Are New Antiretroviral Treatments Increasing the Risk of Weight Gain?

There is a growing body of evidence from both observational and randomised trials implicating integrase inhibitors, particularly dolutegravir and bictegravir, with the development of weight gain and obesity in people living with HIV. Evidence with cabotegravir, the newest integrase inhibitor, is limited. Reasons for weight gain are currently unknown. Proposed mechanisms include improved tolerability, direct impact on adipogenesis, and gut microbiome disturbance. Clinical trials have found that weight gain with integrase inhibitors is greatest for women and people of Black ethnicity. Evidence suggests that the nucleoside reverse transcriptase backbone has additional effects on weight gain, with tenofovir alafenamide potentially enhancing the weight gain effect. Weight gain and obesity have long-term consequences, including metabolic syndrome, development of type 2 diabetes mellitus, cardiovascular disease and adverse birth outcomes. However, the current evidence for the medium and long-term effects of weight gain associated with integrase inhibitors is limited. There is an urgent need for clinical trials with longer follow-up periods and standardised endpoints to evaluate these effects. New thresholds for weight gain should be established as guidance for clinicians to stop treatment where weight gain is excessive. Novel treatments such as doravirine could offer a suitable therapy alternative, with current evidence showing efficacy with limited effect on weight gain.