HIV Glasgow Highlights 2024

Join Paul E. Sax and Laura Waters as they summarize the highlights from HIV Glasgow 2024 in this webinar, HIV Glasgow Highlights 2024.

The webinar highlights key points from the HIV Glasgow conference and related discussions. Here are the main takeaways:

Discussions emphasized advances in treatment, including long-acting medications like cabotegravir and rilpivirine, which proved successful for patients with poor adherence. Updated guidelines highlighted a shift away from abacavir to integrase inhibitors to reduce cardiovascular risks. Two-drug regimens, such as dolutegravir and lamivudine, were found to be as effective as three-drug options even at high viral loads. Studies on weight gain associated with TAF (tenofovir alafenamide) yielded mixed results, while semaglutide showed promising benefits for weight loss and liver health. Results from the PURPOSE trials confirmed lenacapavir's efficacy in preventing HIV among high-risk women. Discussions on HIV cure explored genetic editing and stem cell transplantation, though risks and challenges remain significant. Lastly, the increasing prevalence of cancer as a cause of death among people living with HIV was highlighted.

The summary underscores new advancements and persistent challenges in managing and preventing HIV.

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

Supported by an educational grant from ViiV Healthcare

Full transcript:

[00:00:00] Magnus Gisslén: Great. So welcome to this HIV highlight meeting. My name is Magnus Gieslein and I'm delighted to to host today's session. I'm an infectious disease physician and professor of infectious diseases in Gothenburg, Sweden. And we will discuss key insights from two recent conferences, HIV Glasgow 2024, and maybe not ID week, but sort of more general about other type of news.

[00:00:35] And it's my great pleasure to welcome our two distinguished speakers. And first, Laura Waters, if you please could just introduce yourself.

[00:00:45] Dr. Laura Waters: Of course. Thank you so much. Hi, everyone. I'm Laura Waters and I'm a consultant physician in HIV and sexual health based in London, in the United Kingdom.

[00:00:55] Magnus Gisslén: Great, great to have you here.

[00:00:57] And Paul Sacks,

[00:00:59] Prof. Paul E. Sax: please. Hi everybody, I'm Paul Sacks. I'm an ID doctor and HIV specialist at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. And as Magnus said, I'm going to be doing a kind of year in the review, the greatest hits of HIV medicine for 2024. I do want to Take a quick moment to thank Mediahuset for, uh, coordinating this symposium, as well as thanking VIV for the unrestricted grant that they gave to allow us to do it.

[00:01:29] Magnus Gisslén: Great. That sounds fantastic. So, so happy to have both of you here and, and I also would like to thank Mediahuset for providing the platform and opportunity for us to hold this meeting. Also, your engagement is important, so please share questions and comments in the Q& A section. And with that, so let's get started and we start with HIV Glasgow and Laura, please.

[00:01:56] Dr. Laura Waters: Fabulous, thank you very much indeed. Let me get my slides shared and just confirming that those slides are visible. Give me a thumbs up so you can see it. Perfect. I know we'll get an A OK from Dr Sacks. So thank you so much and thank you for the invitation to speak. This is me. Just a quick note, I don't know about the rest of you, but Twitter's getting more and more bleh.

[00:02:20] Um, so many of us have joined Blue Sky, which is in theory a kinder platform on which to share information. So that's why I've been focusing my attention. I've also been experimenting with LinkedIn. I'm yet to decide if that's a good way to share information or not. Perhaps we can discuss that in the Q& A because, as Magnus has alluded to, perhaps some of the data from the most recent conferences was a little bit thin on the ground.

[00:02:46] These are my disclosures in terms of trials I'm involved in, sponsored by Viv, Gilead and MSD. And I've received speaker or advisory fees in the last 12 months from Viv, MSD and Janssen. And I'm going to be touching on, although it's not original data, there were a couple of important updates to the European guidelines, which I'll touch on.

[00:03:06] Some of the abstracts on long acting and then oral antiretroviral therapy options. Brief mention of some toxicities and comorbidities, finish on prevention if we have time, um, and then move on to a more, uh, varied potpourri of the year from my co speaker. So I think one thing I had to mention first, though, was the University of Liverpool Drug Interactions website, which I suspect all of us have used in the last week or so.

[00:03:35] I've used it today already. It was there 25 years ago. anniversary and this website really has become so embedded in the resources that we use to best manage HIV care and importantly for people who are able to and happy to have it on their phones. Certainly a lot of the people we see in clinic have it on their phones so that they can be at the center of our care.

[00:03:58] understanding if there are any important interactions between what they're being recommended to take and their HIV meds. And for those of you that know the British Royal Family, that is Princess Anne, daughter of our dearly departed Queen Elizabeth II, and she was at the conference to Give this award to David Bakunseku, the founders of the Liverpool website.

[00:04:20] So that was a lovely moment of the conference. Moving on to guidelines. Now, these are the US guidelines from September 2022. What kind of conference update is this, Dr. Waters? But I think it's important because the DHHS guidelines were the first to remove abacavir from their first line of recommended options.

[00:04:43] So before DHHS, actually very similar to the British HIV Association guidelines, which I always promote, second generation based integrase inhibitors, With that additional option of darunavir for people with recent exposure to cabotegravir for prevention where a resistance test isn't available, but otherwise it's dolutegravir in various permutations or it's bigtegravir currently only available with sofavir, allophenamide and emtricitabine of course, but in the March update to the DHHS guidance, the abacavir option has gone.

[00:05:14] And so what was new at Glasgow in terms of what was shared, the EACS guidelines, this was the October 2023 version and if we look and see what came out of these, you can see just jumping back and forth, it was again Abacaville and Mivudine in combination with Dolutegravir first line. EACS was quite unusual in that it still had Raltegravir as a recommended first line option, but that too has gone.

[00:05:39] The British HIV Association dropped Raltegravir from its kind of preferred table in our last update in 2022, uh, due to a number of issues, including the pill burden, but also its efficacy, particularly at higher viral loads. So it was good by abacavir from those two sets of guidelines now. And I think again, although I'm jumping back slightly, I think it's really important that reprieve showed us that this issue of abacavir and an elevated risk of cardiovascular disease is not the only unique to people with high cardiovascular risk.

[00:06:11] Certainly our own national guidance has long recommended switching away from abacavir in people with an estimated cardiovascular risk of 10 percent or greater. And in reprieve, where we saw a 40 to 50 percent higher risk of major adverse cardiovascular events in people with former or current exposure to abacavir.

[00:06:33] It's really important. point here is that that average risk at baseline was just four and a half percent. So a reminder that even in people with a low to moderate cardiovascular risk, abacavir is still associated with additional cardiovascular harm. So no additional efficacy benefit in the context of a second generation integrase for abacavir, and certainly a suggestion of harm.

[00:06:56] So I think that was one thing to pull out. When did you last use abacavir first line?

[00:07:09] Oh, you're on mute for me, Paul.

[00:07:16] Prof. Paul E. Sax: Sorry about that. Um, it's been a good long time. Uh, one, one, you know, you, you mentioned that cardiovascular risk, um, in addition, I was involved in an ancient clinical trial called 5202 that showed that it was less effective than tenofovir, uh, in people with high viral loads. That, to me, always was a signal that maybe the lack of synergy with lamivudine was a real problem.

[00:07:37] Uh, and then, uh, uh, The, the pill is gigantic. Uh, which, you know, the, the Abacavir lamivudine dolutegravir pill, which was kind of res, you know, dolutegravir resuscitated abacavir in the United States because of, because it dolutegravir is so great, but the pill was very large. So it's been a long time.

[00:07:57] Dr. Laura Waters: Same, same here, same here.

[00:07:59] And I think it's, it's really time. I mean, clearly it's still going to have a role, particularly at global level, where it may be the only non tanoff of their option available. And you know, that whole debate around how many NRTIs we need, of course, in the context of a lower barrier core agent, like we still, I saw someone this morning who actually had switched to a real pivoting based regimen for various tolerability issues.

[00:08:19] Not something I start, um, at all anymore, but, but still have a role for some of these lower barrier agents. And I think occasionally, uh, you can. And they'll come up with an argument that a back of ear is a reasonable choice. But I think it's counting on your hands type numbers. So moving on to long acting again, I'm aware this isn't necessarily new data, but I do think that it was a really excellent session.

[00:08:45] Some really good plenaries, but one of the ones that stood out for me was this. Uh, plenary from Monica Gandhi, uh, long acting treatment for non virally suppressed people. And I think Monica really is the, the, the sort of doyenne of challenging these regimens, challenging the licenses, and using these treatment options in people who really, really need them.

[00:09:04] Because who needs new options more than people who haven't been able to achieve viral suppression? Um, So it was a really fantastic plenary and, and really, really worth watching. Um, of course, we know that the license for long acting cabriolet pivorine, our current only whole long acting regimen available, that that license is for virally suppressed people.

[00:09:25] We're really stuck in England because drugs can only be used. within their license unless we create a separate evidence based policy. But as Monica pointed out, the data for long acting cabral pivarine outside the context of viral suppression is actually pretty scant. So it remains to be seen whether or not we're going to build up a strong enough case.

[00:09:46] Of course, the DHHS and the IAS USA guidelines now both include scenarios where you could use injectables in people who aren't virally suppressed. I think it's fair to say it's clear that's really where there are no other realistic options. And one of the things that Monika has been very vocal calling for is the option of investigating capotegravir in combination with lenacapavir because of course at global level rilpivirine requires refrigeration.

[00:10:14] We know that non nucleoside resistance is very common at baseline, um, in people in many of the low and middle income countries and Lena Kapovic could be a solution for that. Uh, Monica had led a publication of a case series of 34 people on CAB plus LEN plus minus real Piverine. And there was a small study at ID week in nine people.

[00:10:36] all with rilpivirine resistance, and I think one with CAB resistance, looking at CAB rilpivirine plus LEN. Quite why you give the rilpivirine at all in people with NNRTI resistance, I'm not entirely sure, um, but it was a very small study. Um, but certainly the case series that Monica published, although it was short follow up, the median duration of follow up was just 4 to 12 weeks, but high rates of viral suppression.

[00:10:59] So, a study has been approved, ACTG 5341, investigating CAB plus LEN in 38 people. And I think that really is a fantastic step forward, but clearly to really address whether this particular long acting regimen can help sort out some of those challenges at global level, then we're going to need bigger and global studies, but I think it's certainly a step in the right direction.

[00:11:21] Um, so not something I can use because we can only prescribe cabotegravir with rilpivirine in the context of a license based prescribing policy. Lenacapivir we can use, but unfortunately not with cabotegravir. What about you, Paul? Have you used this particular novel combo?

[00:11:41] Prof. Paul E. Sax: Right now we have, uh, We have two people in our, uh, cohort on cabotegravir and lenacapavir, both of whom had ropivirine resistance and both of whom had, uh, HIV acquired, uh, by, via the perinatal route.

[00:11:58] Okay. So they are in their, uh, one is, uh, in his early 40s and one is in her late 30s.

[00:12:06] Dr. Laura Waters: Yeah.

[00:12:07] Prof. Paul E. Sax: And, uh, they have, uh, Very, very high level, uh, drug resistance, with the exception of susceptibility to, uh, caboteg, uh, integrase inhibitors. That's their only active drug. And so they're getting that, uh, exactly as you would predict, um, many years of bad regimens plus it's sculpted here and it's exactly as you'd predict.

[00:12:28] Dr. Laura Waters: Yeah. It's, um. Sorry. Yeah, go on. No, no, go, go, Magnus.

[00:12:33] Magnus Gisslén: I have a question here for you and I think it's, it's, it's, and that's about long acting real people in caboteg around here. So, actually, three questions. How widely is it used in your clinical setting, the first, and then what type of patients are typically, typically considered?

[00:12:51] So, so, so. Is the patient's preference alone sufficient for sort of justifying the prescribing of this? Yep.

[00:12:58] Dr. Laura Waters: So, um, how widely not vary. So we have only about 1 percent of our cohort of 4, 700 people on injectables. Um, so it's about 45 people, um, which types I think it's, it's a broad range. I think it's safe to say that everyone is within license and within policy.

[00:13:17] Um, we're just, the difficulty is if we prescribe off license, we have to self fund the drug. Um, And, uh, the financial, uh, situation for most sexual health services, um, it will be a challenge at the best of times, and it's particularly difficult at the moment. Um, so, so, uh, a variety, but yes, patient preference alone is a sufficient reason.

[00:13:38] What we find is intramuscular, two monthly, Most people who would have been interested in eligible drop out at that point for a small number, although I think, um, it's probably a little bit perhaps over emphasizing our current guidelines and we're looking at toning it down a little, but the small risk of biologic failure despite on time injections is not.

[00:14:01] the major reason that people aren't going for injectables. It's simply the logistics. So they say, come back to me when it's every six months or come back to me when, you know, I can book a time slot and have this done at home. Um, but, but beyond that, yeah, that's why it's, that's why it's quite limited.

[00:14:16] Paul, what about you?

[00:14:18] Prof. Paul E. Sax: It's very similar, uh, and. The people who, who started and, and are, are on it, love it. And, uh, the people who hear about the coming to come into the, uh, difficult to park academic medical center every two months. And, and then I actually will say that some people, if they hear that they're fully, they're fully on time and they're meticulous with their, with their injections, they still have a 1 percent chance of treatment, failure, resistance.

[00:14:47] That's enough to spook some people off. Yep.

[00:14:50] Dr. Laura Waters: Yeah, absolutely. And it is for some, um, you know, we always have the conversation that, that ultimately that's an, you know, assuming that the two monthly and the, um, IM injections are acceptable, um, that, that risk about, of biologic failure is, is very individual.

[00:15:04] And I think only an individual can determine if the potential benefits outweigh that risk.

[00:15:09] Prof. Paul E. Sax: I think one, one, one part of the conversation is that if that failure occurs, which is rare, then they can't go back on what they were taking previously. And that's, that's, That's That's a disincentive, but the people who are on it love it.

[00:15:25] Dr. Laura Waters: Yep, no, same with us. We've had two people discontinue, but they were both entirely predictable in that they had a list of antiretrovirals previously longer than my arm, and all of the switches have been for tolerability reasons. And in every, I've got one person I see in clinic who's absolutely wonderful.

[00:15:41] He's incredibly well informed. I love seeing him in clinic. Um, He's actually the person who ended up on real Pivarin based therapy that I mentioned earlier. Um, but he typically switches, has a honeymoon period, everything's great, and then the side effects start to kick in, and I'm probably perpetuating all of this by switching so often, but when you've got a well informed person wanting to switch away, it's quite hard to do anything but, isn't it?

[00:16:02] So Excuse me. Right, so moving on. So what do we have here? Here we have some data on a weekly regimen, and I think weekly is sufficiently infrequent to be considered long acting. So this is the 48 week data from a phase 2 study of izlatrovir with lenacapavir as a weekly oral option. Environmentally suppressed people, so often these studies are people who've been suppressed for a long time on a modern regimen, in this case it was bictegravir, emtricitabine and TAF, and randomized one to one.

[00:16:35] To continue their BicTAR V or switch to the Izlatrovir Lenacapavir weekly option. Now of course, Izlatrovir has been beset by concerns about lymphocyte toxicity, CD4 count and total lymphocyte counts, with the higher oral dose, the original dose going forward with, was, 0. 75 milligrams, but as it became apparent that there was a relative attenuation of CD4 rise associated, uh, directly with his atrial concentrations, various modeling work and looking at different arms in the phase two studies means it's the 0.

[00:17:06] 25 dose going forwards and the two milligram weekly dose based on pharmacokinetics is predicted, like the 0. 25 dose, to have little or no impact on CD4 and total lymphocyte counts. So the baseline population, it's a phase 2 study, so there's only just over 50 people in each arm, uh, and it's all fairly typical high CD4 counts, everyone's virally suppressed and most people on average in the slightly overweight category.

[00:17:33] But these were the results at week 48. So 94 percent and 92 percent remained virally suppressed in the novel two drug regimen versus continued three drug arm discontinuations. None of them were for virologic failure. So small phase two study looking promising thus far. And the other key things which I've just summarized in one slide is No grade 3 or higher adverse events, serious adverse events or drug related adverse event discontinuations.

[00:18:02] No significant difference in the CD4 or total lymphocyte counts for either arm. So switching to is lactrovir did not impact CD4 or total lymphocytes. No difference in body weight or BMI, which I think is fairly typical. We've seen various studies removing TAF from the equation and you don't tend to see an impact on body weight.

[00:18:20] Still doesn't convince me necessarily that TAF doesn't have an impact, but that's a whole different discussion. I'm not focusing on weight in this particular presentation. Very high adherence, as you would expect from participants in this type of study. But there are now two phase two, phase, I should say, phase three, I do apologize, two phase three studies planned.

[00:18:38] ISLEND, I think it's ISLEND, Paul will soon correct me if it's not, because there was something else I was saying wrong earlier this year, I can't remember what it was, but ISLEND one and two, looking at this in larger phase three studies. So my questions are, um, Hepatitis B, I mean, there is a real move to, uh, non Hep B active II drug regimens.

[00:19:00] Now, doyuteglamivudine, of course, you've got a partially active Hepatitis B drug in there. Lamivudine not recommended for Hep B treatment, of course. We've seen from cohort studies in non immune people that lamivudine does confer some protection against incident Hepatitis B compared to no Hep B active drugs at all.

[00:19:19] Tenofovir, of course, fares much better. But if we are switching people who have got isolated core antibody positivity, all those people, particularly who may have actually cleared hepatitis B on hep B treatment in the past, should one, we'd be recruiting them to trials without hep B active drugs. And if we are, should we be monitoring hep B DNA routinely?

[00:19:42] We saw at the IAS conference in Munich, an analysis of some of the Dolutegra Lamivudine studies showing no hepatitis B rebounds. But in those studies, there was no routine hep B. BDNA measurement. Hep BDNA was only sent reactively for people with clinical hepatitis or unexplained transaminitis. So should hep BDNA be routine?

[00:20:05] And I guess other than the weekly dosing, is this regimen adding anything to what we have when we think about our unmet needs? And I think hepatitis B is one of those unmet needs. Is this combination meeting those beyond the fact, of course, that it could be our first weekly option? So I'm going to bounce those.

[00:20:22] Paul, what do you think?

[00:20:25] Prof. Paul E. Sax: Well, first, I think the hepatitis B story is, um, is, is unclear at this point. I, I, you know, the first I get to cite something that the hepatitis Bologists like to say, which is that they describe, they describe the isolated core people as isochores, which I, I'd never heard that term before.

[00:20:49] Magnus Gisslén: Me neither.

[00:20:50] Prof. Paul E. Sax: Okay, so, so now we can all learn this new term isochore. Anyway, um. The Isocore people, people with Isocore, they generally don't get into trouble unless you do something really extreme to their immune system. And that type of thing is you deplete their immune system. their lymphocytes using a drug like rituximab or something, they're generally okay.

[00:21:18] So I, I don't think it's going to be necessary. Uh, and then, and as far as, so that's my opinion. Uh, as far as the second query about the once weekly, I, I think that's enough. I think, uh, you know, you, you're right. Um, maybe it's not offering a lot of other benefits, but once weekly dosing is very popular when you run it by your.

[00:21:42] Your, your patients. And so I'm excited about this combination much more so than another single pill option. Uh, that once daily.

[00:21:52] Dr. Laura Waters: No, I, I, I agree. I agree entirely. Um, and, and actually people, people in clinic, I think it's one of those things and it wouldn't be the first time when like physicians in particular, amongst the variety of healthcare professionals we have involved in HV care, physicians in particular can really get it wrong in terms of what people want, I think.

[00:22:11] For what I understand, you ask most physicians, they go once weekly, what benefit is that? That's, I'm the same as you when I mentioned this in clinic, uh, because we'll be participating in one of the ISLEND studies. People are really excited about the option of once weekly, whether they take daily pills for other things or not, they are still excited.

[00:22:28] So I think that's a good thing.

[00:22:29] Prof. Paul E. Sax: The other thing I got to just want to put in a pitch. I think the way they've done designed the two trials is really is really excellent because one of them is open label and one of them is blinded. And this way you'll get a sense of side effects much more clearly.

[00:22:42] Dr. Laura Waters: Yeah, I agree.

[00:22:44] It's exciting stuff. Obviously exciting, one of your favorite topics, Professor Paul Sachs, is broadly neutralizing antibodies. I won't dwell much on this because it was basically a joined up presentation of two previously presented analyses, but it was an oral at Glasgow, so I've popped it in. So you've got terapavimab, zinlervimab.

[00:23:03] and of course Lenacapivir, known to their friends as, oh I didn't change it, they're not known to their friends as that is Tab, Zab and Len, of course, Tab, Zab and Len. So we'd actually seen some results already. So these two broadly neutralizing antibodies, what's exciting about them is they fill that six monthly gap because you've got poor old Lena Kapovic at this six monthly party all by itself.

[00:23:27] There is nothing else to combine it with. So about half of clade B virus is susceptible to both TAB and ZAB, 90 percent susceptible to one or the other, so with susceptibility testing as a whole, barrier potentially to their future use, the susceptibility testing per se, the fact that optimal sensitivity thresholds have not yet been established, and whether this susceptibility testing is even accessible in a meaningful way, all remain to be seen.

[00:23:52] Six monthly things, excitable. We'd already seen results from the two different cohorts, and at Glasgow we saw a combined analysis. I won't dwell on this much because what we saw was 16 people in each arm, two different doses of Zab. kilo versus 30 mg per kilo, and you can see most people were susceptible to both, some susceptible to one or the other.

[00:24:14] And the key message is that as long as you're susceptible to at least one, and you're on the higher dose of Zab, you seem to do okay. Again, these are relatively homeopathic numbers. Where viral rebound occurred, it was almost all in the 10 milligram Zab arm. Now these are only results out to week 26. I think again, you know, it's a one dosing interval.

[00:24:36] It's not really enough to make any great judgments. This was more information on the people who did experience viral rebound. One developed a capsid mutation. Um, but the other two did not, but again to emphasise they were all in the lower dose ZAB arm. So next is a phase two study looking at switching to twice yearly, again a twice yearly whole regimen here, twice yearly LEN, TAB and ZAB versus continued baseline therapy in people with HIV, highly susceptible, Now, I cannot give a talk without making some point about language.

[00:25:13] Um, you know, I think increasingly now it's, it's standard that people avoid. And so they should, the term HIV infected person or people, lots of discussion about language, lots of discussion about the appropriateness or not of retiring the term AIDS, which could probably be a whole other presentation. But I, again, I'm being a bit pedantic here, but people aren't susceptible to the BNABs, they're viruses.

[00:25:35] So I've just corrected that to people with virus, highly susceptible, but not really anything new. Um, Paul, you know what I'm asking next, are you more or less excited about BNABs than you were before? Or are you neutral? I

[00:25:48] Prof. Paul E. Sax: think they're, they got a long way to go still. I mean, I'm, I'm. Still perplexed by the fact that there are people who undergo all of this pre screening, uh, and then they still have failure, uh, you know, I, I've yet to see a convincing study that shows they offer some advantage over what you and Jose Arriba's termed classical art.

[00:26:18] Dr. Laura Waters: Classical art. We go to classical art concerts at least twice a year.

[00:26:23] Magnus Gisslén: Yeah, and Laura, are there any data yet on those two for other subtypes than subtype B?

[00:26:29] Dr. Laura Waters: Not that I know of, but to be honest, Magnus, it's not a topic that I seek to keep myself, you know, to the minute up to date on. Paul, are you aware of any?

[00:26:39] No. And again, when we think about global unmet, unmet needs, uh, KB isn't one of those, is it?

[00:26:48] Prof. Paul E. Sax: No, I, I just, I think the, the be a story has been, uh, sustained by the fascinating science behind it. Yeah. More than by the, the individual clinical benefits of each of these studies. So, um, it takes, uh. Clinicians like you, Laura, to push back.

[00:27:08] Dr. Laura Waters: Yeah, and I think that, but you know, and I think the trouble is, is all the sort of fuss around them as, as you know, replacement antivirals, then it sort of makes so much noise that the really important issues, for example, around prevention of vertical HIV transmission, you know, in the context of breastfeeding and things.

[00:27:25] I think that's really exciting, you know, using was part of the, not mega heart, but mega drug regimens that maybe we'll be using at some point in the future for cure. I mean, it's that, that's where the focus should be. I understand why, because of the six monthly dosing, but yeah, I, um, I hope to prove them wrong.

[00:27:45] So this is my question as, as, as we are the judge and jury, but we've addressed this already.

[00:27:51] Prof. Paul E. Sax: Yeah, it's, it's, it's, there is such scientific interest and there is also, there's commercial interest. So, you know, as, as you said, we, we would love to be proved wrong. Yeah.

[00:28:06] Dr. Laura Waters: There's a challenge for the people who make them.

[00:28:09] Right, oh that's, I don't know why that one's in there, apologies. Right, so moving on some new daily art data, um, I've put in a Dolce study, really I think it's only the British guidelines that worry about this, um, but there was in the original Gemini trial, which of course was the first phase three randomised trial looking at Dolce and Gabbana.

[00:28:31] versus turn off of it, MgCitabine, Dolutegravir, a two versus three drug regimen, first line. I remember that might sound like, uh, well, of course it's going to work now. At the time, certainly for sort of, you know, stuck in the mud cynics like me, Dolutegravir, if you deem was a high risk to drug strategy, and we didn't know if it was going to work.

[00:28:49] And now we do. Now we know clearly it does. We've got a wealth of data supported by the guidelines that I showed at the very beginning of this talk that doluteglamifedine is a recommended first line option across the board other than in the WHO guidelines. But there was a signal for people with a low baseline CD4 count.

[00:29:07] So relative to the three drug regimen, doluteglamifedine underperformed in people with a baseline viral load below 200. Now when you looked at why, it wasn't treatment related. differences. So it wasn't that there were more virologic failures, it wasn't more than more treatment related discontinuations, it was just probably down to chance.

[00:29:26] And that's how most guidelines interpreted it, but the British HIV Association guidelines didn't. And we still say now that dolutegrelamivudine is not a recommended option for people with a CD4 count below 200. So this study, the Dolce study, which was undertaken in Argentina and Brazil, took adults with a CD four count below 200 and randomized them to a two or three drug regimen, exactly the same as we saw in Gemini.

[00:29:52] Do Lamivudine versus dol, tenofovir, nfe, disoproxil with emtricitabine or lamivudine two to one, relatively small study. But then actually with most people starting at higher CD4 counts these days, I think they did very well. Baseline characteristics, I'm not going to go into any great detail, um, about one in three had CDC stage C HIV, um, and about 50 50 heterosexual and man half sex with men populations.

[00:30:19] with a ethnicity spread as you would expect from those nations and these were the results. So here we have dual therapy in the dark blue on the left and we have triple therapy in the red on the right and you can see across the board there is no difference between the two arms. The two and three drug regimens they're in just as well.

[00:30:39] If we look at the bars on the far right, that's people with a baseline far below the blue. 100, 000. Of course, there's been much debate about the impact of viral load on dolutegavir limivudine efficacy because the viral load was capped in the Gemini study. And there's been lots of discussion, even though actually between screening and baseline, A small proportion of people in GemIIni had moved into a higher viral load category, and it's actually really uncommon to recruit people with very high viral loads to any first line study.

[00:31:11] But this data was reassuring, and if we look at it in a bit more detail, what we see here is the bars the other way round and you've got overall, dual and then triple in each little cluster. And what you can see across the board, overall, viral load above 100, 000, viral load above 500, 000, numbers getting smaller of course, and a small number of people with viral loads above a million.

[00:31:36] There is no difference between the two and three drug arms. Now again, numbers of participants are small, but there really is no signal at all. In fact, if you absolutely had to. that your entire mortgage or whatever debts you may have on one or the other, you would just say numerically actually dual therapy is faring at least as well.

[00:31:55] None of these differences are statistically significant. Of course. What else? There were 11 protocol defined virologic failures, seven and four on the dual and triple arms respectively, but no emergent resistance. Again, a very common theme with the second generation integrase high barrier regimens first line.

[00:32:13] Similar CD4 rise actually numerically a bit more on dual therapy as it happened, the median CD4 baseline was a bit lower in that group. So both groups ended up at exactly the same CD4 at week 48. Post Holth analysis, a very special type of post hoc analysis. Apologies for the typo that uh, dual therapy was non inferior at higher baseline viral loads.

[00:32:33] The adverse events were almost identical and the conclusion was this supports the efficacy and safety of dolutegralamibidin at high viral load and low CD4 count. So I guess the question Paul is, were you doing that anyway? Does this make any difference to your practice? Um, and obviously I've already mentioned which guidelines have a CD.

[00:32:52] Honestly, my typing, I've. been beset by migraines recently. That's my excuse for all these typos. Which, which guidelines have a CD4 caveat? I've already told you the answer to that. Now, I don't know if this resonates outside of the UK, but we have this, if Carlsberg wrote, or if Carlsberg did, so the idea that Carlsberg is the best lager in the world, which it clearly isn't.

[00:33:11] There are many lagers that are much better. But if Carlsberg wrote guidelines, then it would write the British HIV Association guidelines, of course. But yeah, I think we are the only guideline that worries about this signal. So. Paul, what does it mean for your practice, or is it not a concern?

[00:33:26] Prof. Paul E. Sax: You know, just the strength of the study is that it's randomized.

[00:33:29] And, uh, also they had a very clear, uh, study question that with the weaknesses you alluded to is the sample size and it's open label. That's not necessarily weakness, but it does, Limit the conclusions you can make somewhat, um, probably, uh, it, it really reinforces that double decker very limiting is a very effective first line option.

[00:33:49] And if, if it were, uh, if it were, you know, not for the fact that, that The first line option we use most commonly in the United States is Bictegra FTC TAF, which has a very similar safety profile, then, uh, it probably would, would become the first line regimen. And I think that one of the more exciting projects that I'm about to get involved in is, uh, uh, an effort to make, uh, dolutegra valivudine more applicable in a global setting.

[00:34:18] Because. people who are committing to a lifetime of TLD with tenofovir DF, uh, could be seeing some real problems down the line with long term tenofovir DF use. Um, problems that they're not seeing in the first 96 weeks. Um, one other question about this study, I would imagine that they have weight measurements or they reported them and, and what were they?

[00:34:43] Dr. Laura Waters: I don't think they did. So it's certainly not, I don't know where it came out in the questions afterwards, and I didn't make a note of it, but it wasn't included in the presentation.

[00:34:51] Prof. Paul E. Sax: You'd have to assume that in a population that starts with a low CD4 and a high viral load, that they would basically have the most weight gain, and that you might see some differences between a TDF containing regimen and one that doesn't have TDF.

[00:35:05] Dr. Laura Waters: Yep. Absolutely, absolutely. And I think, you know, the point about TDF longer term is, is a really important one. Um, uh, and that's coming from a big TDF fan. I think the other thing that's really challenging when you put TDF and dollyutegravir together is that well described impact on creatinine. And again, I saw someone in clinic this morning, it was This is honestly true.

[00:35:23] It's great that my clinic this morning has furnished me already with so many anecdotes for this feedback, but I saw someone and the person in question, I've reassured them again and again and again. They do not have renal disease. We don't have easy access to cystatin C at the moment. So sometimes we resort to an isotopic GFR just to prove that it's a dolutegravir tubular secretion effect and not true renal impairment.

[00:35:45] And we've got some people with marked differences between their measured and their estimated GFR using kratnin based methodology. And he said to me again, but I definitely don't have chronic kidney disease, do I? Because what happens here is primary care check the renal results that automatically creates a chronic kidney disease condition in their kind of handheld electronic records they carry on their phones.

[00:36:07] And I spend a lot of time, at least with doluteglamivudine, I'm getting to the point, I promise, at least to doluteglamivudine, I can say it absolutely is not true. renal impairment. When your creatinine goes up and you've got TDF on board as well, I think the interpretation can get a bit more tricky. So I think it's um, a good option.

[00:36:24] Prof. Paul E. Sax: Especially older, older individuals. It's really, it's, it's because, because everybody knows that the kidney specialists say that renal disease is multifactorial. It's never, it's rarely one cause. Yep. Absolutely.

[00:36:39] Dr. Laura Waters: Absolutely. Right. Moving on. Toxicities and comorbidities were nearly there. Um, now you said yourself.

[00:36:46] To sacs that, uh, Bictegravir, emtricitabine and Alafenamide is like dolutegravir a very well tolerated regimen, yet this belief that Bictegravir is inherently better tolerated than dolutegravir persists. So it's not to say there aren't people we know, you know, there's some quite good pharmacogenomics dose response type work showing that indeed dolutegravir can be associated with neuropsychiatric symptoms and side effects as can bictegravir.

[00:37:13] I think the reason. The poor old doll eutegraphy is, is perhaps over blamed is of course the fact that as you've said already we're using it with Abakavir an awful lot and those original Gilead studies, um, of which you were a first author on at least one of them, 1489 versus 1490, comparing Bic and Doll, but in one case Abakavir and maybe Dean Doll, in the other case, TAF 1.

[00:37:36] 490 that gave us that cleanest head to head comparison. No difference between the two in terms of tolerability, but Abacavir, Limivudine DOL versus Bictegravir, Emtricitabine and TAF, there was significantly more nausea and numerically more insomnia. There's also the fact, I think, that by virtue of when they became available, that you're on the, the, um, older new drug and then you switch to the newer new drug because you've got side effects.

[00:38:01] I think quite naturally the cohort data will be biased towards switching from DOL to BIC by the nature of the temporality, if that's a word of when they came about. So the MIND study briefly was a small study, virally suppressed people with neuropsychiatric issues at BIC. baseline. So they took people with sleep disorders or mood disorders or substance use disorders and they randomized them in a blinded fashion.

[00:38:27] So it's small, but it's perfect. Uh, so you've got, uh, Devato versus, sorry, doyteglamifedine versus Bic M15 TAF placebo or vice versa. And these are the baseline characteristics. So I won't go through those in detail, detail, but you can see high rates of insomnia, anxiety, depression, And other such things, and they made the point that actually these may just be the people that would be excluded from participating in classical clinical trials.

[00:38:54] And of course there's a fact that what we have learned is people with pre existing depression or other such conditions are more likely to develop depressive symptoms or worsening of depressive symptoms in antiretroviral trials. So week 24 only, um, but in terms of discontinuations three and two in the Bictegravit and Dolutegravit arms respectively, we can see the reasons there.

[00:39:18] Um, although the grades were relatively mild considering these drove discontinuations, certainly it was only grade one in each. I'm not sure how you can grade an adverse event that led to a discontinuation as grade one, but again, that's a topic for another talk. But it was this type of data. I have not included all of it.

[00:39:33] This is just one of the patient reported outcome measure slides, but for insomnia, depression, treatment, satisfaction, anxiety, et cetera, et cetera, you can see the lines for the two. Options are super imposable. So strong data that in a small population predisposed to neuropsychiatric adverse events, there was no difference between switching to the big tag of it or the dollar tag of a based option.

[00:39:58] Any thoughts on that one?

[00:40:02] Prof. Paul E. Sax: Uh, you know, it's, it's, it's sort of brings us back to the very 1st, uh, dollar tag of here versus a favorites clinical trial. Uh, which, of course, comes to mind because it was blinded and lo and behold, the insomnia signal was stronger in the abacavir, dolategavir, uh, abacavir lamivudine dolategavir arm, which surprised everybody and, and, and you've, you've made a compelling case that it's the abacavir that is, um, Probably responsible, uh, are you going to discuss any of the other outcomes from this study?

[00:40:39] Dr. Laura Waters: No, I wasn't planning to. What have I missed?

[00:40:42] Prof. Paul E. Sax: I mean, I think, I think related to one of your, your, your hobbies, which is the weight issue, is that this, these are people on dolutegravir limididine, right? And that's what they're doing. basically doing if we assume that FTC equals 3TC and big tegravir equals dollar tegravir is they're kind of intensifying it by adding tenofovir alafenamide.

[00:41:02] So if, if this, there's a weight signal for adding TAF, this might show up in this particular study.

[00:41:12] Dr. Laura Waters: Yeah, although what were they on at base? I can't remember what they were on at baseline, isn't that? Truly terrible. Um, but they weren't, they weren't, it wasn't that everyone was on Devata at baseline. I don't have, no, I don't, I'm going to check that out during, I can multitask and during your presentation, I'm going to double check, I'm going to double check that and come back to you if we have time.

[00:41:34] All right. The other thing, just on this, on this topic, I just wanted to include this again, it's another oral abstract. Positive Voices is a large survey undertaken periodically here in the UK. Uh, they select people who are representative of the general population living with HIV in the UK, and the most recent survey undertaken in 2022, um, this is data from 4, 247 people, and they really focused here on mental health.

[00:42:02] Uh, what I just wanted to point out, I think it's things that we, we kind of know about. already, but seeing it in such a sort of big, well conducted, uh, cohort analysis, I think is good. It's a one in four reported depression, anxiety, which actually declined over the last decade. So that's good news that the prevalence of these symptoms has declined.

[00:42:20] As you might expect a really clear correlation between both depression and anxiety symptoms with socioeconomic factors. So people with unstable housing, people with unstable employment, people without money for basic needs, or more likely to report symptoms and also the social factors and stigma. So.

[00:42:36] people who felt shame about their HIV status or people who lacked social support. Now, of course, one might hope that education and support to reduce shame around HIV status, using peer support to, you know, address lack of social support might improve these symptoms. Um, it kind of feels inherently obvious that they might, but I don't think we have very strong data to show that.

[00:42:57] I think the problem we have here is that the charitable sector. which includes much of our peer support is kind of seen as this added luxury. And I think we kind of lack some of that really hard cost effectiveness data to show that actually funding decent peer support will improve outcomes. The other thing I think is really important is something clearly that HIV clinics can advocate for and encourage the prescribers of the relevant medications to address is there was a Marks demographic variation in treatment coverage.

[00:43:26] So they looked at the ratio of treatment for depression, anxiety, relative to the prevalence of symptoms. Now, not necessarily the most scientifically accurate way to address this, of course, but that more than 75 percent of gay and bisexual men have sex with men. who had symptoms were on treatment compared to less than 40 percent of black African heterosexuals.

[00:43:46] Now there are other confounders here, but it's hard to believe that at least a significant part of this wasn't down to sort of inherent differences in terms of access to health care and what health care is offered once people get into a clinic. So anything surprising for you there?

[00:44:07] Yep. So very briefly now, prevention, not much to touch on here and, and Paul, I know you touch on, um, purpose, but I think, you know, it's, it's, it's been a very purposeful year, pardon the pun, um, great data for Lenacapavir, great data for Capotegravir as well. Paul, and, and Paul to quote you I'm sure, it's because long acting options have addressed the adherence problem because we know that the suboptimal performance of Tenofovir based oral prep in pretty much every study, You is down to adherence.

[00:44:37] When people take tenofovir based PrEP, it works, but a lot of people don't, and guess what, then it doesn't work. So, um, I think we'll see lots more data coming out of PURPOSE, and of course, we've got other studies ongoing, um, addressing needs in, in particular populations, including PURPOSE 4 in, um, people reporting injection drug use.

[00:44:58] DoxyPEP big focus, not much new to be honest. Again, there was another good plenary. That's what I love about Glasgow is they do a really fantastic summary of the year. Um, and some really, really nice talks, um, including one on Doxypep, which summarise, you know, the three big studies we know about Ipigay, Doxypep and Doxyvac, all reporting high efficacy in terms of chlamydia.

[00:45:19] and syphilis in people using Doxypep and that's a stat dose up to 72 hours after condomless sexual intercourse. Of course, we also know, and this is a real reminder of the original oral PrEP studies and indeed the Tenofovir arms of the recent PURPOSE studies, um, that poor efficacy for Doxypep in women in Kenya, very much driven by low adherence, there was no significant difference.

[00:45:42] This graph looking at first episode chlamydia because women simply weren't taking it. So I've put this study in simply because it was an oral abstract, um, and also it means I'm going to rip the mickey out of the font that they use, because there is no place for Comic Sans font in a modern PowerPoint presentation.

[00:45:59] I'm a bit of a pedant when it comes to this. But the pride Pre docs, pre doc study. Again, another language thing. Impact on high risk MSM. Can a person be high risk themselves or is it perhaps a behavior they partake in? Again, I'm aware I'm being a language pedant, but it's one of my favorite hobbies. But this was essentially a cohort of 189 people.

[00:46:19] So, um, perhaps not as much of a trial as I think the title might have suggested, but it was 189. people, um, who use Doxypep and it was looking at what happened before and afterwards. So this is a population, many of whom were on PrEP, um, more than 10 sexual contacts a month, um, high rates of chemsex use and high rates of STIs.

[00:46:45] And what they showed as you might expect based on the randomized trials in this kind of real life cohort using people as their own controls, a significant reduction in instance of all three of our main bacterial STIs, so chlamydia, gonorrhea as well to a lesser degree, and syphilis. And they showed that amongst the gonorrhea acquisitions where they were able to undertake antibiotic sensitivity testing, there was no difference in gonorrhea resistance rates before and after doxypep use.

[00:47:16] They were high before and they were high afterwards and they were all susceptible to keftraxone. So again, nothing particularly surprising here and those were the conclusions proving that this works in a real world setting. Uh, no emergence of multi resistant germs. No RCID doctrine. moment how often you hear the term germs, um, but ultimately bacterial resistance, the microbiota requires further evaluation.

[00:47:41] So I took three things. I love vintage, I love vintage clothes, but firstly the comic font, secondly it's presented in a 4 3 ratio. I remember when I first moved to 6D9 in the kind of online era, thinking how stretched out the slides look, and now if I have to present in 4 3 they look very squashed. And germs, what do you think of the use of the word germs in adult infectious diseases?

[00:48:01] over to the infectious diseases expert, please. Well,

[00:48:04] Prof. Paul E. Sax: I'll tell you, it's, uh, in, in the lay press, um, it is very commonly used. And when you look and when you read patient educational material, it's incredible how often that word is used. It's sort of. Yeah. Broad category for microorganism because microorganism sounds so scary.

[00:48:27] Dr. Laura Waters: Yeah, yeah, I mean you could always use microorganism once in bracket germs and then just stick to microorganism. To me it just makes you think of sort of cleaning adverts. Kills 99. 9 percent of all known germs dead. And that really would be an effective DoxyPEP result, wouldn't it, if we saw that? But, uh, yeah, nothing new to be fair.

[00:48:44] So to finish on a slightly unrated closing thought and a very arrogant closing thought, because I'm taking a point I made in a presentation that I gave. Isn't that terrible? Um, I'm going to finish on me. Um, so there's a picture of me. I was mortified slash overjoyed to be used for the poster promoting the charity run.

[00:49:02] So, uh, my dear friend and colleague, Alex Schneider, who is a fantastic community advocate, He organizes these charity runs at various conferences and he did the same for Glasgow. It was a 5k. I did the 10k in Munich in, for me, incredibly high temperatures and that was exhausting. Um, but there were a fair few of us up early in the morning to do the 5k run.

[00:49:23] Um, but I also presented a case on statins in the University of Liverpool drug interaction session. Again, I will reach the point, but one thing I just really wanted to point out emphasize because this is something that we're going to need to think about in the UK is the European hypertension guidelines have just been updated and they have this new name, elevated blood pressure.

[00:49:43] So an office systolic between 120 and 139 or a diastolic between 70 and 89. And hands up, I must admit, these are the sort of readings that I would say, Hey, your blood pressure's fine. See you in six months time. And what's important is they recommend school. It's like any other kind of cardiovascular risk.

[00:50:02] There are people who don't treat, there are people who definitely treat, and everyone else in the middle category undergoes this score assessment. And one of the additional risk factors is HIV. So, I think it's important about whether or not this is going to shift the thresholds for the rest of us. It'll be interesting to see what our own National Hypertension Guidelines say.

[00:50:22] But the thing that I have learned, and I don't know why I've got that point, Damn emoji thing bang in the middle. Uh, I'm going to get rid of it because it's important to actually show, um, there with me. Where's my slideshow mode gone? Here you go. Is Can you see that slide again? Good. Is just How complex a routine or a good routine blood pressure measurement is, I'm not going to go through this in great detail, but things like quiet room, remaining seated, not talking, no smoking, caffeine in the 30 minutes prior to your blood pressure, we routinely measure people's blood pressures in a busy clinic when they have run in a few minutes late because the London Underground was delayed, clutching their coffee of choice.

[00:51:10] The reason I'm making a point about this, firstly I think if we're going to do anything we should do it well and I certainly in our clinic don't think we're measuring blood pressure very well but it also makes me a little bit anxious about relying on cohort data to look at the impact of various factors including antiretrovirals on hypertension because I don't think we're doing it properly hoc analyses of randomized trials I would wager that many clinical trials aren't necessarily being as stringent as this when it comes to measuring blood pressure accurately.

[00:51:41] And I've got an idea, are you ready for this Orsax, that you might like this? I've sent it to Steve Grinspoon already. Instead of reprieve, if we are actually thinking that people with HIV might need a different threshold for blood pressure intervention, as possibly suggested by the European Hypertension Guidelines, is we need a reprieve for blood pressure.

[00:51:58] Bepreave. Bepreave will be the next study. So I shall finish there. Thank you for listening. I'll stop sharing my slides and thank you very much indeed.

[00:52:08] Magnus Gisslén: Thanks a lot, Laura. It was great. I think we take just one question from here and that it's for you and maybe for Paul too. And it goes for the Duluthegravir 3TC as an actual treatment in naive cases.

[00:52:24] And we, and you said, I mean, the low CD4, it didn't matter. So do you still take the highest viral load limit into account, like 500, 000?

[00:52:35] Dr. Laura Waters: And the answer to that is, is no. Um, we have a clinic policy and, um, it's a debate for, for the, the woman who likes to stand up and go, what's the evidence? Well, for people with very high viral loads, we quite often do start four drugs.

[00:52:48] Um, and that's based not, yep, I know that's not based necessarily on evidence that four is better. Uh, it's. But it is based on evidence that all regiments underperform at very high viral loads. So for us, generally speaking, it's small numbers and smaller, I suspect, than they saw in, in, uh, in, in Brazil and Argentina.

[00:53:06] But for people with viral loads above a million, we'd start war. Don't judge me.

[00:53:10] Prof. Paul E. Sax: No, I'm not judging. We, the Latin, we, we had up, uh, I'm, Unfortunate case, although the outcome turned out to be okay, of someone admitted with acute HIV infection complicated by meningoencephalitis, and so he was in our neurologic, neuro ICU, very, very sick, and his HIV RNA was greater than a million.

[00:53:31] And yeah. We chose to use four drugs. I mean, it was, it was an extreme situation, so I don't know whether it was needed or not, but.

[00:53:39] Dr. Laura Waters: Yep. No, no. And that's the thing. It's hard. It's, it's, it's hard to know. And I think when we now have the luxury of being able to find four drugs that are all pretty safe and well tolerated as easily as we can find three, then it is something that we do tend to do.

[00:53:55] But yes, I have no concerns about wherever I'm comfortable to use three drugs, I'm comfortable to use them.

[00:54:03] Magnus Gisslén: So, so I mean, probably doesn't matter if it's four or three, but at least there is no end.

[00:54:08] Dr. Laura Waters: Yeah,

[00:54:09] Magnus Gisslén: absolutely. Good. So great. Thanks again. And let's go on. This is the

[00:54:17] Prof. Paul E. Sax: review of the year,

[00:54:18] Magnus Gisslén: Paul.

[00:54:19] Prof. Paul E. Sax: So, so what I'm going to do is, uh, share my screen first, and I want confirmation that you can see that.

[00:54:25] Yes. Good. Good. And, and, uh, because IDWeek has got relatively little in the way of new clinical trials in HIV, and most of them I've been working with. Actually, we're already discussed by Laura. I've decided to just do a recap of the top studies in HIV medicine for 2024, and they'll be grouped by treatment complications and prevention.

[00:54:50] And it's got to be interesting to both clinicians and clinical researchers. And, uh, I confess already my bias towards a certain journal called Clinical Infectious Diseases. And at the end, we'll all get to vote, I think, at which we think is the number one. And you know, uh, what are the criteria for interesting?

[00:55:11] Well, uh, it's gotta be something that Dr. Borders and I think is interesting. Magnus, you can vote also. Okay, great. So, so the first study I want to review, this is actually from CROI, and this is the Latitude Trial. Remember, this took people who would not typically be good candidates for cabropivirine. They had adherence barriers.

[00:55:33] They had, you know, they met criteria for having treatment failure. And at the beginning, they got, uh, assigned to, uh, just go on oral ART with, with, uh, With very important conditional economic incentives, they were paid hard cash to take their A. R. T. And then once they achieved, if they achieve virologic suppression, they would then get randomized to either continue their standard of care oral A.

[00:55:59] R. T. that they were on. Uh, all conditional economic incentives dropped. Uh, or switch to cabotegraviropivirine. And then the plan was to go on for 52 weeks, and eventually everyone would get their long acting injectable, and then they'd be followed thereafter. Extremely difficult study to enroll. We were a study site, uh, as you can imagine, the kind of person who would meet criteria for a study like this is typically the kind of person who enters into randomized clinical trials for a variety of reasons.

[00:56:31] Uh, and one that maybe they didn't want it, the randomization. Two is maybe they did not have the wherewithal or the ability or the desire to do the regular follow up that's required for a clinical trial for whatever reason. It was very hard to enroll, but it was Accomplished covid notwithstanding, and, uh, we have the baseline characteristics here.

[00:56:52] Not typical at all for a U. S. Based study. You can see that it's a younger group. It's more women than typically in U. S. Based studies, more racial and ethnic minorities and then a higher proportion with current or or previous injection drug use. So, uh, the big news was that the study was stopped early.

[00:57:12] Now, the primary endpoint did not meet statistical significance, but these two secondary outcomes did. You had virologic failure, which favored the cabotegraviropivirin arm being significantly lower, and you had Treatment related failure, meaning people just couldn't be on the regiment at all. And so when you combine those two, the data safety monitoring board said, time to stop the study, there's overwhelming evidence of benefit of cabral pivarine versus oral ART.

[00:57:39] Uh, and so, uh, there were some people who had treatment failure with resistance, but, you know, there were actually about the same number in both arms, not surprisingly on cabral pivarine, there was a sort of broader range of resistance mutations detected. But overall, I thought this study meets criteria easily of being one of the most important of the year, even though it's not published yet, because we have now this solid prospective evidence of a better strategy for people who struggle with COVID 19.

[00:58:08] Adherence, uh, population engaged was different from usual and, you know, I think we're going to see some fascinating data on the use of economic incentives for, uh, health outcomes from this trial. I can't wait to see that. The other thing that's going to be really interesting will Who were the people who didn't make it to the randomization point?

[00:58:31] That is going to be fascinating because remember, there's a significant fraction of them, even with the economic incentives, couldn't couldn't somehow get to viral electric suppression. So that was my first choice. Um, related, I wanted to highlight the first of the CID studies. This is not actually a surprise since this Ward 86 experience in San Francisco has been so broadly discussed.

[00:58:59] In fact, you just heard Laura discuss it already with Monica Gandhi's plenary at Glasgow, but this is the largest group so far. Of people who are have viremia at baseline and gets treated with long acting injectable therapy. And at week 48, you know, just like a clinical trial, you know, 81 percent are still on capropivirine and virologically suppressed and 7 additional participants or support people in this cohort are virally suppressed on different regimens.

[00:59:28] And yes, there were some adverse virologic outcomes. But when you look at the baseline characteristics, this really does lend itself to a, a, uh, a new strategy, one that I think we should be more broadly adopting. Licensing Limitations notwithstanding, so we ended up modifying our ISUSA guidelines because of these data, and we basically said, you know, we have now the, the, the, the cohort from Ward 86, and we also have this, uh, latitude study, even though it's not directly related.

[01:00:04] So under certain circumstances, we recommended this. We did not think it should be applied to everyone. treatment failure and viremia. Um, we thought it should be only those people who already we had tried everything and also had high risk for disease progression, a CD4 under 200 or a history of an AIDS defining complication.

[01:00:27] Um, we did want people to have virus susceptible to https: otter. ai Drugs. Now, this is different from DHHS. DHHS does not comment on these factors. And I think they're sort of leaving it more open to the to the, to the clinicians. But we thought we didn't want people with, for example, a CD4 cell count of 700 and HIV viral load of 500.

[01:00:47] Three thousand necessarily to go on this regimen, where if you have a treatment failure on this regimen, you then end up potentially jeopardizing your future options for years to come. Anyway, um, thoughts about, uh, the guidelines change and what do you think the British are going to do? And what about Sweden,

[01:01:08] Dr. Laura Waters: Sweden, Sweden first?

[01:01:10] Magnus Gisslén: Yeah. Okay. So first, I mean, we are using so little capotegory in long acting due to other reasons, but actually I think the studies are sort of impressive in the first ones. So, and actually I've used this in two cases, exactly those type of patients with high viral loads and other difficulties and starting and it worked perfectly well.

[01:01:31] So good to have the option in rare cases.

[01:01:35] Prof. Paul E. Sax: Yes.

[01:01:36] Magnus Gisslén: Rare cases. Okay.

[01:01:38] Dr. Laura Waters: We're looking at this for the BEEF guidelines at the moment. Um, it's still on discussion and I don't know if they have to go out for consultation, but I think it's fair to say that most of the guidelines panel feels very similar to this, that in those exceptional circumstances where, you know, and it's always difficult to be 100 percent certain, but where with your best knowledge and best intent, that the benefits are likely to outweigh the risks, then we would support it.

[01:02:04] Even so again, for England, we are going to have to pursue, and we are currently pursuing a separate prescribing policy. So even if our national guidance says similar to this, we still need a separate policy from, from our national health service to be permitted to do so. But that's something that we're pursuing at the moment.

[01:02:19] Prof. Paul E. Sax: Okay, great, great. I just wanted to say what's, what's planned. Um, there is this study, uh, which is called the crown study, uh, that they are, uh, doing a, a randomization at the outset. So, uh, imagine people like in the, uh, in the, the San Francisco cohort, so there are people with viremia, uh, and they get randomized to oral ART or recalcitrant.

[01:02:47] Because the FDA said they had to, uh, I actually disagreed with this, but that doesn't mean they care what I think. Uh, I think you've, if you have people who already, uh, have shown they will not take oral ART, why, why have a randomization to oral ART? In fact, uh, we could use that, the data from the Latitude trial, that first part of the Latitude trial to give you an indication of, of what a historical control would be like.

[01:03:14] You know, those are people who. We're put on oral ART and we're paid. And so that's a sort of best case scenario. Anyway, the other point is just related to the Lenacapavir and Cabotegravir combination, which, as I alluded to, we have two people on this. And I think it's very exciting, uh, in, in many ways.

[01:03:33] It's not, uh, There's no synchrony in the dosing, unfortunately, or there's very little synchrony. You have to give one of them six times a year and one of them twice a year. But, uh, it, it is, uh, promising and shows what's available in the future. Moving on to the next, uh, long acting injectable study that I thought warranted inclusion in this greatest hits package.

[01:03:54] And that's, uh, capropivirine in Africa, the CARES trial. It was an open label trial, uh, and the patient population, very different from those who were in the phase. three, uh, Atlas and Flare trials. 57 percent women. Um, many of them had been on prior NNRTI containing regimens, although no known history of treatment failure.

[01:04:18] Uh, and they're, they're on standard therapy here. They're on a tenofovir, lamivudine, or m tricitabine regimen, plus either an NNRTI or dolutegravir. biologically suppressed. No, no hepatitis B. And then you can see the study design is very, very similar to Atlas and Flare. It isn't, you know, although the oral lead in was optional.

[01:04:42] Notice how infrequently their HIV RNA is measured. Every 24 weeks, every six months, very different from how we would have predicted. done it initially when we first started out with this, uh, and the results are, were a resounding success. Uh, again, non inferiority displayed, um, high rates of treatment satisfaction.

[01:05:07] There was one person who had virologic failure on capropavirin and additional virologic failure. with, uh, with that ended up, the person that ended up dying during the course of the trial. And sadly, uh, but very exciting results. I do, um, I'm very disappointed to have heard that the, uh, ropivirine is not being made available in, uh, the parts of the world that need it the most, uh, because that's, uh, that's, uh, That's tricky.

[01:05:35] I know that the makers of ropivirine have have closed their infectious disease research area, but then I maybe someone will will take ropivirine off their hands and to make it more broadly available. Now, I want to mention a couple of other things about this trial. One. is pro viral DNA genotyping. I gotta say this is one of the more contentious areas in our little world of HIV specialty.

[01:06:05] To find that there are 10 percent of people in this trial with no history of virologic failure who had ropivirine resistance, but even more surprising, 8 percent with cabotegravir resistance just makes you wonder what's the, uh, I don't know what's the validity of that. So I put a little question mark there.

[01:06:24] I want to say, though, that doing the study made a lot of sense. You know, it's basically was successful in, you know, diverse viral subtypes, measuring viral load every six months, very high rate of obesity among participants. You know, that was one of the risk factors for treatment failure with resistance in some of the, some of the studies and also prior in an RTI exposure.

[01:06:45] And I don't know what to make of the profile DNA resistance testing. And you've, either of you figured that out? Uh, just

[01:06:54] Dr. Laura Waters: Well, I mean, whenever it's a resistance question, I don't understand. I ask someone who's much more likely to than me. Uh, which for me is Anna Maria Greti. Um, Unless, unless the other person of course who you work very closely with is Dan Kuritskas, um, who I will always corner at conferences as well.

[01:07:13] But I'm pretty sure Anna Maria asked this when it was presented around, I think, something that's related to her definitions about whether this would be true resistance mutations or whether perhaps they were over interpreting some of the polymorphisms. And of course, the accuracy, accuracy of pro viral DNA, because I think different labs do different things about hypermutation and APOBEC this and that, you know, I'm entering realms that I'm really not familiar with, but, but the validity of some of what's reported, um, I think is really key.

[01:07:42] And I think there is sometimes when studies present pro viral DNA results, they perhaps don't explain what did they do to deal with, you know, erroneous. nonsense. How did they pull that out? Um, and exactly how did they interpret and define resistance? So I think it's possible that sort of those numbers are overestimates.

[01:07:59] And of course, but what we know when we look at 184, the longer it's been there hiding in the background, the less important it is. So is this true resistance that just was no longer a meaningful level?

[01:08:09] Prof. Paul E. Sax: I, I, I gotta, I have to say, uh, given the consequences of treatment failure, uh, on this regimen, even with this result, I would not recommend use of either of these drugs in someone with known resistance to them.

[01:08:24] Yeah, me neither. Yeah, okay. Okay. Well, um, moving on to oral ART, uh, I wanted to summarize three trials, all of which were presented, uh, this summer, um, and they are the DEFT trial, the VIZEN trial, and the GESCIO, uh, study, uh, and what they basically have Confirmed is the findings from from Nadia, even even better than Nadia, actually, and the two S.

[01:08:53] D. Studies. What they basically tell us is that use of Dolo Tegrever and big Tegrever in people with an R. T. I. Resistance can be done Successfully, regardless of their NRTI resistance, which is a really extraordinary thing when you think about it. So let's take a look at the DEF trial, uh, and that is the pronunciation.

[01:09:12] I've, I've been told by investigators that it's the, you know, the two is silent, uh, and it started out as a comparison between standard of care in people with second line treatment, second line treatment in most of the world, you know, as people who have, have a prior failure. Uh, on an NRTI plus 2 nuc background, uh, backbone, and their, their, uh, stand of care for years was to recycle the nucleosides and use boosted protease inhibitor here at Diverunivir Ritonavir, and their, the experimental intervention was a way to do that.

[01:09:45] Two new drug intervention with Dolutegravir plus Darunavir, Ritonavir. And this was trying to redo those earlier second line studies that had Raltegravir, arguably worse drugs in those drug classes. So here now we've got the better drugs. And, uh, in the middle of this study, Nadia came out and they said, Oh, let's modify it and let's include a recycled nucleosides plus doluteg of your arm.

[01:10:11] And they ultimately completed the trial with 96 weeks of follow up. And, uh, the results are, uh, impressive of first the baseline characteristics, uh, Not surprisingly, again, it was done in Africa and Asia, a high proportion of women, uh, and a high proportion of people who are, uh, black or Asian. Um, CD4 of 20, viral load of 20, 000, 5 years of ART, and I don't think there's any resistance data on this one.

[01:10:42] Is there? I don't think so. I'm looking at my co faculty. No. Okay. The answer's no. Good! Anyway, what they showed was that this dolutegravir arms are superior to the uh, the uh, standard of care. That's not just the experimental regimen of darunavir, ritonavir plus dolutegravir but also the collagen's.

[01:11:03] Dolutegravir plus, uh, recycled nucleosides. Now, again, we do not have resistance data from this trial yet, so it's possible, like with Nadia, there might be a few cases of resistance that crop up in the Dolutegravir arms, but we have not seen that yet. So this is then, uh, Bracketed or supported by the Vizen study, and when I present the Vizen study, I like to present there's actually two studies in here.

[01:11:31] There's people in, uh, with HIV and living in Zambia, and they are on a baseline regimen of a favorins or nivirapine plus, uh, tenofovir, uh, XTC, and there are two different groups. There's Arm A. group, and they're virologically suppressed. You'll notice their HIV RNA is less than 1, 000. Then there's arm B, and these are people with virologic failure.

[01:11:57] Their viral load is greater than 100, 000. And so the interventions are different. In arm A, everyone gets dolutegravir, uh, plus, uh, either a TDF or a TAF based, strategy. In arm B, those same two arms are repeated, but we now have a standard of care arm, which, as in the previous study, is a boosted protease inhibitor.

[01:12:18] But this time, it's the old guys. It's lopinavir, not azanavir, and it's Zidovodine, Zidovodine, so that's the WHO guidelines, uh, in years past, which said that if you're on tenofovir at baseline, you switch to zidovodine, and that makes sense from a genotype perspective. So let's take a look at the, uh, baseline characteristics.

[01:12:42] So in RMA, um, mostly fully suppressed. Okay, Viral Load 84, CD4 491, RMB, however, woof, not, not so great. Viral Load 150, 000, CD4 225, and they did have resistance analyses for RMB, and it was whopping. Um, 56. 5 percent had no predicted tenofovir activity, 75 percent had no predicted tenofovir activity. XTC activity and, uh, the boosted PI arm, um, they, they, a lot of them had zidovitine resistance.

[01:13:17] So, so lots of resistance in the, in the people who had treatment failure. So the suppressed group, the TAF and the TDF arms, did fine. We haven't seen any virologic differences between TAF and TDF really in any study. But then when we look at the treatment failure arms, they actually show that the dolutegravir arms are now superior to the boosted PI arms, whether it's lopinavir or or adizanavir ritonavir.

[01:13:49] Uh, not surprisingly, this could be driven by zidovanine and its poor tolerability. Imagine taking lopinavir ritonavir with zidovanine in 2024. Uh, you would never prescribe that even to your worst enemy. Uh, so, so maybe this was all about tolerability, but it is very reassuring. And even more reassuring are these resistance results, um, Nobody developed major dolutegravir, uh, mutations in the course of the trial, uh, which is very, very exciting.

[01:14:20] Uh, I have to say, this is bet, these are better results than we saw in the NADYA trial. So, uh, these two studies gave us evidence about dolutegravir. This GESCIO study gave us evidence about dolutegravir. Bictegravir. This is the first such study done in Bictegravir where you have people on second line therapies who have experienced treatment failure and they have now, uh, they are suppressed on a boosted protease inhibitor and the randomized one to one to get Bictegravir FTC TAF or continue their current regimen.

[01:14:51] Uh, results here, uh, very much in line with what has seen in other studies, that the Bic Tegra RFGC TAF arm maintains virologic suppression in a non inferior way to staying on the boosted PI, was nearly significantly better. We have, uh, Pro viral DNA results of this that are been submitted to CROI, and not surprisingly, the patients at baseline who were on the second line regimen in Haiti ended up having quite a bit of, uh, of of of nucleoside resistance.

[01:15:24] No surprises there, and nobody in this trial experienced virologic failure with Bictegravir resistance. So, uh, this, um, studies, uh, have have really, I think, changed the way that that we think about drug resistance in resource limited settings. And I was actually communicating with Jeremy Nell recently from South Africa, and he said, We don't even think about, uh, ten off of your resistance or limiting resistance when using dolategravir any longer.

[01:15:54] And I was wondering, is that set the case for you as well? I mean, do you K 65R, 184V? Go ahead and switch them to TLT or PICTEGRAVSTTAF

[01:16:07] Dr. Laura Waters: or, uh, Well, yeah, we're, we're a bit more, we're a bit more cautious. So I think it depends what you have available. It depends on the balance of risks. It depends on how frequently you can monitor viral load.

[01:16:17] And when someone's got an absolute contraindication to a PI, I think then you're going to take more risks than somebody who's actually doing entirely well, and I think what's really challenging is, is where resistance data is available. it's not necessarily addressing every concern. So we have this kind of, I have a little WhatsApp group with, with, um, uh, Anna Maria Goretti and then, uh, Nikki Mackey, a colleague of mine in central London who, um, is a clinician who, uh, knows much more about resistance.

[01:16:46] And I do, Marta Bofito is another example. We sort of test each other, how many NRTI RAMs before you say no to Bix Harvey. And it's, it, I, There's only great rules. I think being frank, it probably varies certainly for me from from one day to the next, uh, that one set mutations one day will be a no, the other day it won't.

[01:17:05] Again, it's going to depend on the characteristics and what the person that you're seeing wants to do. But yeah, what about an isolated K65R? Because from what I understand in Nadia, almost all of the K65R was in conjunction with 184, which is that sort of, so, so what about K65R on its own? How many TAMs before you start getting anxious?

[01:17:22] And I just Just don't think we know, and I think, you know, inherently, while I believe bictegravir, you can extrapolate from dolutegravir, you know, again, in this study, it was a virally suppressed population, wasn't it? Bic hasn't been challenged in people with viremia and extensive resistance yet.

[01:17:40] Prof. Paul E. Sax: I think those are reasonable caveats.

[01:17:42] Uh, but these now, there's now, there are five studies, uh, you know, two, two with, with, uh, Uh, three with, with, uh, treatment failure and two, two with viral electric suppression that really three with viral electric suppression. What am I saying? Voxend is really too. I think it's really impressive.

[01:18:01] Dr. Laura Waters: No, no, I agree.

[01:18:02] And then the thing is, and certainly our practice has shifted. We're using second generation entities where we would only have thought about using PIs, you know, two, three, four years ago, but guess what? England, what does the license for Bic, Tegra, M Tris, Twin, TAF say? It's only changed recently in the U. S.

[01:18:18] that you can use it with a 1. 8. 4. In Europe, the license for Bic F TAF is no resistance to any of the components, which means that we risk not being able to use that particular option. We can use taf, emtricitabine, dolutegravir, but we risk not being allowed to use Bictegravir, which clearly is far from logical.

[01:18:41] Yes. Um, but this is a difficulty when the licenses and people say, oh, the UK guidelines, the UK bodies, it's great, but the licenses make it really hard for us to be, uh, more artistic.

[01:18:52] Prof. Paul E. Sax: Okay, uh, Magnus,

[01:18:54] Magnus Gisslén: you know, fortunately, we do not have to take the licensing into account in

[01:18:58] Dr. Laura Waters: Sweden.

[01:19:00] Magnus Gisslén: So, so I would say, but, but I mean, if we have a patient with multiple in RTI resistance with K65R and multiple, M184V and a lot of others, then we normally has used it.

[01:19:13] For both PI and, and the insti, for example, subclass to the Tegra pair is sort of an easy two tablets, but maybe it's not necessary. I didn't know. We will, but that's what we are using. What about you? We,

[01:19:27] Prof. Paul E. Sax: you know, we we've, we've gone ahead and made it pretty much, uh, You know, when, let's take a sort of an older person, uh, who's on multiple other medications and they have viral electric suppression and a boosted protease inhibitor and, and terrible old nucleoside resistance, we, we've switched pretty much all of them, uh, to, to big Tegra, FTC, TAF, usually, or Dolutegra, Vira.

[01:19:52] FTC TAF because it works, you know, the, the, the, the, the old study of nucleosides activity in the face of resistance are really showing that they still have activity, uh, either through intrinsic antiviral activity or just reduction in replication capacity. It's an interesting quandary, this, this dolutegravir plus darunavir, ritonavir arm, though, in the, uh, in the DEFT study.

[01:20:20] Enabled the DHHS guidelines to actually add it to their, uh, recommended regimens in certain settings, uh, you know, for, for people with a history of treatment failure. All right, moving along, I went back to this slide. I'm going to actually sort of say what we're looking forward to in the next five years.

[01:20:39] Uh, we've got, you know, I think long acting ART in diverse populations. We already talked about once weekly oral ART. Uh, this Bectegravir Lenacapavir replacing complex regimens, that's, that's a one pill daily regimen that, uh, I'm not going to highlight beyond saying that it's being studied in people on complicated regimens and it's probably going to work.

[01:21:03] Uh, there's a, uh, long acting therapies to extend the intervals, especially with Cabotegravir. And then what about cure? What about cure? Well, uh, let's talk about cure. Why not? Okay, it wouldn't be a greatest hits of the year if it weren't talking about cure. So we got these two cases, we've got the next Berlin case.

[01:21:26] This is a 60 year old man, uh, developed leukemia and then his donor, they couldn't find a, uh, someone who had. CCR5 delta 32 homozygosity. I get to say that they couldn't find anyone. So they found someone with a single mutation, uh, as a donor. And that person, after the engraftment, that person expressed some CCR5 in their cells, but it was low.

[01:21:53] And that person stopped ART in 2018 and has not had rebound. It took them six years to present this case. They were very patient. Amazing. And then this other case, uh, this person's, this paper has now been published. Um, a person with diagnosed in 1990, myeloid sarcoma in 2018, uh, matched stem cell transplant and with no, Delta 32 mutations in the donor, and that person stopped ART in 2021 and hasn't rebounded.

[01:22:24] So, those are two cases where, uh, CCR5, Delta 32, homozygosity is not present. But they, of course, both required a stem cell transplant, so not exactly practical to, to use. But what about, uh, Excising HIV from the, from the, the, the cell. Just take it out. Why not? Uh, so this is EBT 101. Uh, six people, um, suppressed.

[01:22:52] And this adenovirus vector, which was given intravenously, was, was well tolerated. And then after 12 weeks, they, They stopped ART and all of the participants rebounded, but one of them may have been delayed, although it's a little hard to say, that's compared to historical controls, and there was one analysis showing that it could have had Um, some, some decline in the reservoir.

[01:23:17] Uh, these excisional strategies seem to be more at least seem to me, more appealing than the sort of, you know, stimulate the reservoir and then, then, uh, you know, enhance the immune system to inactivate the disease. replicating virus. That to me doesn't strike me as a good strategy, but we'll see. But then as I was getting enthusiastic about these excisional strategies, I I came across this paper.

[01:23:45] Um, and this was basically using CRISPR. Um, and in this in vitro analysis, It caused unintended deletion of surrounding cellular DNA. And if I can highlight the concern there, uh, that this, uh, as the loss of chromosomal sequences may cause oncogenic cell transformation, unintended large deletions form a potential safety risk in clinical application of this antiviral application.

[01:24:18] So this is just a reminder to us, who are talking about CURE with our patients, is that We have very safe and effective ART now, and, and if indeed some of these strategies could introduce a risk of, uh, of cancer, which is already, as we know, elevated in people with HIV, it would be, it would be very unfortunate.

[01:24:38] So we have to be extra careful that these interventions are safe. Did anything else from the care world, cure world, uh, attract your attention this past year? I could have covered some, you know, autologous generation of monoclonal antibodies, but we've already. blasted monoclonal antibodies enough.

[01:24:56] Magnus Gisslén: Yeah.

[01:24:57] But, but does this tell us that the CRISPR Cas is not that precise as we thought it should be? And that is not, yeah, I mean, that's not just for cure. It's for other, other

[01:25:08] Prof. Paul E. Sax: indications.

[01:25:10] Magnus Gisslén: Yeah. So interesting study.

[01:25:12] Prof. Paul E. Sax: Yes. Very interesting. And I also, um, You know, I'm wading into territory that's really outside of my domain since I'm not a laboratory researcher, but, you know, I do try to keep up with this cure stuff at least so I can sound reasonably intelligent to my patients who, on seeing me often yearly now instead of twice yearly, they say, well, so what's new in the cure area?

[01:25:33] Laura, do you ever get a question like that from any of you? No,

[01:25:36] Dr. Laura Waters: I, I, I do. And again, I think it's one of those things that, that, that, that, that cure, just, I guess it feels scientifically still so far away and, you know, proof of concept, proof of concept, proof of concept. Clearly high risk with something like this of potentially unintended consequences.

[01:25:52] But again, it's, it's a really common question from, from patients, but, um, yeah, I tend to come up the same old tired line that not before I retire, but it's just that retirement, it's getting closer and closer every time I say it.

[01:26:04] Prof. Paul E. Sax: All right. Next section complications. And we're going to talk about Dr.

[01:26:09] Waters favorite complication to talk about, and we'll lead off with this study, the Paso Doble study, which generated lots of buzz among the HIV treaters when it was presented this summer. As you know, it was people who were suppressed in Spain on a current regimen, and the regimen had to be kind of suboptimal.

[01:26:30] They couldn't be in the study if they were already on the side. state of the art regimen so, you know, the regimen cobasistat containing, or favorins, or TDF, no history of virology failure. Importantly, they had never been on dolutegravir or bektegravir. That's part of the issue. Criteria, no hepatitis B, and then they're randomized to either dolategra lamivudine or bictegra RFGC TAF.

[01:26:57] And, you know, I won't bore you with the, the, the virologic outcomes, which are, you know, very much predictable in this suppressed population with no history of human failure. We know from Tango and Salsa and, and cohort studies that Dolategavir lamivirin maintains suppression very well. But this difference in weight was significant, that there was more weight gain.

[01:27:18] There was weight gain in both arms, but more in the, uh, in the Bictegorif, the TAF arm. And it was only observed, uh, to, and predominantly observed in people switching off TDF or Abacavir. So this study was, uh, got a lot of attention. We're still kind of grappling with it. Not sure exactly what to make of it.

[01:27:39] Um, could it be that there was a direct effect of TAF on appetite that wasn't borne out in the questionnaires, uh, in the study, there was nothing that sort of suggested that they were eating more. Could it be something that TAF is slowing metabolism? Uh, not, not known. It's certainly being looked at. Um, meanwhile, there are other studies that have, uh, Looked at this, including this randomized trial, which was just published in Open Form Infectious Diseases.

[01:28:08] Um, now it says that, you know, this is a people on baseline Bictegravir FTC TAF, so a different patient population. Uh, and they are randomized to continue that or to switch to Dolategravir Lamivudine. Now it was an open label trial, uh, and with that, comes the caveat that there were more drug withdrawals on the dolotegravir mividim arm and you know, I won't, I won't fall for it and say it's proof that dolotegravir is not as well tolerated as bictegravir because Laura will tease me if I say that, but it could be what's known as ascertainment bias and that someone goes in a new regimen and they have any kind of symptom, they might blame it on their new regimen.

[01:28:47] But they did not see a difference in weight at week 48, and I just want to, let's take a closer look at this. This is from the actual paper. Uh, now these are the weights. Uh, you could see that dolutegavirilum avidin. There was actually a, a bit of weight loss. Um, Whereas people on Bictegra were a bit of weight gain, but this was not statistically significant and the same is true about, uh, BMI, um, this part, you know, the study was looking for this, the subjective reports of obesity, weight gain, weight loss, and changes in appetite, very rare in both study arms, no difference in weights, circumference, and then the, uh, New onset diabetes or prediabetes has occurred in 3 percent of those in dolategravir percent in bictegravir tetaf.

[01:29:36] So I think this study is perhaps more, at least for us in the USA, more representative of the question our clinicians have than the Pasadoble study. The Pasadoble study is people never on bictegravir or dolategravir. This study, it's people on bictegravir or dolategravir. Bictegravir FTC TAF, which is a giant number in our country, and people want to know, will switching to dolutegravir lamivudine lead to weight loss?

[01:30:02] And it depends on how you look at this numbers, certainly not statistically significant and not a big difference. Um, but I ask you, I ask you, Dr. Waters first, Laura, what do you think about these two trials? How do you put, how do you put it together?

[01:30:18] Dr. Laura Waters: Well, so I think they're actually very consistent in that you, you've already pointed out in Pasadube, people already on TAF.

[01:30:24] didn't see a difference whether they stayed on TAF or switched to doytag lamivudine. So in very scientific terms, I believe people already on TAF have maxed out whatever mechanism is accountable for this. And then the reason removing TAF doesn't make a difference is that There's a difference between precipitating and perpetuating factors and TAF is a precipitant, but I don't necessarily believe it's a perpetuating factor, which is why when you're not on TAF, and I accept there was the arm, not on any of these things, which throws my argument out the water a bit, but the people on the back of ear or TDF, adding TAF in drove some weight change more than you see on DOL and that removal of TDF effect as well.

[01:31:06] So I, I still think that TAF is a precipitant for weight change in people who've not been on TAF before. You're absolutely right. What question is more clinically important? That would depend on your population. For us in the UK, the question around, I've already gained some weight on they kept half, you know, we're switching away all to that.

[01:31:26] I think we can say categorically no, but you're in clinic and we've got somebody who's on abacavir amivudine raltegravir, which option am I least likely to see weight change on? I think based on pasadoblate, I would say it's not clear cut, but the signal is switching you to dolamivudine may be less likely to cause weight gain and switching you to Bic F Taf.

[01:31:45] That's how we can interpret it. But again, it's a luxury that we're debating these finer points of small differences in weight change, isn't it?

[01:31:55] Magnus Gisslén: Yeah, thanks, uh, Magnus. Well, yeah, a little bit complicated for me, Laura, but, but it sounds good. But, but I'm a little, I don't like studies when they just say not significant.

[01:32:06] It would be very interesting here to see is this Close to 005 or, I mean, it's a relatively small study and it's, well, it's not one kilo in 48 weeks. It's not that little. I mean, it's, what about in the 96 weeks and in the largest study? So, I mean, agree, it's not significant, but it could, might be close to, I don't know.

[01:32:30] Prof. Paul E. Sax: Yeah, well, uh, I, I might, I might have, uh, edited out the p value and it might be in the paper, but I, I can, I'll check, uh, I do want to just throw this one out there to you again. Uh, this is, uh, going to be published very shortly in CID, uh, and here is a comparison between Duraverine and CID. Eslatrevir versus TAF as initial HIV treatment.

[01:32:57] So, you know, uh, virologic outcomes were, you know, pretty similar, although there was one case of virologic failure with resistance. But this is, these are the weight results. The weight results, weight gain was comparable between a control arm with both an integrase inhibitor, sometimes implicated, and TAF, and a regimen with neither.

[01:33:18] So, how does this one fall into your, uh, into your worldview on this issue, uh, Laura?

[01:33:26] Dr. Laura Waters: When it clearly doesn't fit with my narrative slash rhetoric. Um, I don't know. I really don't know. But, um, What's that old saying? The exception that proves the rule. So this is the exception that proves me right after all.

[01:33:38] Yeah, I don't know, and I think there's very little in it. For me, and I know you've heard me say this before, I just want to be more certain when I reassure people that TAF isn't driving their weight change. That's, that's, that's all, that's all I really want, is to be able to counsel people with more certainty.

[01:33:56] Um, yeah.

[01:33:57] Prof. Paul E. Sax: I thought, I thought you had a great idea for a study. We've talked about it before, where you have people on, uh, you know, they, they add synophebroliphenamide to a dolotegavir lamivudine containing regimen to see if there's a change in weight. That would be very interesting. And that's why I asked about that study that you mentioned that, that, was it called the MIND study?

[01:34:17] Dr. Laura Waters: Yep. Yes, yeah, and you were absolutely right. Of course, you were right. Um, everyone was on Dolly Teglum if you didn't baseline. Um, I, I, yeah, I, I missed that, uh, important element. Um, yeah, it's a shame, um, but company that we were hoping might fund it. Um, yeah. discussed it a lot. We had some really good discussions about it, but, um, yeah, so I don't know if someone will fund it.

[01:34:42] We can still do that study, but I don't know if you can get us some cash, Dr. Sachs, then, um, yeah, we'll be

[01:34:49] Prof. Paul E. Sax: good. Okay. Well, listen, uh, I am, I'm just going to show you this. This paper that I was part of a large group of investigators, including all the representatives from the major HIV drug makers. Uh, and we, we tried to summarize the, the knowledge as best as we could find it, and we found very, very strong evidence.

[01:35:09] that the tenofovir DF has a weight attenuating effect, especially when combined with efavirenz. And that was, that was, you know, unequivocally seen in study after study after study. And it's amazing to think back, we didn't really appreciate this very much. It kind of reminds me of the way that we didn't appreciate that stavidine was and zidovanin were causing lipoatrophy until people had been on it for years and then they had alternatives.

[01:35:39] Just sort of want you to keep this paper in mind as, as a sort of nice review of some of the literature. Um, not saying we know the answer, but this figure is in there. Thanks. Thanks to David Wall. What about these amazing drugs? TLP 1s. I have to highlight this paper. Uh, this is actually a randomized clinical trial done by, uh, led by Grace McComsey.

[01:36:05] She was not the lead author, but she was the senior author. And first, let me just say, uh, Grace McComsey's clinical trials unit in Cleveland is, is one of the most astoundingly good Accomplished ones in the world and these single center studies that she does are really remarkable. And this was a placebo controlled trial of seme, uh, semaglutide, uh, in, in people with, uh, HIV related lipo hypertrophy.

[01:36:30] Uh, as you can see that there's significant weight loss in people who get semaglutide, and there's significant decline in their, uh, body mass index. I mean, tons of benefits seen. It was well tolerated. Adherence was excellent. Weight went down, total fat went down, central and peripheral fat depots, decreased lean body mass was somewhat concerning, but, but subsequently, they didn't think that was a big deal.

[01:36:58] Uh, they did not find a benefit to liver or pericardial fat, but as I'll show you in a moment, some other study did. They did notice that people with lipoatrophy appeared to look worse. Uh, and some of the patients complained about that. Uh, this is probably true, um, For everyone on these medications and it may be highlighted in people who have already experienced lipoatrophy because of the old toxic treatments we had.

[01:37:25] I'm going to stay in the same topic, which is the slim liver study. Um, this is an open label trial done through the ACDG. And you can see the enrollment criteria, and IHTG stands for intrahepatic triglycerides measured by MRI, uh, and the intervention is semaglutide, given at relatively low dose, uh, and, uh, the results are, uh, excellent.

[01:37:52] In fact, they were much better than I expected, uh, so, 58 percent of the participants had a 30 percent positive result. Relative decrease in intrahepatic triglycerides, and 29 percent had complete resolution in their metabolic associated steatohepatic liver, static liver disease, which is, I guess, sometimes called Masl now, sometimes called other things, they keep changing the name.

[01:38:17] And then additional benefits they saw were weight loss, decreases in BMI, waist circumference, fasting plasma glucose, HOMA IR, hemoglobin A1c, and serum triglycerides. Wow. Wow. Uh, this is an exciting area for, uh, for clinical medicine. Uh, I'm not sure what your experience has been in Sweden or England. Tell us, uh, Magnus and Laura.

[01:38:43] Magnus Gisslén: I mean, it's amazing results, isn't it? Yeah. Uh, one thing, I, I have seen a few patients that are sort of normal weighted with, with this, uh, fatty liver disease. Hmm. You can wonder if it has effect also on those, or is it just sort of associated with the weight change? I don't know.

[01:39:01] Prof. Paul E. Sax: I don't know. I don't know the answer.

[01:39:02] Uh, I'm sure that someone is studying it because that would definitely broaden the population, uh, for whom this could potentially benefit. Uh, Laura, any thoughts?

[01:39:12] Dr. Laura Waters: Yeah, I mean, we, it's available here, not, not as available as it should or could be. There's been the initial issues with shortages, um, of course all about, I can never say in the terse, epatide rather than semaglutide now is what everyone's focusing on.

[01:39:28] Yeah, and clearly they, they work. Um, my general understanding is they work as long as you take them and how long you keep prescribing them for. Um, and a very sobering fact that by 2040, the weight loss drug market will be worth more. that it would cost to resolve world hunger. So that to me, it's another example, unfortunately of medicalizing a political issue.

[01:39:51] Cause I think the issue and undoubtedly there are people who will only benefit from these types of medications, but the whole time countries like the U S and the UK let the food industry govern what people can afford to eat. Then we're going to constantly have to medicalize our way out of this. So I think it's so much more about this political.

[01:40:09] I think it's really reassuring data. I agree with you about that. the potential for this sort of stigmatizing side effects with regards to facial fat loss. Um, and again, you know, it's, it's as Zaza Gabor said, at some point in life, you have to choose between your figure and your face. And if you do stay slim, so does your face, which is why this will probably be, uh, mapped in a linear fashion with a growth in the, uh, aesthetics fillers industry as people with facial fat loss, thanks to drugs like this, uh, fill their faces with synthetic materials to counteract that.

[01:40:40] Prof. Paul E. Sax: So, so is that a true Shazerborg quotation?

[01:40:44] Dr. Laura Waters: Yeah, no, it is. I'm going to, I'm going to be right about something at least once in this discussion. I will find that for you.

[01:40:50] Prof. Paul E. Sax: That would be, that would be great. Uh, okay. So, so, um, onto another complication, which is Hepatitis B. Uh, and this is hot off the presses.

[01:41:00] It just, uh, came out. Week or last week, never, never let it be said that your faculty on these media who said presentations isn't keeping up to date because this I think came out yesterday, but this is the, uh, the what's called the, the beehive study. I think it's a great name. And as it was an open label trial, 561 people with HIV who were non responders or people who did not respond.

[01:41:26] There, Laura, I did it for you. Uh, uh, non responders to the hepatitis B vaccine, and they got, uh, two doses of this newer hepatitis B vaccine with a CPG adjuvant, or three doses of that vaccine, or three doses of the standard hepatitis B vaccine. That's the strategy we used to use. Both of the novel adjuvant strategies were significantly more effective, as you can see in the figure, um, seroprotection seen in about 93 percent and 100 percent of people getting the novel adjuvant.

[01:42:02] This is a more immunogenic vaccine. We have it available in the United States. I don't know if you have it available in your countries yet, but it is definitely, I think, should move toward being a guidelines recommended strategy for hepatitis B people, for people who have not responded to the hepatitis B vaccine.

[01:42:21] Magnus Gisslén: And also 80 percent of the conventional vaccines sort of responded.

[01:42:26] Prof. Paul E. Sax: Yes.

[01:42:26] Magnus Gisslén: Very high. It's not, yeah, not as good, but still.

[01:42:30] Prof. Paul E. Sax: So it's, yeah, but three doses, three doses. Three doses. Three doses.

[01:42:35] Dr. Laura Waters: And I think that's a really important point because I think quite often when we're in clinic, we've, we've moved from paper notes, so one electronic health record to another electronic health record, and how reliably some of the history of previous vaccine is.

[01:42:49] And quite often we ask people, they say, Oh, yeah, I'm sure I had three doses. Um, I mean, it certainly would. imply that trying, trying again, uh, for the, the cheapest option would be a good thing, but absolutely for people who don't respond to a modern readministered full traditional course, I think this would be a great option.

[01:43:07] Prof. Paul E. Sax: Now I cite this paper all the time, because not because it's in CID, but because I think it's really important. And I feel like this is, uh, the what I'm experiencing as a long time HIV clinician and that cancer, non AIDS cancer has become the leading cause of death among people with HIV. That's the this blue color here.

[01:43:30] Uh, you can see that it's it's getting bigger over time. And as AIDS and liver complications have declined. It's become increasingly important. Now, cardiovascular disease is, of course, important also in this aging population, but cancer is outnumbering them. We have a, we're provided a summary each day of all the people with HIV in our hospital, and it is striking how frequently it's a cancer diagnosis.

[01:43:57] So, um, I, uh, Bring that up to both because it was published this year and also because it allows me to discuss the next topic, which is one I have a, uh, a, a strong feeling about, uh, and we're gonna, we're gonna do this, uh, true and false. Okay, you're gonna have to, you have a 50 percent chance of getting it right.

[01:44:18] Uh, the anchor study demonstrated that screening for anal cancer using cytology, the anal pap smear, significantly reduced the incidence of this complication. among people with HIV, true or false?

[01:44:32] Dr. Laura Waters: I got it wrong last time.

[01:44:35] Prof. Paul E. Sax: Thank you. Thank you. You got it wrong last time. So now we've learned. So the answer is false.

[01:44:43] Yeah. The anchor study showed that treatment of high grade SIL, of high grade squamous endothelial lesions, uh, was associated with a reduction in the incidence of cancer. That's all it showed. It was not a. Screening study. Nonetheless, uh, the International Anal Neoplasia Society came out with these guidelines this year that we're extremely aggressive about screening.

[01:45:10] Okay? Um, risk category A, people with HIV, men who have sex with men over 35, trans women over 35, men Not MSM over 45, women over 45, any history of vulvar dysplasia or vulvar cancer, uh, men MSM without HIV, uh, trans women without HIV over age 45, and then solid organ transplant recipients. They all are in category A.

[01:45:39] Okay. And they, uh, would then go into this pathway where they either get a digital anal rectal exam or dare plus anal cytology. Uh, and, and if there's any abnormal result, then referral for high resolution endoscopy. And then this part, repeating the screening every one to two years. Uh, I, uh, have to say, I cannot think of any HIV treatment program that I'm aware of that actually can follow through with this recommendation.

[01:46:13] Say, is that, am I alone in saying that? Or is this,

[01:46:16] Dr. Laura Waters: Absolutely not. I think this is, it goes far to say if it's, if it's not implementable. in high income countries, it's unimplementable.

[01:46:28] Prof. Paul E. Sax: I mean, and then that was, so I have, I have another, I have another paper I want to cite, and it's just this one, and it was just published, uh, in, uh, CID because it, it shows the practical The, the on the ground real world evidence of an anal cancer screening program.

[01:46:49] This is done at Yale, uh, two academic medical centers from five year period and among eligible people for screening, uh, only 50 percent had at least one screening test and only 26 percent had follow up. Uh, the people at highest risk, the older men and the men who had history of smoking were actually.

[01:47:12] They had fewer evaluations and they speculate because they had more comorbid medical conditions that needed attention. In addition, the screening test that was recommended, the anal cytology, was very poor performance. A lot of the results were unsatisfactory. We find this in our center as well. And also very low Sensitivity for detecting H cell, which is exactly what you wanted to detect.

[01:47:37] Uh, so I think that data like this need, need to be sort of applied back to the people who are recommending the screening because they, it's just simply can't do it. All right. I'll get off my high horse.

[01:47:49] Dr. Laura Waters: No, it's a good, it's a good high horse to be on.

[01:47:51] Prof. Paul E. Sax: Okay. Okay. This is proving that screening strategies for cancer are doable and worthwhile is very challenging.

[01:47:59] And so I just think that this is a bit of an overreach. Okay. To wrap up, prevention. What do you think I'm going to talk about? Of course, I'm going to talk about the purpose trials. I'm not going to go into the details beyond that. to say that they were remarkably good. Uh, the, the, uh, the first study, the, the, significantly better than, than the background estimated incidence, significantly better than TDFFTC.

[01:48:25] Uh, you know, no infections reported. Obviously, there will be some reported eventually, uh, No, no interventions, 100 percent effective. And then the followup study just published last week, uh, in, in men who have sex with men and in trans women, uh, showed a very, very good results significantly better than TDF FTC and.

[01:48:46] Significantly better than the background incidents. I think that this, these results are so, uh, exceptional that it's going to really put the test to whether we can implement it. And that's what this, uh, editorial is about from my, uh, colleagues, Rochelle and Lindsay. Uh, they basically, uh, they, they are asking, can we actually make this happen?

[01:49:09] And, and I. I want to just remind everyone that cabotegravir was superior to TDF FTC in two blinded, randomized clinical trials. And they provide a very important recent case study for how PrEP is used in clinical practice. And the last paper I'm going to cite is, uh, this one from JAMA. Looking at the use of PrEP in the United States, so the use of PrEP in the United States, if you can see the figure, this line right here is cabotegravir.

[01:49:39] So right now, uh, the proportion of people on cabotegravir in the USA is about three to five percent, even though it is superior to TDF FTC and superior to TAF. Well, we don't know if it's superior to TAF FTC, but it's By extension, it potentially is. So I think that it kind of remains to be seen how lenacapavir will be, will be implemented, even though the results from these trials are unequivocally outstanding.

[01:50:08] Comments?

[01:50:10] Magnus Gisslén: What's the, do you think this has anything to do with cost or investment? Of course. What's in the U. S.? So it's different, sort of, who got access to it.

[01:50:20] Prof. Paul E. Sax: I mean, the cost of of, uh, generic TDF FTC in the United States is measured and, you know, 10 10 a month, which is not much money. Uh, and and not surprisingly for people who look to their private insurance to pay their private insurance will say, go with the 10 a month option.

[01:50:40] So that's one. And then there's also a cost to it. You know, for the resources required for, for the injections every, every two months. So, but, but still, I mean, I, I don't want to diminish either the, the, the HBTN oh 5 2 0 5 3 results or the purpose results, they clearly were better. So I think that it really puts the onus on us to try to figure out ways to implement the, the best strategies.

[01:51:06] All right, I promised you could vote, and this is a little painful for me because we had, we had an election last month, about which the less said the, the, the better, uh, I, I've, I chose five from this panel, from this, this review, uh, we've got a couple of prevention trials, two long acting injectable trials, and the, uh, The, uh, the treatment experience studies using oral, oral ART, uh, or something else or something else.

[01:51:42] Anyone want to weigh in?

[01:51:46] Dr. Laura Waters: I mean, it's hard. It's how you go to a restaurant and you want to eat everything because all of these have a huge amount of importance, I guess in, in terms of, if I had to choose one, which you are asking us to do, I'd have to go in number one with purpose one. I just think to see a person.

[01:52:05] a prep option and I completely accept that that cab did incredibly well as well. Um, and if you actually truly excluded baseline infection, there were no new HV acquisitions in women on cab either. Um, but, but, but to, to see, to see something that is hugely effective in women who have just, you know, not seeing great results for any non long acting PrEP options.

[01:52:26] And importantly, and this is the differentiator with CAB, something that absolutely will be highly unlikely for the foreseeable future to be affecting first line treatment options, um, in terms of WHO guidance. And then I think for me, it's purpose one.

[01:52:43] Magnus Gisslén: No, I go on. Yeah, I actually, I fully agree on that. Though, since we are broadcasting from Sweden, I also would say number six. And that is from last month from Euro surveillance, showing that Sweden surpasses the United Nations 95, 95, 95. Right. Actually already 19, 2018. And now it's 96, 99,

[01:53:12] Prof. Paul E. Sax: 98. That's amazing.

[01:53:13] That's amazing. Well done. That actually should, should really should have a big impact on your incidents. It must.

[01:53:21] Magnus Gisslén: Yes. So a lot of sort of work or important cases, but, but still support for the, for the domestic cases is decreasing. Okay.

[01:53:30] Prof. Paul E. Sax: That's great. That's so you join, uh, you know, Australia and, and Botswana and other places with those great numbers.

[01:53:38] That's terrific. Um, I am, um, I'm going to say that, uh, probably I would guess that that one in three are probably tied for me just because we have, um, I think three was such a difficult study to do, but the impact potentially could be so huge, um, So that's, that's where I would vote and, uh, which brings me to my last study, which is an acknowledgement study slide, uh, Peter Hunt, Rochelle, Steve Deeks, Jen Manigoler, Amit Akra, Laura Waters, Magnus G.

[01:54:10] Slen, Media Husit, and thanks again to, to Vive. Uh, I think we do have a little time for questions. I'll stop sharing and go from there.

[01:54:19] Magnus Gisslén: Yeah, great. Great. I have a few questions. So one is. about the cure thing with the stem stem cell transplantation. I mean, this is sort of challenging our previous assumption about the Delta 32 Delta 32 necessity.

[01:54:36] So, so what do you think of that? What is sort of, well,

[01:54:39] Prof. Paul E. Sax: um, I don't know if you recall, but there was a case series from Boston where there were, um, people who with HIV who had undergone stem cell transplant, and then. Due to the extremely energetic investigations by one of our junior faculty and unable to find any virus anywhere using all the most advanced techniques, they ended up stopping treatment and then eventually experiencing COVID 19.

[01:55:06] Virologic rebound quite a few months later, you know, on the order of 12 to 18 months later, I believe. And when they experienced virologic rebound, they had acute retroviral syndromes because they had all this susceptible, uh, CD4 cells, and they also had no host immune response anymore to the virus. So it was really bad.

[01:55:27] pretty much of a wake up call that you can't do this in everybody. So, so I, I would say these are the exceptions rather than the rule. And then there's this term stochastic. That term is often used, uh, it, it, I guess when trying to put it in plain English, it means this sort of random, random sampling. And, and if, uh, the viral replication is a stochastic event, meaning that a virus just needs to turn itself on.

[01:55:54] Through some random procedure, then even those long term suppressed people, uh, might eventually rebound. I, I, that's all I can say about it.

[01:56:05] Magnus Gisslén: Yeah, it's interesting. Would be interesting to say. I don't know if anyone has sort of collected all cases of stem cell transplantations. That has been done. It must have been.

[01:56:15] Prof. Paul E. Sax: Yes. Yes, it does reduce the viral reservoir, uh, but, you know, not to the point where you, it's eliminated. The, the doctor who was a junior, uh, faculty member here is, is now no longer junior and no longer here. And so, so he's now in San Francisco working with Steve Deeks. His name is Tim Henrich, and I would bet he has the most information of anyone on what stem cell transplant does to your HIV reservoir.

[01:56:44] Magnus Gisslén: Interesting. Uh, another question from the, from the audience is in this, you showed the, uh, death causes sort of with, with, with the time where more cases of non AIDS, uh, cancers sort of now. So what about, could this be ascribed to an increased age during this time of the cases, or do you know, or is it adjusted for that?

[01:57:08] Prof. Paul E. Sax: So, so the answer, uh, is undoubtedly yes. Increasing age increases the risk of cancer. You know, you don't need to be a doctor to know that. However, when you compare the causes of death in people with HIV to the cause of death in people without HIV, it's actually a higher proportion. And, and that's really, uh, borne out in the fact that, that You know, cardiovascular disease is the leading cause of death still for, for most populations and, and here, uh, cancer exceeds that just the thing to also to say about that study is that, that if you then roll in cancer, I mean, HIV related cancers, it's even higher.

[01:57:54] Uh, so. Yeah, good.

[01:57:58] Magnus Gisslén: And I think the last one is sort of just to clarify again about the people with NRTI resistance and sort of multiple resistance. Is there enough data saying that instances are at least as good as posted PIs in those cases?

[01:58:15] Prof. Paul E. Sax: I, you know, I think the data are, Excellent. Uh, I, I, if someone said to me, I'm not comfortable with that and I'd rather go with, you know, Darunavir, we're still fully active, plus Dolutegavir and forget about the nucleosides.

[01:58:32] Yeah, I mean, that's true that that regimen in the DEFT trial was the best. Um, But I, I, you know, I feel like we now have these, uh, 2SD and Vizend and, uh, the GESCIO trials all basically came up with the same message. Uh, and, and you'll see when we present the GESCIO proviral DNA resistance data that about 50 percent of them had significant NRTI resistance at baseline.

[01:59:00] Magnus Gisslén: Good. So great. And again, thank you both. It has been sort of very nice, as usual, very, very good discussion and very nice presentation. So thank you and thank Media Hypset and thank everyone listening.

[01:59:14] Prof. Paul E. Sax: Thank you very much. Thank

[01:59:16] Dr. Laura Waters: you.

[01:59:17] Prof. Paul E. Sax: Thank you, Laura. And thank you, Magnus. Pleasure as always.