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ART-Related Weight Gain
Not Quite There: Why I Don’t Yet Switch ART in Weight Gain

Released: April 10, 2023

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Key Takeaways
  • Second-generation INSTIs, especially when combined with TAF, have been associated with more weight gain than other antiretrovirals, particularly among women and Black individuals.
  • Although guidelines do not recommend switching ART regimens, a change in the framework of providing care to patients is warranted, such as increasing efforts in monitoring, providing patient education, and collaborating with nutritionists and dietitians.

Antiretroviral therapy (ART)‒related weight gain has become a hot topic in HIV. Current guidelines—which address population-level recommendations—do not recommend changes in ART regimens when this occurs. In practice, however, we are seeing weight gain and metabolic complications such as insulin intolerance and diabetes at the patient level.

What data are available to help us with our conversations with patients? In this commentary, I will address this question by reviewing the current evidence, including updates from CROI 2023.

Weight Gain on ART
ADVANCE was the first randomized study to raise flags about weight gain with integrase strand transfer inhibitors (INSTIs), especially when combined with tenofovir alafenamide (TAF). In this study, which was performed in South Africa, excess weight was observed at Week 96 in treatment-naive participants who received an INSTI-based regimen (7.1 kg in the dolutegravir [DTG] + emtricitabine [FTC]/TAF arm; 4.3 kg in the DTG + FTC/tenofovir disoproxil fumarate [TDF] arm) compared with those who received efavirenz/FTC/TDF (2.3 kg). Of interest, women gained significantly more weight than men. Of the individuals who received DTG + FTC/TAF, women gained twice as much weight as men (10 kg vs 5 kg).

Similar findings have been seen in other studies. In a pooled analysis by Sax and colleagues of 8 randomized, controlled trials of treatment-naive people with HIV (PWH), weight gain was more common in individuals who received INSTIs vs protease inhibitors, particularly second-generation INSTIs (eg, bictegravir [BIC] and DTG), as well as those who received TAF vs TDF. Similar to ADVANCE, weight gain was more common in women, particularly Black women.

Long-term Implications
Is weight gain sustained with continued use? Based on results from RESPOND, a prospective, multicohort study of 14,703 PWH, weight gain appears to be most prominent within the first 2 years of initiating ART.

These results are similar to an updated analysis from REPRIEVE, a randomized atherosclerotic cardiovascular disease prevention trial in PWH receiving stable ART that was presented at CROI 2023. Investigators assessed changes in BMI by INSTI status and stratified by duration of entry ART regimen. When evaluating patients receiving INSTI and non-INSTI regimens, significant increases in weight were observed among those receiving INSTI regimens for up 2 years at study entry. These differences in weight were not observed in individuals receiving their regimens for 2-5 years or more than 5 years.

From these studies, it does not appear that long-term INSTI use is associated with substantial weight gain.

Should ART Be Switched?
Data on switching ART regimens to reverse weight gain are limited. However, 2 recent studies from CROI 2023 are worth noting.

First, CHARACTERISE enrolled 172 participants from all 3 treatment arms of ADVANCE and switched them to open-label DTG/lamivudine (3TC)/TDF. A significant reduction in weight (median 1.6 kg; P = .0125) was observed in women after 52 weeks of switching from DTG + FTC/TAF to DTG/3TC/TDF (n = 41); this effect was not observed among men.

Simplifying to a 2-drug regimen has been evaluated in prior studies (eg, SALSA, TANGO), but none has demonstrated weight loss. Similarly, in Rumba, a prospective, single-center, open-label, randomized trial from CROI 2023 evaluating a switch from BIC/FTC/TAF (n = 43) to DTC/3TC (n = 87), no significant differences in weight/BMI resulted at Week 48. However, individuals who continued BIC/FTC/TAF had more pronounced increases in trunk fat mass and overall fat percentage compared with those who switched to DTG/3TC. Greatest reductions in trunk fat mass were observed in those who switched to DTG/3TC and had a baseline BMI >30 kg/m2.

These results provide potential approaches to switching ART that may benefit specific populations, but further data are needed in a larger subset of patients with longer follow-up.

My Approach to Weight Gain
At this time, it is still unclear if an ART regimen switch should be made in patients who experience ART-related weight gain.

Anecdotally, when I have conversations with my patients who gained a significant amount of weight while receiving ART, many do not want to switch regimens, as they are tolerating their regimen and are not experiencing other adverse events (AEs). Switching ART can be challenging and result in other AEs and increase pill burden, which may negatively affect their adherence and ability to remain virologically suppressed.

If we are going to consider switching ART regimens, we would need clear data that this is the right thing to do, and I do not think we are there yet. Instead, we should think about additional education and monitoring opportunities to include as part of our regular care—really a change in our framework of providing care for our patients.

The International Antiviral Society‒USA guidelines suggest monitoring weight and BMI at baseline and every 6 months, as well as screening for diabetes and cardiovascular risk annually. I would further incorporate talking about diet, nutrition, and exercise—just the way we talk about medication adherence and AEs. These topics are critical and should be part of our discussion with patients when we are initiating or modifying ART. Another consideration is incorporating registered dietitians or nutritionists directly into our practice or ascertaining how to make referrals as seamless as possible. Some centers may do these referrals reactively, but I think with this growing data and from our clinical experiences, we should be more proactive in this approach.

In our clinic, we always talk about bandwidth and our capacity to perform additional services. Although we do not know exactly why this is happening, we see specific populations at higher risk of ART-related weight gain—women and Black persons. When resources are limited, we can use this information to help focus our resources to these specific populations at highest risk.

Your Thoughts?
How do you approach ART-related weight gain in your practice? Have you changed how you have monitored specific patient populations? Join the discussion by posting a comment.