Dr Grinsztejn: So despite effective pre-exposure prophylaxis regimens and antiretroviral treatment as prevention, HIV incidence remains unacceptably high globally. In addition, significant disparities remain in who benefits from this biomedical prevention intervention. Sexual and gender minorities and racial and ethnic minority populations remain disproportionately affected by HIV and do not achieve the full benefits of PrEP in part due to PrEP access and uptake and challenges with long-term persistence to daily oral regimens. Therefore, additional PrEP options that do not require daily oral adherence are needed.

Next one, please.

[00:19:10]

PURPOSE 2: Q6M LEN as PrEP in Men, Transgender People, and Nonbinary People Who Have Sex With Men

LEN is a first-in-class multistage HIV-1 capsid inhibitor with high potency and long half-lives supporting twice yearly subcutaneous injections that is being tested for use as HIV PrEP. So earlier this year in the summer, we heard the phenomenal results from the phase III PURPOSE I study that showed that LEN to have a 100% efficacy and a well-tolerated and – well-tolerated option for HIV prevention amongst cisgender women.

In PURPOSE 2, we evaluated the safety and efficacy of twice-yearly subcutaneous LEN for HIV prevention in cisgender, gay, bisexual, and other men, transgender women, transgender men, and gender non-binary individuals who have sex with partners assigned male at birth.

Key eligibility criteria are listed on this slide. PURPOSE – PURPOSE 2 participants were aged 16 or more with unknown HIV status and no HIV testing in the last 12 years. Participants had at least one condomless receptive anal intercourse partner in the last 12 months and either multiple partners are recent bacterial STI or recent chemsex.

Any prior lifetime – lifetime use of an injectable PrEP was not allowed. Participants in – participants eligible to proceed to the randomized blinded phase tested HIV negative in the screening cohort had an estimated glomerular filtration rate higher than 60 ml per minute and weighted more than 35 kilograms.

And here we present the overall study schema. This was a phase III double-blind active controlled randomized trial, which similar to PURPOSE 1, employed a novel design to achieve the primary outcome. First participants who met the eligibility criteria entered the screening phase where they underwent HIV testing. Those who tested HIV negative were then eligible to proceed to the randomized phase.

Among those who tested HIV positive, further laboratory testing, including antibody avidity testing, was conducted to determine recent HIV infection. These recent HIV infections outcomes were used then to determine the counterfactual or background HIV incidence for use in the primary outcome analysis.

Participants without HIV were then randomized two to one to receive subcutaneous LEN with matching placebo delivered as two 1.5 ml subcutaneous injections in the abdomen or daily oral F/TDF with matching placebo for at least 52 weeks.

On days one and two, all participants received a pharmacological loading dose of 600 milligrams oral lenacapavir or matched oral placebo. HIV incidence in the F/TDF arm of the randomized blinded phase was the pre-specified secondary outcome analysis.

Next one, please.

[00:22:35]

          PURPOSE-2: Study Recruitment

Among those without HIV at baseline and who received at least one dose of study drug, 2,183 were randomized to receive subcutaneous LEN and 1,088 were randomized to daily oral F/TDF across seven countries, Argentina, Brazil, Peru, Mexico, South Africa, Thailand, and the US.

Approximately, 30% of PURPOSE 2 participants were less than 25 years of age. Approximately two-thirds were non-White and over 20% were gender diverse.

Next one, please.

[00:23:17]

          PURPOSE 2: HIV Incidence in mITT Population

Once 50% of participants had completed 52 weeks of follow-up, a pre-specified interim efficacy analysis was conducted. And then on September 11, 2024, an external independent data monitoring committee reviewed the interim efficacy analysis and concluded that the pre-specified efficacy criteria for unblinding the trial early were met.

Here we report HIV incidence in the three groups who used it for primary and secondary analysis. At the time of interim analysis, median follow-up time were 30 – was 39.3 weeks.

Background HIV incidence in the screening cohort was 2.37 per 100 person-years. In those randomized to F/TDF, nine infections occurred over 967 person-years for calculated HIV incidence of 0.93 per 100 person-years.

And finally, only two HIV infections occurred in those randomized to receive subcutaneous LEN over 1,938 person-years of follow-up for a calculated HIV incidence of 0.1 per 100 person-years.

LEN reduced HIV infections by 96% with an incidence rate ratio of 0.04 compared with the background HIV incidence and by 89% with an incidence rate ratio of 0.11 compared with daily oral F/TDF. In addition, since the 95 confidence interval did not include the new value of 1, LEN was also shown to be superior to F/TDF.

As specified in the trial protocol, the interim analysis became the primary analysis of the trial and participants began to learn their trial group assignments and are now being offered the option to receive open-label lenacapavir.

Next one, please.

[00:25:27]

          PURPOSE 2: Safety

In addition to the high efficacy demonstrated, LEN was also safe and well-tolerated. Excluding injection site reactions, adverse events were similar in both the LEN and F/TDF groups. Only seven participants in each group discontinued study drug due to adverse events.

Also, consistent with the known safety profile of F/TDF and reductions in kidney function, there was a statistically significant difference in estimated glomerular filtration rate between the arms at both weeks 26 and 52.

And what about the injection site reactions? To orient you to the chart, green represents no injection site reactions, yellow is – represents grade 1, and red is grade 2. Nodules were more common in the LEN group compared to the F/TDF group. LEN is injected into the subcutaneous space and forms a drug depo that may be palpable under the skin but is usually not visible.

As the drug eludes over time, the depo gets smaller and the nodules resolve or reduce in size substantially prior to the next injection. The frequency of injection site reactions, including nodules, decreased with subsequent doses, also observed previously in PURPOSE 1.

Overall, among 15,239 LEN or placebo injections, among all these injections, only 29 participants discontinued due to an adverse event of an injection site reaction, 26 in the LEN group and three in the F/TDF group.

Of note, these are top-line results that were presented at HIVR4P, and there are several ongoing analyses that are anxiously being awaited about adherence, PK data for both LEN and TD – F/TDF groups, as well as detailed data on the two seroconversions that occurred among those assigned to LEN – to the LEN arm, among other topics that are being analyzed.

[00:27:47]

          Posttest 2

Zachary Schwartz: Great. So I think we'll move on to our first post-test question here to see how much we learned. In the PURPOSE 2 study in cisgender men, transgender women, transgender men, and gender nonbinary people, what was the HIV incidence with injectable LEN? Was it:

A.   Statistically significantly lower than background HIV incidence but not lower than with FTC/TDF PrEP;

B.   Statistically significantly lower than background HIV incidence and only numerically lower than with FTC/TDF PrEP;

C.   Statistically significantly lower than background HIV incidence and than with FTC/TDF PrEP; or

D.   Numerically but not statistically significantly lower than background HIV incidence and FTC/TDF PrEP.

The polls are open. Please vote. Great, I think we have enough votes here, and I can see that by far that most people are choosing choice C, which is indeed true. So back to  Dr Grinsztejn.  Dr Grinsztejn, are you still there?

 Dr Grinsztejn: I'm sorry.

Zachary Schwartz: Thank you.

 Dr Grinsztejn: So great. So, Rafi, are you starting?

[00:29:21]

Faculty Discussion

 Dr Raphael Landovitz (UCLA Center for HIV Identification, Prevention, and Treatment Services): Sorry. Yes. So, Beatriz, I think we – there's no question that that this was probably the most talked about presentation at the conference, and it's a tremendously exciting result to go with the also tremendously exciting result from PURPOSE 1 that we heard about at the Munich AIDS Conference over the summer. It's clearly a highly effective product.

I think the questions in my mind that still remain to be answered from these studies are what – were these infections that broke through lenacapavir, how were they detected? We learned from the cabotegravir experience that testing – conventional testing algorithms can – can be altered, muted, less sensitive for breakthrough infections on long-acting PrEP, and it'll be very interesting to see if there were any challenges with diagnoses for these two infections that were found in PURPOSE 2 and what resistance profile was.

And it would be very interesting, I think, to know the geography of where the infections take place and what we know about adherence in those people. Bea, I don't know what your thoughts were about those issues, but those were some of the questions that came to my mind in – in watching this really, really exciting presentation. And of course, the – whether people will tolerate it long term remains also an important question.

 Dr Grinsztejn: Yes, I totally agree with you, Rafi. I think you raised the most important points, and we are all very anxious to see the next results that there will be a presentation at IDSA next week, and then it will be followed by another presentation in Glasgow, so we very much look forward to hearing to these other results. As with our experience with cabotegravir, we saw challenges with the – with the HIV diagnosis, and it's really important for us to well understand the profile of this infection, the pattern of infection as these options move towards implementation studies and future scale up.

So very much looking forward to those. And as you said, the regional distribution is – is quite important as well.

 Dr Landovitz: Yeah, but there's no – there’s no getting away from the fact that this is an incredibly exciting, potential advance to the field. I think, you know, they – we've noticed also lots of challenges with getting access both in the US and, of course, globally for cabotegravir and getting – making sure the people who need access to this product, if in fact the safety and efficacy continues to be supported, is going to be the number one priority for making sure this – this can have population level effects.

 Dr Grinsztejn: Yes, and – and also there was an initial agreement that was signed that will cover 120 countries, but – with six factories that will produce generics, but many countries highly affected by the HIV epidemic, including most of the countries in Latin America where I am from are not covered by the – by the agreement. So we are very much looking forward to the new developments in this – in this – in this area as well.

And hopefully, we will be able to get this product to the countries that highly contributed to – to the clinical trials.

 Dr Landovitz: Yes, and I think there was a lot of – a lot of activity from – from both clinicians, policymakers, and activists at the R4P conference really demanding that that be – that that happen with this product and really with all future products that – that go into low and middle income country settings. And I think that's something that – that's really important to highlight, that that there are real ethical concerns if – if access and pathways to – to access are not assured at the inception of this kind of work.

Okay. Bea, anything else you wanted to highlight about that? Or should we move on, so we don't bore people?

 Dr Grinsztejn: Yes.

 Dr Landovitz: Okay.

 Dr Grinsztejn: I think so.

[00:33:58]

IMPOWER-22 and IMPOWER-24: QM Oral Islatravir 60 mg vs Daily Oral PrEP         

 Dr Landovitz: All right, great. I'm going to move on and next speak about the IMPOWER-22 and IMPOWER-24 trials, which are study – studies. They're phase III studies, a pair of them that were part of the registration – planned registration pathway for a planned monthly oral PrEP medication called islatravir, which is still in development as part of combination antiretroviral treatment for people with HIV, but is no longer in development for PrEP. And I'll tell you why in just a second.

So these two studies, one done in cisgender men, transgender women, and non-binary individuals, and one done in cisgender women in the global south, and that's 24 and 22 respectively, were looking at people with an elevated chance of exposure to HIV, but who did not have HIV at study inception, were randomized to either a monthly islatravir 60 milligram tablet or daily oral tenofovir-based PrEP. And it was a double blind, double dummy study. So that means people who got the monthly pill were also taking placebos for the daily pill, and people who were assigned to the daily oral tenofovir option received a monthly placebo pill for the islatravir.

In the global south, the cisgender women study, the 22 study, it was – the comparator arm was only FTC/TDF used daily. And in the United States sites for the 024 study, the comparator people were offered either tenofovir alafenamide with FTC or tenofovir disoproxil fumarate with – fumarate with FTC. Outside of the US in the 024 trial, people were only being offered TDF/FTC.

So you probably have heard that the – these studies actually were stopped prematurely. And that was because of a safety concern that arose originally seen in some of the treatment studies that included islatravir, but turns out is true across the entire development program at the time. And that was because an unanticipated toxicity of decreased total lymphocyte and CD4 cell counts that was associated with all the doses of islatravir that were being studied in a dose-dependent fashion.

So these prevention studies 022 and 024 that we're talking about now, they began in, in 2021 and they were stopped on December 13th, 2021. And by stopped, I mean the blinded comparison was stopped and everyone in both trials was offered open-label tenofovir-containing PrEP as people continued to be followed after the discontinuation of the blinded portion of the study.

[00:37:35]

          IMPOWER-22: Safety         

I'm going to start by telling you about the observations from the cisgender women's study. This was the one done in the global south. And what I'm showing you here on the right side of the slide in the blue shaded area is the declines or the changes in total lymphocyte count. This is mean change from baseline and the blue triangles are the people who received islatravir and the red squares are the people who received the daily oral TDF/FTC.

Again, the – the blue shaded area is when people were in the – the blinded comparison. And then what you see on the right in this sort of reddish shaded area is the trajectory of essentially recovery over about a year in total lymphocyte counts when people all were offered the open-label TDF/FTC.

You can see the actual numbers at month three and month 12 in the changes in total lymphocyte on the left upper corner of the slide. And, you know, you're probably wondering why out to month 12 is not shown in the graph on the right. And that's because the numbers got very small and it turns out lymphocytes were only measured every three months. So the numbers actually get really small.

Importantly, there were no extremely severe changes in lymphocytes that reached what is called a grade 3 level, which is a serious side effect as a – as a measure of the severity of those changes, even though they do look quite dramatic on the graph.

In the 024 study, this, this is the same sort of graph. Again, there were no – no extremely severe changes. There were two people who reached that grade 3 lymphocyte threshold, but they were not assessed as serious nor related to the study product by the investigator at the site. And there were no drops in CD4 count to below 200 copies with that – during the double blind phase of the study or within 42 days after stopping of that phase, which represents five half-lives of the monthly oral product, which you would expect therefore to be minimal, if any detectable drug concentration.

Again, here the changes that you see during the double blind phase. And again, they're represented in the graph in the upper left. You can see a trend towards return to – to normal levels without a difference by about 10 months after discontinuation of the islatravir product.

[00:40:21]

          IMPOWER-22 and IMPOWER-24: HIV Acquisition During Study

So a lot of people ask, did anyone acquire HIV during either of these studies? And the answer is not during the double-blind phase and not through 42 days, again, that period in which there would be expected to be islatravir in people's systems after discontinuation of those blinded study products.

You can see that in the 022 trial. Again, that's the cisgender women's trial. There were 23 infections that happened overall in the trial. They all happened in the open label phase where people being offered FTC/TDF. 17 had originally been offered and randomized to islatravir. Six had been randomized to the tenofovir-containing arm. And in the – the 024 trial, which again is the cisgender men, transgender women, and non-binary individual studies, there were seven infections. Again, all occurred during the open label extension. Five originally on islatravir and two in the tenofovir-containing arm.

And importantly, all of these happened a very long distance after the last administration of islatravir. It was 99 days in the 024 trial, and it was over 140 days in the 022 trial. As I mentioned, this drug is no longer in develop – development as a PrEP agent.

And so you're thinking, why are we spending so much time on it? Why do I care? You care, number one, because I think there's an enormous interest and demand and place in the prevention menu for a monthly oral PrEP option. And importantly, there's a follow-on compound called – it doesn't have a name yet. Like islatravir, it's currently referred to as MK-8527, which is in the same class of medications, which is a nucleoside reverse transcriptase translocation inhibitor. That's a class that we haven't talked about before, islatravir, called NRTTIs, different from NRTIs and NNRTIs. It's different.

And this also hopefully, will have the option of being evaluated as a monthly oral PrEP option. It's currently in phase II studies and we're looking forward to those data. So there's this follow-on compound that is not anticipated to have that kind of side effect that was seen with islatravir that is moving through clinical development. So we are not giving up on a monthly oral PrEP option and understanding this history of what happened with islatravir, I think is really important to understanding what's going to happen next. So that's why we're spending this much time on it.

[00:43:19]

IPM 054: 1-Mo vs 3-Mo Dapivirine Vaginal Ring Pharmacokinetic Study in South Africa

Okay. I'm going to stop there and hand it back over to  Dr Grinsztejn for discussion about some vaginal ring data.

 Dr Grinsztejn: Thanks, Rafi. So now changing gears to the dapivirine vaginal ring. So flexible silicone vaginal rings were developed by the International Partnership of Microbicides and transferred to the Population Council in 2022. Monthly vaginal rings contain 25 milligrams of dapivirine and they are approved for use in Botswana, Eswatini, Kenya, Lesotho, Malawi, Namibia, Rwanda, South Africa, Uganda, Zambia, and Zimbabwe.

The IPM 05 – 05 – 054 study reports on a one-month versus three-month dapivirine ring pharmacokinetic study that was conducted in South Africa. This is an open-label randomized crossover phase I study that enrolled 124 HIV-negative women.

The three-month ring is the same exactly as the one-month ring, but contains 100 milligrams of dapivirine instead of 25 milligrams. It has the same silicone, the same dimensions, looks, and feels the same. So this was a phase I open-label randomized crossover trial to investigate the relatively bio – the relative bioavailability of the 25 milligram ring inserted every 30 days and the 100 milligram ring inserted for 90 days in healthy females for male participants.

So the primary objective is to assess the relative bioavailability of the 100 milligram ring compared to the 25 milligram ring by comparison of the dapivirine plasma PK parameters with several other secondary objectives to – to characterize the PK of both doses, the safety of the two ring formulations, and the – the vaginal microenvironment over the course of 90 days of the ring use and exploratory objectives to understand women's perceptions and overall acceptability of – of the rings.

The mean age of participants was 28.5, 92 of them – 92% of them were Black and 80% were single. The three-month 100 milligram ring was shown to be non-inferior and superior to the one-month 25 milligram ring. No differences in treatment-emerging adverse events such as vaginal discharge, vaginal candidiasis, and bacterial vaginosis were seen.

And why a three-month ring is desirable? Only four rings will be required per year versus 12 one-month rings. Reduced burden on user regarding insertions and clinical visits, potential for increased adherence and effectiveness, an estimated cost of U – of less than US$16 excluding the distribution. This is – this means a 60% cost reduction per year compared to the one-month ring.

Of course, reduced waste and environmental impact. That means a lot. And 67% fewer rings and reducing packaging materials per year would be used.

[00:47:01]

          Posttest 3

Zachary Schwartz: Great. So let's see what we learned about this one. Here's our third post-test question. In the IPM 054 study, when compared with one-month dapivirine ring, the three-month dapivirine ring, its pharmacokinetics were what? Were they:

A.   Superior with similar safety;

B.   Superior but with more treatment-related adverse events;

C.   Non-inferior only with similar safety; or

D.   Non-inferior only and with more treatment-related adverse events.

The polls are open. Please do vote. Okay. I think we have enough votes here. So I'm going to close this poll.

[00:47:51]

          Posttest 3: Rationale

And we see that more than half of people said superior with similar safety, which is true. So we'll move on.

[00:48:01]

          MTN-025/HOPE OLE: Dapivirine Ring for PrEP During First Trimester of Pregnancy

 Dr Landovitz: Okay. So we are staying with the theme of vaginal rings. I think there's an enormous opportunity for not giving up on topical on-demand options for HIV prevention. And I think we’re – we've been slow to see regulatory approvals for ring-based products. The dapivirine monthly ring that  Dr Grinsztejn just mentioned as a comparator to the three-month ring only has an approval by the European Medicines Agency for use in Africa, not for use in Europe.

And so, I think everybody is looking forward to there being additional options for this kind of intervention to give people choices and options.

This next study is the MTN-025/HOPE Open Label Extension Study. So this is a follow-on study to the original ASPIRE randomized trial done by the MTN, which compared the monthly dapivirine ring to a placebo for HIV prevention among cisgender women in the Global South and found about a 30% reduction in the initial efficacy analysis with much better protection seen with more consistent use. So this is the open label extension called HOPE of that study.

And one of the big questions with any PrEP agent has to be for anyone of child-bearing potential, whether or not there are any safety concerns for someone who could be pregnant and for, of course, the developing fetus. So this is an analysis of the pregnancies that happened during the HOPE Open Label Extension.

Again, this is the monthly dapivirine ring, the original one that was studied, and its safety during the first trimester of pregnancy. So this is a study that enrolled 1,456 HIV-negative individuals who were not pregnant or breastfeeding at the time of their enrollment. They were required to use contraception as part of this study. And then they received the monthly vaginal ring for the first three months and then a ring quarterly thereafter.

So they had pregnancy testing every follow-up visit, and they were asked to discontinue ring use when they were diagnosed with pregnancy. All the pregnancies were followed to term. So this gave 72 pregnancies for an incidence rate of five per 100 person years, and 82% of them occurred at the time of a ring being present. So they were exposed to some medication from the ring, and we have outcomes for 70 of these pregnancies.

[00:51:11]

          MTN-025/HOPE OLE: Pregnancy Outcomes

And it is worth noting that this is in addition to 101 pregnancy outcomes that we have from the original randomized ASPIRE study. So this is 70 additional outcomes that we have. And you can see in the chart on the left side the outcomes compared to 12 individuals who have pregnancy outcomes from the original randomized study that – that did not have a ring in place.

So there were four cases with only 6% of the pregnant individual having any pregnancy complications. And that's just gestational hypertension, which means high blood pressure. Nothing else was reported. And the infant outcomes, there were five babies that had low birth weight, below 2.5 kilograms. That was 11% of them. And there were no congenital anomalies reported.

So overall, this is a really good result that does not indicate a safety concern for a dapivirine vaginal ring when the – the pregnant individuals and the babies were exposed in the first trimester of pregnancy.

So, I will stop there about that since we need to come on to some other stuff and hand it over back to  Dr Grinsztejn.

[00:52:33]

          CATALYST: PrEP Choice for Women With PrEP Ring vs Oral PrEP

 Dr Grinsztejn: Thank you, Rafi. So as more PrEP options become available, evidence on real-world delivery of PrEP choice is highly needed. So the CATALYST study is an implementation study that provides informed choice of PrEP products to women at public sector PEPFAR delivery sites in Kenya, Lesotho, South Africa, Uganda, and Zimbabwe. The study is split into two distinct stages based on product availability. And we will talk here about stage one that has – that offers both the PrEP ring and oral PrEP.

So the study aims to characterize and assess an enhanced service delivery package for informed PrEP choice for women in existing PrEP sites in these African countries. Participants were eligible to enroll if they were HIV negative, 18 or older, or mature minors where countries permitted, interested in learning about HIV prevention, and PrEP was offered at all sites according to national guidelines.

Participants could choose a preferred method and could switch methods during any clinical visits. So the analysis that I am talking about was presented at HIVR4P by  Dr Elizabeth Irungu that has received a prize for – for this impressive study on behalf – and she presented on behalf of the entire CATALYST team reflecting the interim data from this stage one that aimed to describe PrEP uptake among those offered PrEP choice, explore factors related to method choice using logistic regression, and also describe the reason for choices that were made.

So when looking at actual choice for the 3,967 women enrolled in stage one, 66% of them chose oral PrEP, 30% chose PrEP ring, and 4% didn't chose – didn’t choose any method. Younger women, new PrEP users, pregnant and breastfeeding women were less likely to use the – the PrEP ring. And those with more than one part – one partner in the prior three months and on contraceptive use were more likely to choose the PrEP ring.

As you can see in the chart on the right, when asked about reasons for PrEP choice among those who chose oral PrEP, the majority did this choice due to the ease of use and effectiveness of the product. And among those who chose the vaginal ring, ease of use was also mentioned and the no need of swallowing a pill and both were the most important features ranked.

So, individuals choose PrEP methods that work for them, selecting a method that is easy for them to use. And for some women, PrEP ring was their choice despite its modest efficacy.

Rafi, the 084.

[00:56:04]

HPTN 084 Substudy: LA CAB or FTC/TDF and Hormonal Contraceptives DDI Assessment

 Dr Landovitz: Yes, thank you. I – I'm being told that we're a little bit behind. So I am going to zip through these data so we can get to discussion and get to some other abstracts as well. This abstract was presented by Mark Marzinke. It was a sub-study of HPTN 084, which looked – was the – one of the registrational trials of long-acting injectable cabotegravir that led to its regulatory approvals in cisgender women. And this was a drug-drug interaction study between cab and hormonal contraceptives.

And the long story short is between three commonly used hormonal contraceptives, there were no differences in the concentrations of those hormonal contraceptives in the women who received CAB-LA compared to the TDF/FTC arms of the trial. So it does not appear like there is an interaction between CAB-LA and these hormonal contraceptives.

Interestingly, there also was not an effect of these hormonal contraceptives on CAB-LA concentrations, which is also reassuring. So there are no bidirectional interactions between hormonal contraception and CAB-LA in this study, which is really reassuring.

And complements data that  Dr Grinsztejn has published from the 083 study about effects of gender-affirming hormone therapy on CAB-LA concentrations among the 083 population for people who were using gender-affirming hormone therapy in that study.

[00:57:47]

Faculty Discussion

Okay. So to me, you know, this is all very reassuring for cabotegravir, but I do think that the question that has not been answered has to do with the effect of cabotegravir on hormones when used for gender-affirming hormone therapy. That specific interaction has not yet been formally evaluated and is going to be critical to uptake by people who use gender-affirming hormone therapy to assure safety of use and that the hormones are going to have the desired effect, which obviously is mission critical to PrEP agents being acceptable.

Bea, did you want to comment on that or about any of the ring data?

 Dr Grinsztejn: Yes. I think that – thanks, Rafi, about the – the – the hormone use. I totally agree with you. We are very much anxious to have more data on that and also on lenacapavir and hormones. And – but I think that in regards of the ring, as you mentioned it, it's really important that we keep studying other options so that people can have the possibility to choose what is – what works best for them.

And we are also very much looking forward to the next PrEP product that will be probably once a month that can also bring us further – further options for – for those who are most in need. I think it's better that we move because we are – we are really delayed.

[00:59:25]

Implementing Injectable PrEP

 Dr Landovitz: We're having too much fun.

 Dr Grinsztejn: Yes, indeed.

 Dr Landovitz: Okay.

[00:59:28]

PEPFAR: Large-Scale PrEP Implementation Successful in Reducing HIV Incidence

 Dr Grinsztejn: Okay. So this – this oral abstract was presented by  Dr Akom and reported on a cross-sectional analysis of country-level HIV test result data among PEPFAR-supported PrEP clients who returned for visits after initiation. So this is – they are very – these are very important results because we mostly talk about PrEP initiations and here we are really seeing longer-term longitudinal data about HIV testing.

So quarterly data were abstracted from the monitoring system from – from the PEPFAR for 24 countries in three geographic regions between 21 and 23. And there were 4,450 positive tests among over 3 million positive or negative HIV tests with a positivity of 0.14 to 0.20 by quarter. So this is very good news. New HIV diagnosis among previously HIV PrEP – HIV negative PrEP clients were infrequent across PEPFAR PrEP programming, suggesting the most – that most returning clients were using PrEP effectively.

Of course, we don't have data for those who are not returning, but these look very – like very positive results. So these findings together with the UNAIDS epidemiological data indicate that scaling up PrEP is a highly effective prevention option that is critical for us to get to the UNAIDS goals to end HIV as a public health threat by 2030.

Back to you, Raphael.

[01:01:21]

          USAID DISCOVER-Health LA CAB Demonstration Project in Zambia

 Dr Landovitz: Okay. So I'm going to very quickly tell you about a demonstration project implement – implementing long-acting injectable cabotegravir in Zambia. This is one of the first reports we're having of actual use in programs in the global south. So this is really exciting data. It's still fairly early. And this is in Zambia. And this was a demonstration project that was implemented in six sites in two different districts. And the mean age of people was about 24 years old. Just over half were female.

There was about a third who were adolescent girls and young women. And you can see what they found on the right. So they've limited follow-up at this point. Basically, only two-thirds of people have actually gotten to the point of being eligible for a second injection. But 91% of the people who were eligible for that second injection got it, which is really exciting. So only about 4% had discontinued.

The reasons for discontinuation are interesting. Incident hep B infection was a reason for discontinuation. Two people discontinued because of pregnancy. That's a little unclear why that would have been required, because we now have pregnancy safety data. There's one person with a severe rash on the injectable product. No oral lead-in was used here. And one person discontinued for pain. There were two HIV acquisitions who were successfully navigated to ART.

So again, sounds like it was acceptable. A lot of discontinuations for reasons that we need to investigate further. And we'd want to know more about those HIV acquisitions that happened on this, and we don't know yet. But still very exciting data that complements some data that  Dr Grinsztejn presented from her ImPrEP CAB-LA program in Brazil, which is also presenting really exciting data. But this is the first from Africa.

And, Bea, back over to you.

[01:03:18]

LA CAB PrEP Rapid Start Model in San Francisco Public Health Clinics From March 2022 to May 2024

 Dr Grinsztejn: Thank you so much, Rafi. And now back to the United States, where, despite the promises, there have been real challenges in implementation of CAB-LA. So only accounting for – CAB-LA only accounts for 1.4 of all US PrEP use, and even less of this globally.

So this study – this study that I will present is an innovative CAB-LA program for PrEP in the municipal primary healthcare network, which service – which serves only patients with on public insurance in San Francisco. And this facilitated, actually, CAB-LA access, because they don't need to work with private insurances.

So, CAB-LA was offered at eight San Francisco Department of Public Health primary care clinics, but Ward 86, which is an HIV and sexual health clinic, served as a PrEP hub and had the highest volume.

Overall, the mean age of participants were 37 years old, mostly cisgender men, but also non – 10% non-binary and 5 transgender – 5% transgender women.

Importantly, 57% had a mental health diagnosis, and the most common was depression. Half of the cohort reported substance use, which included several drugs, including stimulant use, opioid, and alcohol. About 30% were living in an unstable housing documented in their medical charts. So having a mental health diagnosis was the only factor that predicted late injections, and other factors like substance use, housing instability, and age didn't predict late injections.

[01:05:09]

LA CAB PrEP Rapid Start Model: Predictors of Late Injections and Discontinuations

So it’s – this – the important historical context of this project is that a similar study was done looking at the rollout of oral PrEP in the same clinics, and there was 60% retention at six months. And what we are seeing with CAB-LA is 85% of injections were on time, meaning very good, much better retention.

[01:05:36]

          Posttest 4

Zachary Schwartz: Great. So now let our – one of our later post-test questions in the study by Heise and colleagues, using a rapid start metal – model for long-acting cabotegravir PrEP, which factor was associated with late injections and discontinuations? Was it:

A.   Age;

B.   Mental health diagnosis;

C.   Unstable housing; or

D.   Switch from oral PrEP.

Polls are open. Please vote. Okay, I think we have enough votes. I'm going to close the polls.

[01:06:19]

          Posttest 4: Rationale

Looks like most people did indeed choose the right answer, that was mental health diagnosis that was associated with both late injections and discontinuations, showing the importance of that.

[01:06:31]

          SeroPrEP: HIV Treatment After LA CAB PrEP

 Dr Landovitz: Great. So we have four more abstracts to get through in six minutes. We can do this. So this – this next abstract is from the SeroPrEP cohort, which is a US-based service that is operating out of – it’s a partnership between the CDC and UCSF in San Francisco. And anybody who seroconverts or acquires HIV when using any kind of PrEP can get assistance with resistance testing, drug levels, and further analysis through this program. And you should go to their website if you've never used it. They have a lot of helpful information there.

Anyway, this is a presentation of three cases in clinical practice of people who appear to have acquired HIV while taking CAB-LA PrEP. So these are rare events, and so we all scrutinize them tremendously. And these are people who were found in clinical practice and referred to the seroprep program.

And, you know, we're not going to have time to go into details about what their testing profile was. You will get these slides and be able to look at them in detail on your own later. But the real question this is trying to answer is, what are the right treatment regimens that you use when somebody acquires HIV in the context of CAB-LA PrEP?

[01:07:53]

          SeroPrEP: INSTI Mutations and ART Regimen Selection

And all of these people, you can see here, received a boosted protease inhibitor-containing regimen. All three of them actually received TAF/FTC, cobicistat, darunavir as a combination single tablet regimen. And one of them, case three, was actually switched to a bictegravir-containing regimen due to some intolerance after their viral load had already started to decline.

Interestingly, there were no INSTI resistance mutations on conventional commercial sequencing. But when super sensitive single copy genome sequencing was done through the – through the study, they did find in two of the three cases evidence of very low level integrase resistance, the mutations you can see in the chart here. One of them, the viral load was too low. It was three copies by single copy assay. So they weren't able to get resistance testing on that.

And the million-dollar question is, what does this mean? Does that mean you can or can't use a dolutegravir or a bictegravir-containing regimen to treat people who acquire HIV in the context of CAB-LA PrEP? And the long story short is, we don't know the answer yet. But all of these people were used what is actually recommended in guidelines currently, which is a boosted protease inhibitor-containing regimen. So more to come about this. This is a really hot topic.

[01:09:20]

          FASTPrEP: LA CAB PrEP With HIV Rapid Detection Tests in Cape Town

 Dr Grinsztejn: Yes. And now we move into South Africa and the FASTPrEP. FASTPrEP is an implementation science project evaluating uptake coverage and effectiveness of a youth-focused decentralized PrEP program.

And the PrEPared to Choose is one of the studies that are part of the FASTPrEP for the delivery of CAB-LA as an HIV prevention option within a PrEP choice context. So as we already learned from HPTN 083 and 084 studies, initiation of CAB-LA during acute infection can result in a delayed immune response to HIV, leading to undetectable HIV RNA, and reducing the generation of anti-HIV antibodies.

And as you all also know, NAT HIV testing detects HIV earlier, but it's more expensive, it's resource intensive, and lacks regulatory approval as a diagnostic test. As such, in order to provide evidence to confirm or refute the superiority of NAT HIV test, FASTPrEP did this comparison using third generation, fourth generation, and HIV NAT for 862 participants who initiated CAB-LA.

So they could find that three out of 862 participants, 0.35%, had discrepant detectable HIV RNA at CAB-LA initiation with detectable viral loads. So one of those were – was tested using a fourth gen, so coming to a 0.18% discrepancy, and 0.68%, two cases among 291, used a third generation HIV rapid test. So those three participants with detectable viral load were urgently required for additional testing, including all confirmatory testing, and were immediately initiated on standard first-line antiretroviral therapy based on dolutegravir. More to come.

[01:11:35]

Faculty Discussion

 Dr Landovitz: Okay. Should we – should we just jump through the – the discussion and just talk very briefly about SPrEP and 091, Bea?

[01:11:48]

Improving PrEP Uptake

 Dr Grinsztejn: Yes. So now moving to SPrEP.

[01:11:49]

SPrEP—Online PEP and PrEP: First Online Platform for Access to HIV Prophylaxes in Brazil

SPrEP is a platform that was developed by the São Paulo City Health Department. So they are – São Paulo is the largest city in Brazil that has the largest number of AIDS cases, but also the largest number of PrEP users in the country accounted for 50% of all PrEP users in Brazil. So the city has developed a systemic approach with several different opportunities for people who are interested in PrEP, in using PrEP.

So, Adriano described at his presentation about this SPrEP system that is an app run by the municipal health department in São Paulo that people can come and ask for consultations either to start PrEP, to do a PrEP follow-up consultation, and also to you to ask for PrEP.

And so that was – this was one of the most popular presentations at HIVR4P. I welcome every – every one of you to come to São Paulo and visit this really very successful program. And people can – actually, after getting a prescription by – in their phones, they can come and retrieve PrEP either in a – in a clinic or in PrEP machines that are placed in – in the subway in São Paulo. So a fantastic program, actually.

Back to you, Rafi.

[01:13:21]

HPTN 091: Multicomponent PrEP Intervention Among Transgender Women

 Dr Landovitz: Okay, last – last abstract. And I just want to say it blew my mind when I heard this presentation and heard about these vending machines in São Paulo and saying, why – why aren't we doing that?

 Dr Grinsztejn: It's just to add that it's all for free at no cost for the client.

 Dr Landovitz: We have a lot to learn from our colleagues in Brazil. That's always true, but for this especially. Okay, last – last abstract. I know we're two minutes over already, so I'm going to be as brief as possible.

HPTN 091 was an intervention for transgender women. It was done at three sites, including in Brazil and the United States. And it was looking at transgender women without HIV. And the intervention was PrEP, and you could choose which kind of PrEP you wanted, and compared for co-located gender-affirming hormone therapy with peer health navigation.

And half of the people got all of those services together, and half got just the PrEP, and then linkage to conventional gender-affirming hormone therapy and case management services. And after six months, then they got the co-located services. It was a delayed intervention. And the idea was to try and prove that the co-location helped with PrEP uptake and retention.

[01:14:43]

          HPTN 091: Baseline Characteristics and PrEP Uptake and Adherence Outcomes

And I'll spare you the details because they'll be on the slides you can look at later. It's a little bit of a disappointing result. It does not appear that there was a difference in the rates of PrEP uptake or PrEP adherence in the last three months, and that includes using biomarkers to assess it.

But to me, the take-home message of this study is there was really great retention in this study. So people who say that it's not feasible to enroll transgender individuals in studies, I think this – this shows that that's not true. You just have to try and use people who are from the trans community as part of your study teams, and you absolutely can. And I think we need more information to understand why the co-location did not appear to affect PrEP outcomes in this study. But I do not think it's a reason for despair. So that's my interpretation of these study results.

I'm going to stop there because I think there are some post questions. And I think Zach has some additional housekeeping items for us. And I apologize, we didn't have more time for specific discussion, but we will get to all of your questions in some form.

[01:15:50]

          Posttest 1

Zachary Schwartz: Yes, thank you. I do want to make sure that we do have time for the questions that are here. So before we jump to those questions, though, I do want to ask the audience to ask – to answer this question to see if we've changed your opinion through this presentation. Could you please rate for me? I am familiar with the data from the HIVR4P conference, and I plan to translate these data into current or future management strategies. The polls are open. Please vote. And in fact, I think I'll have our producer leave this poll open while we let  Dr Landovitz and  Dr Grinsztejn jump right into the important questions that we have from our learners.

Q&A

 Dr Grinsztejn: Okay, so I'm just looking at the questions that people typed in. So somebody was wondering if in the PURPOSE 2 trial, if people with – during the blinded phase, if they received oral PrEP placebo during their active LEN injections, and whether they received placebo injections when they were receiving the oral. And the answer is yes, they did. So there were placebo injections and placebo tablets. So people – that's the answer to that. We have somebody who was wondering about what person years means. And so it's a term that we use to calculate the amount of time somebody spends on an intervention.

So one person spending a year on the study contributes one person-year. Somebody who's only on the intervention for six months contributes half a person-year. Two people on the intervention for six months each together contribute one person-year, half a person-year each. So it tells you sort of how much time overall on the product is – is being experienced by the – the data that's being presented to give you a sense of exposure over the population. I hope that makes sense.

And then we had somebody asking about how were false positive PCRs determined in the UCSF seroprep study. So William, I think – I think the answer to that is, you know, I don't know that they adjudicated that, but, you know, we've presented data from the cabotegravir experience in 083 that low positive RNAs can be disambiguated true positive from false positive by repeating them. And if any testing is positive on a second test, it's a true positive. And if on follow-up testing, it's all negative, that in our experience has been a false positive on the first testing. I hope that makes sense.

Bernice[?] is asking why many of these studies exclude ciswomen. Bernice, you'll have to be a little more specific about which ones because PURPOSE 1 was all in ciswomen. So was 084 and so was the IMPOWER-22 study. So I hope we didn't imply that ciswomen were excluded. They were actually included in those three studies. Usually there's a pair of studies for each product, one of which has been done in – in cisgender women, usually in the global South.

 Dr Grinsztejn: And the FASTPrEP study was mostly women in Africa as well. And the ring – and the ring studies as well.