Michael Saag, MD: Hello. I'm Dr. Michael Saag and welcome to Medscape In Discussion: HIV. Today we're talking about new therapies for HIV.
We picked this topic because it's important to know what's emerging on the horizon of HIV therapeutics. Here's a case to illustrate. A 29-year-old man was diagnosed with HIV 6 years ago. His viral load is undetectable, but he complains that it is hard for him to keep up with taking pills every day. He asked if there are any long-acting treatments that he might be able to take.
The guest today is Dr. Judith Currier, who's professor of medicine and director of the infectious disease division at UCLA in Los Angeles. Judy is an accomplished HIV investigator and currently leads the AIDS Clinical Trials Group, or ACTG, the most established HIV trials group in the world. As such, she is well-versed in the emerging treatment options and the new regimens. Welcome, Judy.
Judith Currier, MD: Thanks, Mike. It's great to be here with you today.
Saag: So to get us started, can you briefly describe a scene early in your career where you realized that you were going to dedicate a large portion of your career to the treatment of HIV?Currier: I guess I would think about the time during my residency in the late 1980s in Boston, taking care of people being diagnosed with HIV at a time when we really didn't have any treatment. There was such a need to help figure out how we were going to care for people and how we were going to treat them, and what would be the best ways to manage this disease. So it just seemed like such an important question at the time. It wasn't a conscious choice. I just felt like, this is what I need to do because there's so much need for it right now.
Saag: I had the same type of experience, and when we look back on the past 40 years since then, it's pretty amazing what's happened. Now we have more than enough treatments there. All, especially the recent ones, are very potent and pretty well tolerated, and it's one pill once a day in many cases. So the question then becomes related to the day's topic: Why do we need more treatments?
Currier: It's a great question. I was thinking about the case that you mentioned, the 29-year-old diagnosed 6 years ago. So this is someone who was diagnosed as a young adult and has probably been on a single-tablet regimen the whole time they've had HIV — one pill once a day. For a lot of people, the regimens that we have today really meet their needs and they do very well on them. There are other people for whom the daily reminder of taking a pill — the stigma of HIV — is something we haven't made as much progress in treating as we have the underlying disease. And for some people, that is a reminder that they're living with HIV.
They have to take a pill every day, and the idea that they might be able to do something less frequently is sort of psychologically very, very appealing. So, I think that new treatments are needed just to reduce the burden of the requirement for daily pills. That's one thing. There are still some people who have not been able to be fully suppressed with the regimens we have.
So we still need new drugs for treating the drug-resistant virus, although that's much less of a problem than it was even 5, 10 years ago, for sure. And until we have a cure, people are going to take these drugs for decades. So we do still have some residual side effects of treatment or adverse events that still occur and people who, for different reasons, are not able to tolerate the regimens that we have. So while we've made extraordinary progress, I think there is still some room for improvement.
Saag: Right. And the guy in the case, he's not taking any other medicine, so a long-acting medicine would basically enable this guy to not take anything at all. The people who are more like 50 or 60 years old, they're on a lipid-lowering agent, they're on blood pressure medicine, maybe diabetes medicine. The need for eliminating one pill once a day isn't quite as great. Do you have people like I just described — in the older group who were on the other medicines, who also want something that doesn't remind them of their HIV daily?
Currier: I just have not been able to predict who is going to want long-acting therapy. And I think the studies of the first approved long-acting therapy, the cabotegravir/rilpivirine combination, were really informative regarding the quality of life. I think a lot of clinicians were not convinced that people would want to take something once a month, an injection once a month, or once every 2 months.
Saag: Right. And the guy in the case, he's not taking any other medicine, so a long-acting medicine would basically enable this guy to not take anything at all. The people who are more like 50 or 60 years old, they're on a lipid-lowering agent, they're on blood pressure medicine, maybe diabetes medicine. The need for eliminating one pill once a day isn't quite as great. Do you have people like I just described — in the older group who were on the other medicines, who also want something that doesn't remind them of their HIV daily?
Currier: I just have not been able to predict who is going to want long-acting therapy. And I think the studies of the first approved long-acting therapy, the cabotegravir/rilpivirine combination, were really informative regarding the quality of life. I think a lot of clinicians were not convinced that people would want to take something once a month, an injection once a month, or once every 2 months.
But the studies just really bore out so clearly that at least people who joined the studies reported such improvement in their quality of life for taking medication less often. So I find that it's really hard to predict who's going to want this and who's not. A lot of people just say, "No, I'm fine with my one pill once a day. I wouldn't want to have to come in once a month or once every 2 months and get a shot. I don't like needles, I don't like shots." For other people, it would be life-changing. So it's really an individual preference.
Saag: So to summarize the options, it's not one-size-fits-all. People have different feelings about what they want to do in terms of their antiretroviral therapy, so that alone is probably a good enough reason to keep looking for new therapies. You mentioned the cabotegravir/rilpivirine combination. What are the pros and cons of that combination in the injection every other month?
Currier: The main issue is that these treatments — the integrase inhibitor cabotegravir and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine — have been studied and are effective in people who were already suppressed on treatment. So that's a really, really important caveat because a lot of times we think about long-acting treatments. This is the ideal thing to do for people who can't take a daily pill.
Saag: So to summarize the options, it's not one-size-fits-all. People have different feelings about what they want to do in terms of their antiretroviral therapy, so that alone is probably a good enough reason to keep looking for new therapies. You mentioned the cabotegravir/rilpivirine combination. What are the pros and cons of that combination in the injection every other month?
Currier: The main issue is that these treatments — the integrase inhibitor cabotegravir and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine — have been studied and are effective in people who were already suppressed on treatment. So that's a really, really important caveat because a lot of times we think about long-acting treatments. This is the ideal thing to do for people who can't take a daily pill.
Right now, all the data we have are in people who were either already suppressed or got suppressed and then switched over. So it's a two-drug regimen, and we've seen a lot of data that two-drug regimens can be effective, but it doesn't include any drugs that are active against hepatitis B, so people who have hepatitis B can't use this therapy.
Some studies are going on to try to determine how to best use these drugs in people who have not yet achieved viral suppression. But at the current time, we don't have data to support that, and the concern is that it could lead to resistance to the integrase class, which would be important. And some of the people who are unable to be suppressed could be harboring resistance to the NNRTI. So more work is needed to really figure out how to best use this new option in people who have not been able to obtain viral suppression with current treatments.
But people who are suppressed can switch over. And initially, it was approved with an oral lead-in for a month to take the pill forms of the medications and then switch over to the injections. But now data are suggesting that we might be able to just go directly to the injections and not have to do the oral lead-in. You know, I think people may vary in whether they'd like to do that or if they want to first see if they have any side effects before they take an injection. That's going to last a couple of months. But that's great to have that flexibility.
Saag: They call that direct-to-inject. What about the volume of the injection, and is that a barrier?
Currier: I think that's also really interpatient variability. They didn't have a lot of people in the studies who dropped out because of their inability to tolerate the injections. And the other thing that's been great is that they continued to present data in 2, 3, and 4 years of follow-up to show that it's not a problem that gets worse over time. You might think that you do okay for the first year, but then you run out of canvas there to inject into. It does not seem to be an issue with people not being able to tolerate it over time. So that's reassuring to see.
Saag: And the resistance that's been seen is less than 1%. The concern, as you mentioned, is that it is an integrase inhibitor — the cabotegravir — and it's very closely related chemically to dolutegravir. So there would be cross-resistance if that were to happen.
Currier: Yeah, and the other big thing has been, operationally, how to make this available. This is something we've really struggled with in our clinic: how to set this up. If your clinic is a freestanding clinic that doesn't have a pharmacy in the building, you know that the patient has to get the medication or you have to get it delivered to your clinic. In some settings, that means the clinic buys the medication and then they figure out how to get reimbursed for it. How are we going to operationalize this new treatment when we get it and it's starting to come together? There's certainly been a delay.
Saag: So that means that it's an important step forward. It does create the ability to have administration just six times a year or so. What are some of the other long-acting drugs that you see on the horizon that you're excited about theoretically, but for which there still may be some issues?
Currier: There was a lot of excitement about two drugs in development, islatravir, and lenacapavir. Both kind of hit speed bumps in the drug development pathway. The development of islatravir, which is being studied as both an oral and a long-acting formulation, was put on hold earlier this year due to some decreases in lymphocyte counts in the people taking the medication on trials both for prevention and treatment. So [the researchers] are kind of going back to the drawing boards and trying to understand the mechanism of this decrease — and whether it's dose-related and the potential ways around it. But there was a lot of excitement about being able to use it as a long-acting treatment.
The other drug that was in development — and these announcements came out just a week apart — is lenacapavir, which is a capsid inhibitor that can be given subcutaneously (subQ) every 6 months, which is a really exciting development. Obviously, you have to pair it with something else. But that drug also was put on hold by the FDA, not because of direct drug toxicity; my understanding is that it was due to something with the packaging or formulation in the tubes in which it was being delivered. I think they're going to be able to work around that.
Saag: They call that direct-to-inject. What about the volume of the injection, and is that a barrier?
Currier: I think that's also really interpatient variability. They didn't have a lot of people in the studies who dropped out because of their inability to tolerate the injections. And the other thing that's been great is that they continued to present data in 2, 3, and 4 years of follow-up to show that it's not a problem that gets worse over time. You might think that you do okay for the first year, but then you run out of canvas there to inject into. It does not seem to be an issue with people not being able to tolerate it over time. So that's reassuring to see.
Saag: And the resistance that's been seen is less than 1%. The concern, as you mentioned, is that it is an integrase inhibitor — the cabotegravir — and it's very closely related chemically to dolutegravir. So there would be cross-resistance if that were to happen.
Currier: Yeah, and the other big thing has been, operationally, how to make this available. This is something we've really struggled with in our clinic: how to set this up. If your clinic is a freestanding clinic that doesn't have a pharmacy in the building, you know that the patient has to get the medication or you have to get it delivered to your clinic. In some settings, that means the clinic buys the medication and then they figure out how to get reimbursed for it. How are we going to operationalize this new treatment when we get it and it's starting to come together? There's certainly been a delay.
Saag: So that means that it's an important step forward. It does create the ability to have administration just six times a year or so. What are some of the other long-acting drugs that you see on the horizon that you're excited about theoretically, but for which there still may be some issues?
Currier: There was a lot of excitement about two drugs in development, islatravir, and lenacapavir. Both kind of hit speed bumps in the drug development pathway. The development of islatravir, which is being studied as both an oral and a long-acting formulation, was put on hold earlier this year due to some decreases in lymphocyte counts in the people taking the medication on trials both for prevention and treatment. So [the researchers] are kind of going back to the drawing boards and trying to understand the mechanism of this decrease — and whether it's dose-related and the potential ways around it. But there was a lot of excitement about being able to use it as a long-acting treatment.
The other drug that was in development — and these announcements came out just a week apart — is lenacapavir, which is a capsid inhibitor that can be given subcutaneously (subQ) every 6 months, which is a really exciting development. Obviously, you have to pair it with something else. But that drug also was put on hold by the FDA, not because of direct drug toxicity; my understanding is that it was due to something with the packaging or formulation in the tubes in which it was being delivered. I think they're going to be able to work around that.
But it's delayed, the ability to get more data about users in people who either have not been on treatment before or — most important — for those who've been on treatment and want to switch to something long-acting. So we had a little bit of a setback in the past few months when it comes to long-acting formulations, but I think we'll get back on track soon.
Saag: We've been spoiled a lot by the smoothness, for lack of a better word, of how drug development has gone in the past two decades. A lot of the drugs just kind of went right through. There were a couple of bumps in the road, but getting to these holds within a week of one another sort of points out, like Third Eye Blind would say, that we were leading a semi-charmed kind of life. The other thing that I want to go back to is the mechanisms of how these drugs work. Islatravir is a nucleoside translocation inhibitor, which for me to explain to people — I really need to use my hands because it's how the nucleosides are built into the growing DNA chamber, a little bit different than what traditional nucleoside agents do.
Saag: We've been spoiled a lot by the smoothness, for lack of a better word, of how drug development has gone in the past two decades. A lot of the drugs just kind of went right through. There were a couple of bumps in the road, but getting to these holds within a week of one another sort of points out, like Third Eye Blind would say, that we were leading a semi-charmed kind of life. The other thing that I want to go back to is the mechanisms of how these drugs work. Islatravir is a nucleoside translocation inhibitor, which for me to explain to people — I really need to use my hands because it's how the nucleosides are built into the growing DNA chamber, a little bit different than what traditional nucleoside agents do.
On a podcast, it's hard to wave our hands around, but what's important for folks to realize is that it is in that sort of reverse transcriptase activity of the lifecycle of the virus. The capsid inhibitors are really interesting because they involve the carrying of the virus from the cytoplasm inside of a capsid into the nucleus through these nuclear pores. And that appears to have two mechanisms of action.
Currier: Islatravir — the nucleoside reverse transcriptase (RT) translocation inhibitor — also basically prevents the opening of the RT nucleoside binding site. And it also changes the structures so that the viral replication is inhibited because it sort of blocks that. But when drugs have more than one site of action, it gives us hope that the development of resistance will be mitigated to some extent. What's interesting about these drugs is that they come in different formulations.
Currier: Islatravir — the nucleoside reverse transcriptase (RT) translocation inhibitor — also basically prevents the opening of the RT nucleoside binding site. And it also changes the structures so that the viral replication is inhibited because it sort of blocks that. But when drugs have more than one site of action, it gives us hope that the development of resistance will be mitigated to some extent. What's interesting about these drugs is that they come in different formulations.
Islatravir was being studied once daily, once weekly, and then once a month, and they were also working on an implant. So that's exciting that different formulations of the drug were also being studied together in a single tablet. It's made by Merck, with their other drug, the NNRTI doravirine. But as we just talked about, unfortunately, it was put on hold. Lenacapavir also was being studied as an oral as well as a subQ formulation, and I think the subQ formulation's half-life was something like 175 days. So it could be given every 6 months, but we have to figure out what we're going to use together because a single agent is not going to be sufficient to maintain viral suppression.
Saag: Even with the double sites of activity, my first thought was, Wow, we might get away with single-drug therapy, but the preclinical development says you still might get resistance. But it might just be two drugs, sort of like cabotegravir and rilpivirine.
Let's talk about another thing you mentioned: doravirine, which is already released and on the market. That's an NNRTI. That is a little bit more resistant to the development of resistance. But what about other things like monoclonal antibodies or neutralizing antibodies that we've seen? What kind of studies do you all have going on that?
Currier: The broadly neutralizing antibodies against HIV is a really exciting area of research, and I think the COVID pandemic really opened people's eyes to the potential therapeutic value of antibodies for treatment that is given by infusion and long-acting antibodies. And we've seen the benefits and the limitations where they can be very active. But when the virus mutates it can develop resistance. There are several different antibodies in development, and they all target different parts of the virus — the CD4 binding site or different parts of gp120 and gp41 and other parts of the virus. And they're now also being formulated to be long-acting so they could be given as an infusion and potentially as a subQ delivery but can stay around for 4-6 months.
Saag: Even with the double sites of activity, my first thought was, Wow, we might get away with single-drug therapy, but the preclinical development says you still might get resistance. But it might just be two drugs, sort of like cabotegravir and rilpivirine.
Let's talk about another thing you mentioned: doravirine, which is already released and on the market. That's an NNRTI. That is a little bit more resistant to the development of resistance. But what about other things like monoclonal antibodies or neutralizing antibodies that we've seen? What kind of studies do you all have going on that?
Currier: The broadly neutralizing antibodies against HIV is a really exciting area of research, and I think the COVID pandemic really opened people's eyes to the potential therapeutic value of antibodies for treatment that is given by infusion and long-acting antibodies. And we've seen the benefits and the limitations where they can be very active. But when the virus mutates it can develop resistance. There are several different antibodies in development, and they all target different parts of the virus — the CD4 binding site or different parts of gp120 and gp41 and other parts of the virus. And they're now also being formulated to be long-acting so they could be given as an infusion and potentially as a subQ delivery but can stay around for 4-6 months.
So, combining a couple of different long-acting antibodies is a potential therapeutic option. In the AIDS Clinical Trials Group, we're doing one study that's looking at a combination of the long-acting cabotegravir with a broadly neutralizing antibody called VRC07-LS. We're also doing a study with two long-acting antibodies that will be given together to people who are already suppressed on treatment with oral tablets. Then they get the infusions of the two antibodies, and then they'll stop the oral treatment to see whether the antibodies together can maintain viral suppression.
So these are exciting ways of thinking about how we might incorporate long-acting antibodies into treatment regimens. As we were just talking about before, you need more than one compound at a time. I think it's really hard if you have one part of your treatment regimen that you get every 6 months and maybe another one that you have to take every day. But it may be that there are ways that we can make these combinations work for people.
Saag: Sort of like long-acting and short-acting insulin.
Currier: Right — exactly, exactly. That's a good analogy.
Saag: The other thing about the broadly neutralizing antibodies — and correct me if I'm wrong — was that part of the reason they were being sought initially was to see which of those antibodies would protect against a challenge as prevention, and with the hope that once they know the structure of the monoclonal or the broadly neutralizing antibody, they could design vaccine products that could induce the immune system to produce that type of thing. Is that your understanding as well?
Currier: The antibodies have been looked at for prevention. There was the AMP trial that studied this as prevention, and the fields are coming together to some extent because it's true that you could learn more quickly about how the virus escapes these antibodies in somebody who already has HIV rather than waiting for it it someone to get infected after exposure. So the user has been looked at, both for prevention and potentially for treatment. And we just have to see whether we can get formulations that could be safely delivered and be long-acting and maintain viral suppression. I think it's really exciting for both prevention and treatment.
Saag: I want to underscore something you said earlier about how much we learned about these antibodies during COVID, not just for treatment but also for prevention. New products, like Evusheld, as we've discovered, actually can have protection when given subQ for up to 6 months, and that's a very exciting thing. Maybe we'll see that with HIV.
As I expected, our time is running out quickly. I want to return to our case. Let's say it was 3 years from now. What do you think is going to be available, considering all these products we talked about? What's the future going to look like?
Currier: I think we're going to continue to have single-tablet regimens that people can take, and a lot of people will maintain viral suppression and do very well. And then I think we'll have some additional options for long-acting therapy — hopefully oral and not requiring injection, not requiring interactions with the healthcare system. I'm really hoping for that and that we'll learn about their activity in all populations — children, pregnant women, a range — and have many more options for people. That's really the name of the game: creating options until a time when we have a cure.
Saag: That could change year to year or decade to decade as people live longer — not just because of side-effect profiles but because of preferences. People may say, "Well, you know, I'm more comfortable taking a pill a day rather than getting an injection or getting these infusions." So the options are very important as we try to end the HIV epidemic, which has been a theme of this entire podcast series that we've had. Judy, thank you so much for being with us today. The work that you're doing is really cutting-edge and groundbreaking and very important, not just for today's patients but also for those patients in the future. We want to thank you for that and also thank you for being our guest today. Resources
AIDS Clinical Trials Group (ACTG)
Cabotegravir/Rilpivirine (Rx)
Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS-2M)
Antiretroviral Therapy for HIV Infection
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV
Initiation of Long-acting Cabotegravir Plus Rilpivirine as Direct-to-Injection or With an Oral Lead-in in Adults With HIV-1 Infection: Week 124 Results of the Open-Label Phase 3 FLAIR Study
Lenacapavir (Pending FDA Approval)
Gilead and Merck Announce Temporary Pause in Enrollment for Phase 2 Study Evaluating an Oral Weekly Combination Regimen of Investigational Islatravir and Investigational Lenacapavir
Drug Database: Lenacapavir
Doravirine Prescribing Information
A5357: A Study of Long-Acting Cabotegravir Plus VRC01LS to Maintain Viral Suppression in HIV-1-Infected Adults
Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV
Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition
Evusheld (Formerly AZD7442) Long-acting antibody Combination Authorised for Emergency Use in the US for Pre-exposure Prophylaxis (Prevention) of COVID-19.
Saag: Sort of like long-acting and short-acting insulin.
Currier: Right — exactly, exactly. That's a good analogy.
Saag: The other thing about the broadly neutralizing antibodies — and correct me if I'm wrong — was that part of the reason they were being sought initially was to see which of those antibodies would protect against a challenge as prevention, and with the hope that once they know the structure of the monoclonal or the broadly neutralizing antibody, they could design vaccine products that could induce the immune system to produce that type of thing. Is that your understanding as well?
Currier: The antibodies have been looked at for prevention. There was the AMP trial that studied this as prevention, and the fields are coming together to some extent because it's true that you could learn more quickly about how the virus escapes these antibodies in somebody who already has HIV rather than waiting for it it someone to get infected after exposure. So the user has been looked at, both for prevention and potentially for treatment. And we just have to see whether we can get formulations that could be safely delivered and be long-acting and maintain viral suppression. I think it's really exciting for both prevention and treatment.
Saag: I want to underscore something you said earlier about how much we learned about these antibodies during COVID, not just for treatment but also for prevention. New products, like Evusheld, as we've discovered, actually can have protection when given subQ for up to 6 months, and that's a very exciting thing. Maybe we'll see that with HIV.
As I expected, our time is running out quickly. I want to return to our case. Let's say it was 3 years from now. What do you think is going to be available, considering all these products we talked about? What's the future going to look like?
Currier: I think we're going to continue to have single-tablet regimens that people can take, and a lot of people will maintain viral suppression and do very well. And then I think we'll have some additional options for long-acting therapy — hopefully oral and not requiring injection, not requiring interactions with the healthcare system. I'm really hoping for that and that we'll learn about their activity in all populations — children, pregnant women, a range — and have many more options for people. That's really the name of the game: creating options until a time when we have a cure.
Saag: That could change year to year or decade to decade as people live longer — not just because of side-effect profiles but because of preferences. People may say, "Well, you know, I'm more comfortable taking a pill a day rather than getting an injection or getting these infusions." So the options are very important as we try to end the HIV epidemic, which has been a theme of this entire podcast series that we've had. Judy, thank you so much for being with us today. The work that you're doing is really cutting-edge and groundbreaking and very important, not just for today's patients but also for those patients in the future. We want to thank you for that and also thank you for being our guest today. Resources
AIDS Clinical Trials Group (ACTG)
Cabotegravir/Rilpivirine (Rx)
Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS-2M)
Antiretroviral Therapy for HIV Infection
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV
Initiation of Long-acting Cabotegravir Plus Rilpivirine as Direct-to-Injection or With an Oral Lead-in in Adults With HIV-1 Infection: Week 124 Results of the Open-Label Phase 3 FLAIR Study
Lenacapavir (Pending FDA Approval)
Gilead and Merck Announce Temporary Pause in Enrollment for Phase 2 Study Evaluating an Oral Weekly Combination Regimen of Investigational Islatravir and Investigational Lenacapavir
Drug Database: Lenacapavir
Doravirine Prescribing Information
A5357: A Study of Long-Acting Cabotegravir Plus VRC01LS to Maintain Viral Suppression in HIV-1-Infected Adults
Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People Living With HIV
Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition
Evusheld (Formerly AZD7442) Long-acting antibody Combination Authorised for Emergency Use in the US for Pre-exposure Prophylaxis (Prevention) of COVID-19.
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