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. Christopher Hoffmann:
Welcome to Viremic. I’m Chris Hoffman, and I’m here with my friend and colleague, Eileen Scully. How are you doing today, Eileen?

Dr. Eileen Scully:
Hi Chris, it’s great to be here, and you know, it’s a pretty good day, and it’s always a little bit better when we get to talk about HIV.

Chris:
For sure. One of the things that comes up in my clinic fairly often is when a patient mentions having heard from the news media, or social media, a friend, or even another clinician, some information about a medication or other health condition, that isn’t quite accurate. What you do in that situation?

Eileen:
Chris, what a really important question. I will tell a story about when I was a medical student, and I was first starting to interact with patients.

I had a patient who was on a low salt diet for his high blood pressure. And he came back in (we had a clinic where we followed patients over time), and his blood pressure was still elevated. I asked him how it was going with the diet, and he said, “I took myself off that diet. I thought if I didn’t have enough salt, I’d get too much sugar, and then I’d have diabetes.”

It was such a moment of, “Wow, communication and understanding where people come from is so essential.” That makes sense if you’re making a cake, but it doesn’t make sense in our bodies, but there’s no reason why he would know that.

So whenever someone comes to me with something they’ve heard, my first step is always curiosity: “Tell me more about where you learned this, and tell me more about what else you know about whoever was talking with you. Is this a person you really trust? Let’s dig down into why this advice was impactful.” Then I start to address the specifics of whether or not a supplement is effective or whether or not the way they’re using their medication is right or wrong.

How do you approach it, Chris?

Chris:
I love your approach, Eileen. I try to understand patients (perhaps I’m not always curious enough) and try to provide some education as well—trying to meet the patients where they’re at.

I love your sugar salt example. Certainly, it’s easy for innocent misunderstandings to become health problems.

That leads us to the case I have today, which is of a 54-year-old woman with longstanding HIV and a BMI of around 35. She’s been struggling with weight through her whole adult life, but had heard through various channels that maybe the medications she was taking were responsible for her current weight struggle and wanted to talk to me more about that.

I’m sure this is a scenario that you commonly encounter as well. What is your first approach when you get questions like this, Eileen?

Eileen:
Questions about antiretroviral therapy and weight gain have definitely become much more common over the last 8 to 10 years. I remember a patient many years ago, and she brought this exact question, whether or not her medication was causing her to gain weight. It wasn’t in the context of anything on social media. I immediately reassured her no, and then you can watch in my notes over time as there did start to emerge some data suggesting that different regimens had different consequences for weight, that our discussion changed.

This is something that has recently come into the forefront, and I imagine you’re going to take us through a pretty detailed discussion of what we know and what we don’t know about antiretroviral therapy and weight.

But my first response usually is validation. Typically, people who have untreated HIV who begin medications will gain weight, period, full stop.

If you have advanced HIV disease and then begin medications, you will gain a lot more weight usually. If you have less complications from HIV, maybe shorter duration of infection, maybe less. But having uncontrolled viremia clearly does burn some calories. Usually, turning off that virus will lead to some weight gain, as we see with antiretroviral therapy. In many cases, this is what we would call “return to health” weight gain, but in some cases, it can actually lead to being classified as overweight or obese. So I always validate that yes, starting medications will usually lead to weight gain, and then I will start a more detailed discussion about whether or not a specific regimen or in the specific scenario we’re talking about, we think that the medications are really the issue. What do you say, Chris?

Chris:
I like that framing. I take a pretty similar approach. Like you, my understanding of HIV medications and weight gain has evolved with the knowledge in the field.

I tell patients starting antiretroviral therapy that they are likely to gain weight, and certainly those who are either underweight or have very advanced HIV disease, tell them that they should expect that, that is a normal process and not a side effect of medications, but a side effect of returning to health.

Making that distinction that you’ve made between weight gain and ART initiation, and after somebody's been on antiretroviral therapy for a while or switching medications. It’s such an important way to frame the whole weight gain issue.

I’m going to provide a little more information about my patient. She was diagnosed approximately 15 years ago. At the time of her diagnosis, her viral load was around 70,000, and her CD4 count was 315, and she had no identified HIV drug resistance mutations. At the time, she was already overweight with a BMI of 29.

She was started on Atripla and soon achieved an undetectable viral load. About 6 years ago, she was switched to Biktarvy to stay current with the antiretroviral therapy regimen changes at the time and on the off chance that her mild depression was related to the efavirenz component of Atripla. At the time, her viral load was undetectable and her CD4 count was 615. Her BMI had risen to around 34/35.

In the 6 years since that switch, her BMI has continued to increase and now is around 38 and she’s maintained an undetectable viral load throughout that whole time. She is specifically concerned that the Biktarvy has led to her weight gain, and she asks if there’s an alternative regimen that may be more friendly in terms of her weight loss goals.

Eileen, how do you manage the question around Biktarvy specifically and weight gain and weight loss goals?

Eileen:
You’re right, Chris. This is a very common scenario and one that can be quite challenging to manage. Weight gain is challenging.

Listening to her story, I hear a couple of features that we can check off to begin with, one of which is that the time where she’s concerned about the medication Biktarvy contributing to the weight gain was a switch. So we can’t attribute this to the effects of suppressing viral load and return to health.

Another key feature is a regimen that she switched from. She was initially on efavirenz/FTC/TDF, which is the regimen that’s associated with the lowest amounts of weight gain. It has led us to think differently about when you change from that particular regimen to others. But that’s not her question. Her question is whether what she’s taking right now is making her gain weight. That’s a really hard question to answer in a couple of ways.

One thing I’ll highlight, though, before we move into the specifics about considering integrase strand transfer inhibitor-based weight gain versus other types of medications is to mention that the patient you’ve described here is a 54-year-old woman. Six years ago, at the time of the switch to Biktarvy, she was likely to be perimenopausal.

There’s some work from Rebecca Abelman in the MACS-WIHS Combined cohort that has looked specifically at switched INSTIs during the menopausal transition with possible bigger implications for weight gain concerns in that specific population. I’d also say that perimenopause, regardless of HIV status, is a period of time where body fat distribution changes, and weight gain can be a challenge for many women.

That’s not a super satisfying answer, but one for us to keep in mind as we think specifically about her trajectory through weight. There’s a lot of different conversations about weight gain and antiretroviral therapy, but why don’t we start specifically talking a little bit about the integrase strength transfers as they were the canary in the coal mine on this question. Do you agree with me, Chris?

Chris:
For sure, Eileen. The real concerns with HIV meds and weight gain came from the INSTI class. To bring this into a wider context, first, there are lots of medications that we use for a variety of conditions, for mental health conditions, for endocrine conditions, and others that can contribute to weight gain. So certainly the concept of a medication and weight gain is very valid and has been clearly demonstrated with a variety of medications. And it could be the case with HIV meds as well.

The first concerns, as you said, were noted with the integrase transfer inhibitors or INSTIs in retrospective studies from the U.S. The first study that I was aware of came from a cohort at Vanderbilt. They observed that patients who were switched from Atripla to an INSTI, compared to those who were not switched, tended to gain statistically more weight, approximately three kilograms versus one kilogram for those who were not switched. This study and other observations around that time has led to a lot of work in trying to understand integrase strand transfer inhibitor and other medications in relationship to weight gain.

Before we get into other studies, I wanted to pause and say that many are looking broadly at populations, sometimes looking at men or women or by age groups, there’s a lot of individual variability depending on stage of life, perimenopause, and other factors. All of those can contribute to weight gain, in any context, whether or not somebody’s living with HIV and may or may not influence how medications mediate or modulate that weight gain. So while the literature tends to look at populations because it’s hard to assess on an individual level how a medication is affecting, I always take the approach that it is plausible that an individual is an outlier in the way their body is responding to a medication.

Eileen, do you have any additional thoughts about the concerns around INSTIs, different time periods and weight gain?

Eileen:
Chris, that study that you mentioned from Vanderbilt was exactly the study that was responsible for the shift in my notes in that discussion with the one patient. In particular, they looked at different types of patients. Women were more likely to show disproportionate weight gain in that original study. That was the first one that we think of as identifying that this might be something that’s happening.

I also want to briefly point to what you said about considering each person as an individual. In the end, whether or not we actually think there’s robust clinical trial data that a medication is causing weight gain is one question. But whether it’s important to validate a patient’s experience with taking a medication is a totally separate question. I always find a way to say, “You know, I can’t say necessarily that there’s good trials that would support that this is happening, but I hear you, and I understand that you’re saying this is what you experience.” This is for any side effect. And then what we try to do is have a conversation about what it would mean to switch, what the profiles of other medication regimens are, and think about that as a true fact for that person’s experience and then weigh it against the other potential effects of other regimens.

Validating an individual’s response or their lived experience of being on a medication is really important. At the same time, we’re also obligated to provide them with the data about whether or not there’s strong evidence that their experience is actually tied to that medication. So Chris, as far as thinking about INSTIs—that paper you cited was the first one. Another study that comes to mind right away is the ADVANCE trial, which was published in the New England Journal in 2019 and looked at dolutegravir plus 2 different formulations of tenofovir, either TDF or TAF, in comparison to the standard regimen at the time in South Africa, which was efavirenz/FTC/TDF. In that study, they found greater weight gain in regimens that included dolutegravir, and this was even more pronounced when TAF was used as compared to TDF.

Building on the theme that you’ve already mentioned, there was substantially more weight gain among women in that trial as compared to men. That was a treatment initiation trial, but it did suggest that there was something happening with the dolutegravir-based regimens as compared to the efavirenz-based regimens. And it also was one of the first times we saw evidence that it wasn’t only the INSTI class that we should be considering, but also potentially the NRTI class.

Chris:
There was a signal there that TAF was also potentially contributing to weight gain. In a follow-up to the ADVANCE study, the CHARACTERISE study, in which individuals who were in ADVANCE were then switched to standard of care in South Africa, which at the time had shifted to dolutegravir plus TDF, FTC, or 3TC. Individuals were observed over time in terms of weight gain and viral suppression. And again, there was a difference. People who were switched from dolutegravir/TAF/FTC, who were women, lost weight after that switch, while men, who had not gained as much weight on the TAF/dolutegravir regimen, did not lose a statistically significant amount of weight after that switch either.

Eileen:
Chris, one other thing I’d like to bring in here though is that we’re talking about weight gain as a negative, because in our modern U.S. culture, weight gain often is a negative thing leading to either overweight or obesity. There have been studies that show that the weight gain is not necessarily neutral, that there are associated complications, either with metabolic syndrome, glucose intolerance, those types of consequences of weight gain. So it’s not just weight gain—there’s also health consequences associated with that.

However, there’s also work that looked at weight gain that is desired. This would be in the context of pregnancy, where women living with HIV are known to not gain the amount of weight that their HIV-negative peers do. Weight gain during pregnancy is a goal. It helps to support the growth of the fetus and better birth outcomes.

There is a trial that looked at women initiating dolutegravir compared to efavirenz during pregnancy, and they showed that the women who initiated dolutegravir had more weight gain between 18 and 36 weeks of gestation. Now, neither one of these groups gained as much weight as they should, but initiating dolutegravir compared with efavirenz during pregnancy was overall associated with getting closer to the goal of weight gain that would have been set for these individuals.

So this I bring that up to point out that it’s not necessarily that INSTIs or TAF (as we have now opened the the suspect to include TAF here as well) are doing something that is negatively impacting the body by driving weight gain. It could also be that there’s a suppressive effect of efavirenz and TDF, such that even when your goal is to gain weight, like during pregnancy, you are less likely to do so.

Chris:
Great point. In terms of the TDF and dolutegravir or INSTI story overall, in addition to the clinical trials that we’ve mentioned, there have been a number of meta-analyses of RCTs that were not focused on weight or weight change, but focused on comparing regimens, just like the ADVANCE trial, that also identified a signal of increased weight with either an INSTI class or TAF. In those studies, typically weight gain was looked at as an absolute number, but then also to your point that there is healthy weight gain and then there’s weight gain that may lead to metabolic complications, many of those studies included either people reaching criteria for obesity based on BMI or an increase in weight when they already had obesity.

Eileen:
Chris, just to level set us here—in talking about this so far, we’ve established that, as you put it so clearly, some medications are associated with weight gain outside of HIV care, and the story that’s been emerging within HIV care over the last decade or so is that it does seem like weight gain is a feature of starting ART and also can be a feature of changing ART, and there may be some regimens that are associated with greater weight gain versus
other regimens.

There’s a couple of studies published in CID in 2020 that look at meta-analyses, one from Paul Sax, which is a pooled analysis of randomized controlled trials, looking at how different regimens were associated with weight gain, and then one from Jordan Lake and Christine Erlandson that looked at switches and the implications for weight (we can put those references in the show notes). There does appear to be some increased weight associated with INSTIs and maybe specific formulations of tenofovir.

But now let’s bring us back to the question of what do we say to our patient and how do we think about what to do about that? Maybe you could briefly talk about some of the studies that have moved past this—so, okay, we accept that this may happen. What can we do? For example, does switching your regimen actually help?

Chris:
Fortunately we have more studies that give us insight into whether INSTIs or TAF truly promote weight gain or whether components of the regimen, such as TDF or efavirenz, lead to suppression of weight gain, and we have switch studies that were designed specifically to see if an alternative regimen would help with weight management or lead to weight loss.

Before getting into those, overall, I wanted to mention while we talk about a proportion of individuals reaching obesity or gaining 10% of body weight, in almost all of these studies, a proportion of individuals actually lost weight on whatever regimen. Reasons for weight loss could be anything. They could have chosen to go on a weight loss program, increase exercise, or other health reasons for weight loss. I mention this because it is not a uniform or universal finding that people gain weight. It’s really helpful when I reflect on that, when I’m talking to patients, that I know that people are able to lose weight intentionally, even when they’re on regimens that may not be entirely weight-friendly.

Eileen:
I would draw attention to the DHHS guidelines. An update in September specifically says that considerations around weight gain should not be a driver of regimen choice. The reason for that is, as you highlighted earlier, there’s variability among individuals in terms of weight gain or weight loss.

We still have the empowered view that likely any impacts on weight gain could be modulated by behavioral changes and or use of other pharmacotherapies specifically for weight management. I do find that data about TDF versus TAF super interesting, but I don’t want the interpretation to be that we should choose TDF for people who we pre-specify as being at higher risk for weight gain.

To that point, there are some populations who seem to be at higher risk, age, female sex. There are conflicting data about whether your baseline BMI is predisposition to gain weight or not. In my clinical anecdotal experience, I haven’t actually noticed that people who are already overweight tend to gain more weight. But again, there’s conflicting studies on that point. We still should be choosing our regimens based on virologic efficacy and overall side effect profile, of which this is one potential consideration, but not the only one.

Chris:
In terms of your point of weight gain and regimen selection, there have been additional studies, including some cohort studies recently described at IAS in 2025. In that one, looking at EMR from 12 sites in the U.S., what you mentioned, individuals who had a higher baseline BMI tended to gain more weight. African Americans or Black individuals also gained more weight. Women and younger individuals gained weight. While the actual regimen that people were on in that study were not associated with weight gain.

In addition to your point of switch, certainly the DHHS guidelines make it very clear that weight considerations are not a reason to switch to an alternative regimen. This is supported by the cohort studies, but also with data from RCTs specifically designed to try more weight-friendly regimens.

One is ACTG study, the DO-IT study, in which doravirine/TDF/FTC was compared to doravirine/TAF/FTC, and with a third arm of continuing an INSTI/TAF regimen that individuals were on. This was a switch study. And there was no statistically significant difference in weight change in those 3 arms. So even selecting an agent that has been shown in some studies to perhaps limit weight gain, that is TDF, when used as a switch agent did not appear to have a statistically significant impact on weight gain.

There was also a study that used a switch from an INSTI to a PI, the DEFINE study. Similarly, there was no advantage in terms of weight change over time. So the take home, at this point, is that efavirenz and TDF probably suppress weight gain. There’s not really a clear increase in weight driven by INSTIs, TAF, or PIs. Thus, the guidelines, as you mentioned, from DHHS do not recommend a switch. It’s unlikely to make a difference for a patient based on the clinical trial data that we have.

So circling back. What should I advise my patient at this time in terms of her current regimen, alternative regimen considerations and her weight loss goals?

Eileen:
The first thing is to assess her level of belief in this association and whether there’s a possibility that her belief that her regimen’s contributing to weight gain might lead her to be nonadherent, because that is a real risk. We can be perfect scientists all we want, but if a patient believes that something is causing an adverse effect, it would not make sense for that patient to continue to take that medication, and they probably won’t.

So my first step is to try to understand the patient’s feelings, perspective on this question, because although I may not have evidence that it will help, there’s also not evidence of harm with switch, as long as it is to another fully effective, fully suppressive antiretroviral agent. As long as we have a discussion about the potential adverse effects of that switch, I’m open to this because I believe that we really need to know where people are coming from, and this is shared decision-making. There really isn’t any data to suggest that there’s a harm associated with switching to another equally efficacious regimen.

The other discussion to have with this patient is about other modalities that are important for weight management. Has she gone through menopause? Has she been seen by a menopause specialist? Are there particular issues that might be addressable there with the understanding that there’s a window for use of hormone replacement therapy that is missed sometimes because we don’t ask people about it and that it may have substantial benefits for quality of life, sleep, and other things that actually might contribute to better management of weight.

The second thing is to discuss specifically behavioral management for weight, including exercise, diet, nutrition referral when possible, and basic education about how to think about optimizing your diet to maintain or reduce your weight.

Finally, to think about pharmacotherapies. While there are only small studies looking specifically at the use of things like GLP-1 therapeutics in people with HIV, in general, those trials have shown that people with HIV respond similarly to those without in terms of both weight loss and loss of visceral fat accumulation and are likely to see many of the same benefits. While there are potential concerns about the considerations around loss of muscle mass that may be associated with some of those agents. It’s been studied in the lower dose range in people with HIV with good results, so that also needs to be part of our conversation with our patients. What do you think, Chris?

Chris:
Definitely, your approach of validating the concern, reassuring regarding an antiretroviral regimen or making a switch if it’s going to be essential for adherence and then providing additional resources and guidance in terms of weight management. GLP-1s have provided success to a number of my patients for their weight loss goals as have various behavioral strategies. One size doesn’t fit all, and trying to bring in dieticians, weight loss experts has also been very helpful for me.

The last thing I want to mention is sometimes I will, or pretty much always will, provide a graph, either hand drawn with Excel or through the EMR, of weight change over time, trying to identify with them changes that they went through at various times that may be correlated with differences in weight gain during that time period. It can help both identify alternatives in their mind to their HIV meds. Or if, when they made a switch, there was a big gain, for example, from Atripla to Biktarvy, understanding that, yes, maybe medications were related, and now we have to figure out a behavioral and perhaps GLP-1 strategy to reach their weight goals.

Eileen:
I love that, Chris, to use a graphical aid to empower the patient, right, to see their own trends and look at their data, validate their experience, or to suggest that maybe there was something else going on, and then to take that as not necessarily the end of the story, but the start.

So now we have this information, and how are we going to move forward?

Chris:
Eileen, I couldn’t agree more. I had a good discussion with this patient about some of the data that we talked about today, perhaps not in such depth, and her overall weight loss goals, validating the importance of a healthy weight for physical function and her long-term health. We decided to continue the Biktarvy for now, although I did offer her the opportunity to reconsider that in the future. We discussed possible GLP-1s. She felt she was not quite ready for that yet and had some concerns from things she had heard on social media, which I did not get into in this visit, but maybe we’ll get into in a future visit. I referred her to a weight loss specialist who can help with some additional dietary considerations. We’ll see how she does from there.

Very much appreciate having this discussion with you, Eileen, and appreciate all who are tuning in today. Thanks so much.

Announcer:
Thanks for listening to Viremic. If you enjoyed the show, please subscribe wherever you listen to podcasts. We’ll be back in a couple of weeks with a new case to discuss.

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.