Starting a year or two ago, some clinicians observed that people starting on regimens that include antiretrovirals in the integrase inhibitor class experience weight gains exceeding those seen in people treated with regimens not containing this drug class.
A long time ago, I was in sitting in a sunny office at work getting scolded by a couple of guys from a drug company. The previous week, at a conference presentation in New York I had told the large audience of HIV doctors to take their patients off the antiretroviral that these guys sell since it was clear that it melted the fat tissue—perhaps in a reverse order of importance—of the arms, legs, butt, and face, causing irreversible disfigurement. These two did not like that, not one bit.
“Do you realize, doctor, the harm you could cause by urging clinicians to hastily change HIV meds?” When I cited recent reports and my own observations, one, a doctor himself, chided that I know (or should know) that association is not the same as causation. Regretfully,
I did not tell the pair to fuck off, but stick tight to my guns I did, saying that: a) their drug is toxic, b) they know it, and c) I would continue to tell people to avoid prescribing it (which, I guess, is basically the same as telling them to fuck off).
A rerun of that meeting plays most times I see the hollowed cheeks of the veterans of those early days of highly active HIV therapy; I ask myself if I recognized soon enough the effects of the “d” drugs—d4T and ddI? Could I have protected more people from their ravages? Such an experience sensitizes you and that makes you less likely to miss the opportunity to act early the next time. So, recently as murmurs grew to a roaring alarm that newer HIV medications may be messing with fat—not melting it but laying it on thick—I thought about the meeting with the drug company dudes, the abandonment of the d-drugs soon after, and a foreboding that here we go again.
Weight gain and HIV therapy
Weight is tricky. People are either trying to lose it or gain it (okay, mostly lose it in super-size-me America) with hardly anyone who isn’t incredibly annoying saying they are at the perfect weight and absolutely happy with where the scale’s needle lands. HIV makes this even trickier. Big-time weight loss can happen in those with more advanced disease and is a tell-tale sign of basement-level CD4 cell counts, but nowadays most people don’t come into care that far along. Rather, like most of their HIV-negative compatriots, those who are newly diagnosed with HIV are often overweight—even if they are down a few pounds from their normal. Once they start HIV meds, the pounds come back—a good sign that the meds are working.
However, not all weight gain is created equal or welcome. Starting a year or two ago, some clinicians observed that people starting on regimens that include antiretrovirals in the integrase inhibitor class experience weight gains exceeding those seen in people treated with regimens not containing this drug class. Soon thereafter, the differential effects of antiretrovirals on weight were looked at in larger and larger datasets of people living with HIV, including those starting HIV therapy and those switching from one type of regimen to another. Pretty consistently, the integrase inhibitors, especially the two newest, dolutegravir (DTG) and bictegravir (BIC), were being linked independently to relatively greater gains
A crescendo of clinical trial data this past year has further moved this from speculation to major concern to fact. Of these, three tell us most of what we now know: the ADVANCE trial, an analysis of Gilead trial data, and the DISCOVER trial.
The ADVANCE trial
The objective of this study was not to look at changes in weight but to compare more modern HIV regimens with older, standard treatment used in South Africa, where the study was conducted. Over 1,050 people were randomized to start HIV therapy with one of three regimens:
• tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) [Atripla]
• TDF/FTC + DTG [Truvada + Tivicay]
• tenofovir alafenamide fumarate (TAF)/FTC + DTG [Descovy + Tivicay]
Approximately 60% of those enrolled were women, and when entering the study about half of all the participants had a body mass index at or above the threshold indicating being overweight. Overall, each of the regimens did a good job of getting the viral load suppressed and were well-tolerated, with some trends favoring the DTG arms. However, it was noticed that there were significant differences in the amount of weight people gained after starting these regimens.
Those treated with DTG gained much more weight than those treated with TDF/FTC/EFV, and these gains were even greater with the use of TAF with DTG. Plus, women experienced greater increases in weight than the men regardless of what regimen they were assigned.
Notably, weight did not plateau during the study but continued to increase over time. Also, based on body composition analyses done on a subset of participants, the accumulated weight seemed due to increases not just in trunk and limb fat, but also lean (non-fat) tissue.
The factors associated with weight gain of 10% or more during the study included not just being assigned TAF and/or DTG but also being a woman, having low CD4 cell count, a high viral load, or a higher weight at baseline.
This study shows very clearly how different regimens impact weight, with DTG leading to greater gains, an effect that is exacerbated with concomitant use of TAF, and that women are more likely to be affected than men.
This trial was done in South Africa among people from that country and neighboring Zimbabwe. However, analyses of data collected from those living in the U.S. have found similar medication, race, and gender associations with excessive weight gain while on integrase inhibitors.
Gilead trials analysis
While the weight gain buzz is swarming mostly around DTG (dolutegravir), there has been little more than speculation available about whether or not its integrase sibling, BIC (bictegravir), has the same impact on weight. Gilead Sciences, the maker of BIC, TDF, TAF, and elvitegravir (EVG, an older integrase inhibitor found in Genvoya and Stribild), reported in the journal Clinical Infectious Diseases an analysis of weight changes measured during eight of their large clinical trials of initial HIV treatment, including, collectively, over 5,000 participants (90% male, 26% Black). These hark back to the 934 trial in which AZT/3TC [Combivir] and EFV [Sustiva] was compared to TDF/FTC/EFV, as well as later studies involving atazanavir and rilpivirine (RPV), and more recent comparisons involving BIC, DTG, and TAF.
In addition to factors expected to predict gains in weight, such as low CD4 cell count, higher viral load, and not injecting drugs, as well as the risk of being female and being Black seen in other studies, there were significant treatment-associated effects observed. Once again, integrase inhibitors were associated with the biggest jumps in weight after the start of therapy with both BIC and DTG having the largest and indistinguishable effects. As was seen in the ADVANCE trial, those treated with TAF became heavier than those receiving TDF or abacavir (ABC).
This analysis helps to outline a hierarchy of weight gain risk with DTG and BIC being very similar and higher than elvitegravir (and likely raltegravir, or Isentress). Among the nucleosides, TAF has a greater effect than TDF and ABC. For the non-nucleosides, a modestly bigger change in weight was seen with RPV compared to EFV. The only protease inhibitor studied was atazanavir (Reyataz), and it behaved a lot like the non-nucleosides.
The DISCOVER trial
All studies, as well as clinical experience, show us that many people starting HIV therapy gain some weight. For some, weight gain is seen to be a consequence of getting healthier, the so-called “return-to-health” phenomenon. As the virus becomes controlled, the idea is that energy is saved and stored as fat. Appetite can also increase as the immune system starts to normalize. Such a phenomenon can be seen in the ADVANCE trial and the Gilead studies where those who entered with indicators of more advanced HIV disease gained more weight than those whose numbers were healthier. This can make it difficult to know if it is a medication itself that is causing the packing on of pounds or its intended (beneficial) antiretroviral effects. By studying those whose virus is well-controlled and who switch their HIV meds we can get around return-to-health issues, but this may not fully answer the question of whether a drug or regimen inherently increases weight. For example, switching from EFV, which is taken on an empty stomach before bed, to a regimen without food restrictions may lead to gains in weight simply because of the more liberal food allowance. The same sort of thing can happen if a regimen that causes some low-level gastrointestinal problems, such as a boosted protease inhibitor, is swapped out for one that is free from such issues. To get around this confounding, we can look at studies done in people who don’t have HIV, like PrEP trials.
The DISCOVER trial compared TDF/FTC (Truvada) with TAF/FTC (Descovy) as PrEP for over 5,000 men and trans women. After 96 weeks, the median gain in weight among those assigned TAF/FTC was about four pounds, compared to one pound in those on TDF/FTC. So, in this PrEP trial, in which return-to-health is not an issue, the differential effects of TAF versus TDF is made clear. Even so, this does not necessarily mean TAF causes weight gain as it could be TDF suppresses weight, or it could be some of both. But, to the person on the scale or trying on new jeans, this is beside the point.
Baseline to Week 96 during the ADVANCE trial (in pounds)
|TAF/FTC +DTG||TDF/FTC + DTG||TDF/ FTC/EFV|
What you should—and should not—do
At this point, you may be cursing your HIV meds (and your HIV doc) for making you fat. But it is really important to understand that weight is complicated and influenced by many physical, psychological, and even environmental forces. For many people who are unhappy with their weight and are on the very HIV meds that have the strongest association with tipping the scales, the drugs might not be the issue at all. It is incredibly helpful to look at trends, particularly for any change in weight that corresponds to the initiation or change in HIV therapy.
Someone whose weight has hovered between 250 and 260 pounds before and after switching their regimen from TDF/FTC/EFV (Atripla) to TAF/FTC plus DTG (Descovy plus Tivicay) cannot pin blame on the new meds. In contrast, a jump in weight that occurred soon after starting TAF/FTC/BIC (Biktarvy) without any major changes to diet, exercise, or other medications would squarely implicate this regimen as the cause.
What to do in such cases where the smoking gun leads to the HIV regimen? This, sad to say, is still unclear as there are no data to rely on for guidance. We know that excess weight can be a serious threat to health and has been associated with diabetes, hypertension, fatty liver, sleep apnea, and wear and tear of the joints, among other problems. In addition, weight gain can be a serious hit to a positive body image. Therefore, this is not something to simply tolerate.
In clinical trials, the new non-nucleoside doravirine (Pifeltro) combined with TDF/FTC (Truvada) or ABC/3TC (Epzicom) has been found to produce small changes in weight among those starting HIV therapy that are on par with those seen in the study participants treated with these nucleosides and EFV or darunavir/ritonavir (Prezista/Norvir). Whether switching to doravirine from DTG or BIC reverses weight gains is of interest but has not yet been studied, although it would be reasonable to assume it might. Also, whether cutting calories or carbs and/or exercising more can beat back excessive fat despite the continuation of the offending HIV med is not clear—but there are compelling benefits of these lifestyle changes, and so they are recommended, regardless.
Some may ask whether we should continue to use the HIV meds that are linked to greater weight gain, given the health and body image risks. Is not excessive weight gain the lipodystrophy of our time? These are valid questions and if we learned anything from the d-drug debacle it is to never be complacent.
However, there are several ways in which, at least right now, this is not a replay of d4T and lipoatrophy. Foremost, the newer integrase inhibitors are otherwise really, really good medications. They are potent, have minimal other side effects, play well with other medications, and have a super-high barrier to resistance. The recent pushback by many women living with HIV against any blanket limitations to DTG use following initial concerns about an association with birth defects is telling and speaks to the benefits of these newer meds.
TAF’s advantages over TDF are also pretty clear—just ask all those critical that it was not made commercially available sooner.
Further, it seems that a lot of people do not experience major weight gains on these meds. In the ADVANCE trial, around half of the women and close to 70% of the men in the TAF/FTC + DTG group had minimal change or even a decrease in weight after 96 weeks—and, as mentioned, some of this weight gain was probably influenced by factors such as advanced HIV disease and simply starting on HIV therapy.
Still, more data will reveal the depth of the problem and if the risk-to-benefit analysis changes.
People who think HIV meds could be responsible for an increase in weight should discuss this concern with their clinician. A look at the records can tell if any changes in HIV therapy correspond to changes in weight.
It is important to also look for other causes, such as starting a new depression medication or stopping smoking at around the same time, or changes in activity levels or eating habits that could confuse the picture.
When starting initial HIV treatment, it is critical that clinicians warn patients about the potential effects of certain meds on weight and then monitor weight over time. Again, given their overall advantages over older drugs, the newer antiretrovirals continue to make sense to use in most cases. However, for those at highest risk of excessive weight gain, such as a Black woman who is obese and trying to shed pounds, avoiding BIC, DTG, and TAF may be justified. It is absolutely essential that all such decision-making be shared between the clinician and the patient.
There is clear evidence that newer HIV medications including DTG, BIC, and TAF can cause greater increases in weight than other antiretrovirals and that women, especially women of color, are at higher risk than men for experiencing greater gains in weight on therapy. The mechanism explaining the differential effects of HIV medications on weight remains unclear and is likely to be complicated. People living with HIV and their providers should track weight carefully and look for unexpected or unexplained changes to determine if antiretroviral therapy could be the cause. More research is planned to understand if switching from suspect HIV medications to those that have not been associated with excessive weight gain can lead to a drop in weight. Until these studies provide guidance, practical interventions including the adoption of a healthful, plant-based, diet and regular exercise should be attempted along with informed switches in HIV therapy based on the data that are available.
David Alain Wohl, MD is a professor of medicine at the University of North Carolina at Chapel Hill. There he leads the HIV Prevention and Treatment Clinical Research Site and sees patients in the university’s Infectious Diseases Clinic.
For more on weight gain see "Fatty Tissues" in CROI coverage in the May+June issue.