Viremic – Cases in HIV

Announcer: Welcome to Viremic – Cases in HIV, a podcast that explores quandaries in adult HIV clinical care. In each episode, Drs. Eileen Scully and Christopher Hoffman, HIV specialists at Johns Hopkins, discuss a case, review challenges in the plan of care, and highlight evidence and guidelines that inform clinical decision-making. Now, here are your hosts, Eileen and Chris.

Dr. Chris Hoffmann: Welcome to Viremic – Cases in HIV. I’m Chris Hoffmann, an infectious disease clinician who cares for people with HIV. And I’m joined today by my friend and colleague, Eileen Scully.

Dr. Eileen Scully: Hi everyone, welcome. I couldn’t be more excited to be here today with Chris to do something that we love to do, which is think about and talk about the care of people with HIV. Thanks for joining us.

Chris: Eileen, I know you’ve got a good case to discuss today. I’m excited to hear more, so take it away.

Eileen: For this podcast, we’re going to take an example case each time. These cases are adapted and merged from other individuals who we’ve cared for or who have been discussed in our clinical rounds. None of them are actual people. They’re all combinations of different cases to try to bring out a couple of the challenges that present in clinical care.

Our first [is a] 48-year-old man, he has a history of HIV and prior use of methamphetamines (meth). He was diagnosed about 12 years prior at a mobile outreach testing site, and he was actually quite surprised by the diagnosis and didn’t immediately engage in care. About 3 years later, so 9 years prior to this visit, he did engage in HIV care, and at that time, started on EFV (efavirenz; Sustiva), FTC (emtricitabine; Emtriva) and TDF (tenofovir; Viread), which is known by the brand name of Atripla, achieving initial viral suppression. He had a good response.

A few years later, he had a period of heavy substance use and what would be best described as suboptimal engagement in care, with missed visits, and then re-engaging in care during that time, and incomplete adherence to his medications. We know this based on his prescription refill(s), but also during that time, he does have documented viral loads that are non-suppressed. He has 1 viral load that was about 8,000 copies/mL and several in the range between 100 and 900 copies/mL.

He presented to you about 1 year after his last visit, reporting no recent use of antiretroviral therapy (ART). He’d been in recovery for substance use disorder and had not used meth for about 8 months, back at work as a paralegal, doing really well, feeling good, and ready to reengage with his care.

Before he came in to see you, he had some baseline labs done: his viral load was 250,000 copies/mL; his CD4 count was 230 cells/mm³; his creatinine was 2.4 mg/dL, which is a substantial change from his prior baseline of about 1.1 mg/dL; and he has a new diagnosis of diabetes.

He’s eager to start back on ART and is wondering about the options he will have. A genotype that was also sent just before he came into see you returns only a single mutation, the K103N, in the non-nucleoside reverse transcriptase, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based testing.

Chris: Interesting and common challenge, Eileen. I had a few questions. It sounds like it was about 9 years ago when he started HIV treatment for the first time. Is that right? And that was with EFV/FTC/TDF (Atripla). He took that for a while off and on or up until just a year ago.

Eileen: Yep, exactly.

Chris: Do we know more?

Eileen: Yeah—he initially did really well and had full viral suppression for about 2 years and then had a period of about 4 years [when] he was sometimes taking medications and sometimes not by his report. During that time, he has sporadic clinic follow-up but does have a few of these documented viral load values that are definitely non-suppressed, one of 8,000 copies/mL and several in the range of 100 to 900 copies/mL, with [none] suppressed after that initial period. He was always detectable after that initial period.

Chris: It sounds like viral loads low enough to suggest he was taking his medications, but not low enough to suggest that he had full suppression. So ongoing viral replication.

One other question, not directly related to his HIV, but perhaps some of his ability to continue to adhere in the future. Sounds like he’s doing better in terms of his meth use—off of that. Working.

Do you know a little bit more what triggered the initial meth use and why he was using meth heavily?

Eileen: That’s a great question. I think always with individuals with substance use disorder, it’s important to not immediately assume that they can’t be adherent to medications. I’ve always been humbled by clinical experience, but you find individuals who have very active and serious substance use, some of whom can actually maintain full viral suppression. For him, that was not the case.

He is a man who has sex with men, and he was using meth primarily in the context of sexual encounters. Then it got out of control and was disrupting his usual patterns of life. During that time, he would be using for a while and then try to not use for a while.

I think one critical part of his recovery and his maintaining not using meth has been the ability to develop relationships and have satisfying romantic relationships without the use of methamphetamines, which he has been successful at doing.

So, it does feel like he’s at a different point, that his nonadherence was mostly related to substance use, which it isn’t for all people, but appears to have been for him, and that he’s in a really different position now.

Chris: That’s great for him. Certainly does suggest that he may have more success with his health goals. Go ahead, Eileen, tell us more.

Eileen: As you highlighted initially, Chris, now he’s 1 year off of antiretrovirals, and his viral load is about 250,000 copies m/mL. That’s probably what we would call his untreated set point or where he sits when he’s on no therapy whatsoever. And that 8,000 copies/mL value, which you noted from several years back, and the ones that are in the 100 to 900 copies/mL range, raised the concern for the optimal recipe for resistance, which is exposure to some drug, so you have some pressure, you’re not at your full viral set point without any therapy, but not enough to stop replication. So high risk for resistance.

One of the things I wanted to ask you, Chris, is how do you interpret a genotype 1 year off therapy? He does have the K103N, but what does that mean to you, and do you think that’s really all that he has there?

Chris: Fortunately for us and for him, he has only been exposed to 1 regimen and so only can have resistance related to that regimen. The K103N causes high level resistance to the EFV component of that regimen and is a mutation that does not hurt the virus—that is, does not have a fitness impact on the virus.

Virus with K103N and wild type can compete equally, and the 103N remains detectable for a long time. Given his long-term challenges with adherence, it’s likely he developed other resistance mutations, certainly the M184V, which confers high level resistance to the FTC component of Atripla. And he may also have developed some tenofovir resistance, given the long-standing period [when] he had adherence challenges and just enough adherence to cause some suppression, but not full suppression.

I would certainly assume that he has M184V along with the known K103N and possibly also the K65R mutation that causes tenofovir resistance.

Eileen: The first point to highlight here is that HIV is not homogenous. When you have a viral load of 250,000 copies/mL, each one of those viral particles is likely slightly different. And this is also true for resistance, meaning that you may have resistance mutations on some of the viruses and not on others. Although we’re able to see the K103N, that’s because, as you say, there’s no fitness cost to that mutation, and it can replicate efficiently.

When we do a standard genotype from the blood, for someone who’s viremic, a standard RNA genotype, we can only detect mutations that are at about 10% or 20% frequency in the population of viruses. What you’re alluding to with the M184V likely being present is that that’s a poorly fit virus. It really doesn’t do well in competition with a wild type virus. Although it is still likely present, if it was ever there, it will be at a very low frequency. When you do a standard genotype, you won’t actually see that that mutation is there.

This principle that you’re bringing up here, which is there’s a couple of different ways to evaluate a genotype, and one of them is how recently was the individual exposed to drug pressure? In old studies—a lot of which are based on nucs [nucleoside reverse transcriptase inhibitors]—things like 3TC [lamivudine; Epivir]—it was identified that as early as 4 weeks after stopping medication and therefore removing the drug pressure, you can no longer find mutations that were clearly there when the drug was present. Those mutations are in what we call the reservoir or are archived in the body, meaning they’re still in CD4 cells and can come out if conditions are favorable. Those conditions would be the presence of the drug to again pressure them.

This individual hasn’t had any ART for a year, so it’s a very unpressured genotype. While we see the K103N, it’s helpful to know that’s there, it doesn’t mean there’s nothing else there. And exactly as you raised, the other 2 components that might have developed resistance would be 3TC or FTC component and also the tenofovir, with the M184V being much more common than the K65R.

Chris, could you comment on how you counsel someone who’s re-engaging in care or what you would say to him? Personally, I always lead with saying, “Welcome back. We’re happy you’re here and we’re excited to start this next phase of focusing on your health.”

What kind of things do you like to say to individuals coming in after they’ve been disengaged in care?

Chris: I try to take the same point. Most people respond more to rewards than concerns about consequences and reward of affirmation, both the affirmation that they’ve taken steps to change their life that have already been rewarding themselves in terms of relationships they’ve been able to nurture and being able to take some steps to help their health is the starting point for me [sic]. And then the second thing is taking a perspective of what their goals are, and within those goals, looking at harm reduction.

I’m very glad he is off meth, but I do have patients who engage in chem sex or using meth to accentuate their sexual experiences for a variety of reasons. I work with them to support adherence to their HIV medications while accepting that they have other priorities as well.

Eileen: The other real positive for this particular patient is that his CD4 count is still over 200 cells/mm³, and while he is definitely immune compromised, he has not achieved the level of susceptibility to most opportunistic infections. As they say, the best time to plant a tree is 20 years ago, but the second-best time is right now. He’s in a great position to initiate therapy and get all of the benefits that we know result from viral suppression.

All right, let’s get into it.

As we talk through the potential options for him, thinking about kidney function and how that might play into your treatment choices will be another thing we can talk about.

This is an individual with a viral load of 250,000 copies/mL, CD4 count of 230 cells/mm³, baseline resistance of a K103N and a history of treatment failing him in the past, and the specific treatment that failed him was EFV/FTC/TDF (Atripla).

It’s always important to start with the most obvious choices, and as one of the fellows that I recently trained said, “Well, isn’t the answer always Biktarvy?” And by that we mean bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF], which is one of the lead recommended regimens for people with HIV.

Let’s talk through that. Chris, do you think that Biktarvy would be an option in this case?

Chris: Well, as you said, Biktarvy is often, at least if it’s not the answer, something to consider. Circling back to his kidney function, it sounds like that’s the first creatinine we have in a while that shows that he has likely reduced kidney function. I’d want to confirm that. He does have this diagnosis of diabetes, which could accelerate any kidney problems. It may be real, but just guessing a little bit, I think a creatinine of 2.4 mg/dL would correlate for him to eGFR of around 30, which is when multiple medications, including TAF, are questionably recommended or no longer recommended. I would be very cautious of including an agent in his regimen that is not recommended to be used for somebody with an eGFR of less than 30.

Eileen: BIC/FTC/TAF does have some creatinine limitations, as you mentioned, although eGFR is the better way to think about it. Less than 15, definitely excluded, and then 15 to 29. Although, it’s interesting because in the package insert, the restriction around the 15 to 29 is actually related to the FTC component, which is classically, dose-adjusted 3TC, FTC, all of those equivalent medications for changing renal function.

However, over the last several years, the guidelines have been updated to reflect the fact that many of us in clinical practice don’t actually adjust 3TC or FTC dosing anymore because the therapeutic index for these components is so wide. There isn’t really an additive exposure toxicity issue. Sometimes in order to allow a fixed dose combination, we’ll use FTC at higher than what would be formally recommended for renal function because we know that it’s actually well tolerated and safe.

For this individual, I key into the same concern you have though, which is that while TAF has a much lower risk of renal insufficiency, it’s not zero. And there are still some people for whom, as you’re trying to figure out what is going on with their creatinine, you would like to just take off the table considerations about their kidney function. For those situations, I will often try to look for a regimen that does not include a tenofovir-based component, so we don’t have to have at every visit that question of the tenofovir contributing to any renal insufficiency or further kidney injury that might be ongoing.

But for purposes of the exercise, pretend that the creatinine is not an issue, and let’s go back to our interpretation of the genotype. We have a K103N, an NNRTI mutation, [which] has no implications for BIC/FTC/TAF, but possible other nuc resistance within his archived or hidden background virus.

What do you think about using Biktarvy (or BIC/FTC/TAF) if you think someone has a baseline M184V for example?

Chris: On the face of it, he should have full activity of the BIC, given that he’s never had exposure to an integrase strand transfer inhibitor (INSTI) in the past; however, he almost certainly has resistance to the emtricitabine (or FTC) and may have resistance to the TAF if he has the K65R. So, he would be on 1 or maybe 2 active agents of this regimen, which in traditional teaching would not be the right thing to do. However, given the effectiveness of BIC and several studies suggesting that BIC combined with TAF or even an INSTI combined with FTC or 3TC is sufficient for virologic control, it certainly is still something to consider and not to rule out at this time.

What are your thoughts of that, Eileen?

Eileen: I agree. The data that we have in this is a little bit limited, but let’s talk about what we do know.

There’s a couple of studies that have looked at does BIC/FTC/TAF work in the presence of an M184V? But the majority of those are switch studies. So, these are individuals who are already suppressed. They’re on a regimen to begin with, and they’re switching to BIC/FTC/TAF.

The first I’ll mention is study 4030 [Sax PE, Rockstroh JK, Luetkemeyer AF, et al. 2021]. This was a study done by the drug manufacturer. They enrolled 565 individuals, stably suppressed to less than 50 copies/mL on dolutegravir (DTG; Tivicay) plus FTC and TDF or TAF for more than 6 months prior to screening if they had a history of resistance. So, they were enrolling people with resistance, but required that they’d already been suppressed on DTG plus FTC, TDF, or TAF. This study overall showed that there was a good maintenance of viral suppression through 48 weeks among those who switched to Biktarvy, including 47 out of the 500 individuals who had a documented M184V. All of them maintained suppression after the switch.

There’s another called the BRAAVE study [Andreatta K, D’Antoni ML, Chang S, et al. 2024] that enrolled specifically black adults who were suppressed on a regimen of 2 NRTIs plus a third agent. They didn’t specify the agent in this case for more than 6 months. And they allowed resistance again, although they did exclude the K65R. These individuals are then randomized 2:1 to switch over to Biktarvy or stay on their baseline regimen. And then at 24 weeks, even those who stayed on baseline also crossed over. What they saw in that study, again, was that in the 11% of individuals with a baseline M184V, there was no difference in blips or viral failure based on resistance at baseline.

In both of these cases, we see that people can switch to a BIC/FTC/TAF regimen in the presence of an M184V.

It’s important to separate that from the case we’re talking about right now—an individual who has viremia. It’s not a stable situation where someone’s been suppressed for 6 months. Importantly, one could argue that it’s not that surprising that if you’ve already been suppressed on DTG plus the same 2 components that you remain suppressed switching to Biktarvy. What those studies show is the equivalence of BIC with DTG as opposed to showing whether or not on its own, BIC can achieve viral suppression when you have an M184V.

That’s the summary of data for the BIC side of it. We do have a bit more data for the ability to achieve suppression with an M184V from the NADIA studyPaton NI, Musaazi J, Kityo C, et al. 2021]. This study was in the New England Journal of Medicine. It was a practical public health approach study done in sub-Saharan Africa. In this setting, if you fail your first line therapy, you switch to a second line therapy. And this is done algorithmically, not with lots of hemming and hawing and patient preferences and provider thoughts. It’s an algorithm that is followed to maintain viral suppression in the maximum number of individuals in the country.

What they studied was whether or not you should switch your components based on resistance testing and whether or not DTG as a second line agent, [in] someone who had virologic failure and was switching to their second line agent, would perform as well as darunavir/cobicistat (DRV/COBI; Prezcobix/Tybost) or DRV/ritonavir (RTV; Norvir) rather. What they showed in this trial was that even if you had baseline nuc resistance, including an M184V and in many cases a K65R, [and] switched to either DTG plus FTC/TAF or boosted DRV plus FTC/TAF did still achieve viral suppression.

Those results were very reassuring for something that’s a little bit more similar to the case we’re describing here, where the individual has a detectable viral load and whether or not you can achieve viral suppression even with background nuc resistance.

That data speaks a little bit more to what we might be able to do, but it’s important to take that into consideration when we’re thinking about resources and the setting. We’re not in a situation where we’re forced to switch to a mandatory second line regimen. We’re in a situation where we can tailor therapy for this individual. While it is likely to work, we don’t actually have to make that choice here. And you can question whether or not that is the best choice.

Chris: Good points, Eileen. I get a little hesitant, especially in somebody with a relatively high viral load of 250,000 copies/mL, about starting a regimen where we may only have one active, albeit a really effective, potent, and high barrier to resistance, agent. What other regimens were you thinking about for him?

Eileen: Let’s focus back on what our options are. My concern here for a K65R is probably a little bit lower than what you’re expressing. The TAF is probably active. However, with the kidney function, I do feel some kind of way about maybe eliminating a tenofovir component from his regimen.

I’ll take that aspect of the case, and let’s talk about what our options would be if we were going to not include TAF in a regimen, and we’re trying to achieve what we think are likely 2 active drugs achieve viral suppression.

Really important to mention here that step 1 when you’re considering removing tenofovir is hepatitis B status determination. We often forget that hepatitis B is efficiently and effectively treated by tenofovir, and as we know from the package labels and clinical experience, if you suddenly remove hepatitis B therapy, you can have rebound hepatitis that can be severe.

One of the key things to do before transitioning someone to a regimen that does not include tenofovir is to make sure that you understand their hepatitis B status. Chris, do want to walk us through how you do that?

Chris: Sure, so 2 things. He was in care, so we can look at his prior hepatitis B testing and certainly both surface antigen and surface antibody and perhaps see his vaccination records. We should also repeat that, given that he’s been out of care and is at risk for hep B either through sexual transmission or using injection meth, and repeat a surface antigen and a surface antibody. If he doesn’t have any prior testing, then I would typically also check for a core IgG antibody for hepatitis B.

Eileen: Fortunately, he is hep-B immune. Now let’s talk a little about options for a TAF-sparing regimen. One option is DTG plus 3TC. There’s some data about use of this combination therapy, including where there’s a risk of or documentation of an M184V. There’s no need to do that in our setting because it does expose individuals to higher risk of failure. That was shown in a treatment initiation study [Rolle CP, Berhe M, Singh T, et al. 2021]. What they showed was that if you didn’t know about the M184V, you could quickly change them once you found out about it.

There’s very few cases where you’re forced to only use DTG/3TC. In the study that was presented at IAS in 2023, they discussed a number of cases of individuals with known M184V and showed that switch of those individuals to DTG/3TC did not result in failure. There’s a nice review in OFID (Open Forum Infectious Diseases) that goes over all of the cases where they have looked at switch to DTG/3TC [Kabra M, Barber TJ, Allavena C, et al. 2023].

Again, I’m just gonna’ underline that that’s quite different than the case that we’re talking about, which is an individual who is non-suppressed. This is not a situation where I would challenge the possible presence of an M184V and risk a potential monotherapy. So that one I’m gonna’ take off the table, at least for the start.

DTG/rilpivirine (RPV; Edurant) is another compact 2-drug regimen. In this case, we don’t think he has any resistance to RPV, so it would be 2 active drugs. But I’m also gonna’ take this one off the table because that medication combination was studied only in switch and not for treatment initiation during its approval. This is not something that should be used to start individuals on treatment. You can switch to it as that’s what it was shown to be effective for, but not start.

Keep in mind that RPV does require a substantial meal—usually I say about 400 calories to my patients—in order for adequate absorption, and you can’t take antacids. Those are important things to be aware of and always talk to people about—how regularly they eat and whether or not they have trouble with stomach acid.

Moving a little bit further down the list, let’s take one that I’ve said we can’t use and try it in combination. How about DTG/3TC and add doravirine (DOR; Pifeltro)?

It’s a little less well studied, but there’s a couple of case series. There’s a small case review series from Washington, D.C., of about 21 individuals on DOR and DTG that was published in 2022, [and] showed high rates of viral suppression [with] that combination [Denyer R, Zemskova J, Benator DA. 2022]. There’s also a retrospective analysis of 2 drug regimens with DTG that compared individuals on DTG/RPV, close to 500 on DTG/3TC, and then about 85 on DTG plus DOR, and showed overall good results, but maybe a slightly higher rate of virologic failure in the DTG plus DOR [arm], although that’s the only one of those regimens that’s actually not a single pill [Rossotti R, D’Amico F, Bana NB, et al. 2024]. This is one that I kind of favor in this setting, because it gives you the advantage of 2 fully active drugs, and then also the 3TC.

My interpretation, at least in part of the data from the NADIA trial Paton NI, Musaazi J, Kityo C, et al. 2021], is that nucs like 3TC have some activity, whether or not they’re fully active; that documentation of how those drug combinations can still work, even when you have some resistance, motivates me to sometimes include it in regimens, even when I think it’s possible that the M184V is in there.

What do you think about that? That’s my leading candidate right now.

Chris: I share your hesitance with somebody with a high viral load in starting them on DTG plus 3TC. I have patients who have had suppression for a long time who I switched to DTG/3TC even in situations where there may be an underlying M184V.

I think probably DTG monotherapy would work for most people, but not all people. And we don’t want this individual to be one of those people who it doesn’t work for. Adding DOR would overcome that problem and would be very reasonable. I would discuss with him whether taking 2 tablets would be something that he feels he can do, and how he can be supported with that.

Eileen: I agree that [we] definitely want to avoid monotherapy. And one of the things I always have to keep in front of mind when discussing that is that the rate of monotherapy failure is not 100%, but it also doesn’t occur right away. If you change someone to an effective monotherapy regimen or start someone on an effective monotherapy regimen, you can’t expect to get your feedback loop of whether or not it works in 1 to 2 months.

Most studies that have shown the inferiority of single drug therapy have gone out to 52 weeks or longer. This is the kind of thing that can emerge over time. And you can’t be reassured by an initial switch and positive result, which I’ve seen a couple of times [when] people are like, “Oh, well, we did the follow-up viral load and it was still good.” But you do have to give it enough time for the virus to actually come back before you can feel confident about that.

All right, we’ll put that one out there as currently leading draft picks. Couple of other things we should probably just touch on.

I would not consider an RPV-based regimen for this patient because RPV has a lower barrier to resistance development. And if we’re trying to spare TAF, there is no combination outside of the DTG/RPV we’ve already discussed that would be a 2-drug regimen that would include that.

We could also consider DRV/COBI (boosted darunavir) plus 3TC. This combination was studied in the ANDES trial, that did show relatively good results, including for treatment initiation for individuals for whom it was preferred to avoid tenofovir [Figueroa MI, Sued O, Cecchini D, et al. 2024].

But, a 48-year-old man, once we get the HIV under control, the primary thing I’m going to be thinking about for him when I see him in clinic is his risk of cardiovascular disease. Adding a booster, although the modern boosters are much more palatable and have fewer side effects, is not something that I usually want to do when I can avoid it. So, I probably wouldn’t favor that one.

And then the other thing I thought would be on the table at some point for this individual would be cabotegravir/rilpivirine (CAB/RPV; Cabenuva) injection-based therapy.

I don’t know what your level of use of this in clinic is these days, Chris. There are some people who prefer injectable, and CAB/RPV can be given once a month or once every 2 months.

It is something that I discuss with my patients. One thing I always say is, we do know that for CAB/RPV, for reasons that are not totally clear, even with on-time injections, there is a failure rate of about 1%. That is higher than oral therapy. If you take oral therapy every day, there is no risk of failure unless you had pre-existing resistance to the components.

I’ll just mention about CAB/RPV that, while all of the guidelines now mention the potential use of CAB/RPV for treatment start, which was not how it was approved, but actually is necessary in some cases when people simply cannot take oral medications.

This would not be an appropriate case to consider it. This is an individual who’s coming in, who’s ready to engage, who’s happy to take pills. And if you were going to consider CAB/RPV, I would achieve viral suppression and maintain that for some time before I considered transitioning to an injectable. But based on his history, that might be an option also.

Chris: And that, in my practice, really comes down to patient preference. I bring up the injectable long-acting CAB/RPV frequently, or patients bring it up to me, often asking questions because they’ve heard about it or seen advertisements. Then the discussion goes down the path of the potential benefits, which include not having [to take] a pill, especially [for] individuals who have a lot of shame around their HIV, then they are not reminded on a daily basis of having HIV. They just are reminded every 2 months when they have to come in. And finally, some of my patients don’t want to be seen with a pill bottle and may hang out with friends or travel, visit friends a lot and prefer avoiding unwanted disclosure of their HIV status.

The downside though is showing up every 2 months to get the injection and a bit of associated pain, especially with the RPV injection. I go through that and I would agree that he may be a good candidate if this is what he wants. And I agree, I would want to see his viral load suppressed before pursuing CAB/RPV. Partly also it just takes a while often for the approval process and setting things up. And given his motivation right now, I think the right thing is to get him on the right meds as soon as possible.

Eileen: There are other medication options that we didn’t discuss, but these would be the ones I would be most likely to reach for. Other injectables, like lenacapavir (LEN; Sunlenca), or novel agents like fostemsavir (FTR; Rukobia), have their uses. But in an individual who has not failed other treatments, I still strongly favor use of agents for which we have much bigger experience. The numbers of individuals who’ve been treated with those novel treatments is much smaller, so I tend to reserve those agents for the cases in which we have exhausted the options which have the most data on, where we best understand the adverse effects, how long they’re going to be effective, and in what patients they work best.

Chris: Eileen, any comments about his diabetes and these regimens—either the DTG/3TC plus DOR or your less favorite, DRV/COBI plus 3TC?

Eileen: I am still mindful of the drug interaction between DTG and metformin. I know the package labeling has been updated. Previously, we capped metformin dosing at one gram daily when in combination with DTG. The reason for that is not a contraindication, but a boosting of levels that increase the risk of lactic acidosis in individuals who are on metformin. The risk was highest in those with co-occurring renal insufficiency.

In some patients you can push the dose higher. I have seen at least 3 cases where individuals had lactic acidosis in the context of DTG and metformin at high doses. So, I do avoid it and generally maintain the one gram or less per day in combination with DTG.

That is not true for BIC. BIC doesn’t have the same level of boosting, so you can have a little bit wider dose range with that. As far as the DRV/COBI, older protease inhibitors (PIs) had unfavorable effects on glucose metabolism. And the data on whether or not the modern generation of PIs, including DRV/COBI has as much of an impact on glucose control [are] less convincing.

But in general, I don’t think that protease inhibitors and their boosters are favorable for lipids or for glucose control. And if you can avoid them, I usually do. DRV/COBI will always have a special place in my heart as a very high barrier drug that saved many of my patients before the emergence of INSTIs. And there is still an important role for it in care for people with HIV today, but when you have options that don’t have a boosting component, generally I favor them, in particular in the context of diabetes or concerns about lipids.

What’s your practice on those things?

Chris: Very similar thoughts as you Eileen.

I run into many drug-drug interactions with the COBI, especially in patients with comorbidities, less so with diabetes, but with managing cardiovascular risk and hypertension that I try to get patients off boosted regimens if there are other excellent options. I think for him there are.

Certainly, as you mentioned, a lower dose of metformin can be used. Given his diabetes, he’s likely going to be on additional medications anyway, targeting his glucose and A1C. I think all of that favors the DTG/3TC plus DOR.

Eileen: I should just mention here that, for DTG/3TC, the labeling indication actually recommends not using it [with an] eGFR of less than 30. But actually, that’s related to the 3TC dosage. As I mentioned before, in the guidelines for both the HHS and in other sites, many clinicians no longer adjust the 3TC dosing because the higher doses are tolerated. And in order to allow the fixed-dose combination, we use the unadjusted DTG/3TC without any significant risk of increased adverse effects.

Eileen: Well, thanks so much, Chris. As you know, I’m always excited to talk about HIV, and I look forward to our next case discussion.

Chris: Thanks for everyone who’s joined. Really appreciate you taking this time out of your day. Hope you found this an interesting discussion and look forward to joining with you again for another session of Viremic. Have a great day.

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Viremic is sponsored by the Clinical Guidelines Program, a collaborative effort of the New York State Department of Health AIDS Institute and the Johns Hopkins University Division of Infectious Diseases.

Visit the program’s website at HIVguidelines.org.

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with appreciated assistance from Jesse Cicotte and Laura Lebrun Hatcher.

Viremic’s case discussions are presented for informational purposes only and are not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use, not an endorsement.

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References Cited

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