IDWeek 2024 and HIV Glasgow 2024

Monday, November 18, 2024

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CCO Independent Conference Coverage of IDWeek 2024 and  HIV Glasgow 2024

Start: [00:18:33]
HIV prevention
DrDarcy Wooten (Washington University): I am going to be presenting some updates on HIV prevention.
[00:18:38]
PURPOSE 1: study design
And really one of the most exciting things in HIV prevention, as I’m sure everyone here is aware, is lenacapavir and so there were some updates from the PURPOSE trials at Glasgow that I’m going to review. But first, just want to orient us to PURPOSE 1, which was a multicenter, double blind, randomized, controlled trial of cisgender women – younger, cisgender women who had not received PrEP or PEP or had been tested for HIV recently, and they were randomized to one of 3 different arms: so to receive lenacapavir as a subcutaneous injection twice a year, or to daily oral PrEP, either FTC/TAF (in orange) or FTC/TDF (in green). And the really exciting and big news that came out of this, which you probably have heard and read about in the New England Journal, is that there were no infections in the individuals who were receiving lenacapavir. 
What was recently presented as a current subanalysis was characterizing the annual persistence of these different regimens. 
[00:19:47]
PURPOSE 1: persistence and adherence
So annual persistence was defined for lenacapavir as the following: receiving on time injections both at baseline and Week 26, as well as having on time follow-up visit at Week 52, and this was assessed in a preselected 10% of the sample throughout PURPOSE 1. And what we can see in the table is that annual persistence to lenacapavir as well as to the placebo injections that individuals in the oral PrEP groups were receiving was quite high, 79.5% in the lenacapavir group specifically. And if we compare this to annual persistence in daily oral PrEP, that was much, much lower, 5.25% as measured in dried blood tests. So really a big difference in terms of annual persistence for lenacapavir compared to daily oral PrEP, which I don’t think is particularly surprising. 
On time injections with lenacapavir are quite high, over 90% for both Week 26 and Week 52. 
And again not surprising, adherence to oral PrEP was low and declined over time, and when this was compared among matched controls, there was a lower chance of HIV seroconversion in those individuals who had medium or high adherence to daily oral PrEP compared to those who had lower adherence. And this tracked with those who ended up seroconverting in the daily oral PrEP groups had declining adherence. So I think this kind of highlights the idea that it’s not that daily oral PrEP doesn’t work, or that lenacapavir works better just because of the medication or something specific about the medication, but it’s really this persistence and this ability to adhere to PrEP that – injectable PrEP that really attributes or accounts for most of the benefit that we see. 
[00:21:52]
PURPOSE 2: study design
There was also an update on PURPOSE 2, which was very similar in design to PURPOSE 1 with a few differences that I’ll highlight. This again was a double blind, randomized, controlled trial, this time of cisgender men, transgender women, transgender men and nonbinary individuals. And in this case, there was not a TAF containing arm, so individuals were randomized to either receive twice yearly lenacapavir as subcutaneous injections, or daily oral PrEP with FTC/TDF. And I’ll review the results which have already been presented elsewhere in just a second, but what was presented at Glasgow was really a current report to look at the global, racial, ethnic and gender diversity of the participants in PURPOSE 2. And this is really important and something that the investigators really emphasized, because we want to be able to find strategies and PrEP options for subgroups in which the – that disproportionately bear the burden of new HIV infections, and so that was the focus here.
[00:22:59]
PURPOSE 2: participant characteristics 
And this – these tables demonstrate the participant characteristics. So you can see individuals were enrolled across 7 different countries, many from South America, and really had a great degree of racial and ethnic diversity. So 76% of participants identified from racially minoritized groups such as Black, Indigenous, and people of color, and 22% of participants identified as transgender or nonbinary. So I think, again, really important and really great to see these groups represented in these PrEP trials to really help us understand the impact that lenacapavir can serve in terms of preventing HIV acquisition here.
[00:23:44]
PURPOSE 2: outcomes
And again, this just reviews the results which have been presented elsewhere, but just like what we see in PURPOSE 1, really great results in terms of HIV prevention with the twice yearly lenacapavir. This was a median follow-up of 39.4 weeks. And there was a significantly lower HIV incidence in those who were receiving lenacapavir compared to background HIV incidence, as well as compared to individuals who were in the group receiving daily oral FTC/TDF. 
There were 2 infections that occurred in the lenacapavir arm and I’ll talk about those a little bit more in just a second. You can see in the figures on the right, this just highlights in terms of the HIV incidence rate ratios really favoring lenacapavir, both to – compared to the background HIV incidence as well as that that we see in individuals taking daily oral PrEP with FTC/TDF.
[00:24:42]
PURPOSE 2: HIV seroconversion on LEN
And this just summarizes the HIV seroconversions that we saw in the 2 individuals in the lenacapavir arm. So the first individual (or participant A) was diagnosed at Week 13, had a viral load of over 900,000; and then participant B was diagnosed at Week 26 with an elevated viral load as well. Importantly, both individuals were identified as having this important capsid mutation and so important to kind of keep in the back of our minds. But, overall, in terms of how well lenacapavir works as a PrEP modality is really, really encouraging and excited to see further data on this. 
[00:25:27]
TRIO health cohort: LA CAB PrEP in the real world
So I’m going to now transition from talking about lenacapavir as PrEP to talking about cabotegravir as PrEP, which we’ve had in use for the past couple of years in the US as a every other month injectable PrEP option. So now we’re getting some real world data and real world experience to see how this compares to outcomes and ability, feasibility and ability to implement in the real world. 
And so this first set of data were presented at IDWeek 2024 and this comes from the TRIO health cohort, which is a retrospective cohort that takes place across 12 different sites throughout the United States. And they extract data from the electronic health record and they were able to measure and look at persistence, adherence, efficacy and safety with long acting injectable cabotegravir for PrEP over the first 2 years of your use. And so, of course, included individuals who did not have HIV, had a weight greater than 35 kg, a prescription for PrEP in the EHR, and they excluded individuals who had participated in a clinical trial for cab PrEP. 
The participant characteristics are shown in the table. Mean age of 32, 32% of individuals identified as Black, 14 individuals identified as female and 9% as transgender. I should have highlighted there were 526 individuals in this cohort in total. I do want to highlight that this was a very PrEP engaged group, so 70% of the participants of these 526 had received a prescription for oral PrEP within the past year, so important to keep in mind as we’re thinking about generalizability of these results. 
[00:27:23]
TRIO health cohort: persistence and adherence
So, first, looking at persistence and adherence in this cohort, they had a median follow-up time of 7 months and 85 of those 526 individuals (or 18%) met the discontinuation criteria. They followed this group and they did not identify any seroconversions during the 12 months following discontinuation. Of the 85 who discontinued cab PrEP, about half of them (56%) remained in care. Half of those who remained in care were switched to oral PrEP, the other half were not continued on PrEP. And about 15% were actually reinitiated on cab PrEP. But what I want to draw your attention to and really highlight in terms of an area where we need more information and data and better strategies is this 28% of individuals who were lost to follow-up and coming up with ways that we can engage these individuals and keep them retained in PrEP care, and also follow them to know what happened. 
In terms of adherence, there were delays in injections for that second injection. About 16% of individuals had a delayed injection, relatively long, median delay of 22 days. For subsequent injections, third injection or beyond, there were also a fair number of delays, but not quite as long, median of 12 days. So what we’re seeing here is that more challenging to implement cab PrEP compared to what could happen in a clinical trial, which is not particularly surprising but important to be aware of and think of strategies to try and mitigate some of these barriers and challenges. 
[00:29:06]
TRIO health cohort: efficacy, testing, and safety
This slide reviews the efficacy, testing, and safety of cab PrEP in this cohort. And just by way of reminder, I’m sure folks are familiar, CDC recommends that both a fourth generation HIV test (so an antigen antibody test) as well as an HIV RNA be used before each injection, so that’s every 2 months in individuals who are receiving cab PrEP, which just thinking about that is challenging to comprehend that that’s going to be feasible and that’s actually what we see in the data. In this cohort, though, I will say, to their credit, 97% of individuals were screened for HIV at least 30 days prior to the first injection, and this is going to be contrasted to data that we see from a different cohort study. But when you look to see at HIV testing and how did it adhere to CDC guidance, only 34% of individuals sort of had, quote unquote, ‘adherence’ to the guidelines, so had both an antigen antibody as well as an RNA test, and only 63% had some sort of HIV testing done at each of the injections. So speaks to sort of the limited feasibility in terms of the frequency of injections – frequency of testing with injections per current guidelines. 
In terms of tolerability, injection site reactions were pretty infrequent and match what we see in clinical trials. And this cohort did not identify any individuals who underwent seroconversion, but that’s with the caveat that testing wasn’t as frequent as is recommended by guidelines. 
[00:30:42]
OPERA: LA CAB PrEP in the real world
So that was the TRIO health cohort and we see a similar report from a different cohort, the OPERA cohort, looking at real world cab for PrEP use. This is actually a prospective cohort taking place at multiple sites across the US, again extracting data from their EHR, and here they looked at not only individuals who selected cab PrEP but also those who had selected to go on to oral PrEP – oral daily PrEP, and they matched these baseline characteristics between the 2 groups. But what I want to focus on in terms of endpoints is looking at adherence to on time injections, HIV testing pattern and then acquisition or seroconversion in this cohort. 
[00:31:29]
OPERA: initiation and follow-up injection outcomes
So this is a pretty busy slide, and I’ll orient you to the left side. In terms of looking at individuals who completed initiation, so getting those first 2 doses of cabotegravir within the first 60 days, 85% of the individuals in this cohort of over 600 participants were able to achieve this, but 15% had incomplete initiation, which would require an additional injection.
And then in terms of looking at the table in terms of delays and injections overall, 31% of individuals within this cohort had any delay in injection. And what we see and I’ll just sort of summarize this, is that these delayed injections tended to happen more during the continuation phase, so after the first 2 doses. There were a substantial number of participants, so 32% of the overall cohort, who went 91 days or more without receiving an injection. And then these individuals would have been recommended, per package insert, to receive an additional injection to kind of get caught back up, but only 42% actually had documentation of having this additional injection. And then in terms of individuals who missed more than 2, who were outside of the target window 2 or more times, that accounted for – 19% of individuals accounted for that metric. So again, we’re seeing the challenges in terms of on time injections in these real world cohort studies. 
[00:33:07]
OPERA: HIV testing and seroconversions
In terms of testing and seroconversion, again we’re seeing a similar theme here. And this first result was actually quite alarming in that only 65% of individuals had HIV testing at time of initiation of cab PrEP, which I would really want this number to be much closer to 100%. And we also see that individuals that met that criteria for having HIV testing with every injection, so every 2 months, only 50% had this done at all subsequent injections. So we’re just seeing that it’s very, very hard to adhere to those CDC guidelines of having HIV testing with each injection. 
In this cohort, there were 2 individuals who had seroconversions, so still a very, very low rate of 0.3%. The first case (in blue) is an individual who had been on daily oral PrEP and then switched over to cab PrEP, but did not have HIV testing at the time that they switched over to injections. And the only HIV testing was done after Day 92 of cab PrEP and had a positive antigen antibody test at that time. So kind of unclear, since the HIV testing hadn’t been done, about when this individual would have been exposed to HIV. 
And then in Case 2 what we see is an individual that was essentially sort of lost to follow-up and out of PrEP care. So they were on daily oral PrEP for 65 days, switched over to injectable cab PrEP and then they were out of care and off of PrEP for about 130 days, re engaged in care and started – and tested – had a negative test, started on daily oral PrEP with FTC/TAF and then, 9 days later, had an acute retroviral syndrome, had testing done and had a viral load that was greater than 100,000. So, again, somebody who had been sort of more out of care before their test had turned positive. 
So very, very rare events, these seroconversions, but still important to be aware of and think about in terms of when we’re thinking about implementation and strategies for on time injection and retaining individuals in PrEP care, I think still some more work to be done. 
[00:35:27]
LA CAB PrEP in a community pharmacy setting: Wk 26 analysis
And then the last PrEP study that I wanted to highlight came from IDWeek. This was sort of a demonstration project looking at the feasibility of administering cab injections for PrEP in a community pharmacy setting. And the idea here is that we know that we are very far from the – achieving an ideal PrEP to need ratio and that we need to expand the ability to offer PrEP to individuals and have different points of access. And so the idea was could we potentially increase or fill this gap by offering injectable cab in the pharmacy setting? And so this was sort of a demonstration project of administering injectable cab as PrEP at a community pharmacy. They enrolled 50 individuals, looked at outcomes, which I’ll review on the next slide, and also surveyed the individuals receiving cabotegravir to get their perspective and perceptions on acceptability and feasibility with receipt of PrEP in this setting. 
[00:36:32]
LA CAB PrEP in a community pharmacy setting: acceptability at baseline and feasibility at Wk 26
And so here are the results of their – of the patient surveys, and you can see that the vast majority, if not all, of the individuals reported that they felt very comfortable and confident about receiving cabotegravir injections in the pharmacy setting. Interestingly, very few felt or had markers of stigma, so reported that they didn’t feel or wouldn’t feel ashamed if they knew that people – if people knew that they were receiving injectable cab, which I think is interesting but may not be generalizable to other populations. 
And then when you look at outcomes such as retention and adherence to on time injections, a fair number (81%) for whom they had data were retained in PrEP care, but again, importantly, wanting to know about what’s happening to those individuals that are not retained and are potentially lost to follow-up. In terms of adherence to on time injections, absolutely amazing numbers, 94% of injections were given on time.
So I think a really interesting and novel demonstration project of administering injectable cab in the pharmacy setting. Questions of how we can retain individuals and can we expand this to other pharmacies that might have access to different resources is still somewhat of a question.
[00:37:56]
Key takeaways
So I will wrap up with some key takeaways. We see from PURPOSE 1 that lenacapavir has this really profound persistence that’s much higher than what we see with daily oral PrEP and perhaps accounts for why we see such good outcomes in terms of HIV prevention with lenacapavir. 
We got to see really, really nice racial, ethnic and gender diversity in PURPOSE 2 and this is going to really be helpful for us in terms of helping to support and provide PrEP for disproportionately affected populations.
We see some real world data about the challenges as well as the really impressive effectiveness of cabotegravir PrEP from the TRIO cohort and OPERA cohort, but in terms of HIV testing and adherence to CDC guidelines, that’s definitely an area for potential improvement. 
And then, finally, this demonstration project of administering cab PrEP in a community pharmacy setting is really interesting, but still more information on how to retain individuals and how to expand this to other pharmacies could be useful. 
And with that, I’m going to turn it over to DrOrkin to continue the rest of the presentation.
[00:39:11]
HIV treatment
Dr Chloe Orkin (Queen Mary University of London): Thank you so much, DrWooten. That was a wonderful summary, I thoroughly enjoyed it, and I’m going to talk about treatment. 
[00:39:19]
DOLCE: study design
So I’m going to start with this fantastic study, which was presented by the father of 2-drug therapy himself, Professor Pedro Cahn, and he presented this study answering a crucial question around using dolutegravir/3TC as first line therapy for people living with HIV and CD4 counts less than 200. And this was a multicenter, exploratory, open label study assessing this therapy in people living with HIV in Argentina and Brazil and this was important because this population was underrepresented in the GEMINI studies, in the phase I studies – phase III study, sorry, the registrational phase III studies for this therapy. 
So this study recruited adults on first line treatment with CD4 counts less than 200 and viral loads greater than 1,000 and, importantly, they had to be negative for hepatitis Bs antigen. And it was a large study considering that it was a study of 2 countries. There was 152 people on both arms. One arm was dolutegravir/3TC, the other arm was dolutegravir plus TDF or – and XTC once daily. The primary endpoint was achieving an undetectable viral load at Week 48 within the snapshot window, with safety and CD4 counts as secondary endpoints. 
[00:40:44]
DOLCE: baseline characteristics 
So in terms of baseline characteristics, what you can see, the median viral load was 180,000 in those people receiving dolutegravir/3TC. And you can also see that nearly 23% had viral loads greater than 500,000 and 10% had viral loads greater than a million, and that the median CD4 count was 109, and that nearly half had CD4 counts less than 100. So this study really recruited the population as it said it would do so. 
[00:41:16]
DOLCE: efficacy at Wk 48 by FDA snapshot
And if we look at the efficacy, regardless of whether we look at the intention to treat analysis, the per protocol analysis or the ITT E analysis, what you see in those with viral loads greater than 100,000 copies is that the dolutegravir/3TC (in blue) is doing as well, it’s noninferior to the 3 drug regimen. So that’s a very important finding. 
[00:41:40]
DOLCE: efficacy at Wk 48 and virologic outcomes in participants with high HIV 1 RNA at Wk 48
And it’s really important also to look at the actual outcome. So what we need to understand is the virological success is in blue, the people in whom there was no virological response is in orange, and then we have this large group of people that we see in these studies, which are people in whom there was no virological data. In other words, people who left the study, people who relocated, people who left due to adverse events or for whatever reason, but it’s not virological. And then what we see – this analysis allows us to look at those people with viral loads greater than 500,000 and greater than a million and what we see is that the virological nonresponse is very similar, OK. So we’re seeing very, very similar outcomes and that’s really reassuring. 
So virological nonresponse data is n equals 11 and n equals 6 in dolutegravir/3TC and dolutegravir/QD respectively, and of 11 virologic – people who experienced virological failure that were successfully amplified, that was 7 in DTG/3TC and 4 in DTG/QD plus TDF/XTC, there was no NRTI or integrase inhibitor resistance found. So they didn’t – they weren’t able to demonstrate resistance in anybody on either arm in those people where they could amplify the genotype. 
[00:43:08]
DOLCE: safety
In terms of safety, you can see that serious adverse events, treatment related, as well as deaths were similar and that cases of suspected IRIS were also similar. So there was no differences in terms of safety. 
[00:43:23]
Posttest 2
So in the DOLCE study in people with CD4 cell counts less than 200, compared with DTG/XTC and TDF, the virological response rates were: 
A.    Lower, regardless of baseline HIV viral load 
B.    Similar, regardless of baseline viral load 
C.    Similar, but not if the viral load was greater than 100,000 copies
D.    Similar, but not if the baseline viral load was greater than 500,000 copies
So vote now and I’m going to give you some time to put your votes in. 
OK, let’s close that. OK, so that’s definitely increased and we can see that, in the DOLCE study, you can see that B was correct because regardless of viral load or CD4 count, the outcomes were very similar. So this study has really answered that question in terms of, you know, safety and efficacy in that lower viral load – I mean lower CD4 count, higher viral load population. 
[00:44:48]
Once weekly ISL + LEN for virologically suppressed people with HIV: study design
So the next study I’m going to talk about is this very exciting treatment that we now have, which has been evaluated in a phase IIb study and that is once weekly islatravir plus lenacapavir, so it’s all – it’s a once weekly oral therapy for virally suppressed people with HIV. And this is this phase II study and that’s why the numbers are quite small still, about 52 participants in each arm. And you can see the doses of islatravir are 2 mg, lenacapavir 300 mg weekly, and the comparator was bictegravir/FTC and TAF. And people who recruited were adults who were undetectable for at least 6 months, been on bictegravir/FTC and TAF for 6 months with CD4 counts greater than 350 and no hep B infection. And we looked at the 48 week endpoints, which were viral load greater than 50 in a snapshot analysis. 
[00:45:44]
Once weekly ISL + LEN: virologic and immunologic outcomes at Wk 48
So what you see here is noninferiority for weekly combination vs bictegravir/FTC and TAF. Importantly, adherence was high in both groups and this is something we do need to study, because we haven’t studied how well people do taking a treatment weekly. You can see that the rates were very similar. And you can see that in terms of the outcomes in terms of no data in window, sometimes this was related to adverse events or other reasons and there were 3 cases of viral loads were actually undetectable and there was some missing data. But what we see here is that there were no significant differences in mean change in CD4 count or in the lymphocyte count. So there was no concerns relating to the islatravir in this study in terms of CD4 count. There were no discontinuations due to decreased CD4 count or lymphocyte count, with no grade 3 or 4 adverse events and no clinically significant lab abnormalities except for one person who developed an acute HBV seroconversion, and this is definitely a concern for all 2 drug regimens, which is why I think that vaccination is so important prior to putting people on 2 drug therapies in the absence of TDF and XTC. 
[00:46:59]
LA CAB/RPV + LEN in people with HIV, adherence challenges, and INSTI/NNRTI resistance mutations 
So the next set of studies I’m going to talk about is looking at using long acting cabotegravir/rilpivirine plus lenacapavir in people with HIV, who had adherence challenges and who also had either integrase inhibitor or NNRTI resistance mutations. And this is a case series of 9 people in Mississippi and these were people who had recurrently – were currently viremic and who were known to have either historical or current rilpivirine or cab mutations and to have partially or fully active cab, according to their mutation scores. And they received cabotegravir/rilpivirine after a one month initiation in 2 doses and then they received oral lead in and lenacapavir. And they went through a multidisciplinary team and the endpoints were viral load greater than – less than 200, it was important to reach that and also if they developed treatment emergent resistance and if there was any change in their CD4 count. 
[00:48:04]
LA CAB/RPV + LEN: outcomes at Wk 24 36
So what we see in these 9 people is that 6 were female, 9 were Black. And you can see the CD4 counts were 420 to 9 with, but high viral loads of more than 36,000. One person had cab mutations at baseline, nine people had rilpivirine RAMs. And the person who had cab mutations had a 155 and 97A, conferring low level resistance to cab.
Between Weeks 24 and 36 all participants managed to suppress to less than 200 with no resistance emerging. And in participants with baseline CD4 counts less than 200, there was a significant increase in CD4 counts, so a good success rate for these people. 
[00:48:44]
Real world cohorts assessing LA CAB + RPV: virologic failure rate and emergent resistance
So the next studies we’re going to talk about are 2 evidence synthesis studies of real world cohorts at HIV Glasgow. And this was assessing cohort – this was based on a systematic literature review which identified 13 real world cohorts and nearly 3,000 people who had received cabotegravir/rilpivirine on label, so in other words, were virally suppressed people, and reported on post virological failure regimens and re suppression outcomes. So this is an important thing because we know that if virological failure occurs, you know, potentially resistance might occur, so what regimen should you give people? 
So as I’ve said, this was for people that were virally suppressed, in whom there was virological failure and described resistance mutation testing as virological failure. And what was important in these studies is that the definition of virological failures were very different. Some people defined it very loosely as a single viral load greater than 200, some people required consecutive testing. And the rates of virological failure were variable. Across real world evidence it tends to be less than 2% and this is what we saw in this – across this evidence synthesis, but there was one very small cohort where it was higher. 
So in terms of the conclusions, what was seen here is that existing real world data suggested that treatment emergent resistance with cabotegravir/rilpivirine was very infrequent, but it’s important to keep monitoring the real-world data. 
[00:50:21]
Post-virologic failure and resuppression outcomes in real-world cohorts assessing LA CAB + RPV
So here, as I said, this is the other study looking at – not only at virological failure events but also at resuppression. And this evidence synthesis looked both at randomized controlled trials and also at real-world evidence and they looked at all of the suppression regimens that were used. And what was found is that, across the phase III trials, 30 people experienced virological failure and almost everyone resuppressed and a majority in the trials actually use protease inhibitor-based regimens to resuppress people. But across the real-world cohorts, interestingly, when people experience virological failure according to these very variable definitions, in most cases, the clinicians tend to continue the cabotegravir/rilpivirine and, actually, nearly 80 100% of people suppressed. So the commonest regimen was actually to continue on cabotegravir/rilpivirine, but regardless of what they did, almost everybody resuppressed on the subsequent regimen. 
[00:51:23]
Key takeaways
So the key takeaways from treatment is that the DOLCE study demonstrated that people living with HIV with low CD4 counts and high viral loads, their virological response rates were comparable for 2-drug dolutegravir with 3TC vs 3-drug alternatives. 
In the once weekly islatravir and lenacapavir study for virally suppressed people, this regimen was well tolerated and maintained high rates of suppression through Week 48. 
In a study looking at – in a case series study looking at people who had resistance to NNRTIs, and one person also had resistance to cab, low-level resistance, it was actually possible to suppress these people with the addition of len then giving cabotegravir/rilpivirine. 
And then finally, the evidence synthesis showing that treatment-emergent resistance is uncommon, but actually when you resuppress people the outcomes are actually positive. 
[00:52:18]
STI prevention
PRIDOX: DoxyPEP for men who have sex with men at high risk for sexually transmitted infections
And I’m going to come on to STI prevention, finally, and I’m going to talk about this study called the PRIDOX study. This is a study looking at DoxyPEP for men who have sex with men who are at high risk of sexually transmitted infections. And what we know from existing studies like the IPERGAY study, DoxyPEP and DoxyVAC studies is that when you use 200 mg of doxycycline within 24-72 hours of sexual intercourse – and that is what DoxyPEP is – you significantly reduce the risk of STI. This study assessed the impact of DoxyPEPn on incidence of STIs in men who have sex with men at a higher risk of STIs. 
What you can see in this baseline characteristic table, nearly 40% were using chemsex and 35% were – had more than 10 sexual contacts a month. You can see that a large proportion of people didn’t use condoms at various different frequencies. 
And what you see in terms of incident rate per hundred person years of the first episode of each STI, is that prior to DoxyPEP you can see the incidence for chlamydia was 31.8, after DoxyPEP it went down to 8.53. For gonorrhea, it was 41.7, went down to 26.6. For syphilis, it was 21.6, went down by 2.52. So all of these are very significant drops after using DoxyPEP. 
So to put this into context, the CDC data in 2023 show that new syphilis cases increased by 1% after years of double digit increases, whereas primary and secondary syphilis infections have decreased by 10% since DoxyPEP. 
[00:54:09]
Key takeaways
So the key takeaways in this study show that DoxyPEP significantly reduces the incidence of STIs in men who have sex with men who are higher – at high risk of STIs, but further studies are still needed to support these conclusions. So this was interesting because it showed a significant reduction across all 3 STIs. Some other studies have shown, you know, reductions in syphilis and in chlamydia, but less so in gonorrhea, but in this study showed it very clearly across all 3. 
[00:54:36]
Posttest 3
So in the PRIDOX study – posttest question one – study of men who have sex with men and who are at high risk of STIs, DoxyPEP significantly reduced the risk of: chlamydia, but not gonorrhea or syphilis; chlamydia and syphilis, but not gonorrhea; chlamydia and gonorrhea, but not syphilis; or all 3, chlamydia, gonorrhea and syphilis, option D.
Vote now. 
OK, let’s close the poll. Excellent. So that’s correct. As you see in the poll, it was all 3. In the PRIDOX study of men who have sex with men and who are at high risk of STIs, DoxyPEP significantly reduced the risk of chlamydia, gonorrhea and syphilis. 
[00:55:32]
Posttest 1
So could you vote now? I am familiar with the data from IDWeek and HIV Glasgow and I plan to translate these data into current or future management strategies. Could you vote now on these? 
[00:55:50]
Poll 2
And then could you also please type in your response in terms of one change that you – so everyone, so we can see there’s significant agreement, almost everyone has improved. And could I ask you, while we’re taking the questions, to type in your response to one new change that you plan to make in your clinical practice based on these findings?
[00:56:15]
Question and Answer Session
So we are going to take some questions now and give you a chance to ask some questions. So there we go, I’ve got Darcy back. 
So there’s a question on – a question on the lenacapavir PURPOSE study: is the seroconversion assumed to have been an infection prior to the first injection? So Darcy, if you want, I can take that or if you want to take that, up to you.
Dr Wooten: Sure. I would love to hear your thoughts. My take on it, because of the 2 participants, one was diagnosed and tested at Week 13, the other at Week 26. And so I think, at least for the person at Week 26, I would think that that would be maybe less likely that they had assumed infection prior to starting. The Week 13 may be more difficult to say, but still sort of fairly far into exposure to lenacapavir, but would love your thoughts on that, yes.
Dr Orkin: Yes. Thank you for that. So I think it’s a really interesting question. It’s a really interesting point and what it does is it really exposes the difference in the study designs between the PURPOSE 1 and 2 studies and the cabotegravir studies for PrEP. And I think what’s really important to say is that these outcomes from these 2 types of PrEP studies can’t be compared, because the cabotegravir was compared against an oral comparator, OK, and it was powered to be compared against an oral comparator, but oral PrEP. But this study was based on – it’s a counterfactual design based on baseline incidence. So the primary endpoint was number of infections vs the number of infections that would have occurred in the baseline cohort over the same time period. So what that means is that anybody who was diagnosed at baseline went straight into the baseline cohort and they became part of the baseline cohort, because the baseline cohort was from baseline all the way to the time point. So these were seroconversions that occurred at that time point, unlike with sort of the cabotegravir studies where that was different, where the baseline infections may have slipped through.
[00:58:34]
So what are the annual cost differences for the PrEP formulations? OK. So I think, at this point, the PURPOSE study has not gone through regulatory requirement, so we don’t have a cost yet. So I’m afraid we can’t answer that. 
[00:58:50]
And then is there any data on cab in pregnancy, from your experience, and what’s the general feeling for the near future? Darcy, up to you. I can – if you want to take it or I can take it.
Dr Wooten: I will just briefly summarize that I think –
Dr Orkin: Yes, go for it.
Dr Wooten: Yes. We do have very limited data but looks to be as though things are safe, but something that we want to monitor closely. But from the limited data that we have, yes.
Dr Orkin: So there was a presentation at the last meeting, at the AIDS 2024 meeting in Munich, and there was more than 100 outcomes – pregnancy outcomes, comparable pregnancy outcomes based on the extension of the 084 study, people who had ever received cabotegravir as PrEP and then people who rolled over onto receiving it in the second part of the study. Then those people were asked – those people who became pregnant were asked if they were able to enter a pregnancy study and they were monitored, and basically there was no difference in pregnancy endpoints and also no difference in weight gain for the fetus to people who hadn’t – to oral therapy. So it was all very encouraging, not concerning, but as Darcy says, it is something that’s important to follow up on.
[00:58:50]
So somebody has said that the data in DOLCE for high viral load are not convincing. Would you initiate dolutegravir in a patient with greater than 500,000? They would not. 
So I think what I would say is I think these data were actually very convincing. I think we didn’t have a lot of data in viral loads greater than 100,000 copies. These people had – the median was greater than 100,000, it was closer to 200,000 and the CD4 counts were very low. So I felt very convinced by these data and I think that these data could be something that should be seriously considered by international guidelines. I don’t know, Darcy, what do you think? It would be interesting to hear whether – how you read the data.
Dr Wooten: Yes, I agree the data are convincing and I don’t know that I would jump to a 2 drug regimen over a 3 drug regimen in starting an individual on therapy, just because I don’t know what the advantage would be of starting dolutegravir/3TC vs TLD or bictegravir/FTC/TAF, for example. And you could always, you know, if you’re worried about longer term toxicities with 3 drugs and a tenofovir-containing regimen, like always switch to dolutegravir/3TC. So I agree the data are reassuring and look very good, but you also, right, need to have baseline resistance testing, ideally make sure patients don’t have hepatitis B co infection. And so if you’re doing things like rapid start and there’s not a huge advantage to being on dolutegravir/3TC over a 3 drug regimen, at least, you know, for the short initial term, I don’t know that it’s necessarily going to change my practice.
Dr Orkin: Yes, I think it’s interesting that you say that. I mean, I think that there have long been concerns about this, the issue of high viral load and low CD4 count, because of the under enrollment in the GEMINI study. And I think that while I agree with you completely that, you know, there’s no need to do it necessarily, I think that the reasons not to do it are reducing now.
Dr Wooten: Agreed.
Dr Orkin: And I think you’re – what you’re saying very much fits in with rapid ART, but I think not everybody’s getting rapid ART. And I think in the context of not using rapid ART to start, let’s say someone didn’t want it, the arguments for not using it are certainly getting weaker, I would say, although I completely hear what you’re saying. 
[01:02:36]
So somebody’s asked – what else are people saying? For the most – I didn’t answer that. I’m just trying to comprehend this question. For the most difficult – I’ll try and take this question. For the most difficult to reach marginalized, poorly adherent populations a harm reduction approach may be an intermittent injection strategy. 
Yes, I really don’t think that an intermittent strategy with an NNRTI is going to be an option with this combination. So I think it’s very important, you know, what we do know, these injections must be given within a week of their due date. So I would definitely say that an intermittent strategy is not an option. 
[01:03:29]
Someone has asked about the benefits for lenacapavir vs licensed cabotegravir, and I just think – Darcy, I’m happy for you to come in here, but what I would say is I don’t think you can compare these drugs. The study designs are different. You know, they’re completely different and I think that, you know, these are both very novel strategies. We know that they’re given at different time points. But I don’t think cross-comparing against completely differently designed studies is, you know, an appropriate way of assessing these drugs. I mean, I don’t know what you would want to say, Darcy.
Dr Wooten: I agree, and I think – and that may be something interesting to look at moving forward, although I don’t know that that will ever be done. I think cost and access are going to be probably some of the biggest drivers in terms of just in the real world, practically, what can people actually get access to and afford and be able to use. So, again, sort of analogous to what we saw with lenacapavir vs daily oral PrEP, daily oral PrEP works, you know, if you can take it. So whichever PrEP people can take is probably the best PrEP for them.
Dr Orkin: I’m going to – I’ll take a question from Jules Levin, because I always like to give Jules the mic wherever I can. His question is, is there a chance of late delay for HIV with len like there is with cab? 
So I think it’s important to say what Jules is referring to is LEVI syndrome and I think we’ve got 2 cases, so it’s almost impossible to actually, you know, say whether a LEVI syndrome is or is not going to occur. There are thoughts that LEVI syndrome may be related to the high genetic barrier of the integrase inhibitor class and that because the capsid inhibitor potentially has a lower barrier, this may be less likely to occur, but it’s absolutely unknown and I don’t think that we can – I don’t think that we can comment on that. I don’t know, what do you think, Darcy, do you agree with me?
Dr Wooten: I agree, and I think the potential for that is there, but I think we’ll have to see.
[01:05:46]
 : So I think someone’s asking about OIs, people are asking about OIs and the DOLCE study. There were people who had OIs and IRIS was similar in the 2 arms. There was no difference in IRIS. So I think, in terms of guidelines, you would want to start treatment as quickly as possible unless you had an illness like, you know, meningeal cryptococcus or meningeal TB, in which case you would do things differently. Otherwise, you would start treatment regardless of an OI, and the IRIS rates were similar. 
End: [01:06:16]