Achieving Excellence in HIV Treatment and Prevention: Closing Gaps in HIV Care with Long-Acting ART

It's wonderful to be here with all of you to really talk about what I think is a really exciting topic in HIV medicine today and really some new tools in our toolbox in terms of helping some of our most vulnerable patients. And I want to kind of frame our discussion today by starting with a case of a patient that you might be seeing in clinic.

[00:04:40]

Case: Person Living With HIV, Unstable Housing, Viremia

So this is a 33-year-old man who was diagnosed with HIV 5 years ago. At that time of his diagnosis, his CD4 cell count was 250 with a viral load of 400,000 with a wild-type genotype. He has been prescribed bictegravir/TAF/FTC, but really hasn't been able to take it consistently. Every time he gets labs, his viral load is quite elevated, greater than 50,000.

He does have a lot of barriers to adherence, including unstable housing, methamphetamine use disorder, as well as PTSD. The good news is that he has been reengaged in care for the past 2 months, coming to clinic visits, but he still is struggling to take his bictegravir/TAF/FTC.

The table on the right shows his most recent labs. So his CD4 cell count has dropped to 125. He still has an elevated viral load. No resistance mutations are detected, and normal lipids and kidney function. He does have a new diagnosis of syphilis with an RPR of 1 to 256, and his LFTs and viral hepatitis studies are unremarkable. Notably, he is immune to hepatitis B.

So just keep this case in mind as we go through some of the more recent literature and data and guidelines.

[00:06:06]

Can LA ART Help Close the HIV Treatment Gap?

So how are we doing with respect to ending the HIV epidemic in the U.S.? The answer, unfortunately, is not great. We still have a lot of gaps in care, with only 65% of individuals with HIV being virologically suppressed. And there are many reasons for this, including adherence barriers.

And in studies, we found that reasons that patients struggle with adherence include a number of things, such as forgetting to take their pills, being away from home, changes in their routine, depression, mental health, substance use disorder, and then this issue of secrecy or stigma imposed by society and external factors, but also self-stigma as well. And these really make it difficult for some individuals to take their daily oral therapy.

And so the question comes in: can a long-acting injectable ART help with this?

[00:07:00]

Poll 2: Would you recommend LA ART as an option in a person with adherence challenges but who has viremia?

So with that in mind, let's look at this poll question and think about it with respect to the evidence. So would you recommend long-acting ART as an option for a person like this patient who has adherence challenges but also viremia?

1. You wouldn't because there's not evidence to show this; or
2. You wouldn't do it because it's not an FDA indication; or
3. You would do it even though it's not an FDA indication because there actually is strong evidence as well as guideline support for this strategy.

So go ahead and vote.

Zachary Schwartz: And I think we have enough votes. Let's close the poll and see what people said.

Dr Wooten: All right. So the vast majority is going with option C, which I completely agree with. And we'll go through not only the data, but also some recent changes to guidelines that really endorse this approach to patients like the ones we saw in the case.

[00:08:00]

2024 IAS-USA and DHHS Recommendations for LA CAB + RPV

So there was updates to both IAS-USA as well as the DHHS guidelines over the past year for individuals who have viremia and struggle with daily oral adherence. And what those guidelines say is that we can consider specifically the regimen of long-acting injectable cabotegravir and rilpivirine in individuals who are unable to take daily oral therapy after exhausting all efforts to support them in this strategy. Their virus is still susceptible to CAB and rilpivirine.

And IAS-USA calls out specifically that individuals who are at really high risk for a bad outcome, such as having a low CD4 cell count or history of AIDS-defining illness. And then the guidelines also recommend that what we should do for all patients is continue to treat their co-occurring conditions, such as substance use, mental health issues, if these are at play in contributing to the patient's health outcomes.

[00:08:58]

What Studies Examine LA ART in People With Adherence Challenges or Viremia?

So what is the data for using long-acting ART in patients with viremia?

There's actually a growing number of studies. And the left side of the slide shows the published data, which we'll go through. And we also have some studies that will be coming.

And so I think it's important to really understand the details of these studies and how they apply to your specific context, as well as to your specific patient, when you're thinking about using long-acting injectable therapy for a patient with viremia who struggles with oral adherence. So we'll go through some of these.

[00:09:32]

ACTG A5359 LATITUDE: LA CAB + RPV in People With Suboptimal Response or Nonadherence to Oral ART

One of the strongest pieces of data that we have comes from the LATITUDE trial, which was a randomized-control trial of people who struggled with daily oral therapy. These individuals had an elevated viral load or who had been out of care. Everybody in the study got started on daily oral antiretrovirals, and they had economic incentives to take their medication and to get to a viral load less than 200. Once they met that threshold, they were randomized to either continue their daily oral standard of care antiretroviral therapy or switch over to long-acting injectable CAB-rilpivirine. And notably, this regimen was given every 4 weeks in this particular study.

[00:10:16]

ACTG A5359 LATITUDE Included People With Viremia and People With Unstable Housing

And so when we look at the baseline characteristics, a couple of things that I want to point out. Even though everybody at the time that they were randomized had a viral load less than 200, when they measured individuals' viral loads on the day that they received their first injection, there were actually quite a few, 17%, in the CAB-rilpivirine group who had viremia at that time of their first injection.

So this is exactly the question we want to know. How does this regimen work in individuals who have active viremia? And the table on the right shows that these individuals also had a number of barriers and social determinants of health that negatively impacted their ability to adhere to daily oral therapy, including things like unstable housing.

[00:11:06]

ACTG A5359 LATITUDE: Efficacy Outcomes

And so when we look at the efficacy outcomes, there wasn't a statistical difference in the primary outcome between regimen failure. Although you can see in orange the individuals who are receiving the CAB-rilpivirine look to be doing a little bit better. But what was really remarkable is that there was a statistically significant difference in secondary outcomes of virologic failure and treatment-related failure that CAB-rilpivirine was actually superior to daily oral therapy.

[00:11:34]

And because of this, the Data Safety and Monitoring Board had to stop the study early due to superiority in efficacy in the CAB-rilpivirine arm. So really robust data. And I don't think it's surprising that people that really struggle with daily oral antiretroviral therapy, that is what they are struggling with, and so did better on long-acting injectables.

So that's randomized-control trial data.

[00:12:00]

SPLASH: LA CAB + RPV in People With vs Without Viremia at Baseline

We also have a growing amount of observational and real-world data. Probably the largest comes from the SPLASH cohort, which is a cohort of individuals at Ward 86 in San Francisco.

The data reported here includes 370 individuals. And you can see in the table on the left that about a third of the people in this cohort had viremia at the time that they were started on CAB‑rilpivirine. You can also see that this population was enriched for unstable housing and substance use. So a more challenging patient population to be able to support.

And in terms of virologic outcomes, you can see that really whether you started with viremia or if you started with virologic suppression in blue, the rates of virologic suppression at week 48 were quite good in each of these arms. So really nice real-world data to see the impact of this regimen, particularly in people with viremia.

[00:13:00]

Systematic Review of Observational and Interventional Studies of LA CAB + RPV

One of the things that we worry about in using CAB-rilpivirine or any regimen in individuals that have viremia or very high viral load is the risk of virologic failure and what happens when virologic failure occurs in terms of the development of resistance.

This is a really nice systematic review that if you haven't looked at it, I recommend it. Combining all of the observational and interventional data, looking at CAB-rilpivirine, and specifically, the study focuses on what happened with virologic failure.

So they included 33 studies of over 9,000 participants who experienced virologic failure and also a number of them that specifically looked at and investigated the emergence of integrase resistance.

In the table, in the orange box that's shown, what you can see is that they looked at individuals who started CAB-rilpivirine when they were suppressed, and they also had individuals who started CAB-rilpivirine with viremia. And what's really important to take away from this is that rates of virologic failure were quite low regardless of whether you were virologically suppressed at the time you started injectable therapy, but for those few people that did develop virologic failure, you more often than not developed integrase resistance, and that's a theme that we'll come back to as we look at other studies today, is that when you develop virologic failure with this regimen, although it doesn't happen often, you tend to have resistance to both NNRTIs as well as INSTIs.

[00:14:38]

IMPALA: 48-Wk Study of LA CAB + RPV in Adults With Poorly Controlled HIV

Now what about CAB-rilpivirine in low-income settings?

We now have data from the IMPALA study, which was similar in structure to the LATITUDE trial but took place in Uganda, Kenya, and South Africa, included individuals just like LATITUDE, who really struggled with daily oral adherence, who had viremia, who had been lost to care. Everybody was started on daily oral therapy and then randomized to CAB-rilpivirine or to continue on their daily oral therapy. And I'll just highlight that in this study, the CAB-rilpivirine was given every 8 weeks, in contrast to the LATITUDE trial, which the therapy was given every 4 weeks.

[00:15:20]

IMPALA: Outcomes at Wk 48

So in terms of outcome, really, really equivalent outcomes in those who were receiving the CAB‑rilpivirine compared to continuing on daily oral therapy and quite good outcomes altogether. So, around 90% rate of virologic suppression in both groups.

This study also looked at subgroup analyses based on BMI, whether individuals had a baseline BMI greater than or less than 30. This is a question that we'll come back to a little bit later on, but there had been early concerns that having an elevated BMI might impact the efficacy of CAB-rilpivirine because of PK issues potentially.

And what you can see here is individuals that had an elevated BMI of greater than 30 in the CAB-rilpivirine group had quite excellent virologic outcomes. So, additional support, and we'll hit on some of the additional data a little bit later, that elevated BMI is really something that we don't have to worry about as much as we initially did.

[00:16:28]

IMPALA: Characteristics of Participants With CVF With LA CAB + RPV

So there were 5 individuals in this study who developed virologic failure, and again, this theme that we'll come back to, those individuals who did develop virologic failure, not very many, but when they did, they developed both NNRTI as well as INSTI resistance mutations which are shown here in the table. The good news is that all of these individuals were able to re-suppress on a daily oral regimen.

[00:16:54]

Ponce LA ART Program: LA CAB + RPV in People With Viremia

And then more recently we have some observational data from Atlanta from the Ponce cohort study looking at CAB-rilpivirine as well as some other injectable regimens and combinations therein, looking at their, again, real-world experience of how individuals who really struggle with daily oral therapy did on these various injectable regimens. And with CAB-rilpivirine specifically, rates of virologic suppression were quite high, above 90%.

So additional data and support for this regimen in individuals who really struggle with daily oral therapy.

[00:17:32]

Ponce LA ART Program: Characteristics of Participants With CVF With LA CAB + RPV

Two individuals experienced virologic failure and they did have resistance mutations as we would expect. They were able to achieve virologic suppression when they were switched back to an oral regimen.

What Are the Risks of Virologic Failure With LA ART?

[00:17:46]

So we've been talking a lot about virologic failure, and I think this gives us an opportunity to really kind of re-examine and delve into what are the risk factors that we need to be thinking about when we're starting an individual on this regimen to understand what is their likelihood of developing virologic failure because we know that there are significant consequences, specifically resistance mutations that will develop if virologic failure occurs.

[00:18:15]

Poll 3: In people with which of the following should LA CAB + RPV be AVOIDED? Choose all that apply.

So we'll have a poll question here. In people with which of the following should long-acting CAB and rilpivirine be avoided, specifically thinking about the risk for virologic failure? So choose all that apply.

1. Having HIV subtype A1;
2. HIV subtype A6;
3. An elevated BMI greater than 30;
4. Having preexisting resistance; or
5. You just don't have any genotype data about that individual.

Go ahead and vote.

All right, and it looks like we've got a variety of answers, with 88% of people saying that if you have preexisting resistance to either agent in the regimen, you really shouldn't use it, and I agree with that, or unknown genotype, 38% of people were maybe anxious or worried about using this regimen, but fewer responses in terms of being concerned about elevated BMI greater than 30, 25% of people were concerned about that.

So let's go through some of these risk factors and look at the data and newer data that helps to inform our practice.

[00:19:30]

Data From 2023 or Earlier: Risk Factors for Virologic Failure With LA CAB + RPV

So after the initial registration studies for CAB-rilpivirine came out, FLAIR, ATLAS and ATLAS‑2M, there was a really nice multivariate analysis that was done looking at what were the predictors or what were the risk factors for people to develop virologic failure or confirm virologic failure, CVF.

And what you can see in the table on the lower left is that individuals that had baseline resistance to rilpivirine had the highest odds ratio of developing virologic failure, but other factors that shook out in the analysis were having a low Week 8 rilpivirine trough concentration, having infection with subtype A6, A1 they kind of combine those together, and then having an elevated baseline BMI.

Really, what's notable here, though, is even if you have none of these risk factors, there's still a risk of developing virologic failure with that, right, with this regimen. It's quite low, but that is something that's important to talk to patients about and to make sure that they have an understanding that this is a very, very low likelihood that this could occur, but if they are incredibly risk-averse, having that information may impact their decision-making on whether they would do daily oral therapy or inject an injectable regimen. Even having 1 risk factor didn't really significantly increase your risk for virologic failure it was when you had 2 or more of these risk factors and in particular having that baseline rilpivirine resistance mutation that were the most notable in terms of risk for virologic failure.

So this was sort of kind of our older way of thinking about things, but we've had more data come out that I think has changed this in some important ways to think about.

[00:21:12]

CARES Study of Switch to LA CAB + RPV Included People With High BMI, HIV Subtype A1, Baseline Resistance

And in particular, the CARES study, which was a study looking at very similar to ATLAS, FLAIR, looking at CAB-rilpivirine in people that had a high BMI, had infection with subtype A1, so about 55% of the participants in this study had A1, and then we had—and I'll just point out that 21% of the population in this study had a BMI greater than 30, and there were some individuals who had rilpivirine or CAB resistance mutations at baseline as determined by archived proviral DNA analysis.

Now this type of testing is very controversial and very challenging to interpret in the clinical context because they are both false positives as well as false negatives with this type of testing in terms of interpreting resistance mutations.

And in particular, APOBEC-related mutations are mutations that show up as being positive and predicting drug resistance, but really our understanding of this is that these are resistance mutations that are being identified in replication-incompetent virus. So essentially, like a false positive result because you're finding it in replication-incompetent virus. So it's really hard to be able to know how to use proviral DNA resistance mutation data when we're looking at it in the clinical setting, and the guidelines really speak to this in that this is still sort of an uncharted territory in terms of how we should be using this clinically. But regardless, we had this information in the CARES study, and we can look to see how this did or did not impact the risk for virologic failure subsequently.

[00:23:04]

CARES: Results at Wk 96

So outcomes in the CARES study at Week 98 were quite good whether you continued on oral therapy or if you had been randomized to the CAB-rilpivirine arm. And remember there were a large proportion of people with subtype A as well as elevated BMI. And so I think what we can take away from the CARES study is that having subtype A, well, initially we thought maybe really increased or increased a little bit your risk for virologic failure. I don't think that's our interpretation or understanding of the reality currently, and it's probably more A6 driving that. And similarly, having an elevated BMI with a large proportion of individuals in this study as well as in some of the observational studies that we've seen where elevated BMI is really not a major driver of increasing your risk for virologic failure.

I think if you do have true baseline resistance to either rilpivirine or cabotegravir that's definitely going to increase your risk for virologic failure. The question is: Are you getting that information from a proviral DNA test, and is that really telling you what that individual has, or is that showing you false positive resistance mutations, is another question altogether. But if you have true resistance mutations to rilpivirine or cabotegravir, that, I believe, will increase your risk for virologic failure with this regimen.

Future Directions for LA ART

[00:24:30]

So hopefully that clarifies sort of our understanding of where the field is at in terms of predictors of virologic failure with CAB-rilpivirine.

Beyond CAB-rilpivirine what other long-acting therapies are coming?

[00:24:44]

Studies and Case Series of LA CAB + LA LEN

So a lot, which is very exciting, and we're eagerly awaiting a lot of data. The regimen of CAB and lenacapavir, a capsid inhibitor, is 1 that people have been quite excited about, and we will talk about LEN a little bit later, particularly in the context of PrEP.

But we use lenacapavir for patients who have multi-drug resistant HIV currently in combination with the optimal background regimen. But people have started using off-label cabotegravir and lenacapavir in individuals where they would benefit from having an injectable regimen, but maybe they have resistance to rilpivirine because they have a lot of NNRTI resistance.

And so there's a number of case series out here that are on the slide anywhere from 8 individuals up to 34 individuals showing that this looks to be a promising regimen, but we really do need prospective studies, and there are some that are approved and are hopefully going to be launched, so we'll have some more information about this regimen.

[00:25:50]

Studies of Weekly Oral ISL + LEN

And then we also have a weekly oral regimen of islatravir, a translocation inhibitor that's given orally once a week with a once-weekly oral formulation of lenacapavir. So that regimen is once a week oral, not injectable, and we've got 2 studies that we'll eagerly await results being compared to either bictegravir/TAF/FTC, or to standard of care oral therapy. But this might be a nice option for people that struggle with daily oral adherence but do not want to do injectable therapy. And I have plenty of patients in my practice who have significant needle phobia, even getting lab draws is a challenge, and so an injectable therapy is not a great option for them. But long-acting oral therapy is a whole other realm that I think is going to open up a lot of options for people that don't necessarily fall into daily oral therapy or injectable long-acting therapy.

[00:26:52]

Take-home Points on Long-Acting Injectable ART

So take-home points in terms of HIV treatment and long-acting injectable therapy. I think we've hopefully shown data that this is a really, I think, nice option for patients that struggle with daily oral adherence who have viremia. We have data, both randomized controlled trial and observational data, showing that this regimen can really work for many, many people.

I do think resistance to CAB and/or resistance to rilpivirine at baseline is a situation in which I would really avoid using CAB-rilpivirine as a regimen because this will increase the risk of virologic failure. But some of these other issues, in particular elevated BMI, are things I think we used to worry a lot about when we were thinking about switching a patient to CAB-rilpivirine in the past, but really now hasn't played out or borne out in terms of what the data is showing us. And we have a lot of new long-acting regimens on the horizon as well.

[00:27:49]

Posttest 1: I would consider a switch to LA ART in a person with persistent adherence challenges but who has viremia.

So that wraps up our discussion on ART. Let's see how we did in terms of the posttest. So this is the same question you saw earlier.

I would consider a switch to long-acting ART in a person with persistent adherence challenges but who has viremia.

1. Strongly disagree;
2. Disagree
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Let's see how you'll vote on it this time.

Zachary Schwartz: Let's see if we get enough people to vote. Oh, it's kind of slowed down. Not everyone has voted yet, but it has slowed down.

I guess this is all the votes we're going to get. Let's go and have a look.

Dr Wooten: So wonderful. We see the vast majority of people are really agreeing or strongly agreeing with using this regimen, long-acting injectable therapy in patients who have viremia and struggle with daily oral adherence challenges.

[00:29:00]

I think we have not only data, but guidelines to support this strategy.

[00:29:06]

Posttest 2: I would consider a switch to LA CAB + RPV in a person without RPV RAMs, without HIV-1 subtype A6, but with a BMI >30 kg/m 2.

And then we've got our second posttest question. I would consider a switch to long-acting CAB‑rilpivirine in a person without rilpivirine resistance-associated mutations without HIV subtype A6 but who has an elevated BMI. Go ahead and vote on how much you agree with this statement.

Strongly agree, A – strongly disagree, A; strongly agree, E.

Go ahead and vote.

All right. We'll take another couple seconds and then see.

Zachary Schwartz: Yeah, I think everyone who's going to vote has voted.

Dr Wooten: Okay, wonderful. So great. I think we see a shift here in more people potentially agreeing or strongly agreeing that even with an elevated BMI, CAB-rilpivirine is going to be a great option for many, many people.

[00:30:16]

So wonderful. Okay. Well, and this I think a lot in part comes from the CARES study, in which 21% of participants had an elevated BMI and were able to achieve high rates of virologic success.

Gaps in HIV Prevention: What Is the Role of LA PrEP?

[00:30:29]

Okay. So now let's switch gears and talk about PrEP, and specifically how long-acting ART or antiretrovirals can be used for PrEP.

[00:30:42]

Need for PrEP Is Much Greater Than Population It Reaches

So how are we doing with respect to our PrEP-to-need ratio, meaning of the people who would be indicated or eligible for PrEP, how are we doing in terms of getting PrEP to them?

And the answer is unfortunately really, really bad. So you can see that this figure shows all of the people that CDC estimates, 2.2 million, who would be eligible for PrEP. And you can see the tiny, tiny teal bar about how many people are actually receiving PrEP, based on their degree of exposure to HIV, whether that's through sex or through injection drug use.

So we have a lot of work to do here. And again, I think long-acting ART is going to be a nice option to help fill this gap.

[00:31:32]

Why Might We Need Long-Acting HIV Prevention?

So we know that when taken, daily oral PrEP works well, but taking it is very challenging, and it's challenging in specific patient populations.

Long-acting prevention can be helpful for unwanted, unplanned sex acts. It can be helpful because it overcomes the adherence issues, which may be impacted by alcohol or drug use, also takes away some of the stigma. And for individuals who travel and change time zones, it can be challenging to take daily oral therapy.

And then whenever we can offer more choices to patients and then give them that efficacy to decide what's going to work best for them and for their life and their health, that always is going to improve adherence and then subsequently efficacy. So there are lots of reasons why long-acting PrEP is really, really important if we're going to try and achieve our goals in terms of ending the HIV epidemic.

[00:32:34]

HPTN 083 and 084: LA IM CAB Q2M vs Daily Oral FTC/TDF for PrEP

So we have a lot of data with cabotegravir given every 2 months as PrEP. And really impressive data showing that it's actually superior to daily oral FTC/TDF in the HPTN 083, which looked at men who have sex with men and transgender women, as well as in 084, cisgender women. There have been, since the initial studies were reported, some additional infections that have been noted in the individuals who were continued to be followed, 18 additional infections in 083. But this is still quite low and still better than daily oral PrEP.

And in 084, importantly, tracking individuals who became pregnant while receiving injectable CAB, no safety issues either in the mother or in the neonate.

[00:33:30]

LA CAB PrEP: Postapproval Studies

We also have observational studies in the real-world, postapproval studies as we're now calling them, that show that long-acting PrEP is quite effective from the OPERA cohort, which is a multicenter cohort study across the United States, looking at over 700 individuals receiving cabotegravir as PrEP. There were 2 individuals who acquired HIV, which is quite low.

And similarly in the TRIO cohort, which is a similar type of cohort, multicentered across the United States, no acquisitions of HIV. And then in the bottom in purple, I'll just highlight a really interesting model for PrEP delivery with cabotegravir injections, showing administration at a pharmacy and showing really great rates of on-time injections and adherence. And we eagerly await outcome data from this model, because I think having not only different modalities of PrEP, whether it's oral, daily oral, or long-acting injectable, but also having different modalities in terms of how PrEP is delivered is really important, again, for that option piece of things.

[00:34:44]

PURPOSE 1 and PURPOSE 2: Q6M LEN for PrEP

And then lenacapavir, as we alluded to earlier, when we're talking about HIV treatment, really has, I think, a great place in our armamentarium for PrEP. A subcutaneous injection with this capsid inhibitor, given every 6 months. And in the PURPOSE-1 and PURPOSE-2 trials, these were very exciting, highly publicized trials looking at, in PURPOSE-1, that there were zero individuals who acquired HIV who were receiving lenacapavir compared to daily oral FTC/TAF and daily oral FTC/TDF. And this was all compared against a background HIV incident.

Since this was originally reported, there have been 2 additional incident infections in the lenacapavir arm. We don't have more information or data about that, but that will be something to definitely keep our eye on and to get more information about, but looks incredibly promising in terms of not only the frequency at which this needs to be administered, which is just twice a year, but in terms of efficacy. And similar types of things that we're seeing with PURPOSE-2, with 1 additional incident infection occurring after the publication of these results.

[00:36:02]

Mitigating Injection Site Pain and Postinjection Recommendations

Injection site reactions are something that we think about both with cabotegravir as well as lenacapavir. These are common, but usually very mild. They very infrequently lead to individuals stopping their injectable therapy.

And this is a really great resource in terms of strategies that can be used within the clinic to minimize injection site pain and to ensure that the medication is administered appropriately. And so, I highly recommend folks checking out this toolkit and taking advantage, and working into your clinical operations, some of these strategies to, again, enhance patients' experiences with this therapy, but also as a way to overcome barriers that maybe people are worried about, what the injection will be like, and pain associated, and ways to overcome some of those barriers.

Can LA PrEP Be Effective in Vulnerable Populations?

[00:37:06]

What about long-acting PrEP in vulnerable and marginalized patient populations? I think this is a really important group to be thinking about and to be focusing on and developing strategies around.

[00:37:81]

Poll 4: Your patient requests PrEP but lives with roommates and does not want daily pills because of stigma. Is this a reason for LA PrEP?

We'll have another poll question here. Your patient requests PrEP, but lives with roommates and does not want daily pills because of stigma. Is this a reason to give them long-acting PrEP?

1. Yes; or
2. No.

All right. We can probably go ahead and close the poll. I think the vast majority, yes, 95% of people think that this is definitely an indication, and I agree very much with this audience.

[00:37:52]

PILLAR: LA CAB PrEP Integration in High HIV Epidemic Priority Areas in the US

This is a recent study that came out, the PILLAR study, looking at long-acting CAB PrEP in 17 different clinics throughout the US and really looking at persistence and HIV acquisition. Outcomes looked great, but what I'll highlight is the baseline characteristics and thinking about marginalized and underserved patient populations. And rightly so, this study looked at really trying to prioritize and engage individuals that are at high exposure to HIV and being able to get this therapy—this prevention for them and showing really great outcomes here.

[00:38:36]

LA CAB PrEP in an Urban Safety Net Clinic Population

Similarly, we have really good data for CAB PrEP in urban safety net clinics. This is from San Francisco at Ward 86, showing high rates of individuals who had unstable housing, high rates of substance use, but still really, really impressive PrEP persistence, as we call it, so receiving on-time injections and being retained in PrEP care at 6 months.

So really impressive, and I think something that really gets around that adherence barrier when your PrEP modality is daily oral therapy.

LA PrEP: Testing for HIV at Initiation and Beyond

[00:39:16]

Now, I do want to go over some recommendations and guidance in terms of how to test for HIV and monitor while individuals are receiving long-acting PrEP, because this is definitely a dynamic target, a moving target, and 1 that has changed recently.

[00:39:34]

Poll 5: If following IAS-USA guidelines, what HIV testing would you recommend prior to starting LA CAB PrEP?

We'll have this poll question first. If following the IAS-USA guidelines, what HIV testing would you recommend prior to starting long-acting CAB PrEP?

1. A point-of-care HIV antigen-antibody test;
2. A lab-based HIV antigen-antibody test;
3. An HIV-1 RNA assay; or
4. A lab-based HIV antigen-antibody test and an HIV-1 RNA assay.

Go ahead and vote.

And our results show that 62% went for what is the correct answer, with a lab-based antigen-antibody test and RNA assay. We'll go through this, and I'll just highlight again that this is at the initiation of PrEP, because we'll see differences when we're talking about monitoring.

[00:40:28]

HIV Testing When Starting LA CAB PrEP

So these are HIV testing recommendations when starting CAB PrEP. Screening should include an antigen-antibody as well as an RNA. I'm not going to spend too much time here, but just refer you to these resources if you do have questions, because it can be challenging if you're starting long-acting PrEP and then subsequently have a positive test that comes back and how to interpret those. And so there is PrEP warm lines that can be consulted if needed.

[00:41:01]

Pretest 3: If following IAS-USA guidelines for LA CAB as PrEP, when should HIV-1 RNA assays be performed?

But I think what's interesting and what has changed is now this next pretest question that, before I tell you the answer, we'll go ahead and ask you.

If you're following the IAS-USA guidelines for long-acting CAB as PrEP, when should HIV-1 RNA assays be performed?

1. Just at initiation;
2. At initiation and then every 6 months;
3. At initiation and then every 2 months; or
4. At initiation and then every 2 months for the first year and then every 6 months thereafter?

Go ahead and vote.

All right, and we can close the poll.

The most common answer, which 43% went for, was at initiation and then every 6 months. The correct answer, which is at initiation only, was the most infrequently selected at 13%.

This is great because there's an opportunity to review some changes that have happened relatively recently in the IAS-USA guidelines.

[00:42:17]

HIV Monitoring on PrEP: CDC

There is a difference between CDC guidelines and IAS-USA guidelines. There's been a lot of turmoil and pause in terms of CDC, of course, currently.

I think that the guidelines will ultimately be more similar than they are, but there have been just administrative and logistic delays here. But what CDC currently recommends is that an RNA and an antigen-antibody test be done with both oral and long-acting injectable PrEP. For oral PrEP, these 2 tests should be done every 3 months. And for CAB, these 2 tests should be done every 2 months.

So that, you just think about it, that's a lot of testing. antigen-antibody as well as an RNA every 2 months, every time somebody's coming in for their CAB injection. And we know in the real world that adherence to these guidelines are quite low because this is really hard to get blood draws every 2 months and somebody receiving PrEP as prevention. But the reason why this recommendation was initially made was because there are delays in diagnosis when one is on PrEP, if HIV is acquired, and this can make subsequent management challenging. And so this was probably a little bit too conservative of a recommendation in terms of the frequency, particularly of the RNA testing for people on CAB PrEP.

[00:43:41]

HIV Monitoring on LA CAB PrEP: IAS Update

What was the update, and what was the correct answer to our pretest question, which you'll get a chance to try again in the posttest question, was over the summer, IAS-USA updated their guidelines to no longer recommend an RNA test when you're monitoring somebody on PrEP. So when you start somebody on cabotegravir, you should get an antigen-antibody and an RNA at baseline. But subsequently, you don't need to check an RNA at every visit thereafter, unless there's a clinical indication.

But really, an antigen/antibody test will suffice. If you're able to do a point-of-care antibody in your setting as well, that's great. But the main point here is that the RNA is no longer recommended every 2 months. And this is because it doesn't have good predictive value, and we'll go through some of that data.

[00:44:35]

Breakthrough Infections on LA CAB

We know that breakthrough infections can occur on long-acting CAB as PrEP, but this is really, really quite rare. We do worry about that long tail, because these are long-acting agents.

[00:44:47]

HPTN 084 OLE: HIV-1 RNA Test Performance

So we have open-label extension data from 084, which looked at CAB PrEP compared to daily oral PrEP. And what I'll do is just summarize the information on this slide to say that the test performance of RNA is really, really poor in people on CAB PrEP. There are false positives that cause a lot of anxiety that turn out to be just false positives.

And they also have the risk of holding somebody's PrEP and then making them in a situation where they could be exposed to HIV acquisition. So putting them at risk as opposed to being beneficial and helpful. So, long story short on this for CAB PrEP is that RNA testing at each visit is no longer indicated per IAS-USA, and that's based on these data.

[00:45:38]

HPTN 083 and 084 Updates: Category of HIV Infections and Overall Summary of Major INSTI RAMs

We do know that breakthrough infections, again, are quite rare, but they can occur. And what I'll highlight is when they do occur, even when they're on, especially when they're on from, occur on on-time injections, the risk of developing INSTI resistance-associated mutations, is real. And something that should definitely be at the forefront of our mind, when we're thinking about a subsequent treatment regimen to start.

[00:46:04]

HPTN 083: HIV Treatment After HIV Acquisition While Receiving LA CAB PrEP

And then, similarly, we see that when individuals do acquire HIV on CAB PrEP, they tend to have INSTI-associated resistance mutations, and you are more likely to develop this if you acquire HIV within the first 6 months of starting CAB PrEP. We still don't know the exact regimen or the best regimen to start somebody on if they do acquire HIV while receiving CAB PrEP, particularly if you don't have a genotype back, then you should use probably a boosted protease inhibitor regimen.

But if you do have a genotype back, understanding which INSTI resistance mutations would allow you to use an INSTI-containing regimen is still something that we need more data on.

[00:46:57]

HIV Testing and Monitoring With LEN: IAS Update

So this summarizes HIV testing and monitoring with lenacapavir. I'm not going to go through data just because we don't have a lot since this was just relatively recently approved for real world. But in terms of what the package insert says, when you're starting lenacapavir for PrEP, you should get an antigen-antibody test before initiation within 7 days. And for most people, if they're being exposed to HIV within the past 21 days, you should also get an RNA at initiation. And then after that, just like with CAB, you don't need to do RNA testing.

So you can do antigen-antibody testing for monitoring when somebody is on lenacapavir for PrEP. Guidelines say at least 6 months. What we're doing in our clinic and many clinics around the country, if somebody is coming in at 3 months for STI testing and you're drawing blood for a syphilis test, for example, you could also do an antigen-antibody test at that time as well, but at least every 6 months. But again, the point here is no RNA testing.

[00:48:00]

Take-home Points on Long-Acting PrEP

So take-home points for long-acting PrEP. We didn't talk about this, but I know that this group knows this well, that all individuals who are sexually active should have a conversation with their healthcare provider about PrEP.

We've got good options, great options rather, for PrEP, including every-2-month cabotegravir and then every 6 months subcutaneous lenacapavir, both with really incredible efficacy. So we've got some options. Daily oral PrEP might be the right answer for some people, but now we have just much more to offer.

And RNA testing, while we do this at initiation, we're not going to do this with monitoring if we're following the IAS-USA guidelines. We just need an antigen/antibody plus-minus a point-of-care rapid HIV antibody test.

[00:48:50]

Posttest 3: If following IAS-USA guidelines for LA CAB as PrEP, when should HIV-1 RNA assays be performed?

All right, and with that, we'll have our posttest question.

So if following the IAS-USA guidelines for long-acting CAB as PrEP, when should an HIV-1 RNA assay be performed?

1. At initiation;
2. At initiation and then every 6 months;
3. At initiation and then every 2 months;
4. At initiation and then every 2 months for the first year and then every 6 months thereafter.

Go ahead and vote.

All right. Let's see. All right, a dramatic improvement here.

Great job, everyone. So 76% of people got the correct answer that the IAS-USA guidelines are really recommending just the RNA assay at initiation. So wonderful.

[00:49:50]

And this is the rationale here. Because of the poor test characteristics for monitoring while somebody is on CAB PrEP.

All right. Well, we will go ahead and open it up for question and answers. And we'll have some poll questions pop up on your screen. So feel free to interact with those as well as we're going through the Q&A.

Q&A

Dr Wooten: We have a question from Keith about the IMPALA study.

So this was in 3 countries in Africa, looking at daily oral therapy compared to CAB-rilpivirine in people who struggle with daily oral therapy. So sort of an analogous study to the LATITUDE trial. And the specific question that Keith is asking, which is a great one, is, was a longer needle used in the individuals who had a BMI greater than 30?

And that question, I don't know the answer to. I would need to go back and look at the IMPALA study. But you do bring up a really great point, Keith.

And what the expert opinion as well as the package recommends is that if you do have an individual with elevated BMI, to use that longer, at least 2-inch needle when giving CAB-rilpivirine. There are some modeling studies that look to suggest that that will be beneficial in terms of administration.

The other piece of that that I think is really important is having very good training for the healthcare providers who are providing the injections, not only for CAB or CAB-rilpivirine, if you're talking about treatment vs PrEP, but also for lenacapavir as well, especially with lenacapavir being a little bit newer. And so using the toolkit that we gave the resource link for in terms of training staff and having a peer-to-peer, near-to-peer teaching so that people get the physical coordination and experience with administration of these medications can be very helpful.

We'll see if other questions roll in. And we also have the questions going through as well. And there's also a suggestion to add information or an additional slide in terms of the annual cost of the different PrEP options. And that's a really great suggestion. Hard to do in terms of for each individual insurance plan and coverage and how that plays out. But definitely the relative cost, I think, can be very helpful. And this is something that a lot of people in the field have been talking about as a really important issue.

We have lenacapavir as an example of a really great, very effective agent for PrEP. And we need to make sure that people who need it all over the world, not just within the U.S., are able to access this really incredible preventative medicine. And I know that there's been a lot of work done in this space in terms of increasing that access through a variety of mechanisms. But there's also more that can be done and needs to be done.

And so I think that's a really great point as well.

Zachary Schwartz: So, Dr Wooten, I know that you mentioned and tested on how the testing requirements for long-acting PrEP have changed. They changed the IAS guidelines. What about other guidelines, and do you anticipate other changes?

Dr Wooten: Yeah, so that's a great question. And I believe, although I am not formally affiliated and don't have great insider perspective with CDC, but my word-on-the-street references say that the CDC guidelines will be changing to exactly what we'll have to see, but will be changing to be more similar to IAS-USA. There's just been delays in terms of getting their PrEP guidelines updated because of everything that's happening right now at CDC.

And we've got another question coming in asking about genotype testing at initiation for PrEP. That's an interesting question. I think that the only situation where I would think about genotype testing at PrEP initiation would be if somebody, if we did their antigen-antibody test, as well as their RNA test, and that came back positive, then I would, of course, that would be somebody with HIV, who has acquired HIV. And so you would do a genotype as part of the baseline labs in anybody who's newly diagnosed with HIV.

I wonder maybe if you're asking about doing, like, a proviral genotype test when starting PrEP, but since an individual – presumably if you do the antigen-antibody and the RNA testing and those are negative, and so the person does not have HIV, that would be somebody that you would be starting PrEP on. I don't think that there would be an indication to do a genotype because they wouldn't have any virus in their body, whether that was virus in the blood or archived virus.

I think generally that would not be indicated unless you made a new diagnosis of HIV, then we would do the genotype as we would do with any new diagnosis.

[END OF TRANSCRIPT]