CROI Highlights 2025

You can now see the webbinar from CROI Highlights 2025 here.

This is a webinar discussing the highlights of the Conference on Retroviruses and Opportunistic Infections (CROI). The conference included discussion of the political situation in the United States and its impact on the treatment of HIV. Studies were presented on the efficacy of various drugs and treatment regimens for both treatment and prevention of HIV.

(this summary is AI generated and not proofread, scroll down for a full transcript of the webinar)

Speakers

Supported by an educational grant from ViiV Healthcare

Full transcript:

Magnus Gisslén: [00:00:00] So, good afternoon, uh, or good morning or good evening, depending on where you are in the world. So welcome to this year's post croy webinar that is as usual, organized by media. Uh, this year's CRO was special in many ways, uh, uh, and a lot of discussion both in the official program among colleagues touched on the concerning situation and the development in US and globally.

But as usual, there were also a lot of. Plenty of interesting studies presented. And today we have Laura Waters from London and Paul Sachs from Boston with us to walk through some of the key presentations. Uh, my name is Magnus ly and I'm an infectious disease physician and professor based in Gothenburg in Sweden.

And I'll be moderating this session. Uh, if you have, and I hope you have [00:01:00] questions or comments. So feel free to use the q and a function, and I will make sure that the question will be asked to the right person. Uh, if I understand correctly, the two of you, uh, Laura and Paul will be altering between the presentations.

And with that, let's get Sta started. I then begin with welcoming Paul Sachs to open the session. Please, Paul.

Paul Sax: Thanks. Thanks very much, Magnus. It's a, it's a always a. Privilege to be here. And I also wanna also thank, uh, media Huit and ViiV, uh, for making it possible. Uh, and a special thanks to my presenting partner, Dr.

Laura Waters. Uh, if she's not well known to you, she should be. She is a sense a, a, you know, sensational medical communicator and educator, uh, and HIV, uh, STI specialist in London. Um, I am going to start sharing my screen. Uh, you're gonna hear from both of us, uh, quite a [00:02:00] bit over the next, um, 120 minutes. It will be so exciting.

The time will fly by, I guarantee it. So let me go to my screen share function. And then I also wanna thank, uh, Dr. Waters or Laura, uh, for this, uh, special design that she dreamed up. Um, how would you describe it, Laura?

Laura Waters: I, I think it is, it is kind of broad sheet chic.

Paul Sax: Okay. Very good. Well, you'll notice that some of the slide, most of the slides have this format banner, headlines, statements, bold statements, uh, and you'll also, uh, notice that some of the boring slides like this one were designed by me.

Um, before we get started with the content of the program, uh, I wanted to actually just highlight something that was alluded to. Just now by, by Magnus. And that is, uh, here in the United States, we're in a very, uh, strange situation right now. Uh, our political leadership is actually, uh, antagonistic to [00:03:00] many of the principles that we hold very dear, uh, as people who care for those who have HIV.

Uh, and I wanted to reassure all of you that, um, the, the leaders of countries do not represent the entire country's population. Uh, that we are still enormously, uh, fond and respectful and desirous of ongoing good international collaborations, uh, and that we still are dedicated to care for people with HIV.

If you have access to the Croi website, I can strongly recommend Rebecca Denison's opening plenary. She described her experience of more than four decades of knowing that she has HIV. She describes the tremendous stigma she experienced as a woman with HIV, the tremendous excitement that she had with all of the research advances, and of course, uh, the great triumphs of her life, which include, uh, working, uh, for, uh, HIV, um, [00:04:00] having a family, uh, and having healthy children and being a strong supporter of those others who have HIVI don't know, uh, Laura, uh, or Magnus, whether you saw this, uh, opening plenary, but I thought it was extremely moving.

Yeah.

Laura Waters: It was Cynthia Outstanding. I, I, I'd never seen Rebecca speak before. Um, and it was, yeah, it was phenomenal in, in so many ways. And I think when the, when the sort of her, it panter her daughter. So she has two daughters, um, ne neither of whom has HIV and it was her daughter and the doctor who delivered her in the audience.

It was incredibly special.

Paul Sax: Yes, it was. Anyway, the title of her, of her talk says it all. Uh, and it was really inspirational. Okay. Um, these are our topics. Are you ready, Laura? I am ready. Okay. We're gonna start off with prep. This is one of the boring slides that I put together. Uh, [00:05:00] I do highlight the fact that we first learned that prep was effective 15 years ago.

Uh, this is the, of course, pivotal, uh, IPR study. Take it away, Laura.

Laura Waters: Right. Stuck. Oh, actually you first.

Paul Sax: Me. You

Laura Waters: over to you

Paul Sax: Paul. Alright, so I'm gonna talk about what probably the prep study that got the most attention. And that was this one. Uh, and I'm just gonna read the headline. Uh, I don't know if those of you are aware, but I do write this, uh, blog for the New England Journal of Medicine and I do really rapid review and the headlines are, are really adapted from that rapid review.

So to read two experimental formulations of Lenna Capr as Im injections, once yearly achieved levels sufficient for annual prep, you'll notice formulation, one given to 20 people, formulation, two given to 20 people, and then the PK curves with a vertical logarithmic scale compared with historical. Data from Lena Capr twice yearly subcutaneously.[00:06:00]

And you don't have to be a statistician to interpret this correctly. Yes, the levels are higher than that achieved with, uh, twice yearly injections. Um, safe and well tolerated, they say. But clearly there were injection site reactions that they said got better with treatment with ice. And I don't know how they know that since they're really only giving one injection and you're seeing just one year.

But I guess they gave second injections and very encouraging, no reported nodules. Uh, you can see down in the bottom figure, um, that the levels are higher than, uh, the twice yearly injections, uh, even including the ranges. Good questions at the bottom. I don't know. Uh, Laura, you wanna weigh in on is there a risk of accumulation and is it the best option for intermittent risk?

And by the way, we're gonna have conversation during this. Go ahead, Laura.

Laura Waters: So I, I mean, I'm no, I'm no pharmacokinetic expert. I think the, the first thing to pull out is when it's a [00:07:00] logarithmic scale on a graph. Those differences can look quite small. When you go to the bottom one, as you pointed out, those trough concentrations are way, way above what you see with the subcut twice yearly formulation that I'd say we are familiar with.

We still don't have UNE access to it in England, unfortunately. But that, that Cmax as well. I mean, again, considering that's a logarithmic scale, you're achieving much, much higher peak concentrations now. It was Doug Richmond, as I recall, who stood up in the audience at the end of the presentation and asked if there was a risk of accumulation.

Um, there was a sort of answer around, they're gonna do modeling to. Pick the best dose, et cetera, et cetera. But I think that would be the concern. And, and that second question around I is a very long acting drug. The best option, I think chatting to somebody at the conference who is a, a researcher and somebody who uses prep, they spoke about the fact that they wouldn't necessarily want a drug.

'cause who knows what the, the, the tale of this is gonna be. I mean, years, isn't it? [00:08:00] It's, what do you think?

Paul Sax: Well, I mean, I, I. Was both excited by this because you could initiate prep and then have protection for such a long time and not have to bring the person back in. But also, you know, understand the concerns, uh, that you mentioned.

The other, of course, is the drug interactions of Lenna Kavir and, um, they, they're, they're, they exist. It's not, they're not as bad as ritonavir or Cobicistat, but, but there's something to keep an eye on. Uh, and one thing that's, since we don't actually have Lenna Capr approved for prep yet, uh, and, and we've just treated a small number of people with Lenna Capr, we really don't have a sense, uh, yet of how clinically significant the drug error interactions will be.

Yeah.

Laura Waters: Yeah. And if there is a dose response, you know, we know that Ritonavir Max, you know, is maximal, um, C 3 0 4 inhibition at that 100 once daily dose. But how do we know that those massive c troughs, I mean, I know Lenner Capr is only a moderate C 3 0 4 inhibitor, but, but at that kind of dose, are we sure that it's not gonna be inhibiting more?

And I just don't [00:09:00] think we've seen the clinical data. Yeah, apparently there's modeling data and apparently there's a submission in to amend the FDA license around the drug interaction risk. But yeah, I, I certainly remain at least moderately concerned.

Paul Sax: Just should emphasize that this, this, uh, research presentation, there was a simultaneous publication in, in, in Lancet, uh, HIV, that that is worth, worth looking at.

The, the plan is to go forward with a phase three study, uh, right away. So there, it's going to be interesting to see the study design. All right, moving on.

Laura Waters: Right. So this is looking at when prep hasn't worked, and it's looking at outcomes in people who have been on Cabotegravir Prep. So a total of 47 men have sex with men and transgender women on the HBTN oh eight three study.

Who acquired HIV either during a trial or most frequently during the, um, I forgot what OE [00:10:00] stands for? The The Open Label Extension.

Paul Sax: Open Label Extension.

Laura Waters: I know you can tell I'm on holiday, can't you? My brain's ready. So what they showed is that overall pre people did pretty well. So they went onto treatment after they acquired HIV and mosted.

Well, 77% Vari suppressed after median of approaching a year. Perhaps not the best ever biologic suppression rates, but, but they seemed happy. I think the important thing is that a lot of people actually did well on an integrase inhibitor. So there was one person who went on to an integrase initially with integrase resistance.

The rest of them didn't. And there are a few who switched. But I think the message here isn't necessarily that you can assume that you can start an integrase based regimen if you do acquire HIV on or after. Cab prep, but it's certainly an option. So a, a significant proportion of people did d well on integrase.

I know certainly Paul, that the US guidance at the moment says, unless, unless you've got resistance [00:11:00] tests showing no integrase resistance, it's a scenario when you might wanna start a pi. And I think the only other thing to really pull out is probably explained by adherence is that the people who had more than six months between their last cab injection and starting antiretroviral therapy had lower viral suppression rates.

That kind of Yeah. Pattern of, of adherence. Of course, the integrators are all second generation. Again, we don't have access to this. So what, what are you seeing, Paul? So, you

Paul Sax: know, this is, this is a, a typical Tor de force presentation by, uh, my friend and colleague REI Ovitz, who. Really puts together beautiful slides with tons of data on them.

So again, I encourage, if you have access to the webcast, take a look. He's got all of all 47 HIV in infections, individually plotted out, uh, with the, with the, uh, proportion who have insti resistance versus don't have SD resistance. Who went on, uh, insti versus [00:12:00] went on something else. Usually boosted PIs.

But I think that the message is, we don't have a lot of data on this. Uh, I would feel comfortable if someone had. Prep failure on cabotegravir using an insti if they don't have insti resistance. I think that's kind of the message. One thing just to say is this is an incredibly rare phenomenon, so therefore I have never seen it in clinical practice.

In fact, it takes a, a large multicenter group to see it in clinical practice. Uh, Laura?

Laura Waters: Yes. So this was the other study on the same topic, the observational US cohort. And as you say, it's. Seven people who acquired HIV after, uh, long acting cab prep. Um, actually most of them. So six of the seven, um, was after on time injections and associated with good cab concentrations.

There was only one of the seven who had, no, sorry, six, they sequenced. One of the six had integr resistance on population sequence, but four out of [00:13:00] six by single genome sequencing. Now, I think what was really difficult is with the more modern drugs and modern classes of drugs, I don't think we're entirely confident about where that sort of threshold for reporting resistance should sit.

Certainly, most people say it's probably around about 5%. So single genome sequencing is probably picking up resistance at too lower level to be clinically important. But again, I don't think we really know. Um, but all virally suppressed all started based art initially very much in con in the line with the US guidance, but then three subsequently switched to, to integrase based art.

So yeah, pretty homeopathic numbers.

Paul Sax: Yes. Well, you know, I just, I just because there have been some prep failures in HPTN oh five two. It, it's gotten a lot of attention, but I gotta just say it is a rare phenomenon. Uh, so it's going to be sometime before we actually, um, have to really manage this. Uh, and I think it's reassuring that it's [00:14:00] such a rare phenomenon.

Um, so, so you mentioned you don't have access to Cabotegravir for prep? No. Do you have access? So do you have, uh, access solely to TDF ftc?

Laura Waters: TTC and also taf FTC where there are renal and bone indications. We can get CAB through compassionate access at the moment, but Nice. The body that makes these decisions.

I think in June they initially couldn't make a decision. I think it's really, really hard when you've got generic oral prep available to prove in what is a low incidence population overall. So I think more, more tweaking of the numbers needs to be done. But then even though you have access, the uptake's not huge, is it for you?

Paul Sax: No, no. The last estimate was that it was still less than 10%. It actually was less than 5%, but that was, those data are old, so I would, I would put the estimate somewhere of about. Five, uh, 5% or so of prep users in the United States are on injectable cabotegravir, and there really isn't [00:15:00] anyone, I don't think, unless there's an expanded access program for it, uh, on Lena Kavi yet.

You know, Lena Kavi for prep is probably going to be available mid this year in the USA. I don't know what the plans are for the UK or Sweden. Uh uh. Either one of you. Yeah. You, no, you don't know.

Magnus Gisslén: So, no. No. Okay. Probably not. I mean,

Paul Sax: yeah,

Magnus Gisslén: of course. Depending on the price, but it,

Paul Sax: yes, yes. Yeah. And we also have generic TDF ftc, and that has, uh, that's by far the most commonly used, uh, form of prep, but we also have a significant fraction on taf ftc.

Um, okay. Moving on to, uh, current a RT. I just wanna highlight this extraordinary figure that David Sata, uh, has generated. Um, he's a uni, he's a Miami based HIV ID doctor, and he put this together to simplify, uh, all of the various drugs that we use. [00:16:00] I like, I like to show this figure, uh, periodically to, to general internists who are thinking of getting back into HIVT treatment.

And I say, yeah. There's just a few of these that we use. But, but this is, this is why it's so complicated for them because this is a sort of blizzard of names and abbreviations and generics and brands and bri and co-formulation. And it really is quite brilliant. Um, I had someone actually, when I was showing off this figure, I was showing it off, even though it's not my figure.

I was showing it off to someone who, who has a design background and he, he looked at it and he goes, that's not simple at all. So,

Laura Waters: no, uh, no, I know you swore then. No, it is not absolute actually, if you put in the European names as well, 'cause some of those differ for us. They do. They do. Yeah.

Paul Sax: All right. Big biggest study of the conference.

Laura Waters: Yes. The biggest study that didn't get an oral presentation rumor is that it's 'cause Troy is a very scientific conference and this was just too damn [00:17:00] clinical. So what do we always moan about in HIV That we don't have enough data in People with advanced HIV and this study called a laptop showed that for initial therapy for people with advanced HIV better virologic outcomes were observed on Bictegravir FTC TAF than Daruna, Cobi FTC taf.

And I think it's that kind of PIs are there to really help out when everything's bad. You really want something you can rely on, could second generation Integrases do as well? And this study shows yes, in fact from a viral virologic perspective and also trends towards some of the clinical endpoints. So that comping composite clinical and virologic endpoint was superior for, uh, the Bictegravir based regimen.

So they did an incredible job. They got nearly 450 from people from seven countries randomized, and this spanned Covid as well. So I think it was an incredible achievement just in terms of enrolling and maintaining people on a clinical trial. And what we can see is that a [00:18:00] very low median CD four, just 41, so 86% of people wear CD four count below a hundred.

Hmm. 45% had a viral load above half a million. Now no surprises 'cause we know Integrases do suppress HIV faster, faster viral suppression, but also fewer virologic failures for Bictegravir versus Darunavir. So just over 13% versus 24%. And the rest was fairly similar CD four adverse events. So I think it was just the poster.

There was not as much detail perhaps as we're gonna see in a, a subsequent publication. But I do think there are some questions and I, I certainly thought that virologic failure rate is, is. Pretty high. I think you do see this and the homeopathic number of people in some of our more standard clinical trials who have the very high viral loads, actually the proportion who do well doesn't tend to be as, as high, although the numbers of course are tiny.

Um, but I think this would probably what be what you would expect. [00:19:00] To be honest, I think second generation industries, of course, are a fantastic, um, combination. And yeah, it was a great study, but didn't get an oral,

Paul Sax: well, you know, I felt bad, felt bad for the, the lead author and I contacted him and strongly advised him to submit this paper to.

A, a journal that I've very, very fond of, that I had, I had to wait until the slide number, what nine, uh, to mention it. So I, I, I said Dr. Baron's, CID would love to see this paper. Um, anyway, it's a very important trial because as you mentioned, enrolling people with advanced disease isn't easy. Uh, and the poor outcomes overall for viral electric failure can sort of be explained by the, uh, confluence of, of psychosocial factors that go into people being diagnosed with advanced HIV disease and, and that you typically leads to, uh, you know, situations of lower adherence.

Uh, [00:20:00] it'd be very interesting to see the resistance data when they ultimately can, can dig it out. Uh, so far there isn't any, which is great, and that's what you'd expect, uh, in, in a study like this. Um. It is worth mentioning that there is a similar trial, smaller, not, you know, called Dolce and Dolce compared, uh, triple therapy to dolutegravir lamivudine.

And actually the results were quite impressive. Uh, and I don't, I don't know, uh, have you done the cross study comparison? Uh, Laura?

Laura Waters: No. Jo, no, I haven't. Perhaps, perhaps when this gets accepted to CID you can ask me to write the editorial to accompany it and I'll do that. Harrison for you then,

Paul Sax: Bob?

Absolutely. We, we will, we'll invite you and we will pay you your normally huge honorarium writing such a thoughtful piece. So,

Laura Waters: and actually one thing with Dolce, 'cause the, the British HV Association guidelines are, are the ones [00:21:00] still still clinging, although I'm not sure if CD four is ever a, a criteria in the other sets of guidelines in that we don't recommend Doeg Lamivudine two drug therapy for people with a CD four count below 200 for first line.

Yeah. Because of that 48 week analysis from from the Gemini study. Yes. So Dolce may be the study that gets that. Criteria removed. Yeah. Guidelines don't say that.

Magnus Gisslén: Yeah, yeah, yeah. Uh, a short comment about the viral load sort of frequency here. We did a study a few years ago with a full Swedish and Danish population of HIV.

Looking at those with viral load, about 500,000. And after one year it was about 20% that were, they were not suppressed, but when continuing following, those were naive, people all got, or almost all got suppressed. I mean, it took longer period of time than one year for many. So I think some of those will probably get negative if you just wait.

Paul Sax: Yes. Yes. That's a very good point. Yep. Um. The other thing is, uh, [00:22:00] the, the other thing that's sort of somewhat surprising is this little, uh, you know, most of the point estimates are favoring BF taf, but this, this, this one over here, you know, SAEs and death, they're, they're on the other side. Just maybe by chance, uh, or you know, there still is this.

Clinical impression that the faster viral load reduction leads to more Iris, uh, and, uh, even though that was not born out in a study called a reality trial, it could, could be that if the comparator is a protease inhibitor, it actually does. 'cause remember the slowest of our antivirals in achieving virologic suppression are the PIs.

The reality trial of course compared TDF ftc, efavirenz plus Raltegravir versus tdf FTC Efavirenz. So, so it's possible that what we're seeing with these, uh, point estimates over here is, is more Iris, but there wasn't information on that, on this poster, 'cause you can't have it on a poster. But anyway, really important trial, [00:23:00] uh, credit to the investigators for a, being able to, to pull it off.

I remember when it first started, it started probably like a decade ago, or almost a decade ago. Yes.

Laura Waters: So, yeah, it certainly feels that long. Yes.

Paul Sax: Yeah. Although of course the period from 2020 to 2023 is sort of a blur.

Laura Waters: No, it's a blurry pause button. But yeah, they did remarkably well.

Paul Sax: Yeah. Good.

All right.

Laura Waters: Right. So, um, the, the, the study we nearly forgot to include Paul, isn't it? Because,

Paul Sax: well, because 'cause it's, it's, we've presented it before, but it's still a ma major clinical trial. True.

Laura Waters: I think we should certainly do, I mean, essentially if, you know, the 48 week results then, uh, you know, the nine, six week results.

So, but for, for skeptics like me, who, when. Perhaps there is a, for me, better than expected outcome at week 48. Uh, stubbornly waiting for the 96 weeks. And an [00:24:00] optimist will say, when did a study show worse results? At 96 weeks and at week 48 you go, well, just waiting, just checking. Anyway, um, suppress which study in Africa?

Injectable cab Rilpivirine versus continued oral art. People could be on, uh, TDF with F TC or three TC and a non or dolutegravir. Most people on dolutegravir. Um, they actually screened more than a thousand people to recruit 512. I think I missed that with a 48 week analysis. That's a pretty high, unless it was down to Hep B.

'cause everyone had to be hep B negative with no failure. Yeah,

Paul Sax: I think, I think some of it was prior virologic failure, uh, 'cause you know, or periods of treatment discontinuation also were exclusionary 'cause so. Yeah,

Laura Waters: that was. And so, uh, just a reminder, everyone, uh, nearly 60% of participants were female, as I said, already most on an integrase inhibitor.

Now there's a lot and lot and lot of discussion first time around and this time around about the resistance 'cause they did [00:25:00] archive provar, DNA. So this wasn't part of the entry criteria and there was no action undertaken based on the Provar DNA resistance test. But the proportion of people with rilpivirine or cab mutations is much smaller now than it was because it's now been cleaned up for those alphabet related mutations, which are definitely defined virus.

And the chances are much of what's been reported is probably still defunct virus. So I don't think this is advocating using this regimen in people with known resistance. But next build please. Um, it was a 97%, 97% injections on time, which as you'll see from some of the cohorts that come up is, is pretty astonishing.

And 97% in each arm thoroughly suppressed. Now, there were no confirmed virologic failures on all therapy. This for slightly, when you look across all the different clinical trials, 'cause typically you're looking at about 1% virologic failure rate on oral third generation Integr art compared to injectable cab Rilpivirine.[00:26:00]

But here, there were none on the oral. There were four confirmed virologic failures on long-acting. Two in each year. And of the three of the four where they were able to sequence a virus, there was dual class resistance. And this is, I dunno, there's anything new. There was a brilliant session on the very last day looking at integrase resistance and sequencing and, and KU from the University of Liverpool I think described it beautifully when he said that virologic failure on injectable cab rilpivirine is low incidence, but high consequence, which I thought was a really nice way of summarizing it.

So I think this is. Great. I mean the, the, the six monthly monitoring has generated lots of discussions about whether we should be monitoring everyone's six monthly for viral load. And as you can see, adverse events, not surprising, no differences really. And actually numerically fewer discontinuations from injectables.

And of course, we have to look at patient reported outcome measures, and that's increasingly standard now in clinical trials. And there was a significantly [00:27:00] greater increase in treatment satisfaction scores on injectables. So Paul, were you surprised by this data?

Paul Sax: Oh, no, no. It's, it's really what's been found was found in the randomized clinical trials that got this treatment approved.

Um, I, I guess I, I don't have much in the way of, uh, of footprint in, um, international, uh, HIV and, and maybe, uh, Magnuson comment, maybe Laura, you know, uh, but, but the, the, the sort of good outcomes from this treatment I think are still contrasted with the fact that this treatment is not available, uh, in the places where the study was conducted.

Uh, is that correct?

Laura Waters: I'm, I'm, as far as I understand that is correct. Magnus, do you know more. Uh,

Magnus Gisslén: no, I, I, I, I, I think you're right. I think that's

Paul Sax: correct. Yes. I mean, a lot of it has to do with the Rilpivirine, uh, which, uh, is of course a key component and I really don't think that [00:28:00] long-acting injectable rilpivirine that there's a sort of pathway to make that inject available, uh, globally.

Um, but may, maybe I'm wrong. Uh, I'd love to hear if any of the participants are aware of whether this treatment becomes available, because obviously we all are excited by this. This is, uh, um. This, this topic is the sort of currently the hottest topic in, uh, HIV treatment, uh, is long-acting injectable of various forms.

And this is the only one we have available to us. Um, so, uh, and then the other thing is, is, you know, low incidence, high consequence. This is the incidence that typically see, uh, this, uh, integrase resistance. It's on, on the order of about one 1% or lower, uh, in cohorts, speaking cohorts. I'm just

Magnus Gisslén: one question.

Uh, there's a question from, from Tristan Barber, uh, for, for all lower, and that is, do you think this study has any sort of impact on the guidelines in Europe and or us, I mean, for vulnerable people, [00:29:00] or do you, what do you think?

Laura Waters: Well, I, I, I think the, this, this particular trial design, I think where people were very well supported to attend, um, I'm, I'm not sure, and I don't know, they haven't described my knowledge, the sort of, some of the classic vulnerability characteristics that have been very well described in some of the cohorts we move on to next.

So I don't think it necessarily addresses that because I'm not sure that this or that any clinical trial truly replicates. Real life care in, in many, if any, settings. So I think not, and I think one of the big questions, um, certainly 'cause I think the, again, the beaver guidance, um, in all our pedantic evidence-based, um, obsession with what's been demonstrated.

We do say that VIR should be checked at, at every injection visit because that's what the registrational studies did. I don't think any other guidelines spec as quite so specific in terms of, of frequency of viral load monitoring. I think this, it probably reassures us that, that less frequent viral load monitoring, although that's not the [00:30:00] big barrier, cer certainly for, in our clinic, the, the barrier is the frequency of visits.

Is the biggest reason followed by, uh, two Im injections. I can't think I've had anyone actually say yes, yes, yes. And then find out that we recommend viral loads every visit and then say no. I think pragmatically you probably could monitor less often, probably particularly after the first year. I think it's hard to pull out trends when numbers of virologic failure events are so tiny.

So, um, yes, Paul, how often do you check viral load?

Paul Sax: Every alt we alternate every, every four months. We have it built into our, into our order set that, that we, every o other injection session, we check viral load,

Laura Waters: which I think is reasonable.

Paul Sax: Yeah. Now, now, um, uh, you know, back to Tristan's, uh, question. This population actually is, is for the setting in which this was done, uh, I would say not a very vulnerable population.

'cause they had no history of virologic failure. Uh, so they were, [00:31:00] they were carefully screened. But you'll, you're gonna come to some real world evidence, aren't you?

Laura Waters: And as if by magic. Here we go. So, um, oh God, let's up the operas a bit higher than the others. So lots of sort of real world studies and cohorts.

Um, these are the main three. So there were two posters from the opera cohorts. So first was overall description of outcomes on cab Rilpivirine. So more than 2,600 people, medium follow up, 11 months. Paul, you know, my feeling about reporting data, and it's less than 12 months of follow up, but medium, 11 months, um, 38% didn't have all their injections on time.

You compare that to just 3% of people who didn't have on time injections in, um, cares. But 95%, uh, suppressed at last far load. Just to point out, sorry, it was something I pulled from the poster. That is possible. Some of those, or maybe even all of those. Not on time. Injections were accompanied by appropriate oral bridging.

They weren't able to [00:32:00] assess whether people had oral bridging or not, so it might not be as bad as it sounds. Um, and as Paul's already said, that very consistent real world virologic failure rate of, uh, 1% confirmed virologic failures. The other analysis was just looking at women. So 381 women just over a year's.

Follow up here, 37%, at least one delayed, 12%, at least one missed injection. Yet again, 94% with follow up, viral load or undetectable, 2% confirmed viral acute failure. No report, no resistance wasn't reported in these two posters. I just wanna pull out that where they had follow-up viral load. So women without follow-up viral load, and I assume the same is true, the other poster weren't included.

So there is a possibility of course, and it was a small proportion, a possibility that those without that follow-up viral load were perfectly fine and suppressed. But it's possible that they weren't. And now this is the nature of cohort studies. I think there is gonna be missing data. Yeah. And I think being realistic [00:33:00] about how we interpret it, but overall, I think it looks good, doesn't it?

Paul Sax: Yeah. Yeah.

Laura Waters: But the second one was so much better. Of course. Um, because the first author was Sax P. So this is actually, Paul, why don't you present this? 'cause this is your data and it would be, yeah, I'll

Paul Sax: present. I'm happy to present it. I'm just gonna say that, that this, this was a very amusing moment at Croix this year.

And I'm standing in the poster hall near this poster, uh, which of course was assembled through the trio cohort. And uh, I'm standing next to Laura, who is basically telling me that it's total rubbish and never should have been accepted.

Laura Waters: And then I said,

Paul Sax: I said yes, I, you know, it's got limitations, you know, there's, it's short follow up.

But, you know, one of the, one of the good things about studies like this is that it compliments clinical trials. Uh, and then I said, and you know, [00:34:00] another good thing about it is that I'm one of the authors of the pastor, which of course. Never let it be said that Laura Waters is shy about expressing her opinion.

I, I do wanna say one thing though that is, is actually nice about the TRIO cohort is that, uh, unlike some cohorts, we have access to dispensing data. So, you know, some, some studies, they, they actually will assign someone a treatment that they never actually received. Uh, and, and that's not the case. Uh, the other thing is that we had gen genotype data before people actually started this treatment, which is shown at the bottom of this, which as you could see, that, that there were some people who started this treatment who had resistance to integrase inhibitors.

They, they were interestingly did not fail treatment. But this does not mean we recommend this for people who have integrase resistance. We do not recommend this for people who have integrase resistance. And 19% had resistance to more than one N-N-R-T-I, including several who had resistance to Rilpivirine.

I think what that tells you is that [00:35:00] in the real world, there's a kind of, some people are maybe not. Quite up to speed with, uh, recommendations or understand, uh, that they should not be prescribing cab rilpivirine to people who have resistance to either drug. Uh, and our results on treatment. Failure and resistance, were actually very consistent with others.

1.6% confirm virologic failure. Um, not everybody got a genotype. It's actually up to eight. We have now eight genotypes. After that virologic failure. Uh, two of them had rilpivirine resistance and one had rilpivirine and cabotegravir resistance. So, you know, if you're doing the math, uh, the, the incidences of detected cabotegravir resistance in this group of, you know, 1,198 people was, uh, less than 1%.

So that's encouraging. Back to you, Laura, for saying, oh, yes, yes.

Laura Waters: Put put it, put it, put it to you in this note. I mean, it's, it's, I it was a knee jerk reaction when I read the poster properly. I realized like laptop, it probably should have had an oral [00:36:00] presentation.

Paul Sax: No, no, no.

Laura Waters: On a serious note, I know I'm splitting hairs.

The numbers are tiny, but could we argue because not everybody who had a confirmed virologic failure, who had a resistance test, had resistance mutations. So three of your five and three of eight. Three of eight did three of eight had resistance. Rest did not. Could we argue that compared to cares were a hundred percent of the three people I know I'm sitting here a hundred percent of the three people who had dual class, that you've got less resistance because you're monitoring viral load more frequently in the us.

Paul Sax: Yeah. Interesting. That's a, a kind of a, a novel way of looking at it, perhaps. Perhaps so.

Laura Waters: It's impossible to say isn't right. And the third of the three, oh,

Paul Sax: sorry. Yeah, I just wanna say why I, can I just Before you do San Diego, why I chose IT Fund? Yes. 'cause I, San Diego, you know, I, I'm speaking as very US perspective.

When, when Cab Rilpivirine launched, it was still kind of in the [00:37:00] Covid era and it was very, very hard to get this started because people were still kind of afraid to come in. And, and I just wanna say that San Diego, the large HIV program at UCSD really led the way in many ways in our country and had one of the largest groups to, to adopt this treatment early on, very enthusiastically.

So, you know, it's, it's impressive to have 465 people from one center on. Caine, I don't know what your centers are in terms of numbers, but we would, we're nowhere near this many at our hospital.

Laura Waters: I, I think e even, I mean the, the, the biggest center by far in the UK is Chelsea and Westminster, and I don't think they've got anywhere near these numbers.

Yeah. Um, we, we certainly haven't, we've got a cohort of about, across two sites, just over five, no, about 5,400 people. Yeah. And I think we've probably got [00:38:00] about 40 people in total. Yeah.

Paul Sax: I mean, that, that's a much, much more typical, our, ours is, uh, percentage wise, a little higher, but we have about a, that same number of, of people on capital Prine.

Okay.

Laura Waters: So, um, this was, yeah, I think in, in a way it was like the treatment version of the, the analysis I showed looking at treatment outcomes after cab prep, that whole kind of fear about what happens next. And again, it's pretty reassuring. So of the 92 people who stopped, which is approaching, well, 20% of the cohort, most of.

Virally suppressed, most of them switched to oral entities. Uh, it seems to be mainly as three drug regimens and actually three quarters switched back to the regimen they were on. 'cause part of the counseling we undertake, what we're talking about injectables is you may not be able to go back to what you're switching off 'cause you may have developed resistance, et cetera.

But actually most people here went back to what they were on before. Again, and I think, I know I'm laboring the point a bit, but again, we need to think of these as, as on treatment analysis really because the [00:39:00] suppression rates are only being, uh, reported for people who had follow up viral loads and just again, don't know what the outcome for the missing maths is.

Terrible. 18 was here thought. Of those who have viral loads checked, you can see most people are virally suppressed, um, and doing well. So again, I don't think this is saying that if you stop cab rilpivirine, you can definitely go to an integrase. But it's saying actually many people clearly can, again, these were slightly different to people who've been on a failing injectable regimen.

'cause most were suppressed at cessation. I don't think any of us would avoid an integr just because somebody came off, uh, injectable regimen with an undetectable viral load. Right. But yet good numbers and good outcomes.

Paul Sax: Yeah. Yeah. And also I think this is a much better assessment of the persistence than, than the clinical trials.

'cause the clinical trials, there's self-selected for people who wanna be in the trial. They also get a, a financial compensation for participation. [00:40:00] They get the support of the clinical trial. I would, this, this 80% persistence is pretty, it's pretty. Pretty solid. Don't you think that's kind of what you're seeing across cohorts?

Good. Yeah.

Laura Waters: No, no, I think it's, no, I think it's good.

Paul Sax: Okay. You have one other point to make.

Laura Waters: What point have I got to make? Oh, so this is just to point out, 'cause one thing we've seen pretty consistent results by subgroups in clinical trials. And just to say that opera presented this, uh, analysis as a nice forest plot, I do love a forest plot.

Um. Now it is been, so it's a factor in the multifactorial analysis, but actually on its own has very little effect and there are cohorts showing it has no effect. That's BMI and I don't think anyone thinks BMI is as important as some of the other factors which got pulled out of the multifactorial analysis of the clinical trials alongside, um, archive non-New resistance and subtype.

A six actually as a side. Um, a one actually was the dominant subtype in the hair study. I forgot to pull that out. [00:41:00] So at a moment, license still says subtype A one six. And they've been grouped together for virologic reasons, but actually a one doing pretty well. But just to point out there were clear, um, sort of ethnicity differences here.

So, uh, people report as being of black race. It's not statistically significant, but again, a bit like the, uh, adverse event signal, um, in the laptop study. It's definitely erring towards that side. Now this may not be surprising 'cause it's a cohort and it's simply describing. You know, inequitable outcomes that we know affect people.

Anyway, I'm not sure, but it was interesting to see 'cause most of the cohorts I've seen so far haven't reported it this way.

Paul Sax: And you have one additional point to make.

Laura Waters: What do I got to make? Oh God. I do like a bill, don't I? Cautionary numbers? Yes. So it is just that the, the opera poster focused on women.

It was a little bit all over the shop with the numbers. So they described 432 women initiating injectables. [00:42:00] 415 was suppressed at the time. We've got the demographic data for them, but only 381 completed initiation, which I assume is the first two injections. And again, it's just, just me being a bit pedantic and just, I'm sure you all do anyway.

But when you're looking at posts, all these presentations do, do look out for these sorts of things. 'cause it's sometimes the lessons are in what's missing. What's being presented.

Paul Sax: Yeah, good point. And, and, and exactly the sort of cogent and, uh, deep analysis we'd expect from you at this point. All right. Uh, I'm gonna discuss this.

I'm gonna discuss this poster. This, this is one of those posters that I think the figure kind of tells it all, but, but, uh, just to, to, to highlight the title. Uh, detailed analysis of CAB and Rilpivirine drug level is found in association between lower concentrations in detectable viral loads, greater than 20 copies per ml.

Uh. We don't measure drug levels in the United States at all. Uh, and yet here is this [00:43:00] study from, uh, I believe it was from France. Um, oops, I'm, I should know the country ahead of time, but I know it was in Europe. 350 samples from 165 people with HIV who were on cab rilpivirine. And the figure tells it all.

I mean, look at this, the people who are less than 20, the levels, the median levels of Cabotegravir are there, whereas greater than 20, they're there. And that is statistically significant. If we look at Rilpivirine, by the way, that is from the poster. It's not my spelling. Uh, you'll notice the same thing is found.

Uh, I mean, you know, this is a, a, a, a really quite remarkable dot plot. Uh, and, uh, I would say that this is, uh. Of interest to us, um, because there are some people who have virologic failure despite on time injections. So it says in the conclusion, unclear if this observed association is associated with true virologic failure [00:44:00] and the findings were in further study.

And I, I would agree with that. Is did, isn't this figure impressive, these figures, Laura?

Laura Waters: Mm, it is. It is. And again, I, I'm not sure necessarily where the work was done, but Sebastian, who's the, the leading center is, um, based in Germany as far as,

Paul Sax: okay, then I take it back. It was not France, it was Germany.

Laura Waters: Be working in France.

Who knows?

Paul Sax: Okay. But um,

Laura Waters: yeah, it is, I think it is, there's kind of a message that came out of getting that multifactorial analysis that that drug concentrations don't matter. Although whether BMI is a sur surrogate for lower cab concentrations, but certainly Rilpivirine concentrations didn't seem to come out.

But there was some data from France as well. I think at one of the conferences last year, not presented quite like this, but a similar message that it's a lower drug exposure that's associated and it would make sense 'cause it's what we know for therapy as well. So Interesting. But again, we do have access, well, not actually, that's not true.

Many centers have access to therapeutic drug monitoring, but it's very infrequently undertaken 'cause it's so hard to interpret unless it's being done in a very [00:45:00] controlled way. Yeah,

Paul Sax: yeah, yeah. No, but it, it would be great to know the predictors of these lower concentrations in order maybe you could intervene in some way or switch people back to oral or whatever, just to prevent these very rare cases.

Okay. Onto, uh, a next study, which is yours, Laura. And it is I think, a very important one.

Laura Waters: Yes. So this is again looking at in long acting art outcomes. It's not just Cab Rilpivirine, although actually 70% of the 361 people they described did start Cab Rilpivirine alone. Most of the rest got Cab Rilpivirine and Lenna Kavir and a tiny number got Cab Rilpivirine, Lena Cap and ibi.

I I, I mean that would clearly be a complex and also in incredibly expensive regimen. So 360 1 people started long acting and 81 of them I. Had a detectable viral [00:46:00] load at long-acting regimen initiation. So they described the people. So most were black, almost half had an opportunistic infection, mostly esophageal candidiasis and uh, pneumocystis 72% had unmet transportation need 51% food insecurity.

And that should say 30 something. I apologize for double percentage sign, but round about a third were high risk for housing insecurity. So this is exactly the type of vulnerable population, um, that Tristan and Barbara mentioned in his question. So, and you look at the 81 people who had a detectable viral load follow up, two had been lost to follow up.

Sorry, the 81 people were detectable at baseline, getting myself mixed up now. Yeah, there, 81 people two were lost to follow up, but 73 of 79 were undetectable after a median of just one to two injections. And it's just. Phenomenal. And I mean, this is sections on time. [00:47:00] Just incredible, isn't it?

Paul Sax: This is amazing.

Laura Waters: Truly, truly amazing.

Paul Sax: Yeah, I mean, so just to, to interject, uh, something that maybe people are aware of. You know, I, I called out San Diego before, but now I'm gonna call out this particular HIV program in Atlanta, uh, which is at Grady Hospital. Um, this is the, the, the, in some ways the, the most challenging patient population we have in the United States.

A, a very, um, very challenged urban poor population that don't access healthcare very often because they can't, uh, and there is, you know, this is exactly what you would predict long-acting injectables could do. And I, I have to say, uh, Jonathan Kanti, he's a wonderful HIV ID doctor. He, uh, he. He, he was had a, a, a, the title of this poster was a tool to end the HIV epidemic.

'cause. 'cause really it is, it is the people who are most challenging [00:48:00] to treat, who are gonna sustain the HIV epidemic. And wow. To get 92% suppression, uh, in, in Atlanta, uh, in this population is amazing. All right, so stop. I'll stop interrupting.

Laura Waters: No, no, no. Not at all. It's, it, it is truly incredible. And here again, so six people who didn't achieve fire suppression.

Two, uh, considered virologic failure with resistance. Two had persistent level viremia. And this is interesting 'cause Chloe Orkin, uh, a good friend and a fantastic colleague, um, and, and the real advocate. She's been doing some work, a a bit of a Delphi process looking at people's definitions and trial definitions of, of virologic failure for the injectable studies and whether we're applying a sort of higher standard to injectables and to oral therapy.

So I think it's fair to say there are some services that wouldn't consider, um, you know, as long as a VIR is below 200, they'd be happy. What's really interesting, I'd love to know more about the two people with pretty good going [00:49:00] viremia, but no resistance and an immunological response. How would you explain those, Paul?

Paul Sax: Yeah, they're, they're, they're unusual. Uh, and I am. Worried that they will develop resistance. 'cause as we know, there's this dose response between low level viremia and risk of resistance that that actually appears across multiple different studies. So, but I, I go back to the, the baseline characteristics where these people had opportunistic infections and low CD four.

And my guess is that these clinicians would not have tried Cab Rilpivirine in this population unless they really had done everything they could to get people, uh. On oral therapy first. So anyway, good, good news for this one. It's another, another, another. Originally, of course, we have to cite, uh, ward 86 from San Francisco with the, the first group.

But this is, this is a little bit of update from them.

Laura Waters: Yes. So, yeah, of course. Um, Monica [00:50:00] Gand and her team and, and really started this conversation and sharing the data and, and, and, and pushing the boundaries when it comes to use of this regimen. So they described outcomes for 370 people. And again, this is a similarly vulnerable population who you may predict wouldn't do particularly well.

In the real world, but they looked at week 24 viral suppression rates. So again, caveat is relatively short follow up, but those viral suppression rates are phenomenal regardless of whether people virally suppressed or not. So 94% of virally suppressed people remain suppressed. 95% of those who weren't suppressed at initiation were suppressed at month six.

So again, really high rates. There was another poster, small numbers, I think only 20 were on injectables, but it was a population of people experiencing homelessness and they saw better viral suppression and better attendance on injectables with or without Len Plus. Versus oral. So the oral therapy didn't.

Well, and again, Paul, I think [00:51:00] emphasizing what you've just said, that this is a population who don't do well, but can do incredibly well on what I think has been labeled a bit of a, a vulnerable regimen in a way that actually works incredibly well for these people.

Paul Sax: Yes. Yes. We, we, we, meaning the modeling group that I work with, uh, published a study, uh, projecting the benefits of long-acting injectable before it was even available.

And, uh, this, this modeling study found perhaps not surprisingly, that the benefits were greatest in a population like this. And that's because, you know, in populations that this drug was FDA approved for. They don't really need it. Yep. 'cause they're suppressed and doing well and have no resistance by contrast.

This population is very, very needy. So I'm, uh, I'm, I'm glad to see these data are now getting out there. I don't know what your ability to use this in the UK and Europe is. We, we are doing it off-label. Uh, but [00:52:00] we can do it. Nope. That, that signal means.

Laura Waters: No, that me, uh, no. We, we can, if the clinic pays for it and most clinics just simply don't have the,

Paul Sax: I got it.

Laura Waters: Budgetary headroom is a phrase N hs England news, which just so it won't get reimbursed unless it's prescribed unlicensed. Now we've drafted a policy to use it in people who have, uh, detectable viral loads. But the NHS is going through a bit of a, a downs downturn and a new restructure again. Uh, so all of those policy approval processes are on hold.

So at the moment, no, we can't. And it's actually, I've actually, the, what, the analysis you've just mentioned, Paul, I've included that in some presentations and the irony that the people where it will be most beneficial are the people who are excluded. I will say though, in defense of England and its pedantic prescribing policies is it's based on the license.

And perhaps if. Pharma companies in parallel. I understand why the clinical trials are [00:53:00] so carefully controlled, but to be able to generate some of this data in parallel rather than waiting for them to be licensed and then getting the data in complex populations. I always like the idea of having a parallel cohort of people who were screened as ineligible for a study.

Paul Sax: Yeah.

Laura Waters: Just to generate this sort of data sooner and, and have some kind of caveat in the licenses that's a little less rigid.

Paul Sax: Yeah. No, I think, I think that's, that's true. I, I, I, to give credit to, to the makers of Cab Piering, they are doing a study now. Yes. Uh, it's not an easy study to do, um, for a variety of reasons, but such this study is ongoing and enrolling, I hope it's enrolling, uh, maybe, maybe it's enrolling also in, uh, in, in England.

Laura Waters: Oh. To be honest, no. I, I not, I'm not involved if it is, but,

Paul Sax: okay. Alright. All right. Switching to a different topic. Uh, I, every, there's a. Poster or a study that I really scratch my head [00:54:00] on over, and this was the, this is the winner of this head scratcher award. And it, it, that the headline says it all, for those experiencing low-level viremia, between 50 and 199, virologic suppression was more likely and those who switched therapy versus those who did not and is an Italian cohort of 4 51 people and they had.

More, one or more episodes of low level viremia. Uh, and then they compared the outcomes of those who switched treatment versus those who didn't. And those curves look like it's a no-brainer. You know, switching must be better. Uh, but I actually caution people to, uh, take a very careful look at the baseline characteristics because the people who switched really did differ significantly from the people who didn't in many ways.

Now granted, you can adjust for some of these in multi-variable analysis, but that probably means that the groups are very, very different. And they are different. And then the other things, some [00:55:00] of the things I mentioned, things like, you know, switching from a protease inhibitor, which is associated with more low level viremia to an integrase inhibitor was not specifically looked at.

Also, if people switch because of baseline toxicity, um, all kinds of reasons might explain this. I want to also emphasize strongly that in studies of intensification for low level viremia, nothing happens. And that has actually been my clinical experience. If you have someone whose viral load is between 50 and 200 and they are taking their medications faithfully, switching their treatment.

Does nothing. Uh, now if that is not your experience, Magnus and Laura, please share with me. 'cause I wanna know what you, what magic you're doing to bring this

Magnus Gisslén: up. I, yeah, I fully agree on that, but I think in those core it's, as you say, it's different type of patients and some others that are not adherent.

And then there is a difference. I mean, then you maybe can do something, but those that are inherent, then we have [00:56:00] definitely the same experience that you have. Yeah,

Laura Waters: yeah. No, I agree. We, we don't, I mean, again, the, the only situation is where somebody reporting good adherence on a more than one pill regimen who switches to a single pill, then sometimes does better.

So again, that, yeah, because what I, the other perplexing thing with that study is I couldn't understand why that hazard ratio was even greater for the, if you're on a high barrier regimen, it didn't make, you know. It just doesn't, it just goes the opposite of what we'd expect.

Paul Sax: I, I, I totally agree. Anyway, I, I, I scratched my head and looked at it and I, I was standing next to Joe Eron when we were looking at it, and, you know, he's, he is, as I've mentioned before, one of the smartest pers people in our field, and he couldn't understand it either.

So it made me feel better, made me feel better.

Laura Waters: No hope for the rest of us.

Paul Sax: Alright, another complicated topic.

Laura Waters: Oh, yes. So resistance mechanisms actually, [00:57:00] literally scratching my head at this. So the key thing here for, for, for the clinicians, any virologists who are listening to this, I apologize profusely for anything you're about to hear, but essentially this exploration of whether mutations outside the sequences we normally look at.

So the integrase sequence for integrative resistance, the protease sequence for protease resistance. When you have people who have detectable viral loads but report good adherence and you're not finding any resistance in your standard resistance assays, is it because of changes in the virus outside of what we normally look at and the way some of this isn't new?

Many, many years ago, uh, a colleague of mine who's gone on to do phenomenally well, professor Ravi Gupta, um, who's now based in Cambridge, looked at n mutations explaining resistance to protease inhibitors, and that was presented at a British HIV association conference, uh, many, many, many years ago. [00:58:00] So what about integrase is considering, that's the drug class we're using the most now we know from a number of papers, but also presented.

Two CRO ago is that n mutations tend to appear before standard integrase sequence mutations and can confer high level resistance. And the way that N mutations work is that they increase infection ies. So the amount of sort of virus getting into the cell just overwhelms the integrase inhibitors as as a drug group.

So what we saw this year is looking at nuclear capsid, which is derived from the gag protein, and basically showed in two papers that nuclear capsid mutations. Can confer resistance. So there's one study that was looking at it specifically in vitro and basically creating these mutations and then showing that they do confer resistance.

And then the other study, the one summarized on the right, is taking [00:59:00] people from an observational cohort using TLD, tenofovir, lamivudine dolutegravir first, second, and third line. And they did whole genome sequencing on 57 sample pairs. They could look at emergent mutations. You got your in vitro study showing nuclear captive mutations.

Do confer, lot of susceptibility, integrases, and then a real world study showing that people who experience virologic failure on dolutegravir based regimens, you see emergent mutations in the nucleo capsid sequence, and then when you do phenotypic testing, they confer sort of moderate resistance to integrases.

So yeah, nucleocapsid not anything that any of us can measure in the real world at the moment, but it's an explanation for some of those perplexing clinical scenarios where you are seeing virologic failure, this point. No detectable resistance. Yeah, I, I,

Paul Sax: I thought it was an interesting presentation and sort of, it, to me, it, it seemed like this is on the pathway [01:00:00] to clinically important resistance.

Not that this alone gives clinically important resistance, but it's on the pathway. Uh, and that, that in fact, you know, you would, you would need eventually to add real integrase mutations. To, to see treatment failure. But, but nonetheless, I thought it was very, very interesting and, and sort of gives us the, the, the, the potential future of what's going to be seen, especially globally, because as I've, as everyone knows, over 20 million people are on dolutegravir.

Uh, it's just an astounding number.

Magnus Gisslén: Were there any sort of information or discussion about if there were differences between different subtypes when it comes to them,

Laura Waters: that that wasn't included? Not that I, I was at both of these presentations and I didn't see any discussion about subtypes.

Paul Sax: I didn't either.

Hmm. Okay. Good question. Good. So, so we are perfectly on time. Brilliant. [01:01:00] Isn't that amazing? Yes. And so we're going to our next section, and it's called Future Art. And you'll notice the graphic. The graphic, uh, I am driving home from dinner. Uh, and there is no driver, uh, because it is the future, and the future is being represented by Waymo.

And I don't know if either of you had a chance to ride in a Waymo, but it is quite an astounding experience.

Laura Waters: It really, really is. And actually bizarrely, I found, you know, being in one was of course strange, but seeing them from the outside was even stranger because of these huge, great things on top and all the cameras over them.

Paul Sax: Lidar,

Laura Waters: quite sinister.

Paul Sax: Yeah. I, I, I, I have to admit, admit my. Waymo ride was proceeded by an Uber ride where the man who was driving my Uber had, uh, decorated his car with actually witchcraft, um, uh, [01:02:00] s symbols and was playing very loud string quartet music in a minor key.

Laura Waters: Oh my God.

Paul Sax: It was truly bizarre. And also, I should say he didn't smell so great.

So, so the Waymo was, was a tremendous relief that

Laura Waters: that was, we had that discussion in our cab that it saves those awkward conversations on the way to or from a restaurant, but yes, it, so, but ours did get stuck. So ours actually a third, third journey. Uh, it was trying to turn left, but there were roadworks, an actual human being with a human stop sign, and basically the Waymo went into some kind of existential crisis and we had to just abandon it.

So yeah, they have their faults. They're not perfect. Okay. Future art. Right. Be abs. Be abs. My favorite topic broadly neutralizing antibodies. So these are studies really exploring broadly neutralizing antibodies as replacements for antiretrovirals. And people who know more [01:03:00] about bean nabs than I do, which is a lot of people think that really where the, the future of bean a lie is prevention and cure strategies.

But they are being pursued because there are no drugs. So if you look one of the ones combining Be abs with Len, there are no. Antiretrovirals at the moment that can be given at similar dosing frequency. So let's start with that first one. Lenna, Kavir, umab and Zumab or Len, tab and Zab. So we already saw presented last year and then published in The Lancet by Joe Aaron, wasn't it Paul?

Your um, cleverest man in the world. The 18 outta 20 people who are fully susceptible to both the BE NS 18 OUTTA 20 people maintain viral suppression after just a single IV infusion of the Be Ns and a single Len. So at Croix we saw a phase two randomized study in virally suppressed Be NAB susceptible people.

[01:04:00] So again, these were people who are susceptible and when you look at some of the data, a lot of people aren't susceptible, but people either randomized to stay on their oral art or switch to Ltab app. Two to one to one. So you had 27 people, sorry, two to 1, 27 people staying on their oral art and 53 people switching to the LEN and BNA regimen.

So week 90, sorry, no, week 24. Week 26. But basically after one administration of these drugs, 96% maintained viral suppression. And there was one confirmed virologic failure who had low len concentrations at week 12, which is clearly of interest and slight concern. And they also had loss of zab susceptibility.

So quite why we saw those PK curves and for the six monthly, uh, len in the prep data that Paul showed us. So low Len exposure at week 12 and some Len resistance and loss of zab susceptibility. But overall looking pretty good. [01:05:00]

Paul Sax: Good. But, but not, not, not very practical, right? Yeah.

Laura Waters: No, and I can't, and again, the, the tester, from what I understand, the testing isn't easy, it's expensive.

A lot of people aren't susceptible. And I just, and I think it's scientifically interesting, but clinically not relevant

Paul Sax: is my what And what about this study?

Laura Waters: Yes. So, sorry, I did slightly weird build. So embrace, so we'd seen data for N six Ls, so it's a single be a, but it's got sort of double action. So it's like more than one be a in one highly technical description there.

So 125 people, and this was a two to two to one randomization. So some people stayed on their oral art, others switched to N six Ls given every four months with monthly cab. And then of those two, that combination in one [01:06:00] arm, it was IV administration of N six Ls, and the other it was subcut. So you've got continued oral versus IV N six Ls plus CAB or subcut N six Ls plus cab, and again, four monthly of the BN and monthly of cab.

So what do we see overall? I mean this number's again, relatively small, but overall again at month six after one administration, oh no, it'd be two administrations now how many administration is where the numbers start freaking me out. But anyway, month six. You are seeing maintain viral suppression in most people.

Again, the trouble is you look at that middle arm for the uh, viral suppression rate, the dark blue, which is the subcut N six LS plus cab. It only takes, you know, a couple of extra virologic failures for it to look much worse 'cause you sample size is small. But there were two confirmed virologic failures in each of the be a arms.

None in the continued oral therapy. All repressed on standard of care. [01:07:00] One in the subcut arm had some ingra resistance. There was no be a loss of susceptibility. Again, tiny numbers, but the IV was better tolerated. And so they're moving forwards with IV dosing of a six monthly formulation combined with CAB of who knows what frequency for the next phase.

So again. Scientifically interesting. Clinically, probably not very practical. And I did ask the question at the microphone, why did they go with Monthly Cab? Because I have long had this little niggle that Monthly Cab Rilpivirine does ever so slightly better than every two months. It's not statistically significant, but numerically you saw fewer virologic failures with monthly than two monthly.

So being a bit of a pain in the backside, I asked, do you not have as much confidence in two monthly and that's why you chose monthly. Um, which, which wasn't, you know, they, they said there, but yes, it's monthly camp. So what

Paul Sax: I mean, I continue to be amazed that every single BN [01:08:00] study we see has a failure despite this extremely high tech susceptibility test done ahead of time showing that they have susceptibility to the B-N-A-B-I.

To me that is a, a achilles heel of these baps. Is that test? I don't know. I don't, I really don't know how we're going to overcome that barrier, uh, to make them practically, uh, deployable.

Laura Waters: I mean, HIV's MO is evading the immune system, isn't it? That's what, that's what the virus does. So it, it, I don't find it particularly surprising that sort of immune based mechanisms of, of treating HIVI.

I just, and I, I think my fear is, and I, I'm sure it won't happen, but I, I, I kind of feel that all of these studies are gonna ruin be Ns and that bean abs will get abandoned. I'm sure they won't, but I think there is real, really exciting data looking at it for different indications. And I think particularly for vertical transmission and, um, [01:09:00] transmission during breastfeeding, it, they could have real hope.

And certainly we'll be touched you later, won't we? But yeah, I just

Paul Sax: maybe, yeah. Maybe, um, lots of, uh, lots of be a studies, lots of very smart people working on them. So I I, I, I'm not, I'm not saying it's impossible, but it's still, it's, it's, it's, you know, my generally optimistic nature, it, it doesn't apply to be a so far, because the data just don't look right.

I mean, this is one of, one of the participants in this study developed integrase resistance. Yeah. That, that's a, that's high consequence outcome. So, yeah,

Laura Waters: no, it absolutely is. And one thing, 'cause I, I remember Paul last year when the first N six LS study was presented. Banner, I think it was, wasn't it? The banner study?

Yeah. And again, I, I, I asked because they didn't do baseline susceptibility testing. Because again, I'm no expert in all of this, but I had a concern that if you give someone a, B, A and then they develop loss of [01:10:00] susceptibility to the BA, which I think some people did in that first study. Mm-hmm. Is that gonna have any downstream consequences?

And the answer at the time was no. I think when we come to look at Rio later, I'm not quite convinced that the answer is no. So we'll touch on that when we reach it, but

Paul Sax: Yeah. Yeah. But first onto something a bit more straightforward. Yes. Doravirine, Isla, VIR, Isla, Ravi, given at the lower dose in two clinical trials, switching to this combination, uh, maintained viral suppression, uh, non-inferior outcome.

So there were two studies. One was an open-label trial, uh, looking at, compared to baseline a RT, you're either continue your baseline, a RT, or you switch to open-label Doravirine ne vir 0.25 milligrams a day. Um. Study oh five two was just Bictegravir ftc taf, and that was blinded. So that's actually important to have that, that data as well.

Um. No impact on lymphocyte [01:11:00] counts. Hooray. Uh, that was the concern with the Avir. In the previous studies, uh, in the open-label trial, there were more adverse events with, uh, doravirine. The avir. That often happens because people switching from their baseline art will often ascribe symptoms to their new regimen, even if they're not drug related.

We will say a few other points about these studies that I didn't put on this slide. 'cause in this new Laura Waters format, there's not a whole lot of room. Uh, there was, uh, one of the studies, uh, they had a person in study oh five one. One of the people randomized, had tons of doravirine resistance at baseline.

And ended up failing. Actually, two patient participants ended up failing rather quickly. So even though that was a protocol violation because they should not have been enrolled in the study, they're telling us something about the resistance barrier I think of as avir, because as monotherapy, it didn't hold the [01:12:00] regimen together very well.

'cause rapid failure with doravirine resistance present at baseline means this vir alone probably isn't gonna do it. And the other is that hepatitis B reactivation, uh, in oh five two. Remember you're getting rid of tenofovir. Uh, there was a little bit of low level hepatitis B reactivation in people who randomized to the, uh, doravirine, his vir.

Arm. And in addition, uh, there were a couple of cases of Hepatitis B acquisition during this study. So here we have Doravirine Svir. Uh, I wish I could tell you that people magically lost whatever weight they had gained on a RT, but there was really no difference. In fact, if you come off a TDF FTC Efavirenz regimen to switch to Doravirine and Ravi, you will likely put on some weight because you're dropping the, uh, weight suppressive effects of tenofovir FTC Efavirenz.

Um, anyway, treatment naive [01:13:00] study of this combination is ongoing. Uh, the one that has, uh, already been completed and published is, uh, with the higher dose. Uh, so we, we shall see. Yep. I do feel like they probably have sufficient data for FDA approval where this will actually fit in. Treatment regimens remains to be seen.

Laura Waters: Yeah. Yeah, I mean, it's, it's, yeah, I think to emphasize that, that to, to see acute hepatitis being a clinical trial, uh, is especially, well, I can't remember. We've included data on the new Hep B vaccine, but I, I think then there needs to be something built into the protocols to vaccinate people who, uh.

Susceptible to hepatitis B. And I guess what's what's interesting here is when we think about the most studied oral two drug regimen so far, dolutegravir lamivudine, you still have a, you know, it's not, not recommended for treatment, but you do still have a Hep B active partially hep B active agent on board, don't you, with the lamivudine.

So you are completely hep B activity free with this [01:14:00] combination. So yeah, I think the, the results are interesting. It matches their modeling in terms of the total lymphocyte and C four count data and lack of effect. But I think as you've just alluded to, where, where's it gonna sit? And I think in an ideal world, um, um, we all see people in clinic who struggle to tolerate antiretrovirals and have been on a long list of different regimens to have another choice, another single tablet choice is great, but is it ever gonna be wide enough use?

Is it gonna be commercially viable? I, I just don't know. It's an integrase free two drug regimen. There

Paul Sax: you, there you go.

Laura Waters: There you go.

Paul Sax: Okay. Okay. I, that's the, that the banner. The banner. Uh, next, next up, novel agents. I, I love these figures. Um, this is the third generation integrase inhibitor. The generations are like, reminds me of, uh, learning about antibiotics.

The cephalosporins become broader and broader. Same with [01:15:00] integrase inhibitors. If you look at this integrase inhibitor, VH 180 4, and you test it against, uh, uh, isolates that have terrible looking integrase mutations, you'll see this little, little red bar right here. That's the loss of in vitro susceptibility.

That's nothing compared to dolutegravir, raltegravir, elvitegravir, et cetera. So good news on in vitro activity given. Orally day one, four and seven, you get a nice two plus log viral load reduction. That's comparable to what we've seen with dolutegravir monotherapy and given daily. So, uh, promising drug.

It's not going to be, uh, really looked at for giving every third day, which is how it was studied in this trial. But it certainly as a proof of concept is actually, uh, quite promising. 'cause it's going to be, um, part we hope of a long-acting injectable regimen. Uh, I should mention, uh, parenthetically, I'm not gonna show the data for time reasons.

There is [01:16:00] a capsid inhibitor that was novel that also was presented here. Again, the goal of that capsid inhibitor will be to be included in a long-acting injectable regimen. So. Comments or that's straightforward and let's move on. I think

Laura Waters: it's, it's straightforward, and if it could be made available and affordably super quickly, then it would be the solution to some of the problems summarized in the very last session on integrase resistance globally.

But.

Paul Sax: Anyway, onto the last study in this new drugs format, and this is the, uh, a form mentioned Rio study of giving two bean abs to people. You, this is the, uh, study design and uh, you either get two bean abs or you get nothing. You get placebo. Uh, saline injections and then art is stopped, uh, and uh, art is stopped.

And not surprisingly, uh, the people who are receiving saline injections, they have gradual return of viremia. Uh, that's actually [01:17:00] not so gradual. VIREMIA comes back. But this group getting the two B nabs, they actually have for 20 weeks, uh, some degree of ongoing viral suppression. They then got a second dose, and that's in the extension of this study.

And you can see that they, they, uh, extended out the time to rebound significantly. Just one thing to point out, and I'll mention this again, in the cure section two of the 34 placebo treated patients did not rebound at all at week one 20. We have to remember this, whenever people have these remarkable observations about some cure intervention, that there are people who can maintain control for quite some time.

Uh, it's not common. It does happen. Uh, another thing that was observed in this study felt to be promising is that there was an enhancement of the T-cell immune response to the virus. If the baps have actual future promise as part of a cure intervention, it is this kind of immune activity that they will [01:18:00] wanna show.

Uh, unfortunately, the viral reservoir was not impacted. And then the other thing to mention, again, getting to sort of the glass half empty part of B nabs, 24% of the people rebounded pretty quickly even though they had virus susceptible to the B nabs at the outset. Uh, and a, a comment that I have to make because it shows that even if your test shows your BNAs are active, that the, the agent may not work.

Anything else about this trial? Uh, Laura, you wanted to bring out Yes.

Laura Waters: Yeah, so I think you're absolutely right and I think five of the people had rebounds to above a million. I mean, and that's coming back to what I was alluding to earlier. It it are is loss of susceptibility to administer b nabs actually having a negative impact?

Is this rebound Plus because of some. For me, describable impact on the immune system. I just, that was super high. So, and then touching on that, um, is then the question. So they [01:19:00] didn't include people with known comorbidities and it was generally a relatively young population, but are you gonna be, want to include in people with coronary artery disease in a study where you might see that level of viral rebound?

And certainly Sarah Fiddler, who presented this brilliantly, did say that they may be looking at sort of more in depth exclusion of comorbidities, particularly thinking about coronary artery disease in, in future studies. But yeah, it was, it's, it's certainly looking hopeful, but a, a again, I think it's this, this cure kind of cure indication where I think the focus should be not on just replacing antiretrovirals

Paul Sax: not on art.

Yeah. Yes. So speaking of cure. And Oh, nice. Rainbow. Exactly. And the, the, the pot of gold at the end of the rainbow. Uh, we'll start with these two cures.

Laura Waters: Yes. So, um, two cases chica, one from Chicago, one from [01:20:00] Oslo. This kind of sort of pattern now of, of naming people by the city. So first from Chicago, a 67-year-old man with, um, a ML had a homozygous Delta 32 mutation, um, allergenic, uh, stem cell transplant.

And they had undetectable RNA and DNA afterwards. So they did an analytic treatment interruption, but there was viral rebound. So they restarted art. The rebound was with our five tropic virus. And then. They stopped again. So rebound back on art, another analytic treatment interruption. And it's only 10 months, but they remain suppressed so far.

So I think what's novel about this case is that initial viral rebound doesn't necessarily mean that cure won't transpire eventually. Again, it is only 10 months follow up. But that was the kind of new point.

Magnus Gisslén: And then the second, Laura, for, for that, what's sort of the hypothesis where the cells that were replicating came from?

Laura Waters: [01:21:00] That that, I don't know. It's, it's, do you remember the rationale? I, I explain it, but I'm not sure I understood.

Paul Sax: I don't know. I mean, I think that this might get to the point that some of these cures are really just unbelievably low reservoirs. And if you're unlucky, you could have a stochastic event and rebound, uh, I don't know.

I, I can't, this one, this one's inex. Inexplainable to me, unexplainable.

Laura Waters: And then the second one was a 58-year-old man with myelodysplastic syndrome, um, who had a stem cell transplant from his HA identical brother who again, homozygous for the Delta 32 mutation, he had an acute prolonged graft versus host disease.

And again, we are talking small numbers when we look at all the cures, but this idea that the graft versus host disease, part of the response may be important if cure is to be achieved. He also, um, because he needed immunosuppressive treatment for that graft versus host disease with a JAK [01:22:00] inhibitor, which again matches, I think it was the London patient case.

Was it London patient? Yeah. Who had a JAK inhibitor as well. Um, so. He remained on antiretroviral for two years post stem cell transplant, and then stopped and remains thoroughly suppressed with no detectable DNA or RNA anywhere. Mm. So meets the criteria for a, a functional cure. So the, the kind of message here was firstly the graph versus host, but is there something about JAK inhibitors that are

Paul Sax: particularly Yeah.

I mean, each, each of these cases teaches us something. They're, they're not, they're not yet. S anything, they're not teaching us something we can actually do in clinical practice, unless you've got a stem cell transplant with a, a CCR five, Delta 32, uh, donor. But there have been acute cases without that. I mean, we'll, we'll see.

We'll see. The numbers are gradually accumulating. We don't have, denominators don't really, people don't report the failures very often.

Laura Waters: Exactly. Is exactly.

Magnus Gisslén: I got that question a few weeks ago and I couldn't answer sort of, we do [01:23:00] have all the se successful cases, but what about the cases that didn't succeed?

So

Laura Waters: someone tried to collate them once, or It may have been, it may have been actually coming back to my colleague, Ravi Gup I mentioned earlier, who presented, um, the second London patient. No, the London patients weren't second. The London patient and. I think he knew of something in the region, 10 to 20 cases then where it hadn't been successful.

Paul Sax: Yeah.

Laura Waters: Where he pulled that from. But again, you're absolutely right. Completely under-reported. I think the other lesson from all of these cases is, is just how patient and generous the individuals are. The sampling that they undergo to, to, to demonstrate that they meet functional cure is, is, is truly phenomenal.

And I think I

Paul Sax: agree. I agree. Now, now you could, you could say they, they're motivated, but at the same time they're generous to Yes.

Magnus Gisslén: And it also tells us how important it is to sort of, to present also the unsuccessful cases in literature. I mean, that is so to learn from [01:24:00] them too.

Paul Sax: Absolutely.

Magnus Gisslén: But that's true for every sort of thing when it comes to the

Paul Sax: now I have to say, um, I always hesitate before including any, uh, compilation of different studies because I.

Doing so has become progressively easier with ai and that has led to a flood of such papers submitted to journals. On the other hand, I thought this one was actually useful because what it did was it looked at 24 prospective studies of analytic treatment interruptions in people who received either placebo or nothing to characterize what's the kinetics?

What are the kinetics of virologic rebound? And 4% of people will not rebound by, you know, three months later. And you could see the median time to be greater than 50 is 16 days, 21 days greater than 400. 32 [01:25:00] days greater than 10,000. And then very importantly, the presence of post-treatment controllers was observed in 6% of those treated early after acquiring HIV versus only 1% of those who started late.

Uh, so I, I would say these data are actually very useful. Uh, and in fact, I, when this paper gets published, I'll probably be citing it frequently, uh, to my, also to my patients who say to me, look, you know, I'm gonna be, I'm gonna be, uh, have a gap. I have a gap of my in our country insurance coverage, or I have a gap that medications because I went on vacation, the median time to virologic rebound greater than 50 is two weeks plus two days.

Uh, so a lot of people are still wanting,

Laura Waters: I think the matches see clinically, isn't it?

Paul Sax: Absolutely. Absolutely. Absolutely. Yeah. So I thought, I thought I decided to highlight this study despite its being a compilation of other studies.

[01:26:00] So this is, these are all cure themes?

Laura Waters: Yes. All, all cure themes. So, uh, this is somebody, um, they, they refer them as an exceptional controller with no other information at all. Uh, that I could see. I scoured the poster for any sort of humanizing feature such as their, oh, well

Paul Sax: actually, actually they mentioned, uh, the person.

What did, who? Yeah, the concert vi violinist. That's what made them exceptional.

Laura Waters: Oh

Paul Sax: no, I'm just kidding.

Laura Waters: I know you're kidding because I didn't actually read it entirely. I properly, um, so they were just an exceptionally controller and yes they go. But anyway, somebody who maintained exceptionally controlled, so completely undetectable viral loads and you know, good or in normal immunological markers and eventually they lost virological control, rather their immune system lost virological control, but to contribute lots of research, sovereign wars during that time.

So, uh, no other details. And essentially they took loads and loads of samples and over 32 years personally suppressed and [01:27:00] then the viral load rebounded. And I don't think, and this is particularly surprising, but again, this may be useful for if you are in. A trial where you interrupt treatment. Could you measure some of these things to reinitiate art before your viral load comes up, I think is kind of what I was alluding to.

So you see the, there changes in the reservoir and M functionality and blah, blah, blah. So this idea, so I think the whole thing is that, that people who have spontaneous viral control is the, the, the term that that we use in our guidelines. People have spontaneous viral control. It's not just a static thing.

There's lots of stuff going in the background and perhaps some of these markers might be useful to predict subsequent viral rebound for earlier intervention.

Paul Sax: I think, yeah, that, that's it. And again, getting back to your comment about the, the, uh, people who work here, the generosity of people with HIV control in contributing samples has always.

Been very impressive. Uh, you know, we follow a cohort here, as I'm sure you do, [01:28:00] and, and they, researchers are so interested in what makes them special and they are giving samples on a regular basis. And I, you know, this is a person who is repeatedly sampled year after year after year. You know, I do, uh, you know, I've been doing this a while.

It just so happens I've been doing this for 32 years and I do follow someone, uh, who has been a HIV controller that entire time. Um, if I could just tell one anecdote though, I've followed enough HIV controllers over the years, not to promise anything because it is. A reminder, this case report in this slide is a reminder that sometime in the future they could lose control even if they're unbelievably stable and asymptomatic.

So it makes sense to continue to check their HIV viral load and their CD F SAR count, even if they, after many years say to you, why am I doing this? Why am I doing this? Loss of control does happen, and that's [01:29:00] what really is notable in this, in this uh, case. It

Magnus Gisslén: would have been interesting to know the age of the person here.

I mean, is this a consequence of the sort of aging immune system? Yeah. Or is it something else? But hopefully we'll learn to know it later.

Paul Sax: Interesting thought. Yeah. Okay. And onto the section called complications. And I will, uh, I took this piece from the New York Times, um, something that we were all experiencing with our long-term, uh, survivors, uh, of HIV, that they have.

Some of them phenotypically seem to be, have more accelerated aging and some don't. Uh, and why we don't know. But what we do know is that, uh. Epigenetic markers of aging are increasingly part of research studies. And we had a blizzard of these presented at co at, uh, CRO this year, although I should probably reserve that for next year's croi in Denver, uh, because that's where the blizzard will be, [01:30:00] not in San Francisco.

But there were many of these studies. I thought this was the most interesting of them because it involved, uh, semaglutide and semaglutide of course is being looked at for all of its various effects. And they, in this is a randomized clinical trial, uh, a small randomized clinical trial. But I think the only one that's been done in people with HIV.

Essentially half, they all had lipo hypertrophy, visceral adiposity, and they got, uh, semaglutide or uh, placebo. And they looked at these markers of aging, uh, chronologic age versus, uh, versus biologic age, mortality risk, another, another marker. And the third is the pace of aging. And they found just after 32 weeks, amazingly, there was already a three year decrease in the second marker in the estimated mortality risk and a 9% decrease in the pace of aging.

[01:31:00] There was a very, very nice figure that I. Probably should have stolen for from the presentation, but I only stole this one. Uh, showing the curve of more accelerated aging being pointed backwards towards normal, uh, in the people in this study, uh, what they then looked is, well, could you just explain this by the fact that they lost adiposity and their inflammatory markers got better?

And the answer was no. Uh, so the investigators concluded that there were these broader effects, and I get to use the fancy term pleotropic effects of these GLP ones on, uh, health. Uh, something that I think is increasingly being reported as it, you know, seems to reduce the incidents of all kinds of problems, not just, uh, be a weight loss drug.

Um. Thoughts, Laura

Laura Waters: thoughts. But my first thought was I didn't need to laboriously put our initials in the corner of each slide. 'cause if randomized spell with a z, it's yours. And if it's spelled with a, it's mine. Um, but yeah, I, yes, it's [01:32:00] interesting. I mean, imagine if 36 weeks of treatment gave you a three year decrease in mortality every time we truly would be able to turn back time and forever, wouldn't it?

I mean, that was incredible. I know. It really is. I, I mean, yes, it's amazing. This incredibly expensive drug that, didn't it double the GDP of Denmark or something? But it, it's, again, it's, it is again, uh, this isn't being pessimistic, everyone. And that I, I was laughing at that pitch you had at the beginning, Paul, with a dark cloud and the rainbow, and I'm the dark cloud and you're the rainbow shining light on it all is, this just isn't accessible to most of the world and no.

No, it's, I know it's really ludite of me, but if we could just support people to be able to enjoy healthier lifestyles, which are unaffordable to many, then they'd also see some of these advantages. But yes, it's scientifically fascinating. I think the fact is the epigenetic improvements reversed, didn't they?

Once you came off Oh,

Paul Sax: oh, you know, benefits. So, so, uh, I don't think they, they, did they study the reversal [01:33:00] afterwards? I, they, they did the weight, the weight loss certainly was reversed.

Laura Waters: They, they did. Maybe it was fatty liver. There was, there was another endpoint that, that got, well, it may not been this one.

You're right. But anyway,

Paul Sax: I think, I think it was actually this study, but not the epigenetic part. Um, but anyway, I did ask, uh, I dunno if you've heard, heard me step up to the microphone. I said, you know, has this phenomenon been reported in people without HIV? And, uh, I guess, uh, that correlates. Said no, but then someone later told me, yes it has.

So we'll see. Okay. Anyway, enough of GLP ones onto this, uh, this analysis of data. Uh. This is basically looking at trying to get at the issue of does TAF cause weight gain? And we've been hearing from the, uh, the, the makers of TAF FTC that it's not so much that TAF causes weight gain, but the TDF FTC suppresses weight.

And the way that they went about proving this was to look at the IPR study. [01:34:00] Uh, the IPR study remember was TDF FTC versus placebo, and then took a look at the, uh, at the weight trajectories of people on tdf ftc, people on placebo, and then going to the Discover trial people on taf ftc. And they had a very competent statistician, uh, Dr.

Glyden do an analysis and found that, uh, the T-D-F-F-T-C arms of both studies had similar weight trajectories and that the TAF FTC arm in Discover had a similar weight trajectory or not significantly different. I should emphasize, uh, compared to the placebo arm of IPR X. Uh, and I am putting the data up here, and now I am going to speak to one of our world's, uh, experts on this issue.

Dr. Laura Waters. What do you think?

Laura Waters: Uh, firstly, everyone, never, never confuse, uh, opinionated with [01:35:00] knowledgeable, or you can be both, but yes, I have strong opinions on this. So, I mean, I, I'm sure I've seen similar before. I'm, I'm not, not with a statistical

Paul Sax: analysis,

Laura Waters: no.

Paul Sax: Sure.

Laura Waters: But, um, I, my pushback is gonna be, however, there was another study I'm not sure we included that really does put my theory.

So my theory as a disclosure is I, I am not certain that TAF doesn't cause some additional weight change. This I accept. Confirms what I think we all accept that TDF has a weight suppressive effect. Absolutely. I think that's accepted. TDF and EFAVIRENZ have a weight suppressive effect. What just isn't quite there for me is that this is in people without HIV.

And it's not impossible that with all of this, particularly all the changes to gut immunity that happen post very, very quickly post HV acquisition, that there isn't some difference. So I think this says people on taf, FTC for prep aren't gaining [01:36:00] more weight. So TAF isn't driving weight gaining neg HV negative to people.

I completely accept that. I don't think it fully answers. It makes tough causing weight changing people with HIV less likely. Again, with each bit of data that comes out, my argument gets undermined a little bit more. I accept that and I think it's highly unlikely T is doing anything specific. The other thing I would say, these were not the people who are experiencing the greatest weight gain in clinical.

Yeah,

Paul Sax: yeah. No, totally not black women. So yes. Yeah. Good point. Good point. But, but they could be just moving on to our next study, uh, men from Spain. Yes. Uh, 'cause there's this trial, uh, or you're, you're gonna summarize this one for us.

Laura Waters: I am. So essentially this, this is, this is kind of a study that I'd been trying to get funding for for a couple of years and, and as Paul well knows, we've discussed it many times that just because removing TAF doesn't lead to weight loss, that's not the same as.

Adding TAF in. So this is a study that kind of did that. It took people who are very suppressed on [01:37:00] dote lamivudine and they either stayed on do Lamivudine or they switched to Bic FTC taf. So if we consider that doll and BIC are certainly legally identical, if we consider that that f TC is three TC or the fluoride group stuck on it there, or thereabouts, that really what you're comparing is TAF versus no TAF being added into ly suppressed people.

And you can see what they showed. You can see the weight trajectory that the red line for BIC and the blue line for doll. Um, they're the same. That's a slightly top line, slightly bottom line if, uh, those cars aren't distinguishable to you. Um, and they didn't show any difference. They, they looked at IL six, they looked at weight, they looked at.

Lipids or they only presented lipid ratio, so I'm not sure if there was an LDL difference. So yeah, it it, this again, this is the one that really I think does suggest that perhaps TAF isn't causing anything. What I don't know is whether anyone had historic exposure to TAF or TDF in the past. I'm not sure that would make a big difference.

The bit that made me laugh the most. 'cause um, this [01:38:00] is, um, you know, uh, very real expert in inflammation. Uh, they do lots of analysis on inflammatory markers. And the bit that made me smile a bit is there's no difference in anything measured, including IRS six, but ongoing analysis or essential to see if there's a difference in inflammation.

I think all the other data we saw shows there's not gonna be a difference in inflammation. Um, of course it'll be interesting to see, but I think this is suggesting that TAF isn't adding anything and this kind of differs a bit from Paa Doble. Yeah, I think we cover

Paul Sax: it. Does it, does we We still, we still don't, I mean, I, I can't totally get my head around the Paso Doble results.

I'm still waiting to see the, the kind of more detailed analysis of the baseline TDF FTC Efavirenz group 'cause, but we'll see. We'll see. Uh, anyway, I'm, I'm, uh. Is it, this is an interesting trial 'cause um, you know, I I think that you have these, when you're thinking about two versus three drugs often, really what we're talking about is two drugs orally is [01:39:00] dolutegravir or lamivudine.

Yeah. That's our, that's our best option. And when we're thinking of three drugs, at least here in the USA, we're thinking of bictegravir, ftc, taf, uh, because those, we don't have TLD generically in our country. So those, those are really our, our where, where we're, what we're looking at. And that's what this study does, which is why I thought it was, was interesting.

Alright, uh, moving on to Hep B vaccine. We, we, uh, have two formulations available in the United States. One of them is the Hep BCPG vaccine. Uh, and the other is the standard, uh, standard vaccine that's been around for a long time. This, this, uh, CPG vaccine is actually, uh. I'm not gonna use the brand name 'cause it probably mean nothing to people in Europe, but it's, it's called Heli Ave and it's not part of the guidelines really yet that it should be used preferentially over the older vaccine.

It's clearly more immunogenic and [01:40:00] in people with HIV. If you look out at week 72, you could see that it's really sustained. Benefic here. So I, I have taken the view that this is the vaccine that we should be using with HIV 'cause we have a prospective clinical trial comparing it to our older vaccine. And you really do have a better response than in the standard, uh, Hep Blum vaccine.

I, I have to say there is a 60% response. The, uh, people who get Hep B alums. So some would say, oh, just start with that and if you don't respond to that, can get more vaccines. But why not use the more effective one? What, what are your, what is your practice, uh, in, uh, in what are you using in Europe?

Laura Waters: No. So the, well Magnus used Speak, speak for your bit, but certainly we are using the standard old one.

Actually saw a colleague present this data a co who knows much more about Hep B than me. Um, and she presented the data only last week and she said what the situation was with our, um, so we have the JCVI, the Joint Council of Vaccines and Immune Immunization. [01:41:00] Um, and I can't remember what she said, whether they're looking at it now or they've, I think the, the thing to mention of course is, is gonna be cost.

Yeah. And the fact that it may be reasonable. But I would say coming back full circle, that if we are gonna recruit people who are not Hep B immune to trials where they're on no Hep B active agents, this vaccine should be part of the protocol. Ah,

Paul Sax: interesting perspective. Magnus, do you have this, uh, more immunogenic vaccine?

Yeah.

Magnus Gisslén: We're using this sort of the standard one. Yeah.

Paul Sax: Yeah. I gotta say that. You know, it's, it's really kind of. Wonderful to be able to generate a, a response in someone who's not been a responder. Yes. And that's really what this trial focused on. They had some people who'd never received any vaccine, but that was a, you know, less important result.

Laura Waters: I think just the one other thing to to mention is sometimes, so I see people who say, oh yeah, no, we've tried several times when actually look back through their notes, they've never had a complete course. Ah, they've had spo added doses here and there. So I, I guess it's the same way that some [01:42:00] people with resistance end up in clinical trials.

'cause perhaps the notes haven't been, or a bit of notes was missing or whatever's happened that, that sometimes revisiting and you realize that somebody hasn't and then they do respond. The other thing, I think, just to mention, it'd be really interesting to see what happens after week 72, because those lines are looking pretty flat.

And imagine that we're gonna see 10 year response rates where it remains this high, then clearly that's gonna impact the cost effectiveness.

Paul Sax: Yeah. Yeah. Absolutely. There's another counter argument that I've heard, which is that some of our protection from Hepatitis B vaccine isn't measured by just antibody levels.

It's measured by amnestic responses, which, you know, kind of hard to, to prove that in a clinical study. All right, Laura, you, you are fond of this one.

Laura Waters: Oh, yes. So doxy pep, big theme, I think. It's a bit like prep Paul, when you highlighted just how long ago? It was? 2010. When that first paper shown prep work, certainly in the uk it took a very long time for prep then to be routinely available.

And doxy pep is an interesting one. At the moment our national [01:43:00] guidance for the UK is out for consultation. Um, I think maybe one or possibly two clinics have rolled it out regardless, but it, it feels a bit slow for such. An inexpensive intervention using a drug that's already dished out like sweets in sexual health clinics.

I'm surprised we've been a bit slow Anyhow. So one of the big concerns, of course, with using Doxy pep, so it's taking a stat dose of doxycycline, 200 milligrams within 72 hours of condomless sex, preferably the first 24 hours. And one of the concerns is around antimicrobial resistance and stewardship, and should we be giving out antibiotics for post-exposure prophylaxis rather than confirmed infection.

But one of the counter arguments is that because you will dramatically reduce the instance of sexually transmitted infections, actually your net use of antibiotics will go down. And this to my knowledge, is the first cohort to measure it. It's also be published very soon in that exemplary journal, CID.

Um. But it's an Italian cohort and they [01:44:00] basically looked before and after their rollout. So they got on with it very quickly and rolled out Doxy pep to people with HIV or people on HIV prep from August, 2022. And they compared STI rates before and after the use of Doxy pep now. Some caveats. It was self-reported doxy pep use.

So perhaps it was under-reported. I can't see why people would say they're on doxy PEP when they weren't. And people having STI screening every three to six months routinely. But you can see from the picture. So this is looking at s comparing STI rates before doxy pep in the red and STI rates, um, after doxy pep in the blue.

And this is actually the measure of days on therapy. So the incidence of STIs were so reduced that you saw a dramatic reduction in antibiotic use. So although you're dishing out doxy, you can see from that top line just how dramatically the net doxycycline use went down because you were treating far fewer STIs with doxy.

Yeah. Or less penicillin [01:45:00] and less ceftriaxone use as well. So that was statistically significant. I think it proves that theory that your overall antibiotic use will go down. Therefore, from an antimicrobial stewardship perspective, this is a good thing to do.

Paul Sax: Yes, ID doctors love that. We love it. That's excellent.

That's a very, it's actually an important study. I had missed this one, so thank you for highlighting it. You're

Laura Waters: welcome.

Paul Sax: Uh, a, uh, on a less happy note. Uh, we did see this, this result of the randomized clinical trial of tecoma for MPO treatment. Uh, it's an a CT G study called Stomp, and essentially, uh, the curves could not have overlapped more.

Uh, this did not lead to more rapid clinical resolution, did not lead to more rapid viral clearance. It was a. Truly negative study. So the treatment was safe, uh, but it was actually very much in line with what was observed in the Palm 0 0 1 trial, 0 [01:46:00] 0 7 trial of Teca Virat. So what to do next? If we have another situation like we did a few summers ago with tons of cases of Empac, we don't really know, uh, we don't have an effective antiviral.

Uh, I will, uh, give huge credit to the A CDG investigators. I, I'm a collaborator with the A CDG, uh, you know, but I'm not one on the study team to, to pull this one off because it included an arm where everybody with serious disease got treated, but the people with mild disease got randomized. And that allowed us really to show that this antiviral unfortunately doesn't work for COVID-19.

I mean, for, for, for MO. Sad. Sad but true. Um, alright, last, last complications. This is really complicated.

Laura Waters: Oh yes.

Paul Sax: This is so,

Laura Waters: so, my trigger warning for virologists, there's a trigger warning for immunologists here. Okay. Right. Letermovir, is that how you say it? [01:47:00] How do you say it? Let

Paul Sax: Letermovir

Laura Waters: fine. She got that right.

So it is an anti CMV drug and this study looked at the effect of giving CMV agent Letermovir to people who've always suppressed HIV to look, see, does it improve inflammation, immune activation, et cetera, et cetera. It does. Inflammation. Better immuno inflammation, better. CD four, improved and physical function, which was measured by the time it takes you to stand and sit five times from a chair.

Paul Sax: It's a

Laura Waters: classic. Classic geriatrics classic. All got better. But the trouble is the study was stopped early because some marker, which you don't wanna go up, went up. Now whether or not they should have just ridden it out, who knows? It's like anytime a study gets stopped early, you're never really gonna know what might have happened if you just waited.

So it's small numbers, but all of those things were better. But the trial stopped for futility 'cause this was a pre-planned analysis. And that particular marker, which Paul know much more about than I do, is not a good [01:48:00] thing.

Paul Sax: No, actually, I mean, just to to to be clear, this was not. Very understandable when you hear a study is being stopped early for futility, you assume it had no beneficial effects, but they found all these beneficial effects, so now we don't really know what to do next.

Yeah. Letermovir, just to let you know, is used in stem cell transplants to prevent CMV reactivation, and it is incredibly expensive. I mean, like mindbogglingly expensive. There is no way that letermovir is ever going to be part. A standard HIV regimen, unless they have a massive price reduction or some other benefits are found.

Uh, but I am was fascinated by these results. They got a lot of attention. Uh, you can see that these, these inflammatory markers got better, uh, but really not gonna, not gonna influence clinical practice.

Laura Waters: Oh. And, and I think, and it is 'cause I actually, because I sit there and I, I, you know, sit and do my screenshots so that I, [01:49:00] I don't go on Twitter anymore, but I go on Blue Sky and LinkedIn and Yeah.

Yeah. Post things with permissions and, um, I had to go back and think, 'cause it, I, I heard that it was stopped early, sort of I, oh, and then it got to the end and I was only half concentrated. Had to go back and read the first slide to make sure I edit it right. Because there were so many

Paul Sax: described, Laura, you're not the only one.

I was sitting next to a very smart, uh, colleague of ours, David Wall. And he said it, it was stopped early because the marker was a good thing. And I said, no, no, no, no.

Laura Waters: Okay. No. Even I even, I thought that bit that it wasn't a good thing. But you're right. It's, it's just, I guess a, uh, semaglutide Plus and that this is an expensive, inaccessible drug which shows, uh, benefits in, in.

So this is new. There was a study from ages ago and I was trolling my old slide sets trying to find it, and I couldn't, where they gave people Ganciclovir or Ganciclovir inflammatory markers got better, didn't

Paul Sax: they? Val Valacyclovir. Yeah. [01:50:00] First author Feinberg. Ah, there you go. There. Anyway, believe it or not, there were three important COVID-19 trials, and I just thought this cartoon was hysterical.

So I'm just sharing it with you. Do you have raccoons in your countries? No, we do. Oh, you don't? You are so lucky. Yeah. We have

Laura Waters: urban foxes, but they, these

Paul Sax: raccoons are adorable, but they are such pests and they are smart and they can get into anything. Alright, and Citro vir, this is actually a really interesting trial because it's going to be fascinating to see how this is used.

Post-exposure prophylaxis in households A, a Centro VIR versus placebo. Over a thousand participants in study arms, and there is a 67% reduction in incidences of COVID-19 with no difference in treatment. Emergent adverse events. Very important study. Never actually. [01:51:00] It's been demonstrated before in any post-exposure prophylaxis study of COVID-19.

Remember that Mira Vir and, uh, neuroma vir ritonavir both failed in this result. So that's, that's the, the, probably the biggest news from Covid from the trial. That paper has not been published yet. Unfortunately, Metformin didn't fare quite as well. This is the gigantic active six trial conducted by the NIH.

I remember Metformin in an earlier study, did reduce the incidence of long covid and had an antiviral effect placebo controlled trial. Nearly 3000 participants mild to moderate disease. No. Observed benefits, at least in this trial. Now, this is a important caveat. It was all done remotely and, uh, more than a quarter of the participants received their treatment a week or more after their symptoms started, and they did a, a retrospective post hoc analysis and found that if people got it [01:52:00] relatively soon, there appeared to be some benefit.

But I don't know whether this is the end of metformin or whether this is just the, you know, that's the limitations of remote studies. And the last study we're gonna highlight is SNS 8 1 12 for COVID-19. Notice I'm only choosing placebo controlled trials, uh, and it is investigational aerosolized treatment of a short interfering RNA antiviral.

It might actually be active against other coronaviruses. And the only reason I mentioned that is because in our lifetime we've had some coronavirus badness, including sars, mers and COVID-19. And it would be very nice to have an effective antiviral. And this study suggests that this inhalational drug could be active.

But this was of course, only a phase two trial. And, uh, we'll have to see more data. So that brings us at last to our take home points. We, uh, Laura, you [01:53:00] and I can alternate. Uh, go ahead. You take the first one. So

Laura Waters: once she, Lena Kavir for prep, but she's promising drug levels.

Paul Sax: All right. Bictegravir FTC TAF better than Darunavir or Cobi ftc.

TAF in advanced HIV disease. But you know what, uh, the primary endpoint wasn't significant, but the virologic endpoint was.

Laura Waters: Cab Rilpivirine in the real world shows effectiveness similar to clinical trials and more favorable results with use in people with viremia, people with the most need.

Paul Sax: Yep.

Doravirine Isla Severer, A novel two drug regimen coming soon.

Laura Waters: Investigational long-acting agents including the capsid inhibitor we didn't share data on, but the third generation integrase and lots of dab. So there's a, a healthy pipeline

Paul Sax: GLP one agonists can do no wrong.

Laura Waters: Uh, two additional H HIV cures following stem cell transplant for other conditions, including the first who experienced transient viremia.

Paul Sax: And in Citra, VIR is promising as pep [01:54:00] in COVID-19. Thank you to Magnus Media. Who? And ViiV, we are still your friends. Europe. Do not listen to the crazy man in charge of our country.

Laura Waters: Although careful, 'cause that flag doesn't include us. We are behind

Paul Sax: it.

Laura Waters: It should

Paul Sax: include Britain,

Laura Waters: Yuni, and Jack is hidden behind.

But that's your fault. Uh, no. Well, not mine, but yes. Uh, some people mind you, you are not really one to talk about the stupidity of your electorate. I, Dr. Fox.

Magnus Gisslén: Great. So thank, thank you so much. This was, it's usual so nice and, and great, and, and perfectly on time. So with that, uh, we say thanks for today both to you too and to me.

Uh, and to all that I've been listening. Uh, so thanks for today. And. Goodbye

Paul Sax: and thanks to also, especially to Media, Huit and Aviv, for helping us put this on. Thank you

Laura Waters: so much. [01:55:00] Bye.