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Weighty Matters: A State-of-the-Art Update on Body Habitus Changes in People Living with HIV

Dr. Richard Elion (George Washington University): Hi. My name is Dr. Rick Elion. I'm a Clinical Professor of Medicine at George Washington University in Washington, DC. I've been active in the fields of HIV and clinical research for over 40 years, and one of my main areas of interest has been weight gain, the association with ARTs and other factors, and therapeutic strategies to make HIV a long-term condition and not be limited by any weight gain. And I'd like to talk about Weighty Matters: A State-of-the-Art Update on Body Habitus Changes in People Living with HIV.

I'm very pleased today to have Grace Mccomsey with me. Grace is a physician who's an excellent researcher and specialist in the area of weight gain, metabolics and impact on health. Grace is the Vice Dean for Clinical and Translational Research and the Director of the Clinical and Translational Science Institute at Case Western. She is also the Gertrude Chandler Tucker Professor of Pediatrics and Medicine and a highly sought after thought leader in our field and an incredible speaker as well.

ART and Weight Gain: Exploring Causes, Charting a Course 

And let's get into the material. ART and Weight Gain: Exploring Causes, Charting a Course.

Weight Gain While on ART is a Growing Concern  

So weight gain is not just a growing concern for HIV. It's a growing concern across the United States. Weight gain impacts over 50% of the current population. And you know by the explosion of therapies for weight gain, including GLP-1, including other therapies with growth hormone to help people lose weight, has been a huge area of interest for both medical population as well as the public.

Weight gain while receiving ART has been a significant concern since 2017. The pathogenesis of this is multifactorial. Weight gain is not simple. There's been efforts to say it's related to A, B or C, which we'll get to in a second, but it's impossible because so many things can impact weight gain. It's crucial about following HIV to follow the - their weight, to follow trajectories of weight, because weight carries with it associations with other diseases such as diabetes, hypertension, cardiovascular disease, all of which are critical to manage if you're going to improve the health of our patients.

The HIV guidelines do not recommend switching ART based on weight gain, because the association of specific ARTs with weight gain has been inconsistent. And so there's no - no recommendation currently to stop or to - to switch these.

Recent data shows that weight gain is not really modifiable by switching. So weight gain is representing something else other than driven by ARTs. However, and in fact, ART, if you've got a successful regimen, needs to be optimized based on virologic suppression, using that marker of virologic suppression as the marker of what you do, not trying to balance it with what you think is a toxicity to someone's weight, because the association of these medicines and weight has not been proven.

Identifying Populations That May Be Disproportionately Affected  

There are multiple factors. Women have been shown to gain more weight. Black race has been shown to be associated with increased weight gain. People who start off thinner, lower baseline BMIs has been associated with an increased risk of weight gain. That's not necessarily bad, but it's certainly been associated.

People who have more immunologic suppression to lower baseline CD4 cell counts have been associated with increased weight gain. Higher baseline viral loads because we know that viremia creates a catabolic state. In other words, a state where people are losing weight because of ongoing inflammation. And this higher baseline viral load is a - definitely a reason why people will lose weight. And then when you - you start them on treatment and you - you suppress their virus, they begin to gain weight.

So those people are people who have normally been run down when they come in to see you. And there's a phenomenon called return to health, which occurs when people who've been affected by viremia and affected by catabolic processes are associated with infection, start to gain weight when their infection gets improved. And that's why that association of higher viral load is there.

And finally, longer exposure to ART has been associated with a significant risk of weight gain. Now, this is a complex association because we're not sure if that association is because we're watching more survival time. And people in most cohorts, we already said that half of the United States is obese. So it may be that more survival time with viral suppression is associated with weight gain, or there might be other factors related to the control of inflammation that leads to this. So this is still an ongoing area of investigation.

Weight Gain in Persons Living With HIV May Be Associated With Adverse Clinical Outcomes  

Well, weight gain is obviously unpleasant for individuals because of the impact on our energy level, how we feel, how we look at ourselves. But there are also significant consequences in terms of our health. There are adverse clinical outcomes that are associated with this that are serious.

The first is cardiovascular disease. The impact of cardiovascular disease based on weight gain is a significant cause of morbidity and mortality today through increased inflammation, through the impact of lipid transfer, through vessels which leads to atherogenesis and - and other factors that can relate to platelet stickiness. The impact of weight gain in cardiovascular disease is a significant risk to health.

The development of diabetes has been associated with insulin resistance, which then also causes vascular changes and increased rates for diseases. There are certain cancers that have been associated with weight gain, and in fact, we know that conversely increased amounts of exercise protect against certain cancers. So weight and metabolism and what kind of shape one stays in affects our immune system, which in turn can affect our susceptibility to certain cancers.

And finally, there's psychosocial consequences. This is obvious to all our listeners, affecting body image, self-esteem, how we look at our health, how committed we are to our health, how we take care of ourselves, adherence to ART. Weight gain is a multifactorial process that impacts quality of life, duration of life and morbidity for everybody. It's one of the leading health epidemics in the United States and of critical importance.

I have struggled with weight my entire life since early childhood and body image issues. I always thought I was fat, even though I might not have been. So becoming HIV positive, at sometimes, I was at the mercy of the medications I was taking.

Beri: I didn’t know how to manage my weight. I leave calories in, calories out, which never worked for me. And then I learned about the metabolism and the role of insulin, insulin resistance, what macros did what? But I also felt I was at the mercy of what HIV medications would do to my weight and my insulin sensitivity. So when they do the research and trials for these medications, I don't think they look at that. And we have to find out as patients, sort of as guinea pigs as to how these medications affect your metabolism, your weight, stuff like that. So for me, my weight was out of control, especially during menopause, I kept gaining weight. And I decided to give a low carbohydrate diet a try.

And that was the key. Keeping my carbohydrates low, intermittent fasting, and trying to get some aerobic exercise in every hour - on the hour, try to get into fat burn. And then the weight just dropped off and stayed off.

Beri: I taught myself how to eat and be happy with what I eat on a low carbohydrate diet. I am mindful of how much fiber I consume, how much protein, and, of course, how - how much carbohydrate. Fat as a macro is not my enemy. It's more satiating and I didn't ever have to deal with being hungry.

My weight is lower now at 70 years old than it has ever been. I have support groups that help me stay - that's language they use is abstinent from compulsive overeating, which I had done my whole life. Compulsive carb eating and alcohol and all.

So I was on this medication that was known to cause weight gain. And I got kind of in a fight with one of my doctors about it. So as a patient advocate you have to be satisfied with the care you receive from your doctor. And if you're not satisfied, you need to make some noise and possibly get a new provider. So, because I'm on HIV medications that are very agreeable to me. I don't think they have a negative impact on my fasting insulin, which I try to get checked regularly, which is an indicator of how my body is either…

I don't think they should be telling patients what to do without an explanation and making sure the patient understands why a suggestion has been made.

Beri: Explore your patients openness to making dietary changes that will help them feel better and will improve their health.

Let's talk about pharmacologic agents for obesity in HIV and what we know.

Cardiometabolic Consequences of Visceral Fat Accumulation Context of HIV  

One clear thing is that ART switches do not improve weight. So I think that became very clear recently. There has been some nicely done switch studies showing even if you switch people from integrase inhibitors to NNRTIs, any switch in ART in somebody virologically suppressed, does not lead to any significant weight loss. So let's take that out of the equation.

So visceral abdominal fat occurring around the organs. That's what visceral means is, is really a problem. It's associated with the release of inflammatory cytokines. So it produce this proinflammatory milieu. It's strongly associated to metabolic syndrome to diabetes and to higher risk for cardiovascular disease.

In fact, there are studies even in people living with HIV associating higher excess visceral abdominal fat to increase insulin resistance to higher 10-year cardiovascular risk and worse lipid levels. So definitely the weight gain in HIV, specifically that visceral deep fat is not just a cosmetic issue. It is associated with bad metabolic consequences.

ADVANCE: Risk of CVD and Diabetes, Age ≥30 Yr            

So let's look, for example, at ADVANCE. It's a very important study that was done and really highlighted the enormous amount of weight gain that people sometimes experience after starting their first ART regimen. So this is a study that randomized people to dolutegravir with FTC/TAF or dolutegravir with FTC/TDF or efavirenz/FTC/TDF.

You see 10 kilograms mean gain in weight in the dolutegravir/TAF/FTC in an enormous amount actually, compared to six kilograms when TDF instead of TAF, and 3.7 with efavirenz/TDF and FTC.

That highlighted two important things regarding ARTs. The first one is that TDF is really weight suppressive. So now we know that TDF by itself cause a loss of weight. So, of course, you know, if you substitute with other NNRTIs like TAF, you are going to see more weight gain than TDF. And also efavirenz has that effect. So both TDF and efavirenz have a weight suppressive effect.

Now looking at the 10-year cardiovascular disease risk. And you see that the weight gain associated with each of these three regimens was associated with a higher 10-year risk of CVD. So that the dolutegravir/TAF/FTC arm had significantly higher 10-year risk of CVD compared to efavirenz/TDF and FTC. So it wasn't just more weight gain. It was also higher risk of CVD.

And same thing for the higher risk of diabetes. So there is a formula for 10-year risk of diabetes. And again, higher risk of diabetes with the agents that produced the larger weight gain which is the dolutegravir/TAF/FTC. So again, it's not just a cosmetic issue really associated with a lot of metabolic concerns and cardiovascular concerns.

How Can HCPs Identify and Treat People Experiencing the Impulse Body Habitus Changes?  

So what do we do? And we have a lot of people in the clinic whose first complaint when they see us is really their body weight. So one thing to recognize, their quality of life, their self-image is really important. And another concern is sometimes they want to stop their antiretrovirals because they think this is what's causing me to gain weight. So it's very important to deal with these issues very seriously and not worry about people stopping or interrupting their antiretrovirals because of the weight gain. So I take it very seriously in my clinic.

It is important to address, you know, what is antiretrovirals doing versus HIV and other factor. Again, not to blame the antiretrovirals for all the weight gain, because that will only lead to people stopping their antiretrovirals, which has a lot of bad effects, obviously. Always start with lifestyle changes, exercise, diet, decreasing or stopping alcohol.

And yes, it's hard. It's hard for everybody. We know that. But lifestyle factors are very important in people's well-being overall and weight gain in particular.

Diabetes Drugs Have Shown Promise for People Living With HIV

So how about diabetes drugs? Metformin has been studied in HIV. Yes, it can lead to overall weight loss, but it has some adverse events. And then also in the days of lipodystrophy, metformin had worsened lipoatrophy. So the peripheral fat loss that people had with lipodystrophy, metformin worsened that. So it's not an agent that we use very commonly, at least not for weight loss.

How about GLP-1 and GIP receptor agonists? So, the data in HIV, which I'll show you, you know, is not a lot yet. We still need a lot more data before we just give them to everybody. So there are some issues with these drugs, even though obviously they do help a lot of people.

Outside of HIV, tons of data now. Semaglutide, which is probably the most common or commonly used GLP-1 receptor agonist. There's a lot of data with the new tirzepatide, which is a combination of GLP-1 and GIP receptor agonist, seems to be even better than semaglutide and the GLP-1 receptor agonists.

Semaglutide in People With HIV-Associated Lipohypertrophy and Weight Loss Outcomes

So what do we know in HIV? There has been only one randomized, placebo-controlled trial so far in people with HIV. This study actually happened in Cleveland. I myself led that study. We randomized people who had gained a lot of abdominal fat after ART initiation, randomized them to either weekly subcutaneous semaglutide or placebo for 32 weeks. After that, we stopped the drug and followed them for another 24 weeks.

So what we saw is a very significant decrease in total fat as well as visceral adipose tissue. However, we saw three things, in my opinion, that we should be careful about.

The first thing is the limb fat, so the fat in the arms and legs did go down as well. Usually not a problem. However, in people with HIV, we still have a lot who had lipodystrophy who continue to have very thin legs and arms. Lipoatrophy may worsen after GLP-1 receptor agonists. So this is something to worry about and honestly specific to people with HIV.

The second thing is the issue with lean mass. So everybody wants to lose fat, but nobody likes to lose muscle. So what happened with GLP-1 is we saw a very significant decrease in lean mass. So it is concerning in a condition like HIV where people have sarcopenia. So we want their muscles to stay in good shape. And that's why it is important for people who take GLP-1 to exercise so they can continue to sustain a good muscle mass.

And the third thing is what happened after we stopped the semaglutide? So yes, people did wonderful. They wanted to stay on it forever. We stopped it for 24 weeks. After the 24 weeks, they gained back almost the entire amount of fat that they had lost with semaglutide. So that is a problem. You know, yes, it's good to give it. People are happy, but you have to continue it. As long as you continue it, they seem to continue to lose weight. But you stop it and everything is back to baseline. So that is obviously a big concern.

Semaglutide in People With HIV-associated Lipohypertrophy Effect on Inflammatory Markers

So what we saw in the study is not only fat muscle went down, but also some specific inflammatory markers. So remember, people with HIV have a lot of systemic inflammation. Even after 10 years, 20 years of being virologically suppressed, they have a lot of inflammation. So what we found is semaglutide was associated with a decrease in several of the inflammation markers, namely CRP and soluble CD163, which is an important marker of monocyte activation.

Semaglutide in People With HIV: Reduction in A1C  

Something I want to mention. We - we also have a publication looking at cognitive function on semaglutide. And even after 32 weeks only of semaglutide, we had some strong signal of improved - improvement in some of the cognitive domains. So - so the reason I mentioned that is there are a lot of potential benefits of semaglutide other than just fat to - to keep in mind.

So how about A1C? Of course, A1C went down. This is a diabetes drug. So A1C in our study, as well as in an observational study from CNICS cohort, A1C significantly decreased after semaglutide. So even people without diabetes, you will see improvement in hemoglobin A1C.

Tesamorelin: Novel Option for People Living With HIV  

So after GLP-1, you know, there's another drug that I think a lot of people forgot that it was FDA approved and continued to be FDA approved for reducing excess visceral abdominal fat in people with HIV. The drug was initially approved in 2010. There was, in 2025, a new formulation so that it can be reconstituted once a week for daily subcutaneous injections in a much smaller volume.

So what the drug does is stimulate pituitary gland to synthesize and secrete the endogenous growth hormone. So it's different than giving somebody exogenous growth hormone. This is stimulate your own growth hormone to be produced in excess.

Tesamorelin in People Living With HIV: Improvement of Muscle Density and Area

So the studies actually have been done some time ago. There were two large phase III clinical trials that showed a very significant decrease in visceral adipose tissue in people who were living with HIV and have excess visceral adipose tissue, kind of the same population than what we studied in the semaglutide study.

So what they found, in addition to the visceral adipose tissue, is a significant improvement in muscle density and muscle area. So - so this is different than with semaglutide where I was very concerned, as I said, about the large decrease in muscle area that we found. Here, they found actually good results on muscle area and muscle density. So how much the muscle is kind of packed. So the density is high, it's good. There's a little bit of fat - less fat versus - versus bad quality muscle.

So it was, you know, better results on muscle area and muscle density with tesamorelin, although the visceral abdominal tissue decrease was very similar to what we saw with semaglutide.

Tesamorelin May Reduce ASCVD Risk Scores for People With HIV

And also tesamorelin decreased the 10-year CVD risk score in people with HIV, and specifically those who had higher risk score at baseline showed the largest amount of decrease in their 10-year CVD risk.

Speaker: I have had a horrible weight gain actually. My body started wasting years ago, so my belly is big. I feel unattractive.

My stomach. I'm being told to tie my shoes all the time, you know? And I'll be like, yeah, okay, okay, you know. But my stomach's so big when I get down there to my thighs, it's like, I got to really sit down and do some different stuff because this stomach is sitting on my daggone lap sometime.

Like it's - it's hard to find clothes or it's hard to wear things because the belly's so big and the legs are so skinny, you know?

I'm trying to do things different. You know, we just have to do things different and think different, eat different. We - some of us got to get up off that couch. Some of us got to get a activity and get a life because there's a lot of us don't even want to come out into the world and be a part of things because of the way you look, you know?

I just wish that, you know, they could do something different and help it to get better. You know, like, I don't want to be feeling uncomfortable my whole life, you know? I've already got to deal with a lot of other things.

So in summary, weight gain in people living - living with HIV is associated with important consequences. I would say the cardiometabolic consequences we're only seeing, you know, scratching the surface. This is a problem. And with time, I do expect to see a lot more diabetes, heart disease as we're seeing now, but even more, unless we do something about the weight gain in people with HIV.

Also, don't forget the psychosocial aspects in my opinion, very important. When you see decreased quality of life, decreased self-esteem, not only it affect, you know, their feeling, their well-being but they can't exercise, right? So it's like a vicious cycle with more and more gain - weight gain, and it start affecting their antiretroviral adherence. You don't want that. Don't want people to stop their antiretrovirals.

Pharmacologic therapies, we do have some good positive data. We need a lot more data with GLP-1 receptor agonists. We need longer term studies looking, you know, in details at all the side effects. Like I said, the effect on muscle concerns me. The short term durability of the effect of semaglutide concern me because, again, you stop it. And then shortly after all the weight is gained again. So we still have a lot of data to get with the GLP-1 receptor agonist. And tesamorelin has a good profile on fat as well as muscle and a potential good decrease in the risk of cardiovascular disease down the road.

So identifying suitable candidates for therapy is really key. And that is something that we need to study more in large observational study.

So thank you for listening today. And hopefully you learned a lot about weight gain and what to do about it.