Clinical Focus Podcast: When and How to Consider LA ART for People Facing Adherence Challenges

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes. 

Dr. Onyema Ogbuagu (Yale School of Medicine): Great. So, first of all, I just want to say again, I'm sure on behalf of Dr. Gandhi and I, thank you, everyone, for joining us. I'm told that we have lots of people joining us from outside the US.

Knowing that some of you practice to US, some of you practice outside of the US, we apologize if we discuss strategies that may not be immediately available to you, but we'll try to keep that in mind.

Assessing Candidacy for LA ART: Questions to Answer

So, let's start with assessing candidacy for long-acting ART. And I think I just want to highlight a few things. I think we do have long-acting ART that's approved independently for people who have multidrug-resistant HIV, but we also do have complete long-acting ART regimens for - for individuals - for who are virologically suppressed as a switch, and then, of course, innovative uses for - for, you know, drugs like cabotegravir, for example, for those who are viremic, albeit off-label.

So, we all know that some of the key things we all think about when assessing candidacy for long-acting ART is. Are there mutations present that can impact the efficacy of a regimen we're about to start individuals on? And I know in different contexts this can be really challenging because this usually hinges on having genotypes available and accessible, especially for those who may have moved from one clinic to another, so that they may not always be readily available, or even sometimes treatment histories. But those are critical because we know that resistance mutations can be a problem for long-acting ART regimens, particularly for cabotegravir/rilpivirine.

Questions such as: has virological suppression ever been achieved? Again, I think that's where a careful treatment history can help us assess the risk that an individual may have failed therapy and having not achieved suppression on some regimens. But I'm sure many of you know that, again, it all depends on how well adherence is for those who have low levels of adherence. Maybe they cannot have viral suppression and not have accrued resistance just because there's no drug pressure, versus those who were kind of suboptimally taking it sometimes on and off, and sometimes that can be a determinant of the risk of resistance, and I'm sure these are concepts that many of you are familiar with.

And then, importantly, right, so the long-acting ART options. We are gravitating towards oral options. So, for all intents and purposes, let's think about those that require injection visits. When we think about initiating long-acting ART, are these individuals able to show up in the clinic to be administered those injections? And - and that would be critically important, right? Because we don't want missed injections, which again, can lead to treatment failure and emergence of resistance.

Importantly, as we assess candidates for long-acting ART, are there contraindications available long-acting options? So even beyond resistance here, so are there things for example, like drug-drug interaction considerations, for example, or reasons why people may not be the best candidates for injectables? Those are important questions to ask.

And then what are the barriers causing failure of oral therapy? We know that long-acting ART, or longer - even long-acting injectable ART doesn't overcome all the barriers that individuals face with oral therapy. And I think it's a really important point of management to make sure that we are thinking about the reasons why people failed. Again, you know, there could be things around housing security, lack of transportation, or even interfering comorbidities, or behaviors such as substance use, or mental health, and all those issues, which we'll delve in a little deeply.

But I think, again, identifying these barriers help you identify what's modifiable. And we know that if we do create structures where we can address these barriers, that we're more likely to be successful oral therapy. So, for example, it can be, you know, impactful to integrate mental health treatment, for example, right? For someone who's struggling with depression, or anxiety, or whatever interfering mental health comorbidity, interfering with oral therapy. And when we manage that, we position people better to do better regardless of what kind of therapy we're offering.

And like I said, the long-acting strategy may not be a panacea for all the barriers that people face, but definitely can - can move the needle in the right direction. And I would argue that when we do offer long-acting agents that it should be just one part of a comprehensive strategy to address the barriers that people with HIV face.

Identifying Appropriate Candidates for LA ART

And so, in general, we know that appropriate candidates for long-acting ART. So, I think one group that's not here are those who are suppressed switch doing fine, who just prefer long-acting ART. That's not necessarily the focus here, but again, that's the group for which, you know, for example, CAB/rilpivirine has been approved for. But again, we think some of the people for whom long-acting can be even the most impactful are clearly people who - who have viremia. And these include people who have struggles with adherence challenges. And hopefully we're going to weave in lots of the experience we've had with clinical trials and even clinical practice and upcoming therapeutic strategies to - to try to address this.

But I think what's been really important has been, like, you know, we know that the guideline bodies like IAS and DHHS, which is a US-based guideline group. In spite of the use of long-acting ART off-label for viremia have really seen the impactful studies again, which we're going to discuss, showing that there could be value to utilizing long-acting ART for people with viremia, particularly groups who, you know, could be at risk of suffering severe consequences for not being treated, including those who have, you know, very low CD4 counts who could be vulnerable to opportunistic infections and really higher rates of morbidity and mortality. And that would be kind of like a thrust of our discussion as we try to weave things along here.

Questions

So, I think this would be our first point where we stop and ask for questions. And maybe just to throw a question at you, Dr. Gandhi, right? This is a population that you've worked on very closely. I'm sure it's very near and dear to your heart, just thinking about candidacy for long-acting ART. How do you think about that in your clinical practice?

Dr. Monica Gandhi (University of California): Yeah, I mean, I think we, from the very beginning of Ward 86 in 2021, just started using it in people with viremia, because we have such a low-income population, lots of in and out of housing insecurity, substance use, lots of challenges, and we just said, "Okay, let's just try it." But other groups too, like the Ponce Clinic at - in Emory, have looked at the use of this viremia long-acting ART, and it was like sometimes the only thing that would save them, and I mean like, life-saving, which is I think why, even though we didn't have a randomized controlled trial, which we're going to talk about next, you know, we - the guidelines really did endorse the use of this with viremia.

We have good data now. We have the A5359 study, LATITUDE, that works in people with adherence challenges. And IMPALA is the second one in low- and middle-income countries. And third is LATA, which just got published in The Lancet just a couple - a week ago, with those who are adolescents and have adherence challenges. So, all that data put together, I would say that, of course, we let people have it who, you know, can stay on oral ART, but we're kind of focusing on the adherence-challenge patient population, which turns the trials on - on their ear, because that's how they started looking at those with virologic suppression.

Dr. Ogbuagu: Yeah, absolutely. And I'm sure you must have heard about this, right? So, the - well registrational study.

Dr. Gandhi: I'll tell about it.

Dr. Ogbuagu: Okay. You tell about it, all right; I'll hold my horses. Yes.

Dr. Gandhi: Yes. I knew we're going to do viremia next. So, let's - let's definitely talk about it.

Dr. Ogbuagu: Okay.

When Should Viremia Prompt a Consideration of a Switch to LA?

Dr. Gandhi: I mean, I think, you know, I - what you were just about to say really is that fundamentally all this data that was generated in those with viremia prior to October 6th was done in observational studies. So, people putting out demonstration projects.

Now, what happened on October 6th, there was a press release on the CROWN study, and what is the CROWN study? The CROWN study is a multi-site study. It's 85 sites, eight countries. The N is 326 individuals, and the very question is: is oral ART better if you have viremia, staying on oral ART or switching over to long-acting cabotegravir and rilpivirine?

And the study was designed, the CROWN study on those for superiority. It was going to be stopped if long-acting CAB/RPV looked like it was superior to oral ART, and indeed, CROWN met its primary endpoint, according to the press release. That long-acting CAB/RPV is superior to oral ART and those with viremia. Not shocking, based on all the demonstration projects that have been looking at this, including the Ward 86 data.

But to have RCT data is really important because now, when the DHHS and the IAS-USA and the WHO guidelines look at long-acting CAB/RPV, they can say we have grade A randomized controlled trial evidence that long-acting ART is superior in those with viremia than staying on oral ART and trying to force that to happen.

So, I will say that we only have a press release. Likely, it's going to be presented at an upcoming meeting in March. But I think it's - it's huge news, because we now have RCT data. So, I do think that it's true that: why do you want to switch? Yes, because you don't want actually someone to take oral ART off and on. That's going to be a setup for resistance. You don't want resistance because, of course, God forbid we have resistance to INSTIs.

Third is that it's terrible to have virologic nonsuppression in not only increases the risk of AIDS and AIDS related illnesses, but also not - inflammatory conditions and then you can transmit it. So, we have good reasons.

So, we have a question.

So, it's how do you use long-acting in patients with low-level viremia? And monthly dosing or every two months, and who do you give monthly dosing? Thank you.

Okay, I'll tell you what we do, and I want to hear what you do, but we used long-acting CAB/RPV. You know, in out of the context of the guidelines in 2021 at Ward 86, and when we started it with viremia, we wanted to be super careful, and we started with monthly dosing. So, why monthly dosing? CAB/RPV is approved in North America for monthly dosing, and we wanted to keep an eye on people. We wanted to see if their viral load was going down appropriately. For example, even the A5359, or LATITUDE study, looked at monthly dosing in those with adherence challenges, so we do it monthly.

Then if you're suppressed and you stay suppressed for, say, three months, then we'll go to every two-month dosing, and we're probably going to stick with that CROWN or not because it's been working for us and it feels like - it feels like we're following people more closely. What do you do?

Dr. Ogbuagu: Yeah, I totally agree with what you said. I think like some of the concern comes from ATLAS-2M, where they were a little bit of numerical differences between people where they compared to every eight weeks, every four weeks, there were numerical differences, but I'm not sure that that -

Dr. Gandhi: [Inaudible] failure in the, every two months in ATLAS-2M. 2.3% versus 1.4% in ATLAS [inaudible].

Dr. Ogbuagu: Exactly.

Dr. Gandhi: Perfect. Yeah.

Dr. Ogbuagu: Yes, yes. So - so I guess that drove some of the concern to have the monthly dosing for people who are viremic. I would argue, though, the low-level viremia is a whole different animal than people who have much higher viral loads, which are much more a stress test for the regimens. But again, I think CROWN starts to address that question with the bi-monthly dosing. And again, we don't have the data, like Monica said, so we don't have like the specifics, but it appears it did better as could be predicted. Even at that dosing frequency. So, I guess we just have -

Dr. Gandhi: To see rates every two months in the CROWN. I mean, as you just said, but just to really, really stress that point because those with adherence challenges and LATITUDE dose every month, and this is relevant to this question, but CROWN went ahead and did the every two months after the induction dosing.

Dr. Ogbuagu: Yeah. And I also wanted to flag this SUPLA study from Taiwan as well. I think that was published in CID as well. That's - for those of you who don't know about that, that was a study from Taiwan, where they also brought in people who were failing oral therapy and randomized them. They had a group that started immediately and a delayed group that started after 24 weeks, or six months. And they also showed higher rates of achieving virologic suppression in those who were randomized to the CAB/rilpivirine arm. And now outside the US, most individuals are using the medication every two months rather than monthly. And so, I think again, we'll see where the data heads from here.

Dr. Gandhi: And we have an international audience here. And I would say that every two months is basically what's available in most of the world. So, even Australia, UK, Europe, Canada. It's really that 600 mg of CAB, 900 mg of rilpivirine every two months that's available. We have this every four-week dosing in the US, but it's not everywhere. So, I think we may be getting towards every two months; we were being super conservative at the beginning.

And I do think we should address this question about low-level viremia, because you just said there's a - there's - that's an entirely other question. I want to ask you this; it's relevant to the question. We used to say that a viral load less than 50 because that's the - our lower limit of quantification in our lab is 30, but a 50 is suppressed. On long-acting ART, we changed, and we said less than 200.

And why did we do that in our program at Ward 86? One, to be consistent with World Health Organization guidelines, if they should never use less than 1,000 but, so less than 200. But beyond that, we were seeing some blips, and I want to ask you a question - and so did the Owen Clinic at UCSD reported this in their description of their long-acting ART program: that between 50 and 200, it seemed like it was happening sometimes with long-acting, probably because at the end of the dosing interval, you know, you have lower levels and then the virus can peak through. So, what do you use as your - as your threshold of undetectability on long-acting ART?

Dr. Ogbuagu: Yeah, I think, so we also have the same issue with low-level viremia. And I think we haven't let that necessarily change what we do. I mean, certainly individuals who are above 200, from a transmission standpoint, obviously, we all know less than 200 is A-OK based on PARTNER study and many of the other transmission studies. I think again, it's a heterogeneous group. I mean, some people who are with low-level viremia will maybe it's a signal of adherence issues, or no, at least in the oral ART era. But again, what it means in the context of on-time injections, I think, is less clear. But for now, you know, we are not really changing what we do with low-level viremia.

Navigating Barriers Related to Adherence

Dr. Ogbuagu: Monica, back to you. So, I think in pregnancy, right? Because I think you've looked at some again want to be careful about, you know, again, the, you know, data on safety and pregnancy again, is still accruing. And - and sometimes independently, right? Because we have CAB alone in the, and rilpivirine, it's kind of like a known entity, and the concerns around especially rilpivirine levels in pregnancy. I mean, I think again, most of us where we have someone who would do poorly on oral ART and viremia, if, you know, long-acting is what you have available and what will suppress the individual. I think many of us would not hesitate to use that even in pregnancy. You could see an argument there for monthly dosing. Again, you know, for better PK levels. So, that would be one group where again, I may want to consider that. I don't know if you agree, Monica, or not.

Dr. Gandhi: Oh yeah, I really agree. That is such a great point. So, what you're referring to is we have good data with CAB from HPTN 084, but alone that that works well. And you know, it's fine in pregnancy there're not safety issues. And then we have rilpivirine; we've used for a long time. But then we have this question of the levels of PK in pregnancy, with slightly lower levels. And we certainly saw that with oral rilpivirine.

So, all that means is that we absolutely just make that decision. We use CAB/RPV in pregnancy a lot, actually, here, because we have people who will present late and we just want to drive down their viral load, and they won't take oral ART - women. But we will use every four weeks, exactly like you said. And sometimes we'll even add lenacapavir. That's a - that's a whole other topic, but that's because we want to drive down the viral load as quickly as we can. We're actually seeing women sometimes, you know, can present to their second, third trimester. We want to reduce the risk of transmission to the fetus, and we will use CAB/RPV/LEN, drive down that viral load quickly, and then possibly take off the LEN.

And lenacapavir in the PURPOSE 1 studies, you know, there was lots of pregnancies, and looks really safe and effective. So yeah, we - we that's a really good point. That's the other situation, I think.

Complex Realities of Daily Adherence

Dr. Ogbuagu: All right, so let's move on here. Talking about the complex realities of daily adherence. And again, Monica, I'd love to hear, you know, you've done a lot of work in this area. And what I usually say is that, you know, I think as HIV providers, sometimes we focus on HIV, but we know we're having an ageing population, there's other comorbidities, but people also have lives, right? That are, you know, with all this interference with substance use.

It used to be that, at least in my practice, half of the people who we have some kind of mental health condition; about a third have a history of some kind of substance use problem. And I'm sure those percentages, you know, vary depending on where you practice. I mean, we're like in inner-city New Haven, and we also have quite a lot of people who struggle with both insurance, housing insecurity, food insecurity, and so many of all those other challenges that impact their ability to engage and remain in care and even take the ART.

And let's not forget a trauma history, right? Like, again, you know, people have been through many adverse life experiences growing up as children related to their sexual identity, related to, you know, their sexual practices, and all those things, right? And so, you know, the person coming to us many times, and these are not in silos, right? Many of them can interact together and can be really formidable challenges that people with HIV face.

And I think I would argue that if you look at a population that's struggling with adherence and coming in viremia, these proportions are going to be much higher relative just to the general population of people with HIV. And I think we always brag about HIV as being a field where we've learned like a whole-person approach to - to managing and treating people.

I think we've pioneered multidisciplinary care where we recognize that we need all these components right in our clinics to make sure that we can meet the really varied needs of people with HIV and not rule anybody out from treatment success. Right? And really take every of these barriers as a challenge that can be overcome. And actually, it's only limited by our imagination and our abilities to innovate, right? To be able to deliver successful treatments to these individuals. And I'm sure many of you on the program may interface with, you know, I guess what's not listed here could even be people who are incarcerated, right? You can, you know, expand this list extensively.

So, I guess bringing everything together again - that remember, we've said that, you know, some of these issues will need to be addressed, right? If we are going to successfully engage individuals with some of these challenges within injection programs, again, they have to show up. They have to get on-time injections. I know there's inherent adherence built into injectable strategies because people come to the clinic, right. And that allows us to monitor when their doses are and make sure they, you know - they come back again to receive the injection, like - like we cannot always do for oral ART. And we just wanted to - to highlight some of these.

Questions?

So we've talked about complexities, right? Of life, of people with HIV, the health challenges. And I think you have such ways, even just by how you've structured your clinic, you know what - what kind of provider types that you've been able to integrate, maybe how you've been able to engage, you know, communities with these challenges and get them successfully treated. And so, just why not just share some like nice nuggets with us about, you know, some of these aspects?

Dr. Gandhi: So yeah, in our clinic, and maybe this is typical for many Ryan White care-funded clinics, we have 46% substance use and about 48% homelessness; like, we are - we are high up there; we're in expensive San Francisco. And so, that all means that we did - before we had long-acting ART. It turned out that oral ART, there's some modelling that shows that you can do what it takes, but you may not get that - you're not going to get that rate of virologic suppression that we've seen with long-acting ART. Do what it takes, or things like incentives, or that patient-centered care, or that holistic approaches and relationships. Absolutely, that all helps with adherence.

Pill boxes coming in once a week and taking a once-a-week pill box. All those adherence interventions that have been studied for so long, but the most important aspect of that became that patient-centered care and everyone knowing you and hailing you when you come in, but still couldn't get those rates of virologic suppression, you know, where we wanted them until we got long-acting ART.

In our last look at the Ward 86 data, at least at 48 weeks was we literally got 98% of people suppressed on long-acting ART. Even when they started with viremia, it was 129 people this 370 total in our cohort. We published this last year in March: Spinelli et al.

So, really, just a 90% was not the 40 or 50 or maybe sometimes 60% that we could get with doing everything we can with oral ART. So, we became really convinced that long-acting ART for certain patients who have structural or individual barriers to taking oral ART was life-saving.

And there was some qualitative data around that too, that it's hard to convey, except if you get to talk to someone, and the qualitative data is there are people who have not been virologically suppressed forever, like they - since they started ART and that feeling of getting virologically suppressed, that you can just get that off your plate did bring people back. And so, that was the other surprising thing is we thought we'd be chasing people all over for their injections, but that's not what happened. Like no matter how hard life was to come in, once every two months after you get a reminder call seemed to work.

So we're gratified to be in this time in history. And then let's acknowledge, like you did at the beginning of this, that the access to long-acting ART worldwide is unacceptable, and - with CAB/RPV. And we gotta change that because we are now five years behind in most low- and middle-income countries to be able to get those medications.

Dr. Ogbuagu: Yeah. Thank you, Monica. So, interestingly, for the last question we asked where people were allowed to free text, there's two things I want to bring up here, which again, will be fascinating to get your thought about this. So, people again are just highlighting that they think there could still be adherence challenges with injectables, right? And I always say with pills adherence is taking them with injections is showing up, you know, for - for your injection and people still are concerned that people may still not return follow-up injections.

So, I guess I want to talk about the incentives, right? So, I know for LATITUDE, people got conditional economic incentives. Right? And that was one way to - again, of course, it was during the phase where there were no oral therapy. But that said, just incentives in general as being something that drives people to show up.

So, for - for people who may still struggle with coming back, are there innovative ways that you found beyond just, you know, someone keeping a calendar, of course, giving a call this low-hanging fruit, right? I mean, that's what we should do, right? You should have a dedicated individual in the practice who keeps a calendar and makes sure people come in with their injection windows. But are there other ways? I mean, I guess we can provide transportation if that's a challenge some people have, but what do you think about incentives? Do they work, and have you used them?

Dr. Gandhi: Yeah, it's a great question because, so taking a step back, what you just said, someone keeping track. That's our pharmacist, so I just really want to like tout the role of the pharmacist in long-acting ART programs. Because our - our supervising pharmacist leads the program, and then a pharm tech is assigned to this program, and they are the ones doing the reminder calls a week before, or a text the week before the injections do, and then the day of.

So, we don't take it out of the fridge; CAB/RPV has to be refrigerated. At least rilpivirine does, and it comes, but the CAB we just stick in the fridge, but we'll take it out of the fridge and warm it up so that we can give it warmer, you know, and not have the pain of the cold injection.

So, those reminder texts or calls is one huge part of it. But I will say that we do give incentives. So, we give $10 gift cards. It's not that much, and everyone can calculate that for their setting, but it's not very much, but it does bring people in.

And then the third aspect to get people in is relationships. And what I mean by that is it's always the same nurses who are injecting it. It's a teeny team; it's three people. We probably give 20 injections a day at Ward 86, but it's always the same three people. And that means that - that becomes a relationship.

And in any DCE, you know, discrete choice experiment, we did this with our pop-up clinic, which are people experiencing homelessness. In the DCE, we said, "Do you want higher incentives, or do you want the same people that you see every day?" And they said, "We want the same people." Because it was relationships. So, I've been surprised by the relationships.

And then I will say one final thing. There are some people we chase around the city, and we have a street medicine program that we interact with, and they will give the injections for some people who are very triggered of coming to a brick-and-mortar clinic in the shelter or in the SRO single-residency occupancy hotel. And in the case of once a month, there's a parking lot at this low kind of budget grocery store, and they will come for their injections there're in a mobile van.

Dr. Ogbuagu: Yeah. And just - that's wonderful. Monica. And just for those of you who are abroad. Right. So, I do work in Africa, and I think, you know, for Liberia, for example, there are ways you - you can provide other incentives, for example, their food programs, which is great because it's a two-for-one deal. You're giving people medication to treat HIV, but where there's, you know, food insecurity, you're meeting kind of two needs at the same time, same thing. Partners In Health does in Rwanda, for example, right?

So, you can always customize your incentive, and many times you're solving more problems than one with things that you offer. People what - they come in. So, I think we can all be creative, right? With finding ways to - to incentivize people to come in for their shots.

Now, Monica, here's a tricky question. So, someone's asking about hemophilia, right? Recognizing that at least the long-acting drugs that are approved now are injectables. Right? So, I guess it doesn't matter sub-q IM, but hemophilia, and I would even add to that. What if people are like full on anticoagulation, at risk of bleeding?

I know in the clinical trials of injectables, we tend to exclude individuals with bleeding diatheses, or even sometimes very low platelets, because you can always imagine that these are invasive delivery methods that could.

So, I think I can take this, and I would say again, the different kinds of bleeding diathesis some are a little more risk than others, but I think this might be an issue. Thankfully, we have long-acting orals coming down the pike, right? So, I don't think this precludes long-acting for everyone. Okay -

Dr. Gandhi: And I would also remind us of, like, what is the actual volume and how much is injected, and how that works. So, cabotegravir/rilpivirine, it's a 3-ml volume for each injection, and they're given intramuscularly. So, a flu shot, for example, of course, is given intramuscularly, but it's a much lower volume. And so, think about the volume when you inject, and IM shots, usually for people on anticoagulation that's routine is usually tolerated. And then the subcutaneous, but not with bleeding diathesis, something that's worse.

And then - and then the subcutaneous formulation of lenacapavir is two 1.5 ml injections to get to a total of 927 mg. And it's given right under the skin. It's given as a subcutaneous injection. Don't go dermal that will hurt, and you want to actually give it 90 degrees angle; that gives us less pain, and we give ice before it.

But it is really a subcutaneous injection despite the fact that it's pretty big volume 1.5 ml, 1.5 ml. And there is nodule formation, so I look again; we do have absolute, since we have so many people on these drugs in our clinic, we do have people on that anti - oral anticoagulants. But - but with hemophilia, I would. Yeah, you're right. They've been excluded from the trials, and I would think about it.

And then you alluded to once a week because you were really instrumental in generating that data. And we should just, yeah, remind ourselves that. Islatravir/lenacapavir once a week, all in one, and two studies presented in Rio, but that's exciting that we're going to get those oral once a week.

Dr. Ogbuagu: All right. So, Monica, go ahead.

Implementing Support for Long-Acting ART: Faculty Discussion

Dr. Gandhi: Yeah so, we in terms of like the actual implementation of this, so we talked about already how we support what you can say is the clinic visit, and that's the definition of adherence to come in to do the long-acting, and we support that by a call once the week before and then the day of that morning.

The problem is that managing missed doses. There is one issue here. Like, let's remember that there's an induction dose. So, there's - they actually both need induction doses. So, if you think about cabotegravir/rilpivirine, how it started is it's a 600-milligram dose of cabotegravir and 900 milligram of rilpivirine on day zero.

Then, four weeks later, you give an induction dose that's called 600, 900 weeks later, and then you can go to that every eight weeks, 600, 900 every eight weeks. But if you miss for long enough, then you are going to need a repeat induction. You're going to need another dose at four weeks of CAB/RPV, and same with LEN; it needs - well, how does it need induction? It's induction; it's not subcutaneous. It's an oral pill: 600 mg on day zero, 600 mg, two 300-milligram tablets on day one. And you give that day zero 927 mg.

So, if you go past, you know what, we think that is kind of a normal ability to go to late. For example, we - the trials looked at seven days. You could miss seven days of CAB/RPV, week late, and 14 days with lenacapavir. If you go too long and you miss a dose, we have to reinduce.

So, we have a protocol for that. And the protocol is super easy because you just have to write into Google "San Francisco getting to zero Ward 86 long-acting ART protocol." And we have a whole document exactly how to manage missed doses.

And then finally, continuity of care. I will say again that people get excited when they get virologically suppressed for the first time, even if there's lots of challenges. And we've been surprised that we that has been really a self-motivator. And then again, I think it's the relationships that matter when it's the same nurse, and you get to see that same nurse every time.

Questions

Dr. Ogbuagu: Yeah. So, Monica, we're having, yeah, interesting questions come in, so I'll throw this back at you. So, oral bridging, right? So, you talked about oral loading, which is again that extra dose for, you know, LEN, for example, and even CAB/rilpivirine, right? Those first two doses happened one month apart. And then you can decide if you're doing monthly or bi-monthly, right. And that's all to get those - those drug levels where they should be earlier on.

And I must say that the oral loading is critical to achieving levels. It's very critical. I mean, studies have shown if you - if you don't do oral loading, for example, with LEN, you may have therapeutic levels four to six weeks down the road. Right? It's that far out. So, again, want to emphasize that.

And so, oral bridging, I feel like it's something that's not fully developed, and I think can be useful. You know, I have people who travel, you know - you know, who may go to Europe, I guess from the US, and have this long experience times, and their injection falls right in there. Some people have changing jobs and really can't even show up at their pre-scheduled injection visit.

So, how do you use oral bridging, and not just a how have you used it, but what do you even use to bridge? Right. I mean, we know their oral CAB/rilpivirine formation - formulations, right, but - and those were looked at in LATA, right? I think some of those older studies, but we don't really have them available. I've had people who have their old regimens that they were taking before we transitioned them and have some pill bottles left. Should you just use anything?

So, what's been your experience? Because I know you have a lot of people on these long-acting therapies. How has oral bridging come in - in your practice?

Dr. Gandhi: Yeah, I totally think this is a great question because I will just say that we never bridge with cabotegravir/rilpivirine oral. Why? Because it's two different pills, and also CAB and RPV, sort of by themselves, haven't - doesn't - don't have the highest genetic barrier to resistance. So, we would never use what was studied in the trials of oral bridging with CAB and RPV; we bridge with something strong like BIC/TAF/FTC, or darunavir/cobi/TAF/FTC. Something high genetic barrier, mostly BIC/TAF/FTC. So -

Dr. Ogbuagu: Cabotegravir/rilpivirine sounds tempting, right?

Dr. Gandhi: Yeah. Yeah, exactly. Yes. Because dolutegravir/rilpivirine looks exactly like CAB/RPV. But even that, like, we don't want the food issues. We're really just kind of going something kind of high dose, but I will say that - that you can't stress enough what you just said, how important that oral loading dose of LEN is.

And this is a really important question: what about leaking LEN from the injection site? Because, okay, just remind ourselves this is super bright liquid, it's bright yellow, it is oily, it is thick, it is viscous; that's what can cause the inflammatory reaction. It's a foreign body granulomatous reaction that causes the nodules, and you inject it, and it can leak out. And - and you inject it in two different places. And the package insert actually says, if one of those gauze is soaked, it means it's leaked out enough that you would reload. That's when you would give that second dose of - or you'd give the oral loading dose.

So, I have to say that's really surprising - and surprising to me that we're kind of on, I think, 1.0 formulations. We need, like, less oily, less thick, less viscous, less leaking out, but what do you do? Yeah. Like, when do you think too much leakage is enough? Like, do you wait for soaking? What do you do?

Dr. Ogbuagu: Yeah. Good point, I think, yeah. So, the Z-track technique, right? So, where you like pull the skin, so keep it in tension and inject, and then you release, and that should release some backflow. I don't know; I feel that works better, IM, than sub-q, to be honest, but I think that - that's, you know, given that there's not that much tissue between - when the entry site and where you're releasing the depot of the drug. But yeah, I think sometimes that can be - I - but I agree, like if you have sufficient backflow, you have a soaked gauze, you may want to consider doing that.

I think the therapeutic index for lenacapavir is quite wide. So, even if, let's say, you're giving them a supplemental dose and you're worried about higher levels, I think it should probably still occur safely.

I guess the other part of your question is, I think also interfaces with a question about oral bridging, right? So, like Monica said, the - the window is plus/minus two weeks for your next LEN injection. And certainly, if someone's missed it more than two weeks, then you probably still want to give the injection along with an oral loading with the 300 mg, two tablets of dose on day one and two tablets also on day two when you've gone past that injection window. So, I hope that answers your question.

Dr. Gandhi: And then this is a really good question because what we just said, is actually most countries do not have the lower dosage of CAB/RPV, right? Like, so the 400, 600 like they are the 600, 900. And so, what could you do if you want to use monthly dosing? You actually could divide by, you know, give less of the injection, right? Like, so rilpivirine is 900. If you want to give 600, you can give two-thirds of the dose. And same thing with CAB; you can give two-thirds of the dose.

And then I will say that there's really no harm, especially if you're inducing someone, because I've really looked at the - the levels of giving 600, 900 every month, that higher dose for a three/four months that there's quite a large therapeutic index, meaning, yeah, it's not likely to give you very high levels and/or two crazy of levels. And you could just do that if you want to give the whole injection, but/or you could back-calculate and give two-thirds. What do you think?

Dr. Ogbuagu: I don't disagree at all. I mean, I think it's just innovative use of - of what we have. Yeah.

Dr. Gandhi: Yeah. Okay. And then I think those were such excellent questions.

But I wanted to say that I just went to Yale for, like, one of the first times last week, and I would be curious about your - in your clinic population. This has been really fascinating to me that we started with the FLAIR, ATLAS, ATLAS-2M studies that only looked at it in those with virologic suppression, and that's how the world started.

And now in the United States, I keep on hearing from multiple centers that it is almost standard to say, okay, I'm going to use it in those with adherence challenges. The A5359 study showed us, even with viremia, the CROWN study is going to be presented. I - guidelines are going to change; it's going to be grade A recommendation to using viremia instead of grade B.

What is your practice, and when did you switch over from saying I am fine using with viremia?

Dr. Ogbuagu: Yeah. So, I will say different practices have their own different cultures. We tend to be early - early adopters of innovative approaches for that. I mean, I think we celebrated some of the moments when you presented some data, right? About how, you know, impactful injectables can be for those who are struggling oral therapy. So, I think we've - really have used this off-label for individuals who are struggling with adherence. I think, and we've done it with many other long-acting ART, right? Remember, we haven't talked much about lenacapavir and ibalizumab, especially where people may have resistance mostly to RPV, then CAB. So, we've also had to like, mix and match and come up with ways to suppress individuals.

You know, one patient easily comes to mind who I've had for almost two decades. I mean, clearly wouldn't take any oral regimen and had accrued multiple resistance mutations, including to rilpivirine, and I couldn't offer - offer that, and you know, so we use a lot of LEN and CAB in that context. Again, LEN is approved for that indication, but again, CAB not in that sense. And it's nice to see the data emerging from so many other centers that people are doing the same thing.

So, I think it's nice to finally have the evidence catch up to what we were actually already doing in clinical practice. Now, of course, it's not always easy with getting insurance approvals. But we have a lot of support from our clinical pharmacists who helps us navigate very challenging scenarios to make sure that we - we get the medications and, you know, for many individuals, this can be life-saving, right? I mean, many of these individuals are literally going to get an OI or even just die within a year or more if we don't treat them. So, we've seen it, you know, really work like magic.

And I think he said something, Monica, that again, many of my patients in our group of patients who we have to do these strategies for, we've started to achieve suppression in people who've never had suppression before or not had suppression in a decade or two. And it's just a wonderful feeling to see that occur.

Dr. Gandhi: Yeah, and I just do want to mention, like, because you brought it up is LEN/CAB is I will say that there are some centers and Ponce Clinic. I'll give you an example in Grady, who's just kind of made this decision that if the viral load is high above 100,000, they will actually start CAB/RPV and LEN drive down that viral load even if they don't have resistance mutations, by the way, and then go ahead and do CAB/RPV because, again, we didn't have the randomized control trial data in those with viremia.

Now, I think when we see the CROWN presentation, if we have enough people, over 100,000 enough people - over 500,000, let's see, we have no idea what the actual starting viral loads were. Maybe we'll be more comfortable with just CAB/RPV as - as but they've been using that CAB/RPV/LEN as an induction.

And then the LEN/CAB data that we have out there is just case series. It's actually really surprising we haven't been able to launch yet a trial. It's going to happen, but - but this it's been challenging times these days. And all that challenge means that we don't yet have the trials off the ground to look at lenacapavir and cabotegravir in the setting of NNRTI resistance in an RCT way.

So, this just got published on October 8th. So, it's 46 people from what 86 in Jama Network Open on LEN/CAB, and they all had it - and almost all of them had an NNRTI resistance. Half of them started with viremia, and they stayed. They got suppressed within 15 weeks, really quickly, and they stayed suppressed for 100 weeks and counting. So, LEN/CAB together seemed to be powerful, at least with NNRTI resistance. And what you just said makes so much sense. We're doing it off-label because it makes sense. If you have NNRTI resistance, you don't want to use rilpivirine. It just makes sense, but then we have to remember that LEN is six months and CAB is every two months. So, think about how to remind people of that asynchronous dosing.

Dr. Ogbuagu: Yeah. And let's try and reassure our audience. Right? I think rightfully so. I mean, people are concerned, you know, CAB isn't dolutegravir/BIC, right? I mean, we know it's not the highest barrier INSTI, and of course, people sometimes get worried if people don't show up for their - their thing, you know, rebound during the PK tail, right? There can be drug resistance implications.

But I think we're in a different era. I think, you know, we saw, you know, a non-INSTI regimen or ISL, right? Come out earlier this year. We have BIC/LEN; you know, I think BIC can still pull its weight even if there is, like, first-degree and first-generation INSTI resistance; there will be LEN/ISL that uses no entities whatsoever. Right?

So, I think we're in an era where, first of all, we need to treat these individuals with injectables, but even in places where we don't achieve success and, of course, where there's resistance that made us worry about their candidacy for, let's say, oral INSTI-based regimens, I think the future is bright with options that, in a funny way, actually simplified options, right? Sometimes single-tablet regimens, small pills, or even weekly oral regimen. Again, one be careful here that many of these have not been studied in virologic BIC/LEN certainly hasn't DOR/ISL has been in treatment naive and a small study for people with multidrug-resistant HIV.

But again, I think again, we have more tools in our arsenal in the face of potential first-gen INSTI resistance that are kind of injectable. So, I would say let's not be afraid to try it again. And I think that the populations are using this for actually; it's not a luxury like some of them really need this to get them, sometimes for the first time, achieving treatment success.

Dr. Gandhi: It's such a good point because we always used to have only darunavir. You know, it's like that was it. Like, if you fail, CAB/RPV, you have to be on a darunavir-based regimen. And darunavir is good, but there's drug-drug interactions, and there's rifampin and TB and all that.

And then you just brought up that LEN really two drugs really changed that, that it always has to be darunavir, which is LEN. And now we have BIC/LEN at least in the United States. And then we have islatravir, which is a whole new class of drugs, and NRTTIs, and that's a whole thing for once a week.

I think your once-a-week data is extremely exciting on the ISLEND-2, and we have ISLEND-1 and - but you just said it. We also need to study islatravir/lenacapavir and those with adherence challenges. We always get the data first in those who are switching over when they're doing final and oral ART. But to really stress the drug, you need to see if those with adherence challenges and/or viremia. So, we need to generate that data, but yeah, it's a very - it's both an exciting time. And then I think you have to - we have to acknowledge the sobering what you said at the very beginning, that everything we're talking about - islatravir/doravirine, bictegravir/lenacapavir, and then maybe soon islatravir/lenacapavir once a week - is getting available in high-income countries first. And we have to work as a HIV community to change that access issue.

Dr. Ogbuagu: Monica, I'll give you the last word as we thank the audience for being wonderful and interactive with us today. And of course, on my end, thank you to you because it's always a pleasure doing this kind of program with you. And I really want to appreciate the - the leading efforts you've taken for this population. I think you've driven some of the early impactful data on this that's galvanized the field to - to look at long-acting injectables in - in a life-saving way for - for the people that we treat.

Dr. Gandhi: So, no, thank you so much. And I really appreciate all your great work. And I have to say, we - you and I both have an interest in pharmacology, and that matters with long-acting ART. So, as we go forward, you know, the pharmacists are incredibly important to us. And so, thank you, everyone, for joining us for this program.