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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
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The Journal of Infectious Diseases, 29 June 2026
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In conclusion, in virally suppressed WWH who initiated INSTI-based ART, weight gain over time was associated with a distinct metabolic profile driven primarily by involvement of PUFA and other lipid-related pathways, as compared with WWH on non-INSTI regimens and WWoH whose weight change profiles were distributed within a broad range of metabolic pathways. Differences in PUFA metabolism and downstream oxylipins support a lipid-mediated, pro-inflammatory contribution to INSTI-associated weight gain in WWH. These findings provide potential insights into INSTI-related metabolic complications and may inform strategies to prevent or mitigate weight gain in this population.
Integrase strand-transfer inhibitors (INSTIs) have become a cornerstone of antiretroviral therapy (ART) for people living with human immunodeficiency virus (HIV) due to their efficacy, tolerability, and high barrier to resistance [1]. However, accumulating evidence indicates that initiating or switching to INSTI-based regimens can be associated with significant weight gain, particularly in non-White women with HIV (WWH) [2]. INSTI-related weight gain can lead to obesity and related comorbidities, potentially compromising long-term health [3].
Despite the potential clinical significance of this phenomenon, underlying biological mechanisms of INSTI-related weight gain in WWH remain poorly understood, hindered by varying individual INSTI molecules, person-to-person variability, and the confounding influence of "return to health" weight gain seen in some ART-naïve individuals initiating first ever ART. Several hypotheses have been proposed, including effects on adipose tissue metabolism, alterations in insulin sensitivity, and changes in inflammatory pathways [3, 4]. However, comprehensive metabolic profiling to identify specific pathways involved in INSTI-related weight gain has been limited.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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