IAS Highlights 2024

Supported by an educational grant from ViiV Healthcare

Full transcript:

[00:00:00] Paul Sax: Hi, everybody, and welcome to our webinar, which is going to be a review of the 2024 Munich International AIDS Conference, AIDS 2024. My name is Paul Sachs, and I'm a physician and HIV specialist at Brigham Women's Hospital and Harvard Medical School, and I'm delighted today to be joined by Dr. Laura Waters, who is a sexual health consultant in London, England.

[00:00:34] And a real brilliant and funny dynamo in HIV care and research. Laura, welcome.

[00:00:42] Thank you very, very much indeed. So also,

[00:00:45] Paul Sax: yeah, I'd also like to thank Media Hussit for producing this webinar and VIV for their unrestricted educational support. So we're going to start right off with Dr. Waters. I'm going to call, we're going to be on first name basis.

[00:01:00] Is that okay?

[00:01:01] Laura Waters: Oh, 100%. 100%.

[00:01:03] Paul Sax: Laura, take it away.

[00:01:05] Laura Waters: I shall indeed, so thank you very much. Welcome everybody, and uh, let me share my screen, and slideshow, and from start. So, welcome. This is the IIS 2024 feedback. This is my portion, but we will be interjecting as we go along, and I'm sure Paul will have plenty to say about some of the topics that I am talking about.

[00:01:29] Uh, so essentially, I'm covering oral art, looking firstly at studies, uh, in people without resistance, then looking at some data in people with resistance, going to touch on injectables relatively briefly, and then finish with some antiretroviral therapy complications before I pass the baton over to Paul.

[00:01:48] So it was a gloriously sunny Munich where the conference was held. This is the conference center, um, huge. These conferences are always massive. This is the conference that alternates with a slightly smaller, more scientific focused meeting run by IAS. But this was the big, very global one. There's a fantastic global village.

[00:02:07] A lot of passion, a lot of colour, a lot of protest. Uh, it truly is a wonderful experience. And there were 11, 000 participants in total. There were 40 oral abstract sessions, so a huge amount of data to try and assimilate, and more than 2, 000 posters. One of my aims is to actually map out how many days it would take to watch every single session of the conference, because there's an awful lot going on in parallel, and I suspect that would run into days or even weeks.

[00:02:35] But we've tried to consolidate what we can for you here. So without further ado, starting off with oral antiretroviral therapy in people with no resistance. And I think one of the most hotly anticipated studies, although when you're actually in the room for some of these studies, you realize that what's hotly anticipated for a weight obsessed doctor in a high income country, isn't necessarily the most, uh, hotly anticipated topic for everybody else.

[00:03:00] for joining us. Um, but all the most important people there weren't they, Paul, because you and I both raced up to the microphone immediately after the session. So Pasa Doble, it's another dance move related trial. This one is from Spain and really it's designed to look at is there a weight difference when you are switching to Vic Tarvey with a TAF based backbone versus Nung.

[00:03:26] Now we know this has been an ongoing discussion for the last several years, really kicked off by the advanced studies in South Africa comparing TAF and TDF, Dolutegravir, the favrins, a lot of back and forth and evolution since and I kind of think where we are at now is generally it's accepted that Dolutegravir and by extrapolation other integrases.

[00:03:49] aren't necessarily independently associated with weight gain. It's probably a legacy of efavirenz being associated with relative weight suppression and there's some dose response stuff there. I think if you pull everything together, including an intensification trial published last year, adding dolutegravir, we can probably conclude that the integrases aren't doing much.

[00:04:10] Where there's still debate, I think it's fair to say that I am one of those relative outliers who still isn't yet convinced that TAF isn't driving a degree of weight gain. Many people think it's all related to TDF, relative weight suppression, so TDF acting like the NRTI equivalent of the favorans, but I've just not quite convinced, and Pasadoble, as you will see, hasn't really helped address that question.

[00:04:35] I think it's actually opened it up further. So what happened? Virally suppressed people with no prior dolutegravir or bictegravir exposure because one of those arms not included in telophobir people couldn't be living with hepatitis B and they were randomized to dovato or bactavir. Dolutegravir may be deemed two drugs versus bacteria made from alpha amide and tracitabine, three drugs.

[00:04:56] And you can see there were over 270 participants in each arm. Loads of studies ongoing, fat biopsies, markers of senescence, et cetera, et cetera. But this was the main meat of the results. So you can see from the population, median age 50, just over a quarter of participants were female, primarily Caucasian.

[00:05:17] These are people who have been on treatment for 11 to 12 years. They've been suppressed for many, many, many months and generally their markers were pretty good. More than half, Switching Stoiotagovirin just under switching to Bic were already overweight or obese, defined as a BMI above 25, fairly typical for a population of this age.

[00:05:38] Now the key thing, of course, if a lot of impact on weight is or might be impacted by other drugs, what are people switching from? And you can see here that the commonest A key backbone agent was tonofovir disoproxyl. So around about 35 percent in each arm were on TDF at baseline About one in five on abacavir and approaching 30 percent were on TAF.

[00:06:01] Others were on just a single NRTI And if you look at the core agent about 50 percent non nukes about 15 percent integrases and the rest being on API, but it's really the backbone That's probably the most important thing as we move through these results Now, I'm not going to dwell on this slide, virologic efficacy, non inferior.

[00:06:20] So switching to either of these modern single pill, second generation integrase regimens was as effective and those forest plots on the right show us that by the virologic failure endpoint at the top, which is the primary endpoint in a suppressed switch study with those tighter 4%, or bottom right, we've got the virologic success endpoint, with those more traditionally wider confidence intervals.

[00:06:43] Here, though, it's 8%, a bit tighter than some of the ones we see usually, classically, 10 to 12. But either way, however you cut it, you can see the non inferior, uh, efficacy for both of those options. Blips, similar, are they important? Who really knows? Virologic failure, incredibly uncommon. Just one case happens to be in the Biktarvi arm, and there was no emergent resistance.

[00:07:04] So far, so good, confirming what we already know about these two very effective regiments. Adverse events, actually, we're going to dwell on this a little bit. Because I think there's still a little bit of, uh, abacavir driven myth that dolutegravir is inherently less well tolerated than bictegravir, and for some individuals that's absolutely the case, and there's cohort data from Germany showing some people with adverse events on dol do better switching to bic, bit less data the other way, though there is some evidence some data that some people who don't tolerate BIC will tolerate DOL, but it's much, much smaller because DOL came along first, BIC's a newer drug, and just the nature of the way these trials happen, there's probably more data around switching off dolutegravir.

[00:07:45] But dolutegravir being associated with more neuropsychiatric side effects is a bit of a hard thing to shift. I think a lot of this, And we'll come to this in one of the later presentations. It's driven by the fact that most or all of the initial dolutegravir use in earlier lines of therapy was within a Bacavir Lamivudine backbone co formulated triumec single pill.

[00:08:04] And actually it's a Bacavir that was probably responsible for at least some of the adverse events that have been attributed to dolutegravir. And that's shown here. Both are well tolerated. But if you look numerically psychiatric side effects, That's actually slightly numerically more on bictegravir.

[00:08:20] That's not statistically significant, but there's nothing here to really say that dolutegravir is inherently less well tolerated than bictegravir. So I'm not denying that some people may get adverse events on dolutegravir, and there's some studies correlating that with drug exposure, which we can't ignore.

[00:08:36] But overall, I think abacavir probably sullied dolutegravir's tolerability reputation in the earlier days.

[00:08:43] Paul Sax: Dr. Waters, mate. Laura, may I ask a question? Yes, of course. Don't you think, uh, these, the adverse event reports, uh, are much better adjudicated in blinded studies?

[00:08:58] Absolutely, absolutely. So you've got, I mean, I guess here, at least both of the arms were switch arms, so integrators were new for everybody.

[00:09:05] I think it's a particularly important issue, as you pointed out, and actually it comes up in one of Studies I show a bit later, dyad, when you are open label switching and some people stay on that regimen. They've been happy on for at least six months by the trial entry criteria. And I think it's a really, really important limitation and we have to be really cautious about how we interpret these.

[00:09:25] 'cause I think the real difficulty is we can sit and debate it. As, as, you know, clinicians and researchers, and the real difficulty is when that translates to patient information and the symptoms of everyday living, which become more prevalent as we get older, they then get attributed to antiretroviral side effects when I think that often isn't the case, and that can become really difficult to manage.

[00:09:50] Thank

[00:09:50] Paul Sax: you.

[00:09:50] Thank you. So, back to the actual point. I've spent a lot of time talking about the other things. Wait. Now this is, will be, and has been, torn apart, and there'll be ongoing analyses, but the key point is. There was significantly more weight gain amongst the participants switching to BicTegravir with a TAF FTC backbone than there was switching to Dolutegravir and Lamivudine.

[00:10:13] You can see quite clearly 0. 9 kilos on Dolutegravir, 1. 8 kilos on BicTegravir, so double the weight change, statistically significant difference. And you can see that that, I mean, with the IFA, that starts to emerge at week six. It's certainly there by month 6, but by month 12, there is that statistically significant difference.

[00:10:35] So for someone like me, if we all like to choose data that supports our opinions, this to me says, Laura, you were right. TAF is driving some excess weight change. For people who don't believe that, they will then look at some of the slides I'm going to show you next and say, actually, it doesn't make sense.

[00:10:53] That's not the case at all. This is just cutting it a slightly different way. This is looking at weight gain. Let's focus on above 5%. You know, that, that's kind of really considered the kind of clinically important, significant weight gain. And that's in a kind of lilac, lilac y color. Again, I'm not going to go into detail.

[00:11:08] These kind of graphs are quite hard to present. I hope you'll agree that that lilac y color, uh, or depending on your ability to see different colors, the bars on the far right of these graphs, you can see that they're bigger, certainly by week 48, for BIC than they are for DOLE. So you're seeing more above 5 percent weight change.

[00:11:26] Paul Sax: My problem isn't seeing the colors, it's remembering the names of them. I would say lilac is pretty good.

[00:11:34] I think, yeah, it's definitely a, it's to me, it's not a purple. It's not as aggressive as a purple. Um, so if anything, maybe it's a bit, maybe a mauve. What about a mauve? I don't even

[00:11:43] Paul Sax: know. These words don't mean anything to me, so.

[00:11:46] See, I love all, I love all these colors. I'm obsessed with paint colors. There's a range. I don't have it in the U. S. Farrow and Ball, which has all sorts of colors like elephant's breath and mouse's footsteps and all sorts of things. So yes, I'm sure there's a whole new career in that somewhere. Um, so this is the slide, and I know I'm not showing the entire Pasadube presentation, but this is a slide that's generated an awful lot of debate, and I'm just going to walk you through it.

[00:12:10] People switching off TAF. And here we have this kind of, I don't know, light mocha orangey brown on the left for BicTegraVir and on the right of each cluster is a blue colour for DollyutegraVir. Switching off TAF, numerically a bit more weight gain on Bic, but it's not statistically significant. Switching off none of those NRTIs, if you weren't on TAF and you weren't on TDF and you weren't on Abacavir, that's the far right cluster, there's no difference actually numerically, a bit more on DollyutegraVir so far, so even.

[00:12:39] But if you're switching off Abacavir, and particularly if you're switching off TDF. You are seeing significantly more weight change. This is against that above 5 percent threshold definition rather than median change. And particularly coming off TDF, it's, it's more marked. And the question is why? And I don't know if anyone's come up with a very good explanation.

[00:13:00] Paul, I don't know if you have since we discussed this last. But there is significantly more weight change on Bic tarvy than Devato when you're switching off a Bacavir or TDF backbone regimen. And considering, if you think about when are you making these switches, when you're sat in clinic, who are you switching to Doluteg and Libidin, who are you switching to Bic, FTC and TAF?

[00:13:21] And I would wager that most of them are on abacavir or TDF. So I'd argue actually that middle cluster is the most clinically relevant group. And we can split hairs about all this, but I take you back to that earlier slide, 0. 9 kilos versus 1. 8 kilos. This has got to warrant further investigation. So Paul, what are your thoughts?

[00:13:41] Why are we seeing this?

[00:13:42] Paul Sax: Well, you know, I'll ask you the same question I asked Esteban Martinez, who presented these data, which is that, um, The biggest effect of any switch is coming off TDF FTC effavirens because there's some synergistic weight suppressive effect of TDF and effavirens that, strangely enough, is not typically observed when people switch off abacavir lamivudine effavirens.

[00:14:07] No one can kind of figure that out. Uh, so it's something about TDF and effavirens together. And I asked him, I said, you know, is it possible there was an imbalance in randomization for that specific regimen? And he didn't have the answer to my question. I noticed that there were more people at baseline on TDF in the Bictegravir.

[00:14:29] Switch arm than the total tagger switch arm. But you know, who knows? I mean, I think this is a this is an interesting study with an unexpected finding. It doesn't. It contrasts with tango and salsa to some extent, but there's no big tagger of your strategy in that. But there's certainly a dropping taff and you don't see any improvement in weight.

[00:14:48] I guess that's more like the 1st cluster of comparisons over on the far left. So yeah, anyway, very interesting.

[00:14:55] Yeah, and I don't know either. I've given it a lot of thought, and yeah, who even knows? But I think it's fair to say it probably opens the question up a little bit more. I think we certainly haven't moved more towards certainty that TAF isn't having an effect, have we?

[00:15:11] So, um, again, this is another way of cutting it, basically showing that people on bactegravir were more likely to move into obesity and overweight categories. So what next? What next has got to be TAF IT? Now, Paul knows all about TAF IT. It's a trial, uh, you know, a few of us, Paul included, have been calling for some carefully designed trials to really pin down that potential, possible TAF effect.

[00:15:37] Uh, TAF IT's a study that I proposed at the beginning of last year, essentially intensifying people on joint hegemony with TAF. In a blinded fashion, because I think that's really critical. Paul, you talked earlier about the impact of open label randomizations on adverse event reporting. And clearly weight change isn't an entire sort of objective thing.

[00:15:56] There's so much that impacts weight and volitional over or under consumption of food and all those things that I just think a blinded TAF intensification type study is the way to go. What are your thoughts?

[00:16:09] Paul Sax: It's a great idea. Plus, it's a really clever name.

[00:16:13] Thank you.

[00:16:13] Paul Sax: So,

[00:16:15] anyone watching who might want to sponsor that trial, just drop one of us a line.

[00:16:20] So, that was Pasaduble opening up that question about weight a little more. Um, another study, a smaller study, Dyad, uh, looked at people already on Bictar V and looked at switching to Devartos. This is, again, much more along that kind of removing TAF type, Tango Salsa, um, type question. Um, and non inferior biologic outcomes.

[00:16:40] And I think that's pretty standard now. I think we have to accept unless there is a specific reason such as NRTI resistance that might limit the efficacy of dilatomorbibic tarvey, there really is no difference between these two. Cratinine, lipids, weight, BMI, and weight circumference, no difference.

[00:16:53] Cratinine is interesting actually, because if you look at some of the studies, there's a kind of hint that you tend to see a bit more of that cratinine rise on dolutegravir than bictegravir. Both of them, both, um, inhibiting that tubular secretion step of Krapney. So this kind of harmless impact on, on estimated GFR doesn't make it not an annoying impact.

[00:17:11] Actually sometimes stressful when you've got someone, some people get quite marked Krapney rises on these second generation integrases. And then if a physician sees them who isn't familiar with that effect, I've had people labeled as having chronic kidney disease stage two when they really haven't.

[00:17:24] They've just got tubules that are very sensitive to that inhibition of tubular secretion effect. Anyway, here, no difference. Now here, again, coming back to Paul's very pertinent point earlier, more drug related adverse events and more withdrawals in the doluteglanifedione arm, which the authors concluded is likely consistent with the open label nature of this switch study.

[00:17:43] Again, you're taking people on a well tolerated regimen and you are open label switching them or continuing. So I think it affirms what we already know. I don't think it adds anything particularly

[00:17:54] Paul Sax: new. Well, you know, I actually like this study, even though it's open label and not Quite large enough for my taste, because at least in, at least in this country, uh, so many people are receiving, uh, Bacteria or FTC Taf that this question comes up quite a bit, you know, will switching them to Dolutegavir Lamivudine improve, uh, side effect profile, uh, weight, um, toxicities.

[00:18:21] And so far, I haven't seen a study that really does show that. Uh, so, well, you know, that, that switch. could just be motivated by wanting to be on fewer drugs than three. That would be kind of the reason to do it. But otherwise, I don't think we're getting a whole lot from that switch.

[00:18:41] I completely agree.

[00:18:42] And I think that that whole concept of being on fewer drugs is better for long term health. I think it remains a really important hypothesis. We just haven't seen that data. The one thing I would mention for us, it may not be the case for you over the ocean. But for us, there's a cost difference in that the one with fewer components is less expensive than the one with

[00:19:00] Paul Sax: three.

[00:19:00] That will, that will certainly be the case once dolutegravir is generic. Um, but right now they're both branded and the price of dolutegravir given, given as a commercial product is still very high. So even if you were to give generic lamivudine and commercial dolutegravir would cost the same as bacteria ref to CTAF in the USA.

[00:19:21] Yeah. Yeah, for us there is a differential, but um, yes, but then you, you pay an awful lot more for your meds in general than we do, don't you?

[00:19:31] Paul Sax: Not a tour of a statin.

[00:19:32] I

[00:19:37] Paul Sax: think the United States is the cheapest for the very high volume drugs that are generic. The United States is incredibly cheap among, among industrialized nations.

[00:19:49] Not all bad, not all bad. Now I must admit I missed this at the conference. It was when preparing for this talk that I came across this one. So those of you that are a bit older will remember the photo study, which stands for five on, two off. Can you routinely and regularly miss a tripler at weekends.

[00:20:09] This is a fixed dose of afidisproxyl mg sitabine and ifafirin single tablet and people, it's fairly small study, people are randomized to continue taking it every day or to basically stop at weekends, have this two day break and it was the intermittent dosing was non inferior. Now, It's a single per regimen.

[00:20:25] Efavirenz and TDF and Emtricitabine have all got long half lives plasma for efn, intracellular for the others. And there's lots of reasons why this might work and it be extrapolated to other regimens who, who even knows. Um, now it's generally the, the remit of, of the, the French. And this isn't me being, uh, making sweeping generalizations.

[00:20:42] If you look at most of the studies investigating, kind of planned on and off treatment strategies, a lot of them are done in in France. Um, so what's quite interesting. Um, and a test of your flag knowledge for the next study is it comes from give you time to shout out the answer Not that I can hear you Taiwan Oh, I should have asked you, Paul, sorry.

[00:21:03] You knew that, didn't you? I wouldn't have done. I had to double check that was the Taiwanese flag. I'm not very good at these things. Um, so, this was a study, and it took 60 people, been virally suppressed for at least 6 months on Victavi, and they randomized them to continue to take it daily, or take it five days and two days off this photo type pattern.

[00:21:25] So what we see on the left is viral efficacy, the lighter grey is taking every day, the darker grey is the intermittent dosing. I've read the study, I can't quite work out why there are some people included in the later time points and others aren't. I think it was just duration of follow up. But let's just look out to week 52 when 30 people in each arm were still on the study and you can see efficacy's identical.

[00:21:47] There's no difference between the two. Again, as you might expect, these are decent half life drugs. They're forgiving regimens. That's great. But the graph on the right, I think, is really important. This is looking at trough concentrations and at baseline, again, that light grey for daily, dark grey for intermittent, baseline, you've got very similar trough concentrations for big tachycardia across the board, but as soon as you start dosing it intermittently, week four onwards, you've consistently got lower trough.

[00:22:16] concentrations. Now, what you'll see from those little whisker plots, whatever they're called, that they're staying above the protein adjusted, uh, 95. So how much drug you need to inhibit 95 percent of the virus. So you've got, you've got enough drug, but the question is, is that enough drug for the chaos of daily life?

[00:22:35] It's enough drug here. But is it going to be enough drug if you then forget to take more doses? Is it going to be enough drug if you forget and take a high dose cation containing supplement to have some sort of drug interaction? Is it enough if you have some situation where you're vomiting and whatever, if there's, you're really losing your cushion, aren't you?

[00:22:53] So for me, this is saying fine, it's a strategy that might work for people who really want to try it, but it's not leaving enough cushion to be reliable in all scenarios. Paul, what do you think? Would you recommend five day a week?

[00:23:06] Paul Sax: No, this is, this is a, uh, proof of concept that doesn't actually warrant adoption in clinical practice.

[00:23:13] I 100 percent agree. Okay. And, you know, we know, we know already from refill, uh, adherence studies that human beings do sometimes forget to take their medicines and they don't forget to take them on a scheduled basis. So if you, if you already schedule someone to do five on, two off, and then they start missing some of those fives, then it's.

[00:23:36] Yeah,

[00:23:37] yeah, no, that's the thing. It's like, you know, I don't know if anyone's had to take twice weekly medication for anything. I have and it's almost impossible to get that right. So, yeah, that sort of intermittent, intermittent dosing does get rather confusing. So, that was the summary of trials looking at oral antiretroviral therapy in people without resistance.

[00:23:56] So, I'm now going to whiz through some in people who do have resistance. I'm starting off, um, with D2F. May I

[00:24:05] Paul Sax: interrupt?

[00:24:06] Yes, of course. I

[00:24:07] Paul Sax: learned from the study investigator how to pronounce this study.

[00:24:12] Oh, I got it wrong, didn't I? How is it? It's

[00:24:15] Paul Sax: deft. The two is silent.

[00:24:19] It's a silent two! Oh my gosh. I will try and change, but, you know, it's like anything.

[00:24:25] The later in life that you learn you've been doing something wrong, then the harder it is to

[00:24:29] Paul Sax: I learned it at this meeting. I was saying D2,

[00:24:32] F2. Yeah. I'm glad we both got it wrong. But I will try. So deft? So deft. It's been presented previously. We've seen the week 48 results. And these are week 96 results and essentially it was second line treatment.

[00:24:47] So people who've experienced virologic failure on two nukes with an NNRTI. Now, initially there were two arms. It was looking at the kind of standard of care, which was two nuclear sites with boosted Darunavir, versus this novel NRTI free Dolutegvir and Darunavir Otonavir regimen. NR2R3 regimen versus then standard care to nukes and a PI.

[00:25:07] However, as the kind of standard care evolved, and WHO guidelines evolved, and actually rather than PIs, dolutegravir became the second line choice as well as the first line choice, they added a third arm. So the third arm. They've also issued recruiting during COVID, and it's, it's a trial that's been ongoing for quite a long time.

[00:25:23] And essentially what we saw at the conference is what we already knew, which is both the dolutegravir arms. outperformed the PI arm, and that these are people with quite extensive NRTI resistance. Now, we already know from Nadia, um, and we already know from Dorning that dolutrecovir holds its own very well against the PI, non inferior to duronavir, uh, superior to lopinavir in people with extensive NRTI resistance, but also this NRTI free arm did very well.

[00:25:53] So superiority for the Dolutegravir arms compared to the two nukes and PI arm. There's not been any sort of statistical comparison of the two Dolutegravir groups, so did Dolutegravir, Darunavir and Tonovir actually do significantly better than two nukes with Dolutegravir? Eyeballing it, probably not. And so it kind of raises the question of if two nukes and Dolutegravir do very well for most people, what role would Dolutegravir play, unless there was some sort of Some, you know, can't possibly have tenorphin because of toxicity.

[00:26:23] But what do you think? Would you use this second line regimen if two nucleotides? You're talking

[00:26:27] Paul Sax: about the nucleoside free regimen? Yeah, yeah, yeah. I mean, it's, it's, you know, this, this is the question that comes up periodically. You imagine the patient with known K 65R, so resistant to Nofavir, and M184V, resistant to Lamivudine.

[00:26:43] So that's in their historical treatment record. And they're virologically suppressed, uh, would you feel comfortable switching them to either TLD or Bictegra RFGC TAF? And as you'll show, virologically suppressed, unquestionably, I'm very comfortable with that switch. The question is on a, on a, a people who are failing.

[00:27:02] Yeah, does that up the risk of failure within the grace resistance? And Nadia showed it. Uh, it did have, I think, 9 participants out of 200. So, in that arm did develop in a grace resistance. We don't know in this study, because the study didn't report resistance. And then you'll tell us about Pfizer shortly.

[00:27:22] I'm getting close to feeling comfortable with it, but I'm not sure we're there yet, at least in where we have the option to use two fully, at least two fully active drugs.

[00:27:32] Yeah, and there is, you know, that numerical difference isn't nothing, is it? You know, you've got an approaching, God, my math is terrible, you've got an approaching 7 percent viral depression difference between the, you know, with that Dolutero, Moderna, Ritonilol, I'm actually doing slightly better.

[00:27:47] Yep. So, yeah, I'm I'm not sure. And again, I, I think this probably won't necessarily change practice, certainly not in the imminent future, but I kind of wonder if it should. Um, but yeah, hopefully we will see more. So here is, uh, Vizend, or is that Vizend? Tell me how to pronounce it. That one I did not ask the investigator.

[00:28:09] So let's assume it's Vizend. Um, so here you've got adults on ifavirazolavirapine, so a first generation non nucleoside with a lamivudine TDF backbone, 1, 200 people, uh, with virologic, uh, failure and depending on the degree of viremia, they were randomized, um, again in this quite complex rainbow of options.

[00:28:30] But essentially what you're looking at is comparing a PI standard of care for many people with an integrase alternative, uh, also comparing TGF with TAF. Um, and Paul, I can't remember why the people with the lower viral loads didn't get randomized to a PI. Do you remember why?

[00:28:46] Paul Sax: Oh, they're considered suppressed.

[00:28:48] Ah, okay. That's it. So it's a whole WHO guideline type strategy. Yes, absolutely. Right.

[00:28:53] Paul Sax: I mean, two populations in this study, which makes it confusing.

[00:28:57] Yeah, no, it is. And actually, I understand it better this time around than I did first time around, because I don't understand it entirely. So people who haven't met that WHO 1000 threshold definition of allergic failure, randomized to TAF or TDF backbones with doyletegravir, and those who did meet that WHO definition, there you've got those same two doyletegravir regimens, but compared to two PI regimens.

[00:29:20] But the zidovudine backbone. So again, it is pretty complicated. The key thing is, like Nadia, for example, very high rates of baseline NRTI resistance, 92%. People who are randomized to get tenofovir with, uh, emtricitabine or olimifedine Nearly 60 percent have no predicted tenofovir activity. Of course, what we're learning more and more from these studies is, is predicted activity, any true marker of actual activity.

[00:29:49] Three quarters have no predicted activity from lamivudine or emtricitabine. And for those found in mice with zidovudine with a PI, approaching half had at least one zidovudine mutation. So. In many ways, relatively similar to Nadia. So these are the results. Let's look at the right hand side, because this is that group with the true virologic failure definition, where you're comparing a PI with an integrase.

[00:30:14] One on the left just shows you that integrase seems to do pretty well. And the top two lines, which are green and red, again, the worst possible choice of colours for people with colour blindness. But there you go. Those top two lines are the two dolutegravir arms and the bottom two lines, which are pink and blue, are the two PI arms.

[00:30:31] And you can see quite clearly that the doluterexifrologic expression on the integrase, uh, are higher than on the PIs. And there was no resistance to dolutegravir. I don't think I've put the table in, but there was some emergent resistance in the PI arms. Yeah. Surprised. Actually, resistance is different, isn't it, to nadiapal?

[00:30:48] It's the opposite to what we saw.

[00:30:50] Paul Sax: You know, I was, I, so the investigator showed no resistance and I said, none. I mean, afterwards I confirmed they have not detected any race resistance in this study, which is very encouraging.

[00:31:06] Yeah, no, I had to, I looked at the table, which I'm sorry, I don't think I've put in, just to check that it hadn't been flipped around because, as you've already pointed out, there was some resistance emergence in Nadia and people who didn't suppress on the doytegra arm, no resistance to darunavir and tonavir.

[00:31:20] Again, you know, it's lapinavir and atazanavir, isn't it? So these are hardly gold standard examples of the PI class, and I suspect there'd probably be no resistance to anything had that been a darunavir comparator, but yeah. All right. There you go. Now, I kind of feel I shouldn't present this, because we look at our name in the bottom left of the slide.

[00:31:40] This was presented beautifully by a man called Paul Sachs. Paul, do you want to talk through this one?

[00:31:46] Paul Sax: Well, essentially, this is the suppressed population that has a resistance profile very much like the Wysand study. These are people in Haiti who are suppressed on a boosted PI, and they were randomized to continue the boosted PI.

[00:32:01] This is the first time a study like this has been done with Bictegravir FTC TAF, you know, we had no reason to think it wouldn't work because the dolutegravir lamivudine, uh, uh, tenofovir regimen works in people on, uh, with suppressed on second line therapy, but here we just showed that it works in for Bictegravir FTC TAF as well.

[00:32:22] Uh, I gotta just mention that I'm presenting it because, uh, The, um, lead investigator, Dr Samuel Pierre, could not make it to Munich because of visa issues, and the senior, uh, investigator, Serena Koenig, couldn't make it because of personal reasons, so it fell to me, I'm a co investigator, and I, I got to present it, so there were really no, very, very few differences in, in outcomes.

[00:32:46] I mean, it's, it's, it's a marker of the quality of the, of the, uh, author's pool. If you, if you're sort of second line backup is Paul Sachs, then you've got a pretty good team, I would say. And Paul, I just wanted to ask you, because that, that's a kind of slightly nail biting confidence interval, isn't it?

[00:33:01] Because then there's, there's, you're getting close to superiority, aren't you?

[00:33:05] Paul Sax: Yeah, it was very close. And the, the Forrest Platt showed that it was close to superiority. Uh, it was an open label study. The caveat about that, and it's easier to take, obviously, a single pill of Bic Tegra FTC TAF than to stay on a boosted PI, which, at least in Haiti, is often Ritonavir, boosted PI.

[00:33:21] Uh, and, uh, plus nucleosides, so it's not the easiest regimen in the world to take. Um, I did hear something interesting speaking of that island of Haiti. First, first, I just want to say the incredible that they were able to do the study because of all the civic unrest that's going on in that country. And second, um, right across the border in the Dominican Republic, that the country has elected to purchase generic TAF, FTC, FTC, FTC, FTC.

[00:33:50] Rather than get the donated TLD. And the basis on the fact that that there is, you know, I think we should just keep this in mind because of all the controversy about weight that they're especially in older people and people with comorbidities. It's very, very hard to sort out. Sometimes the, uh, the renal adverse effects of 10 off of your dies a proxile.

[00:34:12] Uh, and and increasingly we are going to be seeing that. Globally, because, you know, as the patient population grow, uh, ages in, especially in the 20 million or so in Africa who are getting TLD, um, T tenofoviridazaproxil is going to cause some problems. So the solution to that is either a TAF based regimen or a dolutegavirumibidin based regimen, but so far they're not available from, you know, global, global purchasing.

[00:34:40] Yep. Yeah. No, it's a, it's, it's, it's an important point.

[00:34:46] Artistry. So, on the subject of, uh, two drug regimens, Here we have artistry one. So this is all about Bic and Len. So Bictegrafir, of course, an integrase that we can't prescribe without its jacket of tenofoferalaphenamide and tracitabine. Um, we, it certainly can be made that way and I think moving forwards, although the goal will be to co formulate this still, um, but certainly for now we're seeing a naked Bictegrafir given on its own in combinations and other things.

[00:35:17] So basically this is just under 130 people, virally suppressed. Or suppressed on complex antiretroviral therapy, and they defined that as being on a PI or a non nuke with at least one non NRTI drug. So you, yeah, you couldn't just be on a, a boosted PI and, uh, to an RTI backbone, for example, had to be another drug that wasn't an RTI or at least two pills a day.

[00:35:44] or more than once a day dosing. So it's, it's, it's quite a broad definition of complex because some of these people are going to be people who've been on what they've been on for ages and haven't been offered a switch, uh, or don't want to switch, or are thinking about switching. Um, it would also include people who are on non oral combined with oral agents, um, excluding Cavdec or Epirephrine, so of course that brings in your Ibulizumab or, um, that's pretty much it if you've got access to it.

[00:36:11] I don't know if, uh, everyone's got access to Amphetamide anymore, we certainly don't soon because they're discontinuing it for us. I'm sure they'll probably discontinue anywhere. Anyway, so people are suppressed on these various definitions of complex art with no prior exposure to LEN and no resistance to BIC.

[00:36:25] So you could be on or have been on an INSTEA, just no resistance. Again, these are not Hep B active regimens. So, uh, people with hepatitis B exclude in GFR at least 15. So this, um, study randomized people to two different BicLen doses. So Bic75, now those astute amongst you all know that Bic is dosed at 50 in BicTarV, formulation and blah, blah, clever pharmacology stuff.

[00:36:51] It's the same equivalent dose because some people saw this and went, A higher dose of Bic, that means that they're not confident in Bic Len as a combination, so they're giving 50 percent higher dose of Bic. That's not the case, it's, it's pharmacologically equivalent. So you've got Bic with Len 25 or Len 50, or you continue to baseline up, that was a 2 to 2 to 1 randomisation.

[00:37:11] The phase 2 extension will be the fixed dose that I mentioned at the beginning. Um, so these people were 60 on average, living with HIV for close to 30 years, um, and more than 80 percent we didn't see the detail of any resistance yet, but 80 percent were on a complex regimen because of a history of resistance.

[00:37:32] Now again, What does a history of resistance mean if it was from 25 years ago versus last week? Median number of pills was three, and actually the most common regimen was boosted darunavir with dolutegravir and either TAF FTC or an NNRTI. So this is, you know, these are PI. Second generation, second generation integrase and a non nuke 2a backbone.

[00:37:57] Now, um, viral suppression, a pessimist like me is going to look at that and go, Oh, well, um, it didn't do quite as well. I put the key in there. Uh, I do apologize, but take my word that the pale grey on the far right with 100 percent efficacy is the continued art. and the black and the dark grey. Actually, sorry, they're on the table on the right.

[00:38:13] Those are the two BicLen arms. Now, of course, with this type of study, with this sort of sample size, you only need one or two people to get the detectable viral load for those percentages to look quite alarming. But, you know, there is a difference that we're going to need to observe. And then adverse events, again, uh, this was open label, um, people who stayed on their stable regimen.

[00:38:33] didn't have the same adverse event rate but by and large it looks like a pretty well tolerated combination and it could be quite exciting of course how accessible it's going to be will be a very big question um but yet could this novel integrase and capsid inhibitor fdc change outcomes for people who are on complex art because of what went wrong in the past so paul what about you are you hopeful for this as a pairing

[00:38:57] Paul Sax: well i think i think it it's going to work i mean i i suspect strongly it's going to work um I, uh, I do have a slightly dissenting view about how much we need it because as we know from the Vizen study presented just now so well by you, as we know from the, the, uh, Jeskio study, um, presented not so well by me, uh, as, as we know from, uh, the 2SD study from Kenya, people with nucleoside resistance who are suppressed can, can switch to, uh, Tenofovir or Bictegravir ftc.

[00:39:40] taf And maintain suppression. Yeah. Even if they have lots of historical resistance. So you know this. This population is, is not, it's not a, not a hugely needy population for that, that pill. Uh, now some might say, well, why not use two active drugs when you can and nucleosides are only partially active.

[00:40:01] That's, that's, that's valid, but we'll see. What I think would be very interesting is to do a blinded study in people with complex regimens and randomize them to, uh, this fixed dose combination, or. either TLD or Bic Tegra Ref

[00:40:17] to CTAF. Yeah. No, I think it's, it's, um, yeah, it's, it's, it's early, early days, isn't it?

[00:40:23] But, um, yeah, I, I would, um, that, that, that, that small numerical difference was always gonna get me up to the microphone, which it did.

[00:40:33] Paul Sax: Blinded, blinded, we help us, help us know whether it's, uh, it's got any benefits from a scientific profile.

[00:40:39] No, no, 100%, 100%. I'm sure there's innumerable GS blah blah blah 1987 type studies planned.

[00:40:47] So, um, so doi tegur in resistance, again I've only picked out two, two studies here, and this is around continuing the theme that really kind of kicked off at the beginning of this year, uh, and, and is, you know, in many ways predictable, um, that we're seeing more Resistance, integrated resistance in people who aren't suppressed on and integrates.

[00:41:08] I mean, it's gonna happen. And I think we have to remember, I can't remember if it was gone up to 22 million now, but you know, there's at least 21 million people on dolutegravir based art globally. That's, you know, most people with HIV. So of course, we're gonna start to see more emergent resistance to a drug class that's being used in most everybody.

[00:41:25] So the, the, the biggest study was, uh, DG Resist from the. idea network. I don't know if I said that one right. But looking at two years worth of data from June 22 to 24, um, this is data collected from seven African countries, 362 people. Only, um, so half of them had followed above a thousand. And they've got results from 152 people.

[00:41:47] So there's 152 people with viral loads above 1000, uh, on dolutegravir. They've been on antiretrovirals for a median of 11 years. So these are people who've been, you know, weren't using dolutegravir 11 years ago. So these are people who've been on lots of other antiretrovirals for a long time and probably mainly non nucleosides.

[00:42:04] Um, it'd been on Dolutegra for a median of two and a half years. Uh, most were on TLD, that's not for the median Dolutegra of FDC, and about a quarter on two other nukes with Dolutegra of it or not in FDC. So, they managed to get 148 integrated sequences. Not surprisingly for that part of the world, they were all non B.

[00:42:22] Compare that to the subtypes in most phase 3 trials where it's mainly B, of course. but primarily subtype C followed by AG and A1. Now of this population, we don't know how long they've been detectable for on dolutegravir. It could have been for, you know, two of those 2. 4 years, but 22 percent have at least one major integrase resistance mutation.

[00:42:42] And actually I thought, Oh, well fine, because there are major integrase mutations that actually have very minimal impact on dolutegravir. But actually, most people had some form of combination. So 20 percent of people who had their integrase sequenced with borolones, 20 percent had predicted high level dolutane resistance, and two thirds of those had the 118R and 10R.

[00:43:06] 1, 3, 8, A, K combination. Um, so they concluded that compared some of the data that we've seen in trials that dietary resistance patterns may differ by subtype. I also suspect that they will differ by duration of detectable viremia and time taken to do a sequence. So it kind of confirms. And then I'll just briefly show the Brazil one.

[00:43:25] 430 people with viremia on first line TLD. So this is a different group. These aren't people who've got this big legacy of non nuke and therefore potentially more NRTI resistance. So 430 people, about 1 in 10 had a viral load above 100, 000 and 7 percent had integrase resistance. Um, there was less information on, on the precise impact.

[00:43:46] Um, but the most common mutation was 155H with, with only a potential low level impact on dolutegravir and 62 percent were non adherent serontiretroviral therapy. So you've got sort of these, this consistent with what we've, we've kind of seen already. because, um, at CROI there's lots of discussion about this, lots of posters, there was this WHO brief report raising concern about levels of dietary resistance in the real world being higher than in clinical trials.

[00:44:14] I mean, is that really that surprising? I think that's true for many different regimens, but the key thing being that WHO says people should routinely Um, undertake standardized surveillance, which would be a good thing, because it's a luxury still for many parts of the world. So, Paul, what are your thoughts on, on this?

[00:44:32] Paul Sax: This is a definitely something that bears watching very closely, uh, and you can take a glass half empty approach. Which is that it's happening and rising in incidents, and that's true, or you could take a glass half full approach, which is that given the giant number of people on dolutegavir based regimens, it's amazing.

[00:44:50] There aren't more people with extensive resistance. And another, you know, glass half full interpretation is that so far transmitted drug resistance, To integrase inhibitors is incredibly rare, uh, and they are, you know, keeping track of that from in surveillance sites around the globe. But but so far, I have not heard reports that that is increasing.

[00:45:11] And it could be that integrase, uh, resistance mutations don't lend themselves well to transmission, but we are keeping an eye on it. Um, I will say that that the, uh, You know, the, uh, Mattias Egger and his group published, um, another look from that network in a very fine journal called Clinical Infectious Diseases, and they actually reported that the people who switched, uh, who were, uh, had a viral load less than 1, 000 really had incredibly low risk of resistance.

[00:45:45] So I think, I think that that population I'm not as worried about is that. marginally adherent on again, off again, treatment and everything sort of struggles for that group. Yeah,

[00:45:55] no, no, absolutely. And I agree with you and I'm, I'm, I'm, I'm characteristically, uh, more glass half full on, on, on this one. I do think it's, it's predictable.

[00:46:04] It's actually, and then also you, we have to think about your denominator here. Who undertaken? It becomes a very selective population and it certainly doesn't, you know, it's, it's certainly not crisis yet, but I agree with you entirely. It's, it's, It's important to monitor and considering that we're not doing enough monitoring already.

[00:46:21] I think it's a really strong call to make sure that these, yeah.

[00:46:25] Paul Sax: One other thing just to say is that you and I now have all this experience with integrase inhibitors starting, you know, 2007 when we're all Tegra got approved and then, you know, we had a great leap forward with all the Tegra's approval and now we have big Tegra also.

[00:46:41] So, and, you know, these, these, uh, These drugs are amazing. You know, we all of us know in our own practices who the integrates inhibitor resistant virus, which patients have this because it's so rare. It's pretty rare.

[00:46:58] So no, I completely agree. And certainly it's really rare for us. We've got a cohort of 5, 000 people.

[00:47:04] I probably count on my digits how many cases we've seen. And I'd say more than half of those. It's a clinician related adverse event. It's, it's,

[00:47:15] Paul Sax: you know,

[00:47:16] it's just, it's where, it's where a resistance test showing, so particularly people with raltegravir, you know, finding resistance tests actually showed that those supportive drugs actually probably weren't active after all.

[00:47:27] So yeah, there's a couple definitely where it's, it's been a prescribing adverse event rather than necessarily something would have happened otherwise, certainly for us. But again, thankfully, very, very tiny numbers overall. Um, what happens if you get integrase resistance? Well, you can have a new integrase inhibitor.

[00:47:44] So, this is PH184, um, as been pointed out by others, uh, very similar to the 184B mutation. Um, it's a phase one study in people without HIV. Um, there is a bit of a food effect, the half life's good, um, Yeah, but the key thing is, and actually this isn't the best graph, I couldn't find the other one, there's one that's more sort of 3D ones that you don't tend to see very much anymore, but the key message is that this is an integrase, uh, did they call it third generation?

[00:48:12] I can't remember if they did, but we are, third generation integrase, uh, that retains activity against people with high level resistance. This is some real, uh, it's obviously in vitro, but these are samples from people who experienced virologic failure in the SAILING study, which is a treatment experience study, uh, including Donny Chekhovia, so these are people who got more integrase resistance.

[00:48:32] Um, so yeah, next plans are, um, um, study of the oral drug in people with HIV, but also phase one injectable formulation in people without HIV. So it's not going to be hitting anyone's pharmacies anytime soon. But, um, Paul, what do you think? I mean,

[00:48:48] Paul Sax: was it regenerative? It was, wasn't it? Yeah, I mean, this, this, this, uh, tendency for people to advance generations with their new drug in the same class, of course, takes us back to cephalosporins.

[00:49:02] Uh, and it was a great marketing tool then, and it's a great marketing tool now. And so, uh, it does stick in your head. Hey, this is the next generation. I, I will say that dolutegravir and bictegravir really were advances over raltegravir and alvitegravir. So, you know, in that sense, yes, let's, let's give it the generation nod.

[00:49:24] So it's fun to watch and, um, it's always nice to see new drugs emerging. Um, whether they, you know, whether they stay, who knows. I think the maturation inhibitors is a class of drugs where there's not much that lingers for more than a couple of years. But anyway, we shall see. And it's good to know that there are options explored for people to raise resistance.

[00:49:46] Um, this is a bit sarcastic of me. What if you don't have any resistance? Solar 3D. So Solar 3D is a perplexing study. Um, I think calling it a study is, um, generous. It's, it's, if you actually look at it, it's basically a kind of cohort. Um, and it's, I don't know, yeah, it's like when you see somebody who is really crap at acting or singing or something, but they become inexplicably famous.

[00:50:11] This is the trial equivalent of that. Um, because it's, it's had, uh, some, you know, high level attention from a selection of conferences. This was a co chair's choice at IAS, uh, in what I can only assume was some form of act of charity, frankly, but it, uh, certainly, yeah, had a very high level slot. So we've already seen data from, um, week, uh, 48.

[00:50:37] I must have seen week 96 somewhere. This is week 144. And essentially the premise is, can you use dodecaglomifedene in people with a historic 184 mutation? And that's kind of been addressed in other cohorts and bigger cohorts. Italian cohorts started publishing on this, uh, a long time ago. Um, and actually I think more and more we're comfortable that if it's the best option, If someone's got lamivudine resistance from more than five years ago, six years ago, something like that, then it probably isn't important.

[00:51:08] There are some good studies ongoing. Volvo is an example for studying people, Historic 184, who don't have it on DNA sampling and switching them, a much more kind of conservative approach. But hey, 100 people, 50, with 184, 50 without, or switch to Oteglam if you deem. The reason I've sarcastically said, well if you don't have any resistance, is the people with 184, actually two thirds of them didn't have the 184 on pro viral DNA.

[00:51:32] Now the accuracy of pro viral DNA, when it's just a little snapshot of a bit of the DNA, blah blah blah, who knows. But everyone did well. So if you switch people, mainly without the 184 now, even if they had it in the past, it works. I really don't think this adds anything, and I'm not quite sure why it seems to have.

[00:51:50] One an Oscar when it's not Oscar worthy, Paul, am I being too harsh?

[00:51:55] Paul Sax: Uh, well, you know, it is, it was prospective experience in this clinical practice. Uh, you know, I, I, I feel like the right study to do if anyone wants to do it is someone is take people who are suppressed with historic one, eight, four V and randomize them to, uh, double And, and blind it, and then have a primary endpoint be virologic failure, and, and that would really answer the question.

[00:52:26] Yeah. So.

[00:52:27] Yeah, and I think anyone's thinking, oh, that's all well and good, isn't she being harsh, and it's easy saying we know this already, this is purely a follow up, and we probably didn't know this when the trial was designed. There were some slightly grandiose conclusions shared at the end of this, I think it's fair to say.

[00:52:40] Some sort of globe saving, financial crisis alleviating, safe and effective. Anyone who says something's safe and effective when the number of people in the trial are smaller than the audience it's being presented to, that's my definition of grandiosity. So, there you go. Oh, so, we're getting there.

[00:53:01] Injectables. So, um, firstly, um, I've just popped this in. This was the Carlos cohort. It had been presented at Glasgow, which would have been two years ago, because it's a Glasgow year this year, isn't it? Because Glasgow, yeah. Oh, yes. I've never been

[00:53:15] Paul Sax: to that meeting.

[00:53:16] Haven't you? That's, that's, that needs correcting.

[00:53:22] That needs, that's got, that's got to be fixed. It's a great, it's a great meeting. It's a, it really is. It's um, I think I'm going to say the opposite. I don't think I've missed one since, um, I've worked in HIV

[00:53:35] Paul Sax: medicine. You're a bit closer than I am. True, that much

[00:53:38] is true.

[00:53:39] Paul Sax: And you also don't go to ID Week, which is in October every year.

[00:53:43] No, no, no, no. I am a one trick pony. Um, yes, absolutely. So I don't have the repertoire of microbes that you do under your belt. Uh, this is a cohort, again we won't go into a huge amount of detail, it was nicely presented, when this was first presented it's gone oral at Glasgow actually, and again, you know, I recognise I'm a pedantic pain in the arse and I recognise that most presenters don't feel with joy when they see me approaching the microphone because they, whether I'm right or wrong, I'm, I'm, going to be firm.

[00:54:13] Um, I think that's a very important function of conferences and I've certainly learned more by watching people at the microphone, listening to them over the years than I have sometimes in the presentations themselves. So it's an important function. So I remember questioning this one, um, and then being told off for being mean to the presenter.

[00:54:29] I wasn't mean to the presenter. The fact I asked a question they were unable to answer isn't mean. Um, but anyway, this was a clearer presentation. It was a poster, but just really, it's just a bit more real world experience. And I think the reason I put it in is There was here a 1 failure rate at month 12.

[00:54:45] So when you look at the Atlas and Flare studies and the risk of virologic failure, you compare that to the SOLAR study, the most recent phase 3 trial of injectables versus oral, in that case Bictavi, there's a sense that the risk of virologic failure has come down. Um, it is a cohort, but it's a pretty good size cohort, 350 people.

[00:55:03] And just to say that we know this, We know that there is a risk of virologic failure, um, including in people with 100 percent adherence. It's just a reminder of that. So perhaps slightly higher real life than certainly solar, but we just need to gather more data. I think it's a testament to the fact that the implementation challenges for this regimen mean that we're not seeing that.

[00:55:26] bulk of real world data. I think perhaps we'd all imagined we would when it first got licensed, that the uptake has been perhaps slower than any of us would anticipate. Um, and really understanding the implementation barriers is, is critical, of course, but beyond that, nothing much new here, I don't think.

[00:55:45] Adolescence. So this is a, the, the, the mocker studies, it's on the main impact 2017, two monthly injectables in virology expressed adolescence. 140 of the 144 complete out to week 48. No confirmed phyrologic failures. Strong preference. Concentration similar. So these graphs at the bottom, that thick black line is for the adolescents and the blue line is historic data from adults.

[00:56:09] So you've got trough cab on the left, you've trophopyrine on the right, and you can see the concentrations were at least as good as you'd expect in adults. So it's good. Why is this important? Because at the moment the license doesn't extend to this young, younger age group, and hopefully this will be the study that changes that.

[00:56:27] And, Subcut, so it's got an oral presentation. Um, this is people from Flare. They were already on injectables for at least 12 months and there was this sub study looking at subcutaneous cab and realpivirine instead. Now the conclusion, this was interesting, I thought the conclusion said similar cab and realpivirine PK.

[00:56:47] I'm not sure what the pharmacokinetic definition of similar actually is. The word they used in the slide, that was in their conclusion, the word they used in the slide was comparable. Well, anything's comparable. You can compare 100 percent with 5%, but, you know, is that, it doesn't mean they're similar. Um, now let's look at the various concentrations.

[00:57:05] Now let's see, CAB's on the left. Let's ignore CAB, although there is lower exposure with subcut versus gluteal. So it's top three bars. You've got max and min, top and bottom. You do get, you do get slightly better exposure with IM. Is that important or not? Who even knows? I'm probably not going to know.

[00:57:22] Well, if we know, just go to that bottom right corner. For me, there is this step wise reduced exposure at each injection. And certainly by the third subcutaneous injection, that looked like a statistically significantly lower exposure than you get with IM. Now the trouble is, further development won't be pursued.

[00:57:44] Now there was significantly lower injection site reaction acceptability, there was a significantly lower treatment satisfaction score, preference favoured IM, but 34 percent of people preferring subcut to me isn't to be ignored. You can see the the graph there as well. And these are the reasons given for preference, um, and for subcut, the convenience and injections weren't interfering with daily activities, um, as much as IM would.

[00:58:11] So I thought it was a shame that this won't be pursued. To me it was, it was primarily because of this data. I'm not sure if that ropiferine concentration continues to drop with with more subcut injections that it would be the best option, but it was Pedro Khan, wasn't it? Um, The god of HIV from Argentina who did really express that this could be a great option.

[00:58:35] Pedro sees a significant number of people with buttock implants. He often asks about buttock implants at these conferences. And it's that point of if someone can't have an IM injection, it would be nice to have that option. The V presenter, a very good presentation, was very clear that they are committed to non IM options.

[00:58:53] But Paul, what do you think? Do you think they should have tried longer?

[00:58:57] Paul Sax: I think it's going to to maybe take a different formulation or something because I agree the ropivirine drift was concerning.

[00:59:08] Yeah. Um, and then just on the subject of injectables, um, whenever Andrew Hill is involved in a study, there's often, um, you know, big analyses across lots of different studies.

[00:59:21] Um, and he's, yeah, he, he's done some really good analyses, I think, including, and we talked about TGF earlier. Cool. I'm not denying that TDF can indeed have, uh, uh, nephrotoxicity and bone toxicity issues, of course. But actually it was, it was an analysis from, from Andrew that really emphasized that it was particularly in the context of boosters that, uh, T TDF is particularly associated.

[00:59:41] Yeah,

[00:59:42] Paul Sax: in clinical trials population. Yeah, absolutely. Not in clinical practice.

[00:59:47] Fair, fair, fair. I know I'm a big TDF fan, but I recognize it absolutely isn't suitable for everybody, particularly as people are getting older. This analysis of 18 trials, um, 8 injectable capropiparine, 10 dolutegraphate, all suppressed switch, all with 48 week results.

[01:00:03] Biologic failure, same. So highly, highly effective. No one is saying that injectables don't work. They're But this is just emphasising what we already know, but it's just, I think it was just a very clearly outlined reminder that amongst that small number of people with virologic failure, you see more resistance.

[01:00:22] This is integrated resistance. So two thirds of people with virologic rebound on capyralpivirine had integrated resistance compared to none on dolutegravir. Uh, the rams are listed there. I'm not going to go through those, but the key thing is. 40 percent of people with viral rebound on cabriolepivirine subsequently had intermediate or high level cross resistance to dolutegravir.

[01:00:42] And again, you know, 4 percent of these populations. But the key thing being is we must be mindful that there are some people for whom a virologic failure event on injectables will limit the utility of integrases further down the line. For some, there'll still be an option, but as effective in this analysis.

[01:01:03] Paul Sax: Yeah, I mean, it's, it's, it's just part of the counseling when people choose to do this, you know, they, as best as someone can understand. Uh, you know, one out of a hundred people who show up for their injections could fail with clinically significant resistance.

[01:01:21] Yeah, my way to do it at the moment is people standing in a field for some reason.

[01:01:25] I do it the same with statins. And I say, imagine there's a hundred of you stood in a field. One of you. might have a viral rebound. 99 if you want. So again, it's that half glass, full half glass, empty thing. And again, it's very much down to the individual. Does that very small risk that the potential benefits outweigh?

[01:01:42] And for many people, they do outweigh. For some people, they don't. And there will be other options moving forward. Very, very near to the end now, where we've hit an hour. So there's been lots of discussion about, should we routinely be doing drug level monitoring in people on injectable antiretrovirals?

[01:01:57] Again, um, it's something that a French study earlier this year or last year that strongly called for that. This is a German study, real world TDM analysis of 134 samples. And what you can see is quite a lot of people had below trough target concentrations, haven't put them there on the poster if you want to know the nanograms per mil that they use as a threshold.

[01:02:18] but quite a lot of people with, with below target concentrations, but this is where, and that doesn't look great to me, no PK expert, but what I didn't quite get is what you're seeing is, let's take real pivorine, half of the people who had TDM sent had below target concentrations. Of the six, we're splitting tiny hairs here, tiny, of the six with detectable viral loads, Half had low ropivirine concentrations.

[01:02:46] So the proportion of people, again, small n, but the proportion of people with low ropivirine concentrations to viral load matched the proportion of people with low ropivirine concentrations. So I don't understand how this is important, because it wouldn't help you predict who's going to get virologic failure.

[01:03:01] So I thought the strong recommendation to check drug levels was confusing.

[01:03:07] Paul Sax: Plus, you know, they didn't test the strategy of checking drug levels.

[01:03:12] Absolutely, absolutely. But again, this is, depending on how this data gets propagated and disseminated, this, yeah, so I, I just, yeah, so I don't think there's enough evidence to do routine drug level monitoring at all.

[01:03:25] Um, oh goodness, we are so, uh, insomnia. Small underpowered study because they struggled during COVID, but this was to look at really, really in depth measurements in people with insomnia. So people with insomnia on dolutegravir were randomized to switch to BicTavi. or continue their dietary regimen. And they had detailed, very detailed assessments of baseline and month 4, patient report outcomes, functional MRI, soluble markers of inflammation, immune activation, 19 all men, 12 on an abacavir backbone, we'll come back to that, 7 switched to BIC, 12 saved on their dietary regimens, switching to BIC, significantly improved sleep, patient reported outcomes, quality of life, functional MRI, MRI connectivity in areas associated with improved sleep, no change in biomarkers.

[01:04:17] I've got strong opinions about biomarker studies anyway, but that's by the by. And their limitations were small sample size, open label, sex bias, there were no women in the study. I think probably the most important limitation, I did say this at the microphone, I think very kindly, Paul was behind me, I'm sure he'll tell me if I wasn't, but was this all down to removing a back of ear?

[01:04:35] We mentioned earlier You know, the 1 1 4 8 9 1 4 90 studies, which, um, for those of you who don't remember, that was Trium versus BT Avy versus Truvada dolutegravir versus Bic t Avy. And, uh, there was abacavir related differences in insomnia rates. So I, I I think it's, it's, it's interesting. Yeah. Whether it's actually doll versus big or abacavir versus no.

[01:04:58] Abacavir I think is the important question.

[01:05:01] Paul Sax: We don't know. In this, the first study of Abacavir Lamivudin Dolotegravir, which is compared to TDF FTC Efavirenz, the single study, one of the adverse events that was worse in the Dolotegravir arm was insomnia. Worse than Efavirenz.

[01:05:17] Yeah. Yeah. Although I can't remember the details, but Sharon Wormsley always gives me a very good explanation as to why that was.

[01:05:23] It was something to do with how those side effects were ascertained. I, I wasn't involved in the study. It was a

[01:05:28] Paul Sax: blinded trial.

[01:05:29] Yeah, yeah, no, no, I think it's, it's, it's an important point. This is, yeah, it's, it's that graph. I'm sure one of us could dig it out to share with people. It is, it's quite a marked difference.

[01:05:39] Um, reprieve. We all know about Reprive, statins for everybody. Uh, this looks at whether abacavir, we know that abacavir in large cohorts was associated with increased risk of cardiovascular events. Again, it's, it's something that I think not everybody agreed with. Some people still argue that it was all artifact.

[01:05:54] Um, but what Reprive showed is that, uh, current and former use of abacavir associated with a higher risk of, um, major adverse cardiovascular events. Other drug associations not shown, so insties, non nukes, PIs. So you're looking at this 40 to 50 percent higher risk. So I think it's an important reminder and there's an awful lot of people still on the back of ilimifedine, dolutegravir, many of whom could actually quite simply switch to dolutegralimifedine.

[01:06:18] We've seen lots of data show that's a perfectly safe thing to do. And I think there can be a tendency to only think about switching away from the back of it if you still have people on it, if they're at high cardiovascular risk. Now, for us, we use a threshold of 10%. What's important here, independently adjudicated cardiovascular endpoints, this was a cardiovascular endpoint trial, so I think we can feel quite confident in their ascertainment of events.

[01:06:40] But this is a relatively low risk population. We know reprieve had a four and a half percent US based calculation predicted risk of, uh, Major adverse car with the rest of the rents over 10 years, a slight difference between whether people on a back of it or not. That was all accounted for in the adjusted analysis, but just a reminder that unless somebody really needs a back of it.

[01:06:58] You're probably going to be doing them a favor by getting them off it. Is that fair, Paul?

[01:07:03] Paul Sax: I'm completely with you. Um, we, uh, once the efficacy data came out, we, we pretty much stopped using the back of your entirely for reasons you alluded to. Thank you.

[01:07:16] Yeah, no, absolutely. We're very much the same. Um, and then lastly, this is the last slide, uh, in this section, I promise for a couple of closing thoughts, um, HEP B reactivation.

[01:07:29] Now, of course, we don't have any, you know, you, you can use, uh, HEP B active to drug regimens. You could use tenofovir with dolutegra if you wanted to. But I think the ones that we're studying are certainly the ones in the pipeline. a non tenofovir based. So this was looking at Gemini and STAT, two first line studies, including diutechlamyphidine arms, Tango and Salsa, two suppressed switch studies with a diutechlamyphidine arm, and looked at those individuals with an isolated core antibody that was reactive.

[01:07:58] They had DNA testing at baseline, so hep B DNA negative, core antibody positive, no detectable surface antibody. Is it safe to switch them to a non tenofovir regimen? Um, biologic outcomes for HIV comparable, including target not detected, the one that you just throw in for a bit of added graph action, few liver enzyme elevations, one liver discontinuation with somebody with hepatitis E, don't think we can blame that on the drug, no hep B reactivation noted, but importantly, hep B DNA wasn't undertaken routinely.

[01:08:27] So you'd only have a hep B DNA if there was a clinical suspicion of a hep B reactivation. So I think that's the question. Firstly, What about two drug regimens with no hep B activity? So, of course, lamivudine does have hepatitis B activity, not robust enough to be relied on as a single agent, but there is, you know, is that lamivudine providing enough to prevent any kind of reactivation, should they be at risk?

[01:08:50] But also, if we're going to include people who are core antibody positive, surface antibody negative in non hep B active ART trials, should actually hep B DNA monitoring become routine, rather than only if there's a clinical event, uh, at risk. I think yes, and Paul, I'm judging from your non verbal communication, you think the same.

[01:09:08] Paul Sax: No, I'm not. I'm nodding very subtly.

[01:09:11] It wasn't subtle, I could see it from here and my eyesight's terrible. So, I'm done, that's been a brilliant discussion, certainly went on longer than I planned, I timed this to 40 minutes, but just to close, I think one thing, and you know, this is something that is so sobering, there's a brilliant presentation from Anna Turkova of UCL looking at paediatric HIV, 2013 there was a 9 percent gap in paediatric versus adult global art coverage.

[01:09:39] 10 years later, that's a 20 percent gap. It's just not good enough. There's been improvements in both the last half full, but the fact that gap is widening is an absolutely urgent priority. And finally, I've been putting this in talk since 2021, I'm sure pretty much everyone's been putting this sort of thought in talk since 2021.

[01:09:56] Why do we use the same drugs for treatment and prevention? This comes back to that. integrated resistance theme that we touched on earlier, the fact that cavitography for prevention is being rolled out more widely, and potential impacts of that on treatment options, but that's going to be covered very well by my colleague Paul Sachs in his focus on prevention next.

[01:10:16] So here are some thank yous to people who provided slides, and a big thank you of course to my co presenter Paul, who gets a bigger font than everyone else. So I shall finish there, there's my contact details. Uh, and I shall hand over Julie to my co presenter. very much. Thank

[01:10:36] Paul Sax: you, uh, Laura. That was brilliant as usual.

[01:10:38] You did say something that I wanted to highlight though. Um, when I mentioned that I attend ID week, which is of course an infectious disease meeting, You said to me, well, uh, I don't have the same, uh, diversity of microbes under my belt. And I don't think that that's necessarily a compliment.

[01:10:58] I know, but like that, when you, when you say it again out loud, no, that doesn't sound so, that doesn't sound to be so nice.

[01:11:05] No, no, it's about intention. My original intention was the first one that you are far more broadly experienced at a microbe level than I am.

[01:11:13] Paul Sax: Anyway, let me, uh, let me start sharing my screen and I'll cover, cover the next part of this. Uh, hold on a second.

[01:11:31] Oops. I don't know if that's working.

[01:11:34] Can't see anything yet.

[01:11:35] Paul Sax: Okay. I will try a different approach. One second. Uh, share screen.

[01:11:44] How's that look?

[01:11:46] Perfect.

[01:11:46] Paul Sax: Okay. So, um, I'm going to start by a look back on our previous, uh, German international AIDS conference, and then I'll cover some topics that, uh, that Laura was unable to get to, but she did such a good job with art and its complications that I don't need to those. Uh, so the question is, uh, when, Was the last time the International AIDS Conference was in Germany, and where was it held?

[01:12:11] Uh, and I have a, a little hint with this picture. Uh, uh, Laura, you want to take a guess at this?

[01:12:20] So, um, I know that that's Berlin. Yes. When it was, I don't, so it's going to be, it's got to be pre, pre 2004. Yes. I'm guessing, okay, I'm going to put in a guess, and I'm going to say it was in 1990, no 2000, it was in 2000.

[01:12:43] Paul Sax: In fact, it was in 1993. Oh,

[01:12:46] my

[01:12:46] Paul Sax: goodness. Right. 1993. And it was a really grim time in HIV. And I was able to found this, find this. This is, you know, it was actually pre internet, but some of the newspapers have archived some of their old content, including the Los Angeles Times. AIDS meeting ends with sobering appraisals.

[01:13:05] Experts say that progress is slow. The Berlin conference stressed prevention, not cure. In fact, there's There was a large clinical trial done in Europe, uh, of zidovodine called the CONCORD trial that, that demonstrated that zidovodine did not really work in people who had high CD4 cell counts in preventing the progression to AIDS.

[01:13:24] Uh, and so very, very grim time. And in the United States, uh, HIV had become the leading cause of death among young adults in our country. Um, and this was, uh, right then in the early nineties. So, uh, I was just entering the field at the time, Uh, and, uh, knew it was a big challenge. I will also say that this was the very 1st research poster.

[01:13:47] I presented at the conference. Uh, here it is. I have somehow have a picture of it. Uh, if you, if you kind of look at each of these pieces of paper, each 1 is an 8 and a half by 11. Sheet, you don't use those that size in Britain and just tape them together. That's a fancy graphics from that that era.

[01:14:06] That's wonderful.

[01:14:07] You see, you were eco friendly before your time. That was probably way better for the environment than some of the things.

[01:14:13] Paul Sax: Okay, but onto the subject at hand, and that's going to be pre exposure prophylaxis. And the big news of the conference was, of course, this study, which was presented and published on the same day.

[01:14:25] Uh, and it was twice yearly. Lena cap a beer or daily. F. TC TAF for HIV prevention in women. Uh, and Linda Gayle Becker was the presenter. Let's take a look at the study design. I actually think it was quite a brilliant study design. Uh, what they did was they screened the population at very high risk for HIV in, in South Africa and Uganda.

[01:14:48] and those who screened. HIV positive, they used something called a recency assay to estimate what the likelihood, the incidence was, uh, in, in the community. And so there's no placebo arm, which is important. Uh, in fact, the, uh, first editorial that was in the New England Journal of Medicine did, did talk about this and, and didn't get quite get it right, but I spoke to the authors and they've corrected it.

[01:15:12] I said, this is no placebo arm. Those who are HIV negative were then randomized to the two experimental arms, which is subcutaneous Lenacapavir every 26 weeks or oral FTC TAF. Remember, this was not studied in women in the initial trials, and then a sort of reference of TDF FTC, which has been studied in women and we know is effective when taken.

[01:15:36] So, um, the study design included three comparisons, Lenacapavir versus the background incidence. TAF FTC versus the background incidents and then TAF FTC versus TD FFTC. Um, well, um, we learned in June, uh, that, uh, it was stopped early by a data safety monitoring committee, uh, saying that there was so much benefit to one of the arms, the line of capital arm, that There's no point in going on further on that.

[01:16:08] And so that was big news. Um, they then, uh, notified the people running this conference in Munich and said, can we present the data? And they kindly were allowed to present the data. Uh, and what were the data that were so exciting? Uh, the figure shows the exciting results. The, um, background incidents, uh, is in what color is that Laura?

[01:16:32] I'd say that was a duckhead blue.

[01:16:35] Paul Sax: Okay. Okay. Uh, that's a, that's a much bigger bar, uh, than the Lenacaprivir bar, which you can't even tell me the color cause it's non existent and then you'll notice that FTC TAF and FTC TDF, uh, are about the same. Um, and, uh, what about adverse events? We all know lenacapavir when injected does cause nodules, but it led to discontinuation in 0.

[01:17:03] 2 percent of the study participants. So, uh, plenty of efficacy in this trial. Let's look at some of the, oh, yeah. And by the way, Linda Gale Becker, she, she put this little, uh, this shape around the zero and there was spontaneous applause in the conference room, which is very exciting. We've seen that before in some really exciting trials.

[01:17:26] And at the end of her presentation, there was a standing ovation. Um, so let's do the comparisons. Now. The first comparison is Lana cap of your versus the background incidents and the 95 percent confidence interval around the zero. You don't have to be a statistician to see that this is significantly better than the background incidents.

[01:17:46] What about half 50 C, uh, uh, overlaps one. So it's not significantly better. Uh, how about the next comparison, lenacapavir versus TDF FTC, which is the reference intervention. Again, lenacapavir is significantly better than TDF FTC, but when you compare TAF FTC versus TDF FTC, there's really no meaningful difference.

[01:18:11] And uh, I think that some people have misinterpreted this. Result, uh, they have said that that means that tough if you see doesn't work in women, and that is not what this says. This just says the taff 50 C and T. D. F. F. D. C. are not meaningfully different in this patient population. So what can explain these results?

[01:18:30] What can explain these results? Well, uh, we know from some historic trials in women in Africa, taking oral prep that medication adherence isn't always so great. And in fact, in this study. It was particularly poor on. If you look at the bottom of this figure, this is the latest of the great colors and have long the horizontal axis is weeks.

[01:18:54] These are the people who are taking, uh, fewer than two doses of. their oral medications a week, and by week 52, 84 percent and 93 percent in the two oral arms classified as taking fewer than two doses a week. Well, we know that that really doesn't work. Uh, they did do a retrospective case control study and found that in the people who acquired HIV taking oral TAF FTC, That the group who had poor adherence was a significantly larger chunk than the people who were matched control samples.

[01:19:33] So, a very interesting study design, a very interesting trial result. Uh, we can see that this is 100 percent protective in this study. Uh, injection site reactions, though common, did not lead to discontinuations. Adherence was low and worsened over time. This has also been observed previously. Uh, there's a study now, uh, being done in, um, men of sex with men and trans women.

[01:19:56] It's fully enrolled, and results are expected, I heard, actually, by the end of this year. Uh, so that's, that's exciting. There are other studies in Lenacapivir being, for PrEP that are being studied, including in, uh, uh, injection drug users, which is a group that has had a lot of trouble getting on PrEP. And the last bullet is, uh, you know, the very first AIDS conference I went to in Berlin, there was protests.

[01:20:21] That the companies weren't doing enough to try to treat HIV and at this conference, uh, there were protests, uh, already about the price of linocapavir, which is very high, um, in the defense of, uh, the makers of linocapavir. This is not yet approved for prevention of HIV. So we don't know what it's going to be priced at.

[01:20:44] And we certainly don't know what it's going to be priced at in the parts of the world that need it the most, such as where the study was done. So, um, Just taking away our protestors for a minute, uh. Laura, I wanted to just get your reaction to this study when you first heard about it and saw the data.

[01:21:03] Yeah. I mean, it's, it's, I think like, like, like many of us, my, my first exposure to the results was, was by press release and, and press releases are important, but you don't get to see the, the, the, the details. So, so seeing that confirmed, I mean, it's, it's astonishing. And I think the, the rare privilege of being at a presentation and where, as you've described, there's a standing ovation over those results is incredibly, incredibly special.

[01:21:29] I think coming in with, with the, and I'm not, this is phenomenal, zero, zero HP acquisitions is phenomenal, but just coming in with that slightly pessimistic, not pessimistic, but realistic angle. I think firstly, it's important to point out that actually Is Lena Kapovina the first PrEP to have shown no incident infections in women?

[01:21:51] Actually, possibly not because, oh we've got it here, so 084, because it's about how they define, so the LEN study excluded people who transpired to actually have HIV at baseline. And HPTN didn't. I'm probably oversimplifying it. But actually, if you only look at true instant HIV infection, there were none in 084 either.

[01:22:12] And then, um, the other thing was just around the viral load checking. Now, there's debates about, do you do viral load monitoring to exclude HIV acquisition on CABPREP or not? And there wasn't routine. Um, I think that question was asked. But if you look at the paper, there were none. There wasn't routine, it was serology follow up, not HIV, RNA.

[01:22:34] So, although, whatever happens, it's going to be vanishingly low rate. That whole Levi syndrome thing with the prolonged, you know, evolution of reactive HIV tests that you see on CAB, could you see that with LEN as well? But it doesn't detract, that's a couple of tiny little niggles. It's incredible results and it's going to be all about implementation.

[01:22:52] But what are we going to see when you look at this drug in a group of people where oral prep does work? This is a population. As you've already said, where none of the oral PrEP trials have been effective because of adherence. What about when you compare it in, in men and our sex in men, for example, or actually when you look at things like IPPA, gay and proud, you're seeing 97 percent efficacy.

[01:23:12] So, yeah,

[01:23:12] Paul Sax: no, it's a remarkable results and the concerns you had are definitely worth following up on. Uh, I thought it was worth, uh, comparing what it's like to have a study come up, come out in the midst of COVID. And, you know, it was HPTN 084, which is really incredible study. Um, also blinded, also done, uh, this population stopped early by the DSMB had to be presented virtually.

[01:23:42] Uh, but as you noted, there were no failures with on time injections, uh, and I have to say the line of cap of your success in this study is wonderful, uh, but it's not unprecedented. It is very particularly wonderful because it's twice yearly. I think that's really the main benefit, uh, and, uh, it's all going to be about.

[01:24:03] Implementation, as you said.

[01:24:05] Yeah.

[01:24:06] Paul Sax: So, um, moving on to, uh, using H. A. V. R. N. A. as your, um, as your, as your monitoring tool in prep, uh, my pal refueling of its former trainee of ours. Hence, I'm very proud of him. He, uh, he was supposed to be at the meeting and presenting, but. CrowdStrike happened right, right as his flight was about to leave and he, his flight was canceled.

[01:24:34] My flight was only delayed only two and a half hours, which was miserable, uh, but, but his, his didn't get out. So he presented remotely. So if you look at our CDC guidance, which I know this is a predominantly European audience and the CDC is telling us that for people on Cabotagravir PrEP, we should use HVRNA as the monitoring tool.

[01:24:56] And not only should we check it. Each time they get the injection, but they should get the test result before, before you give the injections. And, and why is that? And, and the reason is, is because in 08 3, a different population, uh, PrEP delayed the detection of HIV, uh, compared to standard testing algorithms, you know, using just a rapid test or using an antigen antibody assay.

[01:25:25] And going back on those people who've, quote, failed, they could have had their diagnosis by HIV RNA. Before the development of integrase resistance, so it sounds like you should use this for monitoring, but the test performance of the strategy has never been evaluated. So that's what this did. So this is the, uh, study design at every visit, every visit in the open label extension, they did, uh, rapid tests, antigen, antibody tests, viral load tests, and then if any of those reactive, they then had a committee adjudicate, whether it's a true positive or false positive, and by doing so, they then could.

[01:26:06] Calculate the positive predictive value of a isolated HIV RNA. And so I'm going to show the beautiful slide that Dr. Lanovitz put together. He is quite the slide master, isn't he?

[01:26:20] Definitely.

[01:26:21] Paul Sax: And I'll take you through it. But let me just tell you, this study had a lot of HIV RNA assays, 26, 528. And in that group, only 73 had positive results of some sort or another.

[01:26:37] Okay? If we just focus on the 27 that had just a positive HIV RNA, this led to 22 of these being adjudicated as false positives, and 5 being adjudicated as true positives, which leads to a positive predictive value of a whopping 18. 5%. Even worse, if people had been taking their cabotegravir within the previous 6 months, it was only 9%.

[01:27:09] So, uh, this isn't so great. In fact, I would say what this added was chaos. It didn't add a benefit of new, earlier diagnoses. So I mentioned the low positive predictive value, uh, the chaos led to a hiatus in administration of cabotegravir as this was being sorted out and that potentially jeopardized their protection from HIV, although in fairness, none of the people with those gaps in treatment ended up getting HIV.

[01:27:41] What they, he did mention was that if you then repeated the viral load, uh, you actually then got a negative result in all of the false positives. But the results certainly do call into question the strategy of using viral load testing for all cabotegravir prep patients. Uh, I will also say that they showed a figure where the viral loads in the false positives were lower than the viral loads in the false positives.

[01:28:06] In the true positives, but it wasn't like the true positives were so high. Remember, as we know, from the Levi cases, there is partial viral suppression in people who acquire HIV and cabotegravir. We, I want to confess, and I hope I'm not put in. In a prep jail for this, but we have not done HIV viral loads at every prep.

[01:28:34] injection, nor have we definitely haven't done them before every PrEP injection, which seems to be absolutely impossible to implement. And, uh, I don't know what you're doing for your viral load for your habitat monitoring in Britain.

[01:28:49] Oh, well, it's one of those questions where the answer is we don't have that worry because we don't have CAP for PrEP.

[01:28:55] So we, we're in that hiatus where it's been licensed. Um, Therefore, we can't get it on Compassionate Access, but because the national policy is ongoing, it's, um, out for stakeholder consultation now, we can't prescribe it. So even for, like, we had a really challenging case recently, we really could have done with, with CAMPREP, hopefully we're still going to be able to get a Compassionate Compassionate Access.

[01:29:18] But yeah, so we actually don't, so it's not an issue that we've had to address yet. Um, And I think, I think it's interesting because firstly, because we discussed this and, and, um, uh, my colleague and inspiration, Anna Maria Goretti, um, who I, I know you know as well, Paul, we discussed this at one of our meetings.

[01:29:37] And actually, if you look at the median, um, I know you made the point that the average viral load in the people with true, uh, uh, new HIV diagnosis was higher than the people with the false positives, but the median was still below 50. So it's all, it's partly as a question here about, What, what the labs are reporting and actually should they have been reporting detectable viral loads below a 50 threshold.

[01:29:59] Um, because not, not all of them were, but, but a 50. And then we also, we discussed it with, with my colleagues, a colleague, um, Harry Coleman, who leads our complex prep service. And he said, sure, sure. You know, in terms of people with reactive viral loads, it was numerically more hassle than it was true new diagnosis.

[01:30:19] But when you look at the number, false positives with that denominator of the 26, 000 odd tests that were done, actually still a very, very tiny number. And it is actually is a few more distressing false positives acceptable for those five earlier diagnoses. Probably. I, yeah, so I, I, I don't know. I don't know.

[01:30:40] So I don't know what I don't know what I'm going to do. I haven't seen our guidelines yet. So

[01:30:44] Paul Sax: we, we do, we measure viral loads now every four Months because that's every other injection. Uh, let's see what happens. I think that the guidelines committee will be hearing from dr Land of it sometime. I'm sure

[01:31:00] I'm sure

[01:31:01] Paul Sax: This is a paper that covers the same issue Which is essentially confirming.

[01:31:09] Thank goodness what we're doing then. We're not alone Which is essentially that people who in the United States using cabotegravir prep are not really following guidelines at all. Uh, 37 percent received no HIV tests in the week before starting. That's not so good. Only 15, wait, 15 percent were never tested before their next injections.

[01:31:36] Most people are not tested before their next injections. And, and 6, only 6 percent got a viral load test every time. That's, that's not good. That's not a highly adherent group. So I'm going to actually amend this and say need for revised guidelines because I think that's actually the only way we're going to fall into guidelines.

[01:31:57] Compliance is if the guidelines make more sense.

[01:32:00] I just want to

[01:32:01] Paul Sax: mention that, that since we're on cabotegravir PrEP, it's, it's actually amazing the discordance between people's preference for PrEP and the implementation of it. So this is that same open label extension study. Uh, the end of 083, uh, is the population of men who have sex with men and trans women.

[01:32:24] And they were offered one or the other, uh, and 96 percent chose cabotegravir. And you can see the reasons why they chose cabotegravir, you know, they prefer the injections or they, because it was superior, because we know it was superior. And yet I heard that in the United States right now, where we do have coverage for PrEP, uh, that only about 5 percent of people on PrEP are getting cabotegravir.

[01:32:50] And part of that. Of course, it has to do with generic TDF FTC, which is inexpensive, even in our crazy expensive country. So, we'll see. Um, moving on to this study, which was the, um, 084 again, and looking at pregnancy outcomes. You remember the study design, and then there's an open label extension also. Uh, and, and during pregnancies, they're allowed to choose which, which one they go on.

[01:33:21] Uh, and I should say that the Lenacapivir study, I've mentioned, I should have mentioned this, that they allowed women to stay on the study if they became pregnant and they did not see any obvious adverse effect of being on Lenacapivir for pregnancy. So then the pregnancy outcomes, they looked at it at the bottom of this slide, uh, and let me just quickly cut to the chase.

[01:33:42] Uh, there were basically roughly the same pregnancy outcomes. There didn't really seem to be any differences. Uh, this, uh, spontaneous abortion information is supposed to be, we were told, Watch out, uh, for that because in countries where, where therapeutic abortion is not permitted, sometimes there's some false reporting, uh, in clinical trials.

[01:34:12] But overall, I think this is very reassuring and, and really, uh, people on cabotegravir PrEP who are women, should not stop that. Uh, and there shouldn't be a lot of moaning and groaning about what to do. They should continue it if it's working for them. Laura, do you agree?

[01:34:29] Totally. Totally. And it's again, it's so, it's so good to see studies where if a woman does get pregnant, it's her choice about what she wants to do.

[01:34:37] Um, it's, and it's, it's, it's, So important. I think of all the missed opportunities over the years to have given women the choice to participate in studies you met many women didn't even get that far because the the contraception requirements were so Yeah Complex you had two active forms of contraception to even be considered for a trial.

[01:34:58] So no, I think it's fantastic I checked because I was preparing a talk a couple weeks ago. And at the moment we talk a lot about the antiretroviral pregnancy registry Um as a sort of, you know, good resource for comparing, um, your birth defects by, uh, drug exposure. And at the moment, as of January 2024, there's only one case of somebody in that registry on LEN.

[01:35:18] It's a first trimester exposure to LEN. Um, and that's it. So I think the fact that they're doing the same in the Lenacapivir studies, because it's these really big PrEP studies, where you're going to be getting that, that wealth of data. Absolutely.

[01:35:30] Paul Sax: Absolutely. So this, uh, this wraps up my prep section, and, uh, I'm just gonna actually.

[01:35:38] Ask you this question, you, I can, I can, this is great. I can address this to you. And, and I will say that my another former trainee of ours, Rochelle Walensky, uh, who was head of CDC for a while, wrote this editorial, uh, to accompany the Lenacapivir study, basically saying that it's all well and good to show zero new infections, but now make, make it work.

[01:36:00] in the world. So what do you think?

[01:36:02] I mean, it's, I, I, well, I'm never going to agree with, um, with Rochelle Olenski. She's, uh, incredible as, as every trainee of yours seems, seems to be, Paul. Um, you know, you

[01:36:13] Paul Sax: don't see some, all of them. No, true. I guess,

[01:36:16] I guess there is a bias there, isn't there? Like a kind of, uh, awareness bias.

[01:36:20] Um, but no, and this is, this is the crux of it is, is, it's. It's a necessity, it's a responsibility to now make sure that these phenomenal results get translated into actual action. Um, and that's true of both of our highly effective long acting prep options. It's true of Cabotegravir, which has had a head start, and it's certainly true, you know, you're right, Lenacapri isn't licensed yet, but I'm sure Things can be done to sort of make that as timely as possible.

[01:36:49] Um, and, and yeah, it's, it's when all the standing ovation dies away, how is this actually going to reach the people who need it? Um, and you know, it's certainly not an area of expertise for me, but it's an area of expertise for many, and there are people ready to advise how to make this implemented in an effective way.

[01:37:10] There have to be some really difficult discussions, and cost is at the foundation of all of that, isn't it?

[01:37:16] Paul Sax: Definitely, definitely. Prep doesn't work if people don't take it.

[01:37:20] Exactly. Exactly.

[01:37:22] Paul Sax: All right. Onto a extreme. There's no, there's hardly any way to be a glass half full person when it comes to this topic.

[01:37:30] And, and here's the latest chapter. This is a study called PrEP Vax. PrEP Vax. And the PrEP Vax study was, is a phase two. To, uh, study, not a fully powered study. We have had fully powered HIV vaccine studies, and there's a glimmer of efficacy in one of them, but not really. And then there's no efficacy in most of them.

[01:37:57] But here's here's the study design. Uh, so we're looking at two different vaccine constructs. Uh, and compared to placebo and also there's the same time they're randomized to PrEP initially just to get them started on PrEP and then after that, uh, part drops off and people are referred to community PrEP, uh, distributed PrEP prescribers.

[01:38:28] Um, and then we, we looked at HIV incidents, uh, in, in the course of the study. Now, I will say that once the PrEP trial part of this ended, the use of PrEP dropped off substantially. Not surprisingly, because this is done in settings where PrEP is not necessarily given that often. So, if we look at the results of the, uh, uh, first one, it's alarming.

[01:39:01] It's alarming. So, HIV infections, 3 in the placebo arm, 11 in the AIDS VAX arm, for an adjusted hazard ratio of 3. 68. Uh, and although the confidence intervals are very wide, that is statistically significant, And we have to put that sad face there, because this is not the 1st HIV vaccine trial to show an increased incidence in people receiving the vaccine.

[01:39:30] What is the possible explanation? Uh, some have said that immune activation of HIV vaccination can lead to an increased number of target cells for HIV. But we honestly don't know. Uh, and This was almost observed with the other construct. So, you know, it's not statistically significant this time, but you're still seeing an excess number of new infections in the vaccine arm versus the placebo arm.

[01:40:01] 9 versus 2. Well, uh, this is a surprising and un, un, uh, how do I put it? Undesired result. And so if we take studies like this, and the fully powered negative studies, And the previous study that showed an increase in HIV incidents with an adenovirus vector and many years ago, I think it was called the step study.

[01:40:29] It brings us to this particular question, and I'll ask you, Laura, pessimist by nature, when will we have a safe, effective HIV vaccine that can be widely deployed?

[01:40:42] Yeah, I mean, I, I always say not before I retire. Now, when I first started saying that, uh, 22 years ago, retirement was further away. It's still a little way off.

[01:40:53] Um, I, I, I, I think it's, I think it's probably D. What do you think?

[01:41:00] Paul Sax: Well, um, Bob Mankoff. I was like, He was the cartoon editor of the New Yorker for years. He, he, he is most famous for this cartoon, which is absolutely hysterical. That's what I thought of. If you actually think about this in the context of the Lenacabavir and Cabotegravir PrEP studies, with 100 percent efficacy in preventing HIV with an injection, what, how could a vaccine do better than that?

[01:41:30] Uh, I, I, the study design would have to be mind bogglingly complicated or large to demonstrate effectiveness. I guess

[01:41:41] it's if, if, if you've ever reached a stage where you, you just had to, a single vaccine would be ideal, of course, or, you know, a course of three, something aligned with HPV or hep B vaccination.

[01:41:53] Yes. Then, yeah, obviously you wouldn't have to, but I don't know, there are people who, I know we both laughed about the fact that we're not covering this and I, I'm going to say that word that we acknowledged wasn't in our presentations. This is where some people say that broadly neutralizing antibodies might have a potential role.

[01:42:12] I know I said it. It's terrible, isn't it? It's terrible.

[01:42:16] Paul Sax: It's terrible. We'll see. We'll see. All I can tell you is I, I, colleagues of mine are HIV vaccine researchers. And I posed this question to one of them and he said, you know, we're really back at stage one, you know, we're, we're, we're, we got to, we got to go back to the drawing board and start over because we have not gone down the right route.

[01:42:41] Yeah. Okay. Next section miscellaneous complications. All right. This is you have a 50 percent chance of getting this right. Laura, test question, true or false? The anchor study demonstrated that screening for anal cancer using cytology significantly reduced the incidence of this complication among people with HIV.

[01:43:05] True or false?

[01:43:07] True. It's true. It's not true. It's not

[01:43:13] Paul Sax: true. It's not true. It's not true. Maybe it was a trick question.

[01:43:20] Yeah, I think, I'm sure. Okay. Yeah, there's something in question. What did the Anchor

[01:43:25] Paul Sax: Study actually show? Let's take a look. The Anchor Study looked at the question of whether people already diagnosed high grade squamous intraepithelial lesions should be treated or monitored.

[01:43:42] It randomized people to treatment versus monitoring. And, The study demonstrated that if they got treatment, treatment was usually by ablation, it significantly reduced the incidence of invasive anal cancer. The last point on this slide that I created for this very talk is an important one. Screening strategies for detecting H cell were not addressed.

[01:44:09] So, let me ask you, in your, in your clinic, Do you have a, a screening program?

[01:44:15] No, we don't. So we, we are recruited to a trial called cpac, um, which is ongoing, um, to contribute to data addressing this question. A couple of clinics do, and it is expertise driven, I think, where there is an individual in a large enough cohort to who is able to undertake, um, anoscopy.

[01:44:36] But no, we don't have routine screening.

[01:44:39] Paul Sax: It's very, it very much is expertise driven here in the United States. If you have a dedicated practitioner to do high resolution anoscopy, then you could justify screening and then send abnormals that that person's way to then confirm or not confirm your diagnosis.

[01:45:00] Yes. So the reason I bring this up is because the, uh, International Anal Neoplasia Society Has come out with guidelines now for screening and these screening guidelines have most recently been adopted by our Department of Health and Human Services prevention of opportunistic infection complications as well.

[01:45:25] So let's take a look of what they're recommending because it is quite remarkable for people in risk category a people with HIV MSM older than 35. Live. Trans women older than 35, all men over 45, all women over 45 with HIV. So that's a large population, including a large population who, at least in our practice, are not currently being screened.

[01:45:55] Then these other, uh, issues as well. And then there's a risk category B where you're supposed to discuss the pros and cons and make shared decision making. What is recommended in the guidelines is a, uh, digital anal rectal exam plus anal cytology and or anal HPV testing. And then an abnormal result gets referred for high resolution anoscopy.

[01:46:19] And a normal result, and here's the kicker, repeats screening in one to two years.

[01:46:24] Yay.

[01:46:29] That's

[01:46:29] Paul Sax: intense. That is extremely intense. Extremely intense. Well, so why am I, Bri, why am I bringing this up at, at this review of Munich 2024? Well, in, in New York, uh, a large cohort that's very experienced in doing this. looked at the screening strategies to find the optimal approach. And the reason that they're, they're looking for the optimal approach is that there is not the resources available yet to do high resolution endoscopy in everyone.

[01:47:00] Cause that is how you find H cell. Like if you really wanted to find H cell, you would just send all of your at risk patients for high resolution endoscopy, but there aren't enough people to do it as you pointed out. So then they looked at these screening strategies that are shown in this. What color is that?

[01:47:19] I would say that that is a, oh, thorn,

[01:47:24] Paul Sax: thorn. Good, good, good one. I like that. I would say light brown. Anyway, you can see what the strategies are. And let's take a look at the results. They showed all of the strategies had some utility in finding cases. The highest sensitivity was if you just do high risk HPV testing.

[01:47:50] Uh, but if you did that, you would send an awful lot of false positives to the high resolution anoscopists, and as a result, that was too sensitive. But the combination of high resolution, I mean of high risk HPV testing with cytology was the best approach. That was the most efficient use of resources, and I think that's the one that we're using now.

[01:48:15] So, anybody with an abnormality on Either of those two, uh, I mean, sorry, high risk HPV plus an abnormal cytology would get referred for high resolution anoscopy. All right. This is the DoxyVax study. Remember the result that the interventions tested included doxycycline post exposure prophylaxis, or none, and also the MenB vaccine, which we won't be discussing here.

[01:48:43] But the study was a favorable study for prevention of bacterial STIs syphilis chlamydia in particular, and also a significant reduction in gonorrhea. Although you can see that the efficacy was substantially lower than with syphilis and with chlamydia. And why is that? Well, it's because gonorrhea is highly resistance prone.

[01:49:05] So this analysis, which was done in Specifically, protocol driven found the following, it found that all of the GC isolates in this study were resistant to tetracycline, doxycycline, tetracycline, very, very similar. The rate of high level resistance was higher in the doxyPEP arm, so although the resistance was detected in all of them, it actually increased with exposure to doxycycline.

[01:49:30] One thing that bacteria sometimes do is that they develop resistance to one drug class and it jumps to a different drug class, but fortunately That was not observed in this study. DoxyPEP did not lead to an increase in azithromycin resistance. Hooray! Uh, they did find another cluster of resistant isolates.

[01:49:52] Uh, and, uh, they concluded by saying that ongoing monitoring of gonorrhea resistance is critical. And I completely agree that it's critical. Because knowing what We I. D. doctors know about my Syria gonorrhea. It loves to develop resistance, and it's just a matter of time. I think before doxy pep does not have any demonstrable efficacy against gonorrhea prevention.

[01:50:18] It certainly works against committee and syphilis and we have. already adopted it as pretty much standard of care for some of our frequent flyers for SDI, SDI visits. I don't know, uh, Laura, what are you, what are you doing in London? Yeah, we're on

[01:50:33] the verge of, um, there's, there's certainly a policy, local policy written.

[01:50:38] We don't have national guidance at the moment to support it, but individual clinics. So we, we are, we are one of the busiest sexual health services. Um, in the UK, I think at 5016th Street, the very well known, incredibly busy service is part of Chelsea Westminster. I think they may be doing it already. Um, but we are, we're going to be doing it imminently.

[01:50:56] I think the issue around wanting GC resistance is really important because it's something, you know, back when I first started doing sexual health clinics, I used to do my screens and plate up the old agar with the swabs. But of course with the, with the advent of, uh, of NAT testing, um, And also an awful lot of online testing and home based testing.

[01:51:12] Actually, a proportion of people diagnosed with gonorrhoea who ever have cultures has, has, has shrunk. Um, so you don't necessarily, we still have some sort of proper sentinel surveillance and stuff going on. Um, but how, because if getting culture results is, is, is, I think it's challenging, um, and yeah, so it's, it's about coming up with novel, accessible, demedicalized ways to monitor for resistance.

[01:51:39] Paul Sax: Yeah, no, I think it has to be done in the context of a study. Barely anyone gets cultures anymore, uh, for obvious reasons. Um, we have a, you know, there's a, someone in my, in our faculty here who, who is studying this and we're going to be prospectively collecting these. One other question I have about, about this is that, uh, do you think we're over diagnosing?

[01:52:03] Gonorrhea. Yeah. In our current prep era where we're testing people so frequently.

[01:52:09] Yeah. And this, this has been a really big topic of discussion at home that when you're diagnosing and treating all of this asymptomatic infection here, I think, I don't think there's anyone brave enough to not, not treat people with symptoms.

[01:52:23] Um, but absolutely that they're actually less frequent STI testing. and less frequent STI treatment may be the way forwards in people who don't have symptoms. I think what's difficult, and if we think about men who have sex with exclusively men, then you could argue, not say men don't get complications from gonorrhoea, they do.

[01:52:41] But of course, when we think about untreated infection, it's, it's the impact on, on, um, female fertility, of course. one of the things that's, that's, it's very difficult to measure. And it's also not a complication that you see at the same time as the infection. So I think that that's where it gets challenging.

[01:52:59] Um, rates of gonorrhea aren't particularly high in, in, in the UK, but they're certainly far from zero, um, in cisgendered women. So I, yeah, I think, I haven't had much discussion about attention implications, um, on, on women. Um, but certainly, yes, I think there's, there's strong arguments and lots of clever people doing lots of clever analyses, um, and, and hopefully some good trials to really address that.

[01:53:21] Yeah. Because maybe we have swung to too frequent screening and, uh, we're, we're driving part of the problem through treatment.

[01:53:28] Paul Sax: Agree. Agree. All right. The last complication I want to discuss is, uh, Hepatitis C. I thought this was a really, uh, interesting poster, um, longitudinal analysis of people with HIV, uh, men who have sex with men on.

[01:53:42] PrEP and men who have sex with men not on PrEP, looking at the incidence of hepatitis C over time. And, uh, if you look at the, the table, you'll see the results. The hepatitis C infection rates were comparable in the HIV population and in the population with PrEP. on PrEP, uh, and they were significantly lower for the, the MSM not on, uh, and, and why am I highlighting this?

[01:54:08] I'm highlighting it because I think some people maybe didn't realize that this is a sexually transmitted infection, uh, and, and it doesn't require underlying HIV for it to be sexually transmitted in this, uh, at risk group. Um, and, I just saw one case like, like this very recently, uh, and the person's now being treated and I'm sure will be cured, but, but, uh, of note, uh, he saw, before he saw me, he saw a hepatologist because it's simultaneously being treated for, um, for, for prostate cancer.

[01:54:44] And his, his hepatologist told him he wasn't sure how he got it. And I was like, I'm pretty sure you got it.

[01:54:54] Yeah, it's, uh, I think some Europeans would say that it was, it was a particularly sort of U. S. resistance to accepting the sexual transmission of, of hepatitis C, um, and yeah, but I think it's, but I think you're right.

[01:55:08] I think it's, there's definitely like a hepatology versus ID slash sexual health, um, uh, acknowledgement, but yeah.

[01:55:16] Paul Sax: All right. Last section, last study, cure. What would an international AIDS conference be without a cure? And this person was cured. We called the next Berlin patient. We started with Berlin.

[01:55:28] We're ending with Berlin, uh, even though we were in Munich, kind of ironic. Anyway, uh, let's just recap the previous cures. These, uh, five individuals, um, four of them named very generously have been public about it, and they underwent, uh, allogeneic hematopoietic stem cell transplants for cancer, and they received donors who were Delta 32.

[01:55:55] Homozygous, so that means their CD4 cells lack the receptor that HAV uses to enter the cell most of the time. And what about wild type donors? Well, we have one case, the Geneva patient, still cured, I gather. And then we have a bunch of failures, including two notorious failures here in my hometown, in my hospital, actually.

[01:56:20] They, when they relapsed, they got very significant acute HIV syndromes. So, uh, clearly, you know, something is different about this group. So let's take a look at this next one, and this next one is Uh, a man born in 1964, and he was diagnosed with HIV in 2009, but interestingly, he did not, he did not start therapy until 2015, which is a long delay, uh, and he started a somewhat unusual regimen of raltegravir or bacavir lamivudine, and that same time he was diagnosed with acute myelogenous leukemia, and they were unable to find a homozygous donor, so they found one who was a heterozygous.

[01:57:07] Donor, and, uh, as you can see, he's got one wild type gene and one delta 32 gene. He gets full chimerism, and then he stopped ART in 2018 and, uh, I had to hand it to the investigators. They waited a good long time before presenting this one. 5. 5 years. And he's been extensively studied. He's no virus can be found anywhere.

[01:57:33] His HIV immune responses are gone. And the presenter who did a really beautiful job presenting the case. It's amazing how a single case report can be so thoroughly investigated. Uh, he said that the aloe reactivity The, the act, the action of the host new cells against the virus is critical for HIV control.

[01:57:57] We hope that we'll be able to learn something from these cases because it's certainly not scalable in any way, and it's too dangerous to offer to our patients, but they certainly ask about it a lot. So thanks to a bunch of other people. I want to again thank Samuel Pierre and Serena Koenig for allowing me to present the study, as well as to Rafi Esteban and Laura.

[01:58:20] And let me stop sharing and see if any of our participants have any questions. Uh, maybe I can ask you a question though, while we're waiting for questions to come in. Um, Laura, uh, if you were to, uh, have a patient on a complex regimen, you know, let's say they're on Darunavir or Tanavir twice daily and, uh, they're on Dolutegravir once daily.

[01:58:47] And you know, historically, they're on that regimen because they've got tons of resistance and they're also taking TDF FTC or TAF FTC. Uh, what would you, um, do with this person based on the data that you heard from Vizent and 2SD and Gescio?

[01:59:07] Yeah, I, uh, it's a, it's a good, good question. I mean, the honest answer is that if that person, um, was, um, fine, happy on their regimen, adherent to that regimen.

[01:59:21] There were no treatment limiting drug interactions and the like. I would probably leave them on what they're on. I think would be, it may not be the ideal answer. I think it might be the true busy clinic answer. Um, normally these types of things come up when we've encountered an issue with, with, uh, with Darula virutonavir.

[01:59:39] Uh, one thing I might do for us locally at the moment is we are doing a study replacing PIs with fostemsavir. So I might swap in a PI for, for fostemsavir. Recruitments halted as the first cohort are being, um, replaced. That's great. So that would be an option. Again, that's not a necessarily realistic option for everybody.

[01:59:57] So again, I think it would depend on the nature and the timing of the previous NRTI resistance. And what I'd probably do because we have it and I accept we do it for us more than any measurable benefit is I'd do a profile DNA resistance test. And if that NRTI resistance was, was limited or no longer detectable, then then I would feel pretty competent going for a second generation integrase that's not severe.

[02:00:21] One

[02:00:21] Paul Sax: thing that I found very interesting, speaking with the, uh, HIV doctors in, in, uh, Germany is they had easy access to a DNA, a DNA, Uh, resistance testing, pro viral DNA resistance testing. Do you as well?

[02:00:37] Yeah, yeah, we just, we can just send it. So what we can't do, obviously being a cellular sample, we can't, because let's say someone's forgotten to do a viral load, we can then, we store our samples and go and do a retrospective one.

[02:00:50] So obviously it means having a real time sample. But yeah, we can, we can easily access it.

[02:00:55] Paul Sax: Uh, this is one place where, um, Europe's way ahead of the United States. We have one lab that does it. Okay. The rest of the research labs do not offer this as a clinical service. So we send it to this one lab and this one lab has had this boom in getting these, uh, Tests requested since the approval of cabotegaviral pivarine and it's expensive.

[02:01:17] It's it's one of our costliest tests by far.

[02:01:21] It's it's not. I mean, we don't we don't send many. We analyzed it for a poster last year. We we'd only done 30. I'd say we're probably maybe 100 samples in. entirely in a cohort of, from across our two sites, sort of more than five and a half thousand people. But I think, um, it's interesting because it's because the US guidance at first actually put about considering doing pro viral DNA testing in the guidelines, yet, um, yeah.

[02:01:43] Again, going back to guidelines, making recommendations that People can't implement. Yeah.

[02:01:50] Paul Sax: And then, then, uh, do you, do you think that, that anyone, uh, one other question and then we'll wrap up. Do you think that any of the HIV, uh, clinics are doing the anal cancer screening as per those extremely aggressive guidelines?

[02:02:05] I would say no. What's interesting in that, I was really struck when you showed me that slide, is I think it's the EAC's guidelines have for years recommended annual digital rectal exam, for years, and forget everything else. Is anyone even doing that? even about supporting people to, you know, self digital rectal exam is something that's been recommended by many as well.

[02:02:32] And it just, again, it's just that because that's not a cost thing. That's not an access thing. You don't need a lab to, to, to, to put your finger inside someone's bum. I mean, but that doesn't happen. What, what, what's the implementation barrier there? Because that's, that's a longstanding recommendation. So yeah, I, I, I, but no, the answer to your question is no.

[02:02:54] But my question to, to, to you and to everyone else is why aren't we even doing that?

[02:02:58] Paul Sax: Well, I think that is, has to do with the discomfort that people feel in their clinical visits with, with their doctors for, for all the obvious reasons. And then the Pap smear cytology is a terrible test. It's got incredibly high false positive rates.

[02:03:15] HPV component does help, I have to say. Yeah, well, anyway, uh, great job summarizing the meeting, Laura. I was thrilled to have you here and also to bounce ideas off you and I want to thank again for coordinating this webinar and also thank you for the support and all of you for participating today.

[02:03:38] Thank you for letting me share the stage.