HIV Podcast

Antiretroviral Therapy, Maintenance, and Switching

Michael Saag, MD; Constance Benson, MD


April 06, 2022

This transcript has been edited for clarity.

Michael Saag, MD: Hello. I'm Dr Michael Saag, and welcome to Medscape InDiscussion: HIV. Today we're talking about antiretroviral therapy, maintenance, and switching. I picked this topic because new advances in the use of antiretroviral therapy are emerging every year, and it's always good to pause and take a snapshot of where things stand today. Let's start with a case. A 23-year-old man who has sex with men just tested positive for HIV. He had been on preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (DF)–emtricitabine (FTC) intermittently for the last 18 months, but had run out of medicine 8 weeks ago. When he went back to reinitiate PrEP, he was tested for HIV and his test was positive. His initial viral load was 345,000 and his CD4 count is 560 cells/μL. Today's guest is Dr Constance Benson, an internationally known researcher and clinician from the University of California San Diego. She is known for her pioneering work in the treatment of tuberculosis but is also known for her leadership at the AIDS Clinical Trials Group for many years during the heart of the highly active antiretroviral therapy (HAART) revolution in treatment. Welcome, Connie.

Constance Benson, MD: Hi, Mike. Nice to be here and thank you for the invitation.

Saag: Let's start with just a straightforward question. Briefly describe a scene in your early career when you realized that you were going to dedicate a large portion of your career to the treatment of HIV?

Benson: There are lots of similar scenes to the one I'm going to describe, but this was during my fellowship in infectious diseases. One of the first people with HIV that I encountered was on our infectious disease consult service. I was working in Chicago at the time at Rush University Medical Center, and the patient in question was a young Black man from the South Side of Chicago who had been admitted to our service with pneumocystis pneumonia. He and I formed an immediate bond because he was a golfer — he was aspiring to be a pro — and he also loved Lucille Ball and reruns of I Love Lucy, so we got started on conversations in both of those areas. The first time I saw him, he had a very low CD4 cell count. He recovered from pneumocystis pneumonia but he never really felt well thereafter and developed chronic weight loss, chronic diarrhea, abdominal pain, intermittent fevers, and we made an eventual diagnosis of disseminated mycobacterium avium complex (MAC). I had already been working on that pathogen but in a different population: older women with bronchiectasis. I quickly transitioned being interested in the organism to also being interested in its impact in a very immunosuppressed population with HIV. That was really the launching point of some of the early work I did with disseminated MAC and with the AIDS Clinical Trials Group network. I thought that would be a good case to highlight.

Saag: Yeah, those were the horrible days, and we had an earlier conversation with Paul Volberding and we delved into that a lot. But back then, we didn't have much to offer. The antiretroviral therapy revolution happened, and we've come an enormous way since then but we still have barriers to initiating therapy. What would you say are the top two or three barriers that you're experiencing now with current-day antiretroviral therapy?

Benson: As the pandemic has evolved in the US, some of the barriers that we have to initiating therapy, while they may have been present always even in the earlier days, they seem to be more prominent now with the populations that we're dealing with. For our setting, immediate barriers to initiation of therapy are access to care, access to medications, and some of the sociodemographic factors that interfere with access to care, like unstable housing, food insecurity, being a part of a marginalized population, maybe mental health issues, and substance use. And oftentimes, even though we encounter them when they test positive for HIV, it's more difficult in our current setting to link them to care and overcome some of those barriers to get adequate treatment initiated.

Saag: You have a fantastic set up at your clinic in San Diego, where you're able to address a lot of those. How's it going for your team? I know you have Ryan White funding and some other things, but how is your team addressing those just briefly?

Benson: The biggest challenge to our team has to do with some of the substance use and mental health issues. We have a new director of our clinic and one of her major areas of specialty is dealing with substance use in marginalized populations. She's really reinvigorated our clinic's approach to that by implementing some of the tools — we have to get people in to care for substance use treatment and to build a cadre of people who specialize in mental health issues. We have a whole team now of social workers and psychology and psychiatric service providers who specialize in trying to deal with some of the mental health issues that have emerged more recently with the COVID-19 pandemic but also with the previous issues we've had getting marginalized populations into care. One of the things I'm sure you experience in Alabama, too, is the issue of dealing with an immigrant population or a population that may not be fully engaged in the healthcare system. So we've started a refugee clinic; we also have a clinic for dealing with people that we see from across the border and providing resources and care for some of the immigrant population that we've been dealing with over the last several years. There are a lot of innovative programs ongoing, but as you also know, resources and funding to support some of those activities may not always be accessible.

Saag: A take-home point is that for each clinic and for every provider, you have to do an assessment of what those barriers are and then develop programs like you just described to hit them head-on. But it is an ongoing effort. Let's move a little forward and just say, "OK, you have a new person recently diagnosed." Let's take our case as an example. This gentleman gets referred to you, he's 23, had gone off of PrEP, and became infected. What are the factors that go into your decision-making about that initial regimen?

Benson: I guess one of the first things I would want to know from just pointing back to your case is what were the triggers that made him stop his PrEP. What's going on in his life that may have interfered with his ability to continue PrEP? Were those associated with tolerance of the medication? Were they associated with side effects? Did he have trouble accessing medication or linking to care or following up in care? Were there issues related to adherence? Some of those things go back to the sociodemographic factors that I was talking about. It really requires an initial conversation with the patient to understand what's influencing what's happening with his healthcare right now. Once you get over that point, other things that go into choosing a first regimen obviously relate to the goals of therapy. You want to be able to have a relatively rapid initiation of treatment so that you can reduce transmission. Obviously, he's already been in a situation where he was on PrEP and he is obviously sexually active. You want to reduce his ability, especially with as high as his viral load is, to potentially transmit to others. You want to get his viral load under control pretty quickly and you want to have a regimen that's going to sustain viral suppression. That means one that's easy for him to use, he can access, and is within his realm of bearing the cost or having services or resources to access medications — then obviously looking at some of the issues related to tolerability of individual regimens and any underlying comorbidities that he may have, such as diabetes, cardiovascular disease — although he's a little young for that. But renal disease, hepatitis B, or hepatitis C co-infection all relate to what you're going to choose as an initial regimen for a patient in his situation.

Saag: Those are all wonderful points. And for the sake of discussion, let's say that he has no other comorbid conditions. He's not on any other medicines right now. He had no trouble tolerating his PrEP. He just didn't think to go pick them up and just let it lapse. In that setting, what are the specific medications that you might consider among all the choices that we have in terms of general class and general approach?

Benson: The scenario that I outlined at the beginning of our program — I guess the best way to describe it is there's a plethora of choices which almost makes it dizzying to select. However, we have emerged with a pretty standard approach at this point, looking at ease of use, cost, and tolerability. The integrase strand transfer inhibitor class is really the cornerstone of our initiation of therapy at this point. And this pretty much goes along with published guidelines for what you should use as an initial regimen. Our first choice is an integrase inhibitor–based therapy: dolutegravir or bictegravir are the two that we use most often in combination with either tenofovir or tenofovir alafenamide (TAF) and FTC. Whether we choose three drug regimens or two drug regimen — we probably want to get into some of that discussion as well — really depends on some of his underlying clinical parameters. For example, we choose bictegravir with FTC and TAF on the basis of the fact that he doesn't have any underlying comorbidities. That's a very well-tolerated regimen, easy for him to take. I would probably start with a three-drug regimen in him just to make sure that we're getting adequate control of viral suppression. Obviously, the two-drug regimen of dolutegravir and lamivudine (3TC) is a popular one. There are some caveats with choosing that one. You don't want to use two drugs if you have somebody with underlying hepatitis B disease. But with dolutegravir and 3TC, you would want to know what his most recent viral load, and what you described was 345,000, so he's probably still in the realm where you could consider two drug therapies under 500,000 copies, and he's got a pretty robust CD4 cell count. That would be a two-drug regimen you could potentially select. Our clinic is not using a lot of initiation of therapy with two-drug regimens, but more consideration of the two-drug approach for people once they get virally suppressed. One thing I would consider with him, though, is he was on tenofovir FTC PrEP regimen, which he stopped and got infected shortly thereafter. You don't exactly know what the timing of his infection was. Did he get infected because he wasn't fully adherent to his PrEP? And there would be some concern about underlying drug resistance mutations — either transmitted drug resistance or resistance as a consequence of intermittent adherence with this PrEP therapy — that's another reason why I might not want to go with the two-drug regimen with him, particularly dolutegravir 3TC regimen, just because I'd be a little bit worried about that M184V mutation with failure of PrEP or intermittent adherence to PrEP.

Saag: We have a similar approach at our place. We usually start with the three-drug regimen, usually either bictegravir or dolutegravir anchored. Then we draw all the labs. We usually try, like you, to start the medicines on day 1 because it shows that adherence to visits is better once you start on that first day. But let's say we've done that. We've started him on some of the three-drug regimen. And then he comes back hepatitis B negative and he's got a wild type genotype. He comes back for his next visit. Would at that point, might you switch him to a two-drug regimen of some sort or just keep him where he is?

Benson: I guess that would be a decision maybe I would make together with the patient. And if he's comfortable that he's able to adhere to a regimen and that we feel comfortable, that he's got good linkage to care and understands some of the concepts that we've talked about, the importance of maintaining viral suppression, I would feel comfortable switching him to a two-drug regimen. He's young, and it's nice to be able to limit his exposure to different drugs if we can do that.

Saag: He comes back, and one of the things I was thinking of when I threw this case out there was maybe he's just at the end of the acute seroconversion syndrome and that's why his viral load was high. Maybe it's coming down, but he comes back and he says to you, "I'm doing fine with these medicines. But I saw on TV there was an ad for some sort of injection I could get." How would you deal with that? And do you guys have a setup now in your clinic to administer the cabotegravir based treatment regimen?

Benson: Cabotegravir and rilpivirine is a very attractive regimen for a long-acting injectable drug. I'd have a conversation with him about his ability to adhere with injectable agent like that and his comfort with injecting himself or coming back to a clinic for injections. Obviously, we'd go through the process of switching him to two-drug oral cabotegravir-rilpivirine regimen to get levels up and then switch him to the injectable component. I guess one potential problem and I have been engaged in a whole series of email conversations with colleagues around the country about is how they are implementing the injectable long-acting regimens in their clinics. In some instances, insurance is requiring that the prescription go to some kind of central pharmacy and then the medication then transition to the clinical setting. There are a lot of different providers out there that are imposing certain restrictions on the use of those medications. But suffice it to say, our clinic doesn't have a process fully established at this point that is comfortable for both providers and patients to use. The logistics of administering the cabotegravir-rilpivirine long-acting injectable drugs has challenged us in ways that we haven't been used to doing with infrastructure in many of our outpatient clinical settings.

Saag: We're all struggling with that and I suspect we will work through those logistics in the next 6 months or so. One of the other issues, as you mentioned earlier, is access to the medicines. But in this case, there might be access to payment for the medicines because some insurance companies are requiring the patient to put the money upfront to get it to them. In the few minutes we have left, let's continue the story. Let's say you switched him to dolutegravir 3TC and he had done well for a while and then on a routine visit a year from now, he comes back and his viral load is increased to 600 copies per mL and you see him. But you don't get that lab result until after — a day or two later. How do you manage that situation where there's been an increase? Is that a blip or is that actual antiretroviral therapy failure?

Benson: At the point in time you're describing, I would have to say that's a blip. Fortunately for us, clinically, there is definition for a viral blip at this point. And as long as that viral load is under a thousand copies per mL at that one-time visit, it may still be a blip. With a viral load of 600 copies per mL, we don't know yet whether it's a blip because in order for us to establish that, we would have to understand what happens next. I would repeat that viral load and if it's elevated further, that suggests he may be on a trajectory toward virologic failure. If the repeat is back to undetectable or less than 20 copies, whatever assay you or your clinic uses, then I would consider that to be a blip. And if it was a blip, I wouldn't do anything. I would just make sure that we're seeing each other on a regular basis that he understands that sometimes these can be seen in a clinical setting and don't necessarily mean anything bad, but I might monitor him a little more closely than we ordinarily do. I don't know about your clinic in Alabama, but we're going to every 6 months and sometimes once a year for stably suppressed patients. So, he might be somebody if he has recurrent blips that I might monitor a little bit more closely, particularly since he's on two drugs.

Saag: And it's hard to tell. Sometimes if it's the biology where you get a reservoir of cells just sort of the release more virus in a moment in time and you pick it up. Sometimes a patient has been relatively nonadherent before that visit, you challenge them with the fact that their viral load has gone up and then they start using the medications more or regularly. We only have about a minute or so left. What are the what's the main take-home point you'd like to communicate as we wrap up?

Benson: In this day in time, the take home message I want to communicate is less related to the nuts and bolts of initiating antiretroviral therapy, but more to establishing a trusting relationship with a patient. We've learned through the HIV pandemic and now the COVID-19 pandemic that trust in the healthcare system and trust in the relationship with their healthcare provider — that really cements the framework for patients to adhere to therapy that we recommend and to understand those therapies and really have a relationship with their clinician. I'd like to leave on concept that the most important thing in providing good antiretroviral therapy is establishing mutually trusting relationship with your patient and making sure that you're addressing that patient's needs, even if those go beyond antiretroviral therapy.

Saag: The case that drew you into HIV medicine that you described at the beginning is really a perfect example of getting to know your patient. The guy who wanted to be a professional golfer, you know about his world or that somebody may be struggling with substance use, as you said earlier, or maybe having depression. Those are barriers that we can overcome, but only if we really have established a relationship where we understand this. Through establishing that a relationship, trust is established as well. I knew our time would go by very quickly. Thank you so much for joining us today. The key points were made about initiating therapy, understanding some of the nuances of resistance upfront, hepatitis B or, for that matter, hepatitis C that may be upfront and addressing a lot of the other social concerns and medical concerns with comorbid conditions, substance use, depression — all of that — needs to be addressed. Thanks for joining us. And until next time, we'll sign off.

Benson: Thank you.


Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2021 Update

AIDS Clinical Trials Group

Clarithromycin Therapy for Bacteremic Mycobacterium Avium Complex Disease

UC San Diego Medical Center

Highlights from the Ryan White Clinical Conference

Clinical Effectiveness of Integrase Strand Transfer Inhibitor–Based Antiretroviral Regimens Among Adults With Human Immunodeficiency Virus: A Collaboration of Cohort Studies in the United States and Canada

Key Considerations and Recommendations for Early (Acute and Recent) HIV Infection

Rising Rates of Recent Preexposure Prophylaxis Exposure Among Men Having Sex with Men Newly Diagnosed With HIV: Antiviral Resistance Patterns and Treatment Outcomes

Long-acting Cabotegravir Plus Rilpivirine for Treatment in Adults With HIV-1 Infection: 96-week Results of the Randomised, Open-Label, Phase 3 FLAIR Study

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