.

So having summarized that, Paul, what do you do in your clinic?

Paul:
Well, I basically have taken the view that anyone who’s surface antigen positive is not a good candidate for tenofovir-sparing regimens. I think one of the bonuses of having tenofovir alafenamide is that you really don’t have to worry about renal and bone toxicity. So if they’re surface antigen positive, then they’ve bought themselves tenofovir as part of their ART regimen.

The isolated core patients, or “iso-cores” as some people refer to them, they’re at risk, but they’re very low risk. I realize that there are case reports of reactivation, but what I would propose, and I’m basing this in part on a presentation of a cohort from the CNICS [CFAR Network of Integrated Clinical Systems] cohort at CROI, the reactivation rate is really low (Abstract 142; Haser, G et al., Hepatitis B Reactivation/Infection in People With HIV on Tenofovir-Sparing Antiretroviral Therapy). And it’s by no means guaranteed, so I think if you were to have someone who has, say, isolated core antibody and they really want to go on a tenofovir-sparing regimen, especially if they’re going to often have that motivation for CAB/RPV, I wouldn’t say it’s contraindicated. But I would continue to monitor LFTs on a regular basis and have a low threshold to check for hepatitis B DNA if anything comes up.

Just to give you a sense of how infrequent it was, the study I mentioned [Abstract 142], they looked at over 5,000 people getting tenofovir-sparing regimens, and they found that the reactivation rate was 0.4%. Interestingly, it even happened in some people who had positive surface antibody historically, although they did not quantify the antibody. I was just going to say, yes, serologies are really confusing, but my take homes from all of these is that surface antigen positivity is still an exclusion for tenofovir-sparing ART. Otherwise, you’re pretty good to go.

I would emphasize that people who are surface antibody negative and core antibody negative should be vaccinated because the risk factors for HIV and hepatitis B do overlap, and acute hepatitis B in someone who has HIV already is a preventable event. It really is.

Eileen:
Exactly, and that’s something that’s happened in trials that we’ve been looking at where people are on regimens that don’t provide any hepatitis B activity. There are incident hepatitis B infections, which again just makes us look bad.

Paul:
Actually, I have a patient in my practice (this is an anecdote) who switched doctors because his previous doctor did not give him the hepatitis B vaccine and he acquired hepatitis B. That was for him reason enough to leave that person’s practice.

Eileen:
I’ll mention here that people should also remember that even if you were a prior non-responder to older formulations of the hep B vaccine, including Engerix, the newer version of the hepatitis vaccine, HEPLISAV-B, actually works extremely well including in people living with HIV, as was studied in a trial in the ACTG in the last few years. So, I would offer them that alternative because it can turn some non-responders into responders.

Paul:
Definitely.

Eileen:
What you were saying there resonates also with the intention behind offering CAB/RPV to people who still have non-suppressed HIV viral loads, because we shouldn’t view concurrent hepatitis B as a contraindication to treating HIV. At least I don’t think we should. Even if it means you cannot suppress their hepatitis B, I would still try to suppress their HIV and work on adding a hepatitis B therapeutic at some point. In the past, I think we were like, “Well, they can’t be on a hepatitis B active component, then we can’t use CAB/RPV.” But you can, and I would suggest that you should.

Paul:
Yeah, I totally agree. Hepatitis B has a long-term risk of medical complications, but the proximate risk of untreated HIV is much greater, especially with advanced disease.

Eileen:
Now let’s move on to talking a little bit about everybody’s newest favorite drug, the scientific breakthrough of the year, lenacapavir. There were some updated results from the prevention trials in lenacapavir. The prevention trials done in lenacapavir all have this name, “PURPOSE,” followed by a number. PURPOSE 1 was in cisgender women and included some adolescents, and PURPOSE 2 included gender diverse individuals and men, all of whom have sex with men and who are at higher risk of acquiring HIV. This studied the efficacy of lenacapavir given twice yearly for HIV prevention with different comparator arms. For the cisgender women, they studied it in comparison to oral tenofovir disoproxil plus FTC and also to oral tenofovir alafenamide plus FTC. Initial results for both of those trials have been previously reported [and] showed extremely high efficacy for lenacapavir with zero incident infections in the original reporting for the PURPOSE 1 trial in cisgender women and very low rates of HIV acquisition in PURPOSE 2 as well.

At this meeting, they presented updated data following people further, adding more person years of observation. For PURPOSE 1 (Abstract 128. Ndlovu, N et al, Twice-Yearly Subcutaneous Lenacapavir for PrEP: Updated HIV-1 Incidence and Safety Data in PURPOSE 1), since the primary analysis concluded, among the 5,338 participants that initially tested negative for HIV, there have been 23 additional HIV infections, for a grand total of 77 across the whole study. This included only 2 in the lenacapavir arm, out of 2,134 participants; 52 in the oral FTC/TAF arm, and 25 in the oral FTC/TDF arm, and that was a 2:2:1 randomization.

So, the incidence rates for both FTC/TAF and FTC/TDF were approximately 1.9, close to 2, per 100-person years, so essentially equivalent. This update continues to show really amazing efficacy. I think everybody’s disappointed that they couldn’t stay at zero, but we can’t let perfect be the enemy of amazing.

Here there were 2 cases of acquisition, and they were interesting. One of them, who in the description of all the patients who acquired during the PURPOSE trials is known as “participant C,” received all injections on time. Their last dose was 182 days prior to diagnosis, which is exactly like they presented on their due date for their 6-month visit. Lenacapavir concentration was sufficient; it was above the inhibitory quotient 4 that they used as their threshold, and the HIV viral load was only 78 copies at the time of diagnosis. With a retrospective review finding of 47 copies at a visit about 13 weeks earlier.

The other participant was not similar. They had had their last injection more than a year prior, 487 days, and their lenacapavir level at the time of diagnosis was very low, consistent with not having received drug for some time, and the viral load at diagnosis was 134,000.

They did find similar rates of injection site reactions in other adverse events.

Then, in PURPOSE 2 (Abstract 129, Cantos Lucio, VD. Lenacapavir for PrEP: HIV-1 Incidence and Safety From PURPOSE 2 at End of Randomized Blinded Phase), they similarly extended their analysis to include new events. This showed one additional incident infection in the lenacapavir arm, to a grand total of 3 out of 2,179 participants. This individual, again, had a very high viral load at the time of diagnosis, 2 million, and their lenacapavir level was just below the IQ4 threshold at 14.2 nanograms per milliliter when the [measured] IQ4 was 15.5, so slightly below. It’s a little bit unclear why or how they acquired HIV.

So, Paul, how do you feel about lenacapavir for prevention?

Paul:
Well, it has a much more important role in prevention than it does right now in treatment. Lenacapavir’s half-life is sensational, and twice-yearly injections has the potential to be transformational, especially in settings where people are not going to take oral PrEP.

So far, the rollout is going slowly. It’s still been less than a year since it was FDA approved, but the people who were on it really like it.

There are some people who get injection site reactions, nodules that they don’t like, but mostly it’s not too bad. I’m going to mention this obvious fact, which is that breakthroughs of HIV that occur, which are rare and associated with lenacapavir resistance, do not in any way impair our first-line ART options, which I think is a real benefit as well.

So, I’m optimistic, and I’m also optimistic that the PK data will eventually support a once-yearly IM formulation, which will get rid of the nodules and also allow for once-a-year injections, which will be very exciting.

Eileen:
Just to be clear—you’re not worried about the new infections which occurred despite on-time injection? Or these are the price we pay for use of these amazing injectable meds?

Paul:
I don’t think that there’s a 100% effective anything, even though yes, it was exciting to see, during the international AIDS conference, that zero. No one ever thought it would stay at zero forever. HIV prevention has made enormous strides—a combination of PrEP and ART as prevention. I think this is just another great example.

If I could briefly talk about 8527(Abstract 126, Kapoor, Y. MK-8527 Phase III Dose Selection for Monthly Oral HIV-1 Preexposure Prophylaxis), the nucleoside reverse transcriptase translocation inhibitor being developed for once monthly oral PrEP. 8527 is going to be dosed at the hysterically funny dose of 11 milligrams once monthly. Someone pointed out to me that Tofacitinib also is 11 milligrams. I have not seen a drug that had an 11 milligram dose before. This 11 milligrams once monthly, think, is the only drug that’s dosed 11 milligrams once monthly, but that’s how it is being dosed in its fully powered clinical trials of HIV prevention.

I hope it works because it would be great to have all these options—once-daily oral PrEP, on-demand oral PrEP, injectable cabotegravir, injectable lenacapavir, and once-monthly 8527 (which desperately needs a better name).

Eileen:
Yes, but I do like that it goes to 11.

Paul:
[laughs] Goes to 11.

Eileen:
I think all of these prevention options are amazing, and there should be no disappointment. It is always reassuring when you can say, “If only they were on time, it never would have happened,” but I do think this is just a feature of injectable meds. They have this occasional, despite perfect on-time injections, you see acquisition. I don’t think that’s something I ever told my patients about oral therapy. In fact, I know it wasn’t.

Paul:
Well, there are some breakthroughs even on oral TDF/FTC. PrEP is not 100 % effective. It’s very effective. One thing I want to say is just how effective cabotegravir is. People sometimes ask me, “How do you manage cabotegravir PrEP failures?” I haven’t seen one yet, so it’s not like this is commonly happening. It’s very uncommon.

Eileen:
That is accurate. We had one recently.

But at which point are you no longer on PrEP becomes the question.

Paul:
Yeah, they were missing doses.

Eileen:
Exactly. So you made the point that lenacapavir at this point is much more influential in the prevention space than in the treatment space, with the exception of some of our very heavily treatment experienced individuals with a lot of resistance.

But there was some new data about lenacapavir for treatment. Do you want to comment on the data combining Len and Bictegravir?

Paul:
Sure. I’m gonna call it “BIC/LEN” because BIC is alphabetically before LEN. BIC/LEN is a single pill option that was tested in the ARTISTRY 1 and ARTISTRY 2 trials, and we saw data on both of those. ARTISTRY 1 (Abstract 181. Orkin, CM., Phase III Efficacy and Safety of Switch From Complex Regimen to Single-Tablet BIC/LEN in ARTISTRY-1) was for people receiving, “complex regimens.” Some of them were complex; I think something like 70 % of the people were taking boosted protease inhibitors. A lot of the reasons that they were on these complex regimens had to do with resistance. If you think about it, there was a time when we really did not simplify people’s regimens when they had resistance because we were scared that we would induce further resistance if we didn’t get it right. So that’s why so many people are on complex regimens.

This study population was unusual. First of all, they were older, 60. They had a duration of HIV treatment that was nearly 3 decades. They had multiple comorbidities, and they were then randomized to continue their current complex regimen or switch to BIC/LEN. It was an open-label trial, and the 48-week results showed non-inferiority and no major safety issues. So that’s the ARTISTRY 1 data.

When I heard about the development of BIC/LEN, I was watching at the same time the use of dolutegravir- and bictegravir-based regimens with tenofovir, FTC, or 3TC, and seeing that they were working great even for people who an NRTI resistance. Then along comes the 2SD study, which looked at people on second-line ART in Africa and randomized them to TLD [TDF/3TC/DTG] or to stay on their boosted PIs, and lo and behold, TLD was just as good, and there was no emergent resistance.

Then my colleagues Serena Konig and Patrice Severe did a study in Haiti looking at BIC/FTC/TAF in the same patient population. They did proviral DNA sequencing, and even though more than half the participants had evidence of NRTI resistance at baseline, again, viral suppression was maintained. So that’s the ARTISTRY 1 population—these people with NRTI resistance. They could have simplified their regimens to BIC/FTC/TAF or tenofovir/lamivudine/dolutegravir, but they didn’t, so they were still on complex regimens. And whether BIC/FTC/TAF is better or worse than BIC/LEN, I don’t really know.

But I do want to mention this second study because it was not an oral presentation—it’s ARTISTRY 2 (Abstract 513, Meissner, E. et al. Phase III Efficacy and Safety of Switch From B/F/TAF to Single-Tablet BIC/LEN in ARTISTRY-2). This was a blinded trial with BIC/FTC/TAF as the comparator. I’m really glad that the company did a blinded study because you could say that the safety and tolerability of the 2 were very similar because you really can’t say that in an open-label trial.

However, there was one patient in the BIC/LEN group who had emergent 263K resistance mutation, which is an early integrase mutation that we sometimes see in people failing CAB/RPV or failing first-line dolutegravir/bictegravir. So it raises the question, at least, of whether the resistance barrier when given without nucleosides is not quite as high.

Where this is going to play out, I think depends on your perspective. If you’re a clinician who’s already comfortable switching patients with NRTI resistance to BIC/FTC/TAF or TLD, depending on where you’re practicing, this isn’t going to add that much. But if you are worried about it, then BIC/LEN seems like a better strategy.

We should emphasize also that BIC/LEN does not cover hepatitis B, so you have to take that into consideration too.

Eileen:
That’s a really beautiful summary, Paul. I will say that in our “difficult case” conference, it’s interesting, because I often feel like with these individuals who were, at some point the word “salvage” was used to describe the regimen that they are on, some of them have therefore not changed in 15 years. People seem to feel more comfortable using the newest medications. I totally agree with you that we have probably more data to use compromised backbones with dolutegravir, for example, even from NADIA (the NADIA trial), looking at how well that performed despite the very high rates of nuc resistance.

Paul:
Yeah, although that was in the treatment failure setting.

Eileen:
Correct, so even more of a barrier than just a suppressed switch. Even for some of the patients, though, they have felt like these other classes of drugs, they were told they were gone. So now to say, “They’re probably okay,” it doesn’t feel as good. I’ve recently inherited a couple of patients from some long-term providers and have been testing my own intestinal fortitude in terms of, I can say easily that there’s data to support the switch, but when the patient asks, “Are you sure this is going to work,” it takes a minute, but I think we are.

Paul:
As long as they take it, it’s going to work. One thing that someone said to me is, “Well, what if their adherence is poor?” Well, that would be true even if you added doravirine, or added lenacapavir. Poor adherence can lead to resistance no matter what the regimen.

I’m glad that this option is coming out. I guess I wonder whether it will really be as transformational as some have said it was. I know that there were participants in this trial who were taking boosted protease inhibitors and having terrible diarrhea, and they had drug interactions, and all these other problems with boosted PIs, and getting randomized to the BIC/LEN was transformational for them. But I would argue that maybe their clinicians could have put them on BIC/FTC/TAF earlier and they would have had the same relief.

Eileen:
I think that that’s probably true.

Moving on to another novel combination that isn’t yet available—do you want to take us through the results for the doravirine/islatravir combination trial (Abstract 177, Rockstroh, JK et al., DOR/ISL (100/0.25 mg) vs BIC/FTC/TAF for Initial HIV-1 Therapy: Week 48 Results of a Phase III Study)?

Paul:
Sure. I’m going to sound like a clinical trialist geek here, but I’m just going to say that this study demonstrated the limitations of non-inferiority trials. A non-inferiority trial is best to show that something is not too much worse than a standard regimen. And why not too much worse? Well, it would be fine if that novel approach offered something special.

The best example recently, of course, is CAB/RPV being non-inferior to oral ART. Here, it really doesn’t matter that there are 1% to 2% of virologic failures in the CAB/RPV arm. It’s good that we know that that happens, but you’re getting so much in exchange for the patients who really want injectable. That’s a good use of a non-inferiority design.

But here, the NNRTI doravirine and the nucleoside reverse transcriptase translocation inhibitor, islatravir as a one-pill option, compared to BIC/FTC/TAF, another one-pill option in a blinded trial, you have a non-inferiority design that includes about 500/600 people. To credit the investigators, they enrolled in 20 countries. They enrolled people who had more advanced disease than typically in a treatment-naive study. What they found ultimately, and this was published in Lancet HIV when it was presented, was that virologic suppression was very similar in the 2 arms—doravirine/islatravir 92%; BIC/FTC/TAF 91%. These are standard numbers for great modern regimens. But here comes the “but.” Even though that met non-inferiority for efficacy, the doravirine/islatravir group had no difference in weight gain, so any hope that a regimen that doesn’t have TAF and doesn’t have an integrase inhibitor would have less weight gain, that’s not seen. Two people in this group (2 out of the 269) got resistance to both doravirine and islatravir, and the doravirine resistance included the Y188L mutation, which is a very broad NNRTI-resistance mutation (trivia fans will know that’s the NNRTI mutation that’s seen in HIV-2), and islatravir selected for 184V, which shows that it’s probably not active against it in the dose used in this trial. There was one participant who developed DRESS, and NNRTIs can rarely cause hepatitis, so that clearly is a concern, and there were 3 hepatitis B acquisitions in the course of the trial. So even though doravirine/islatravir was just as effective as BIC/FTC/TAF, it had some limitations, and I don’t really know where this will play out in initial therapy. I think very few people are going to select it as first line treatment.

Eileen:
I have to agree with you that those results were not sending me to change people over to this future drug. But I’ll also just have the humility to say that when doravirine came out, I was like, “I don’t need that,” and I actually do like it. I like the lack of antacid restriction, no food requirement that rilpivirine was plagued with, and the fact that it’s available as a single drug. I’ve actually found I used it a lot more than I expected to, so I’ll suspend judgment, I think.

Paul:
I think doravirine is the best NNRTI. And I do still have some patients on rilpivirine-based regimens, and I wish that I could give them a single-pill regimen of TAF/FTC/doravirine rather than TAF/FTC/rilpivirine, but that’s not available. So I share your feelings about doravirine, and often the patients who have historical treatment failure with efavirenz or nevirapine can still be fully treated with doravirine. So that’s good, but I don’t think this particular combination is going to have much use as initial therapy. That’s all I’m saying.

Eileen:
Agree. So now that we’ve talked about treatment options now, some that are coming soon—the other aspect of CROI is a lot of research. So not necessarily applicable in the clinic right away, but the questions that patients might ask you in the clinic.

Paul, I just want to ask if anything about HIV cure stood out to you from this particular CROI.

Paul:
First I’m going to defer to you on progress because I’m kind of a novice when it comes to translational research. I shouldn’t even say novice—that implies I’m gonna learn. I can’t really judge this translational research the way you can, but I will say that there was one presentation that got me a little concerned, and it was this use of an immune-based therapy to advance the cure agenda (Abstract 140, Pires Dos Santos, AG., Immune-Mediated Viral Control With Budigalimab ± Trosunilimab: First Results of Phase II Global RCT) . It used dual immune modulation with drugs that are known in the cancer space (at least one of them). One is called budigalimab and one is trosunilimab.

And yes, it did show that it delayed viral rebound in some participants, but remember you’re giving someone an immune activating combination regimen, and if you activate someone’s immune system, you can trigger autoimmune disease. And indeed, one of the participants developed diabetic ketoacidosis and then was left with type 1 diabetes after the study ended—not a good adverse event to have.

There have been earlier studies of immune-based therapies using, I believe, PD-1 inhibitor (correct me if I’m wrong) that showed autoimmune outcomes. So, we have to be very careful. People with HIV on suppressive therapy are stable and they’re healthy, and if we do these interventions, we have to make sure we’re not harming them. It raises lots of challenging questions with the informed consent process in all of the cure trials.

What did you think, Eileen?

Eileen:
Paul, I think you’re highlighting a really important question, and there was, I would describe it as a tense exchange between a questioner and the presenter on this particular presentation [Abstract 140] where there was a disagreement almost in whether or not people living with HIV are healthy. One of the central questions of cure research is how much is worth the effort to eliminate treated HIV. I think there are many things that feed into that. There’s the biological inflammation, increased risk of cardiovascular disease, risk of onward transmission, stigma, which certainly has health consequences, all of those things in one bucket. Then in the other bucket is what would it mean to people taking stigma outside of the consequences of stress and just saying what would it mean to someone to say that they are cured of HIV.

I can give you compelling cases where curing HIV would be transformative for an individual, but I can also give you many where, you know, one pill once a day is not that heavy of a lift.

So, while that makes sense, and should be part of how we think about the relative risk benefit of any trial, we do have to push boundaries. We have to do better. We have to see a world where this is possible because I don’t believe that we’re going to be able to totally end this epidemic with just treatment. I don’t think we will be able to totally treat our way out of it. And there are people for whom cure would truly be revolutionary in their lives.

There was another pushback in a separate presentation about an analytic treatment interruption (Abstract 134, Edgar, J. Altered Viral Kinetics at ATI After Dual LS-bNAbs Plus ART: A Preliminary Analysis of RIO Arm B) and whether or not those should be occurring. Within the research field, we worry that if you don’t do one, you don’t have an arm to compare to, then people overinterpret effects in the intervention arm. What I would say as far as progress is, I think we’re getting better at characterizing a diversity of responses. Nothing to date has been successful in achieving something where you have a single statistical result in the way that ART is beautifully successful. But there are some things that have led to meaningful changes, and we’re starting to get better at trying to understand who that occurs in and to try to get at why it occurs. Now, whether or not that’ll lead to a generalizable solution, I’m not quite sure. But I think, as you know, a lot of discussion in terms of research funding and what we should do and how we should go, I feel more and more committed to the idea that we need to do discovery-based research in all fields of healthcare. We don’t know where we can go if we’re not looking. I think HIV cure research is one example of that, and I think looking at the history of HIV research and how far we’ve come, it shows how investment in a single process can open up doors that are applicable across many, different disciplines.

Paul:
You’re inspiring me to support cure research, which I already do. I just want to say that we’re going to have some missteps. One of the things that would be fascinating is if we had an intervention that had, say 20% of people who got it were cured, but there was a small but non-zero risk of a serious toxicity. Then you really go into it with informed consent, but right now, we’re actually not offering people anything except for participation and moving the science forward. So it’s a little different than if we actually had something that worked.

It might be worth mentioning one negative study because I think that people hear the highlights of a meeting and they say, “Oh, gosh, it’s nothing but progress,” but I think you can have progress with negative studies, too.

There’s been some controversy in our field for a while about whether the meningitis B vaccine prevents gonorrhea. We saw at this conference that it really doesn’t (Abstract 197, Seib, KL, Meningococcal B (4CMenB) Vaccination for the Prevention of Gonorrhea in Men Who Have Sex With Men). It was a randomized clinical trial in people at risk for gonorrhea based on their being on PrEP or with HIV and having a history of bacterial STIs. The incidence curves for gonorrhea in this study were perfectly overlap-able. So this takes the MenB vaccine out of the equation, I think, for prevention of gonorrhea. Not to say that it wasn’t worth doing the study. It was because it was still an open question. I’m just glad we finally know.

Eileen:
I agree. I had not gotten around to uptake of that when it was suggested to possibly be something. So, I feel good to just settle back to continuing to not remember to do that.

Paul, thank you so much for this amazing discussion.

I’ll highlight for all of our listeners that the CROI material will become publicly available towards the end of April, typically, and we’ll link to the website where you can find this, and then you can search for any of the abstracts that we talked about on that website and get more of the primary data as opposed to just our summary and interpretation. We’ll also link to any related guidelines or resources, so please do check the show notes for those links. And please join us again in 2 weeks when we’ll be discussing HIV-2.

But for today, thank you so much, Paul, for joining us.

Paul:
Thanks for having me, Eileen.

Eileen:
Please also remember to follow our show and to send us any comments or suggestions for future episodes at viremicpodcast@jh.edu

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