Today Dec 01, 2021

Conversations in Antiretroviral Weight Gain

Description

Speakers:
Paul E. Sax MD
Clinical Director
HIV Program and Division of Infectious Diseases
Brigham and Women's Hospital
Professor of Medicine
Harvard Medical School
Boston, MA
 
Robert Dodge, PhD, RN, ANP, AACRN
Professor of Medicine/ University of North Carolina School of Medicine
Department of Medicine/Institute for Global Health & Infectious Diseases
Clinical Director/ Wake County Health and Human Services
Infectious Diseases Clinic B
Raleigh, NC

Learning Objectives
*Discuss risk factors for antiretroviral weight gain
*Debate the clinical significance of antiretroviral weight gain
*Apply appropriate ART modification strategies for patients experiencing Antiretroviral Weight Gain

Program Summary
Weight gain associated with the use of certain antiretroviral therapy regimens—particularly some nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors—is an active area of research and a topic of growing interest for HIV providers. Data are rapidly accumulating on the matter, but the overall significance of the results and how to address this weight gain are not fully understood. Join Paul Sax, MD, and Robert Dodge, PhD, RN, ANP, AACRN for an engaging discussion on risk factors for antiretroviral weight gain, current thinking on the underlying pathophysiology, and how they respond to this phenomenon when it arises in their patients.

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Transcripts
Slide 1
Paul E. Sax, MD: Hi, everybody. Welcome to today’s topic, which is Conversations in Antiretroviral Therapy Weight Gain. I’m Paul Sax and I’m Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School and I am joined today by one of my long-term HIV colleagues in HIV practice for a long time, just like me, Robert Dodge. Robert why don’t you introduce yourself.

Robert Dodge, PhD, RN, ANP, AACRN: Thanks, Paul. I’m Robert Dodge, I’m a nurse practitioner by trade, but I am a Professor of Medicine at University of North Carolina School of Medicine. I’ve been practicing for a long time, as Paul said. I currently work at the health department, so I run their program at the health department here in Raleigh, North Carolina.

Sax: Great! Thanks a lot for joining me today, Robert.


Slide 2
Sax: So, this is what we are going to discuss. I think we should begin by talking about the issue of weight in people with HIV without effective antiretroviral therapy and Robert maybe you can share with us some of your experiences from the pre-ART era of what it was like managing people with HIV who did not have effective treatment.

Dodge: Yeah, so pre-ART and things we will talk about later, but in the beginning it was just trying to get people suppressed, keeping them healthy and then when we came along with protease inhibitors, and this is what we will probably talk about with the weight gain, is I wasn’t always sure of who was going to get lipodystrophy versus lipoatrophy and it, for a while I thought I could definitely say this person was going to get it, but then as the ARTs got better, it made it more difficult and I think that’s what hopefully you and I can share as we go through with this presentation.

Sax: Yeah.

Dodge: That weight gain is sort of, at least to me that’s how I see it in my mind, that weight gain is (1:47) days with lipodystrophy, who is going to get it, not get it and what do we do about it? 

Sax: You know, I think though, what I was kind of referring to is we kind of skipped a step. I mean before we had effective HIV therapy, weight loss was actually the dominant worry of many of our patients and, not surprisingly, it was a sign of progressive HIV disease and sometimes underlying opportunistic infection. But, then you are absolutely right, when we had effective therapy in the late 1990s we then started to see these strange changes in body habitus that we called lipodystrophy syndrome, and sometimes people had massive fat accumulations in various parts of their body. We were never quite sure exactly what caused it or whether it was a specific antiviral strategy or whether it was something about their underlying genetic predisposition, but that has mostly gone away and what we are left with now is really a substantial amount of weight gain when people start effective antiretroviral therapy.

Before I actually show some data on this, give me a sense, when you talk to your patients, about what you tell them, who are starting HIV therapy, what you tell them about what is going to happen with their weight.

Dodge: Yeah, it’s ironic; I sort of had to rethink how I do my education about initiating ARTs. Probably a few years ago I would never say anything about weight because (3:14) they are going to gain some weight because that is sort of return to health, but now, probably in the last year or so, what I go through what are the common side effects they are going to experience, I also mention that there is some data that says certain ARTs may cause some weight gain. 

So, what I want from you as my patient, I want you to notify me right away, as soon as you start seeing some kind of weight. Don’t wait for your three months or six months appointment because, as we all know, once weight goes on it is sort of hard to come off, so I want to deal with it now. So, my spiel is now another minute or two, let’s talk about your weight. If you get it, call me, so we can address it. So, of course, as I live in the south, the big one is going to be I need to make sure you are not stopping at the Bojangles or some other fast food (4:02 crosstalk). So, I think we have to incorporate that, and yeah I now add weight as a possible side effect that we may have to address.

Slide 3
Sax: Well, it is very important that we discuss this with patients because it is inevitable that they are going to gain weight and I really like this study, which was done from the Kaiser cohort and it really compares people with HIV to people who don’t have HIV and their weight trajectory over time. This is really a very large study. You can see nearly 4,000 people with HIV at normal weight at baseline or underweight at baseline compared to 3,200 who don’t have HIV and what you notice is that the people who start with HIV, the slope of their weight over time is steeper and that is true for people who are normal/underweight. It is true for people who are overweight at baseline and it is also true for people who are obese at baseline and so for each of these 3 categories, we are seeing that people with HIV who start treatment end up gaining weight more than HIV-negative controls.

Now, obviously, some of this is a return to health phenomenon. I mean that’s key. I mean I mentioned before, people without ART would lose weight and I remember seeing someone with pneumocystis pneumonia about four or five years ago, at very advanced disease, and he was desperate to gain weight because he had lost so much weight a lot of his friends and family members thought he was dying of cancer. It turns out he just had a late diagnosis of HIV. But, his primary motivation for going on HIV therapy was to gain weight and start looking normal again. So, that part is good, but there is a not-so-good part, right?

Dodge: Yes.

Sax: So what’s the not-so-good part?

Dodge: I guess, for me, the not-so-good part is the long-term (5:57) is the long-term complications of this weight gain, so how many of these people end up getting diabetes, are they going to get fatty liver disease, other cardiovascular. And for me, I do primary care as part of their HIV, so I have to manage those things, so I need to; and that is part of that weight, the original question you asked me about weight gain, so I want to address that weight early so we can get rid of it. So I don’t want them, five years down the road, to develop diabetes, a fatty liver that is harder for us to manage. So, the long-term complications are the possible side effects that are going to evolve out of the weight gain.

Slide 4
Sax: Yeah, I think this has become front and center in our discussions with patients because the best regimens we have are also the ones associated with the most weight gain and I was very fortunate to be involved in a collaboration of investigators who looked at this question for starting therapy and looking at really this nearly 6,000 people enrolled in phase III clinical trials. So, you know the baseline characteristics at the start of this study are similar between the groups because it’s a randomized clinical trial. 

Then looking at weight changes over time, this weight was collected in all of these studies and recorded partially to calculate creatinine clearance. And what is seen in this figure is that the integrase-based regimens clearly are associated with the most weight gain and then the PI and the NNRTI-based regimens are about the same, there is no difference. Then in the central panel, looking at the three most commonly used integrase inhibitors in these studies, bictegravir, dolutegravir, elvitegravir/cobi, you can see that bictegravir and dolutegravir have the most weight gain, followed by elvitegravir/cobi and all the guidelines recommend using bictegravir and dolutegravir. 

So, that puts us front and center into the weight issue, and then you only augment that, if go to the far right panel of this, by looking at the various nucleosides and a couple of observations here, clearly the most weight gain is with tenofovir alafenamide as a first treatment nucleoside, followed by abacavir and then tenofovir disoproxil fumarate seems to be relatively neutral from a weight perspective, but the worst of these is zidovudine. I say the worst because some might look at this and say, well no that’s good that you have stable weight over time, but these are people starting the antiretroviral therapy. We want them to gain some weight and when you look, zidovudine is actually negative and what do you think that implies about zidovudine?

Dodge: Yeah, so I mean for me, I have two visions on that. So people have such negative visions of zidovudine from the past where they lost their weight and all the toxicities. So, that leads to, especially for my patient’s if they are on zidovudine, they don’t tolerate it and they end up not being adherent. So, they are not going to be suppressed and they are not going to get the optimal care they need.

Sax: So, yeah, these figures, what they do is they give you both, look certain regimens are associated with more weight gain and we have an obesity epidemic in the country, so that’s a problem. On the other hand, they show you, at least with the zidovudine result, that toxicity can blunt weight gain and we are not sure why that is.

Let me also just mention tenofovir disoproxil fumarate because it has special relevance, I think, for when we talk about switch strategies. But, would you say that most of your patients now are starting a bictegravir or dolutegravir-based regimen?

Dodge: I would have to agree probably a good 80-90% of those, but as we go through this, I definitely have started to rethink this, based on the data we are going to show the group, just because, again, I am their primary care on top of their ID and I need to think about the long-term. I want them to live longer than the mean practice, so I need to think about these possibly long-term.

Sax: Let me mention something else we found in this study was that, and this has been replicated in various other analyses, in that there were certain factors that lead to more weight gain and one of them is having more advanced HIV disease and that is because you are reversing the catabolic and ill-health properties of HIV disease. Another one, which has been very commonly observed, is the female sex and black race. So, in addition, we found that younger people had greater weight gain and actually this says higher BMI, but it actually lowers BMI. I’m sorry about that.

But anyway, I’ll tell you this study has been widely cited and I think appropriately so, and again I’m very grateful to the collaborators of this study, who were able to assemble these data.

Slide 5
I was on a different study group looking at the whole issue of the switch and I really want to call out Kristine Erlandson for leading this one. This is really a superb study. It basically did something very similar to what I just described looking at prospective clinical trials of people who are suppressed and really very healthy. And they were randomized to stay in their current regimen or then switched to something else and that again because they are very similar at baseline it gives us a really good idea of what the HIV drug-specific effects are when you make these switches. Because of the previous study, the one that I mentioned about starting therapy, some of that is returned to health. But here we are actually talking about stable people on ART who experience weight gain. 

Before I go over the results, I am just wondering if you have strategies. Let’s say you start your patient on a TAF-based and then a bictegravir or dolutegravir-based regimen, Robert, and they gain back the return to health and then they overshoot and now they’re moving into the obesity category. What do you do first for management, as far as, before you, I mean it could be anything, it could be counseling, it could be switched ART, etcetera?

Dodge: So the first thing I always do is nutritional counseling. I’ll do my part about trying to get a really good history of what their diet is. COVID is a good example of people who have been unemployed or whatever and they have been eating things that shouldn’t be. But if I’ve met with them a few times, then I’m fortunate enough that we have a nutritionist on staff who would then do her spiel and between the two of us, then I start down the track, alright we need to rethink of, do we need to change ARTs or what do we need to do. That is the step that is going to be confusing. I know we are going to talk about some about it, but that is usually that, I’ll do my part, get the nutritionist, and then we have to start thinking about switching therapy. 

Sax: That’s really helpful. You know one other thing that someone mentioned to me because I’m an infectious disease specialist, they go, you know there’s a lot of noninfectious disease causes of weight change and you know it’s important obviously to rule out things like hypothyroidism or patients who may be still on a booster, are they getting exogenous corticosteroids, is the person going through some other hormonal/metabolic changes, have they changed their diet or exercise routine.

Probably the most convincing people who’ve have had ART-related weight gain are to me the kind of obsessional exercisers. I don’t know if you follow any these people who just like exercise like crazy and they know exactly what their dietary intake is and they say I’ve changed nothing except for my HIV therapy and look, I’ve gained weight. Have you had any of those cases?

Dodge: No, unfortunately not.

Sax: Okay. I definitely have you know. There are people who are obsessional about exercise, they never miss, and they are counting every calorie and are very carefully doing things. 


Slide 6
Anyway, so what was found in this study is that there were certain things that lead to more weight gain. And you’ll notice that people who switched off efavirenz and here they switched off efavirenz and even if they stayed within the same drug class, they switched to rilpivirine, they ended up having a significant risk factor of gaining more than 10% of weight. This is the people who gain a lot of weight, more than 10%. So that is 4.2 odds ratio, highly statistically significant, so we tend to think of this as a class effect. Oh, you’ve got integrase inhibitors and they are culpable, but here switching from efavirenz to rilpivirine, staying within the same drug class, it was associated with weight gain and possibly that is because of the advice we give to people when they start rilpivirine, right?

Dodge: Yes. Take it with food.

Sax: Gotta take it with food. You know, and we kind of make it clear that it’s gotta be on a full stomach, not just a snack. I think that has something to do with it, but I also think efavirenz might be doing something in there, but we’ll see. Then switching from efavirenz to elvitegravir, definitely another risk factor. This one we expect because remember this one is an integrase inhibitor and remember the first studies showing that there might be dolutegravir-related weight gain where people who switched off TDF, FTC, efavirenz onto dolutegravir, those were the first reports I recall of weight gain. So, the switch from efavirenz to dolutegravir and to elvitegravir is clearly associated with weight gain. 

Then now on to the nucleosides and this brings us back to that whole part of HIV management, which we so commonly did a few years ago, which is we switch people from old tenofovir, tenofovir disoproxil fumarate, to a new tenofovir, tenofovir alafenamide, and this also is clearly associated with significant weight gain. This has become something that I now say to pretty much everyone who is stopping tenofovir DF. I say this drug tenofovir DF is probably keeping your weight in balance and if we switch, which sometimes is medically indicated to do, you’re probably going to gain weight. I know it is not everyone, but there is almost always some degree of weight gain after switching off TDF. What has been your experience switching people off TDF?

Dodge: I was going to say I totally agree with you and that has sort of become my new spiel; like you’re losing some of that benefit from the TDF, but again they were switched because of medical reasons and probably it’s always those handful who do gain significant weight from the switch. So, I wish, like in the beginning, I wish there was a ball I could say this population is definitely going do it more. I know we mentioned women, African-Americans, so those are the ones I have to be a little more cautious of, but again not all of the get it, so it’s a crystal ball.

Sax: Yeah, I mean one thing that this has done, this particular finding, TDF to TAF associated with weight gain and not just this study but other studies, in particular a study that was done and lead by Paddy Mallon that was just published showing the same thing and then another one from the HIV Outpatient Study, the HOPS group, led by Frank Palella. It has caused many people to think that TAF is causing weight gain and it might be, but you’ll notice that a lot of these studies that show TAF associated with weight gain, a lot of them it is in comparison to TDF, at least to the switches, and I think probably the most illustrative are the people who are on TDF for prep. 

So they are taking TDF for prep or they’re taking placebo. You’ll notice the placebo arm in those studies actually gains more weight than the TDF arm. So, what this strongly suggests, to me at least, is that TDF is doing something to suppress weight, as the placebo certainly isn’t, unless of course the placebo is sugar-covered donuts, which usually it isn’t. So that is actually the point of now my showing you this next slide.

Slide 7
This is a very interestingly, recently presented trial called SALSA, and it takes people who are on stable antiretroviral regimens, a variety of them. So they could be on TAF-based regimens, they could be on TDF-based regimens, it’s about 50/50, and what this showed, and then switching them to dolutegravir/lamivudine and what is shown in this study, which has been shown in multiple studies, that dolutegravir/lamivudine maintains viral suppression without really much any trouble here. These are people with no resistance and they do great. 

But, when you look at the weight trajectories, the people gained weight in this study who switched, and the reason the people gained weight in this study by switching, even though they are not going on TAF remember, is because half the people in this study were receiving TDF at baseline and some of them were receiving TDF with efavirenz and that particular combination is associated with weight loss or lack of weight gain. So, what they are doing is they’re withdrawing those weight suppressive ARTs by going on dolutegravir/lamivudine. 

So, it’s actually quite striking and, in fact, in this study I think 6% of the people in the study who discontinued due to an adverse event reported weight gain as the primary reason they were stopping the treatment on dolutegravir/lamivudine. Does this result surprise you?

Dodge: Well, not really, because like I said, you mentioned that people who were on the TDF, once they went off they gained, and that is sort of some of the same things I see in my practice who I try to simplify them because of comorbidities and I put them off their TDF, on the 2-drug regimen and they would gain this weight, so.

Sax: Yeah.

Dodge: Oops, I did you one favor by solving one medical comorbidity, but then now we have removed some of the factors that help prevent gain of weight, so it’s a balancing act to figure out which is which.

Sax: So let’s talk now about ART switches. Do you think any of the ART switches are going to help reverse ART-induced weight gain? 

Dodge: I’m gonna say anecdotally my answer is yes because some of the things we are going to show are things I do by switching them off TAF, off of integrase and putting them on either a PI or a NRTI. So for me, these studies are going to finally answer am I doing the right things, so these are my mechanisms of trying to solve this problem.

Slide 8
Sax: Yeah. I do want to highlight two studies. Thanks for bringing up the studies and they’re enrolling right now. One of them is this one through the AIDS Clinical Trials Group. It looks at people who are overweight and who have gained 10% or more weight gain over the previous one to three years receiving raltegravir, dolutegravir, bictegravir plus TAF. Then it randomizes them in 3 arms. 

The first is the green, continue their current regimen. The next one is the one above it, which is to switch the integrase inhibitor to doravirine plus TDF/3TC or TDF/FTC. As you remember, doravirine comes packaged with TDF/3TC, which is probably how most people are going to get it, as a single pill, or leave the nucleosides alone and just switch out the doravirine. 

Now this study might answer the question of whether substituting doravirine for the integrase inhibitor leads to weight gain and weight loss or substituting both doravirine and TDF for the integrase inhibitor and TAF leads to weight loss. If I look in my crystal ball, I could sort of predict how this study is going to go. I wonder if you want to make any predictions.

Dodge: So my prediction is based on what I have done in clinical is that people who went totally off their TAF and off of integrase actually have lost weight and still stay suppressed. 

Sax: So you think the key thing is that the dropping of both of them.

Dodge: Yes.

Sax: I agree with you that I think that the purple strategy, that switching both of them is most likely to lead to weight loss, but I actually suspect that it is going to be driven mostly by a reintroduction of TDF rather than the switching of the doravirine for the integrase, but who knows. We’ll see.

Dodge: Will help answer the questions.

Slide 9
Sax: Then, there’s another study which has looked at this, which is basically a similar population of people on integrase plus TAF and here the randomization is to continue what they’re on, or to shift their regimen all to that one pill a day protease inhibitor darunavir, cobicistat, FTC, and TAF. How about your crystal ball on this one?

Dodge: This is the one I am really not quite sure, because you still keeping them on TAF, but is it just enough getting them off integrase to do it? So again, I’m gonna go with my own intuition from the few I’ve done, just doing this switch, and people have done well. So, again I think once we get a larger number of people on, it will help answer. My concern is they are still going to have some TAF, which has shown in previous studies already TAF is a component, so is it just enough to get them off the integrase?

Sax: Yeah, we’ll see. I mean one thing that has been postulated is that some of this absence of ART-related weight gain is toxicity and you know, I mentioned zidovudine is an extreme example, but nobody uses that anymore. But for people who haven’t had much experience using protease inhibitors, protease inhibitors do have the most in the way of gastrointestinal side effects of all of our drug classes, so it is conceivable that there will be some weight loss just by going on boosted darunavir, but we’ll have to see. 

I mean, I think it is sort of ironic. I’m just going to take us back to like the late 2000s when we got raltegravir for the first time and raltegravir, remember, is just this amazingly well tolerated drug, the new drug class integrase inhibitor. It was like the best thing since sliced bread and it did actually save a lot of people’s lives, especially people with resistance. Everyone kind of postulated since metabolically raltegravir was so plain, it would not be associated with some of the problems seen with protease inhibitors and NNRTIs. 

But when we actually looked at weight changes with raltegravir versus darunavir versus atazanavir in ACTG 5257, we did see more weight gain with raltegravir than the other two. I never would have predicted that in a million years that the raltegravir would be the one associated with the most weight gain. So it is possible that just substituting the protease inhibitor for the integrase inhibitor will lead to some weight loss. We shall see. Of course, one gets some other problems with going back on a protease inhibitor, right?

Dodge: Yeah. All the GI, drug interactions.

Sax: Drug interactions. Yeah, I think that’s probably the main reason we have for stopping protease inhibitor use. I mean, obviously it’s a drug class I’m still glad we have, but as far as, you know, the difficulty of using it, especially in older patients who are on other medicines, it is really quite significant. So, any other comments before we go to the polling questions?

Dodge: I don’t. I just think for me as a clinician, these two studies are gonna really help me finalize how do I manage these weight gain issues.

Sax: Yeah.

Dodge: You and I talk about it, I can talk to my colleagues here, and everybody sort of has a different thought or philosophy, so it’d be nice to finally have some good controlled randomized studies to say this is what we need to do to help, if does happen, how do I do it?

Sax: I totally agree. I think those are excellent points. So, let me go now to the polling questions, and here they are.

Slide 10
How many patients do you treat in a week? You get a chance to respond now. You count down and always wonder what to do during these virtual polls, like I wish I had a better singing voice.


Slide 11
Okay, was this content related to your practice? Fortunately these are easy polling questions. And on this one you have to write yes.

Dodge: So I guess while we are waiting, do you know, anticipate when these two studies, the DEFINE and ACTG, when the data will be released. 

Sax: Well the ACTG study just started, so I know you have an ACTG down at UNC, because Joe Eron is practically in charge.

Dodge: Yes.

Slide 12
Sax: Did you enjoy the presentation format of this ClinicalXchange?

So that study is going to actually, it’s going to be a while before we have results of that one. But definitely refer your patients.

Slide 13
Okay. Would you recommend viewing a ClinicalXchange to a colleague?

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