Background: Obesity is a major concern in people with HIV (PWH). How obesity and antiretroviral therapy (ART) are associated with specific metabolite profiles in PWH is not well described.

Methods: We included Swiss HIV Cohort Study participants aged ≥45 years. We analyzed untargeted metabolite profiles and their association with BMI, waist-hip ratio (WHR), and ART, both current ART regimen categorized based on the "third drug" plus individual ART drugs. Metabolite profiles were clustered with hierarchical clustering and visualized as heatmaps and Uniform Manifold Approximation and Projection.

Results: We analyzed 1821 putative metabolite ions in 1302 PWH (median age 55 years, 78% male, 94% suppressed HIV RNA, median BMI 24.6kg/m2, 46% overweight/obese). 94 metabolites were associated with BMI and 66 with WHR; the strongest associations were found with amino acids/peptides. 156, 173, and 60 metabolites were associated with exposure to non-nucleoside reverse transcriptase inhibitors, protease-inhibitors, and integrase strand transfer inhibitors, respectively; most associations were found among carbohydrates. We identified specific patterns of metabolic perturbation for efavirenz, nevirapine, lopinavir, atazanavir, and elvitegravir. Most metabolites associated with tenofovir alafenamide were not associated with tenofovir disoproxil fumarate and vice versa. 31 metabolites were associated with either BMI or WHR and ART-exposure. We found no evidence of any metabolite profiles associated with past zidovudine or stavudine exposure or any interactions between ART drug classes and BMI, after adjusting for multiple testing.

Discussion: In PWH from Switzerland, untargeted metabolite profiling revealed multiple unreported associations with different ART agents, and previously reported associations with BMI.