Longitudinal Serum Metabolomic Signatures Related to Integrase Strand Transfer Inhibitors-Associated Weight Gain in Women with HIV Enrolled in the MACS/WIHS Combined Cohort Study.

Abstract

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH), particularly in women with HIV (WWH), but underlying mechanisms remain unclear. We used longitudinal untargeted metabolomics to identify metabolic signatures of INSTI-related weight gain in WWH. We analyzed serum from 192 participants in the Women's Interagency HIV Study: 38 virologically suppressed WWH who initiated INSTIs (INSTI group), 88 virologically suppressed WWH who remained on their original antiretroviral therapy (non-INSTI group), and 66 women without HIV (WWoH). Samples were collected at baseline (6-12 months before INSTI initiation), 1-6 months post-initiation, and 1-2 years post-initiation, with matched visits for controls. High-resolution metabolomics was performed by liquid chromatography-mass spectrometry. Within each group, linear mixed-effects models adjusted for baseline age and BMI compared longitudinal metabolite changes between weight gainers and maintainers, and significant features were analyzed by Mummichog v2.0 pathway enrichment. Mean age was 45.7 ± 8.9 years and mean BMI 32.4 ± 8.3 kg/m2, with no differences across groups; within each group, gainers and maintainers were demographically comparable (p > 0.05). In the INSTI group, metabolites differentiating gainers from maintainers were enriched in 16 pathways across timepoints, predominantly lipid-related (56%), including the polyunsaturated fatty acid (PUFA) pathways linoleic acid and arachidonic acid metabolism. In the non-INSTI and WWoH groups, differentiating metabolites spanned a broader range of pathways, including amino acid metabolism. Weight gain among INSTI-treated WWH is characterized by a distinct, lipid- and PUFA-dominated metabolic profile, providing mechanistic insight that may inform therapeutic strategies.