Treatment changes do not reduce weight in people with HIV

A randomised trial presented on Tuesday at the 13th International AIDS Society Conference on HIV Science (IAS 2025) showed that switching from medications thought to cause weight gain did not lead to significantly greater weight reduction compared to staying on existing treatment, even when one of the replacement drugs has been shown to suppress weight gain. The study was designed to investigate the effects of swapping drugs associated with weight gain for ones that have not been associated with weight gain.

The integrase inhibitors dolutegravir and bictegravir have been associated with weight gain, as has tenofovir alafenamide (TAF).

Other studies have shown that people taking tenofovir disoproxil (TDF) gain less weight after starting treatment, suggesting that TDF may suppress weight gain in people who have started antiretroviral therapy (ART), whether the weight gain is associated with ART or has other causes.

Dr John Koethe of Vanderbilt University reported results from the DO-IT trial. The study recruited 145 people with obesity who were virally suppressed on a combination containing an integrase inhibitor and TAF. Study participants were randomised to one of three study arms:

• continue existing treatment
• switch to doravirine and TDF, or
• switch to doravirine while continuing to take TAF.

Doravirine is a non-nucleoside reverse transcriptase inhibitor that has not been associated with either weight gain or weight loss in previous studies.

Participants had been taking an integrase inhibitor with TAF and emtricitabine for a median of 3.4 years, had a median body mass index (BMI) of 34.9 and a median age of 49 years. Just under half (49%) of participants were female, 53% were Black and 18% were Hispanic/Latino.

The primary study outcome was the change in weight after 48 weeks of follow-up. Participants in all three study arms lost a small amount of weight but there was no statistically significant difference in weight change between those in either of the intervention arms and those who remained on their existing treatment. Those who remained on their existing treatment lost 1.84kg, compared to a loss of 2.73kg in those who switched to doravirine and TDF, and a loss of 0.47kg in those who switched to doravirine and TAF.

“I was reassured that all three arms lost weight,” Koethe said. “Why was that? We concluded that people who joined a study to lose weight might do other things to help them lose weight, like diet and exercise.”

Race, sex, gender, age, integrase inhibitor type, and history of weight gain on treatment did not affect the degree of weight change when comparing either of the switch options to the bictegravir-containing regimen.

“The A5391 study provides robust evidence that ART regimen changes are not effective in reducing weight in obese people with HIV, and other interventions will be needed to reduce weight-related comorbidities in this population,” Koethe concluded.

“I think we should stop chasing switching as a way of trying to manage weight, and just explain to people that you’ve gained weight because of your health status, your peer environment, your genetic characteristics, and identify those people who are at higher risk so that they are forearmed and forewarned about the possibility of them gaining weight,” said Dr Graeme Moyle of London’s Chelsea and Westminster Hospital in a discussion following the study presentation. Starting or changing treatment should be seen as an opportunity for a more general intervention regarding weight, diet and exercise, he argued.

Weight gain after starting treatment

A large observational retrospective study of people with HIV taking ART in the United States presented at the conference also failed to show any relationship between ART and weight change. Dr Rick Elion of Trio Health reported that substantial weight gain after at least three years of ART was associated with Black race, being female or having a low CD4 count before starting treatment, not current treatment regimen.

The study was designed to investigate the factors associated with significant weight gain over a three-year period of ART among people receiving care in the United States. The study focused on people with the greatest weight gain (at least 10% of body weight) as these are the people most likely to experience biological consequences from weight gain, said Dr Elion.

People with HIV at participating centres were eligible for inclusion in the analysis if they were in care between 2015 and 2023, and had at least three years of follow-up, including baseline and year-three weight measurements. Participants had to be virally suppressed on treatment (<200 copies/ml) at baseline and virally suppressed after three years of follow-up.

The investigators identified 10,413 people eligible for inclusion in the analysis.

Of those included, 41% either lost weight or did not gain weight, 26% gained less than 5% in weight, while 12% gained at least 10% and shifted to a higher BMI category.

Weight gain of 10% or more, coupled with a shift to a higher BMI category, was less likely to be experienced by people over 30 years of age when compared to people aged 18-29. This difference increased with age, such that people aged 60 and over were 80% less likely to experience substantial weight gain compared to those aged 18-29.

Current ART or changes in treatment during the follow-up period were not statistically significant predictors of significant weight gain.

However, changes in treatment prior to the follow-up period proved to be significant predictors of subsequent weight change during the follow-up period.

People who had switched from TAF to TDF at least 12 months prior to baseline were less likely to experience weight gain of 10% or more and shift to a higher BMI category when compared to people who had not been exposed to either drug 12 months prior to baseline.

Why treatment prior to the study period rather than during the study period influenced weight gain is unclear and requires further research.