SPPACE INSTI Study: Sex-specific Predictors, Pathways, And Cardiometabolic Effects of Weight Gain Associated with Integrase Strand-Transfer Inhibitors

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Project Summary/Abstract Integrase strand-transfer inhibitor (INSTI)-associated weight gain in people living with HIV (PWH) is now an established phenomenon of great concern to patients and clinicians. Obesity contributes to adverse health outcomes, including cardiovascular disease (CVD), diabetes mellitus, and hypertension, of which PWH already are at a higher risk compared to the general population, particularly women. Our published preliminary data show that over a relatively short follow-up period, virally-suppressed women switching to INSTIs exhibit greater increases in body weight, other adiposity measures, blood pressure, and hemoglobin A1c% compared to women staying on non-INSTI antiretroviral therapy (ART), resulting in a worsening of CVD risk categories. Our new preliminary data show that among women with clinically-significant weight gain, those who switched to INSTIs had changes in serum biomarkers (adiponectin, TNF𝛼) and the plasma metabolome consistent with greater insulin resistance and inflammation compared to women staying on non-INSTI ART, supporting our hypothesis that INSTIs may perturb insulin signaling, resulting in insulin resistance and increased storage of fat—leading to gains in body weight. This proposal addresses key knowledge gaps, including the sex-specific duration of the observed weight gain, long-term cardiometabolic consequences, and underlying mechanisms related to INSTI use—gaps we will address by leveraging the MACS/WIHS Combined Cohort Study (CCS), the largest and longest longitudinal interval cohort of men and women living with HIV and at-risk HIV(-) controls in the U.S. We propose to integrate the robust clinical data and biospecimen repository of the CCS to better understand INSTI-associated weight gain to inform future risk/benefit assessments during ART selection and identify opportunities for preemptive intervention and/or novel drug targets. Our proposed AIMS are: 1) Evaluate sex-specific patterns and predictors of body weight changes over time following the switch to or addition of INSTIs; 2) Assess changes in cardiometabolic risk by sex following switch to or addition of INSTIs; and 3) Determine sex-specific metabolic signatures associated with weight gain and subsequent cardiometabolic risk following INSTI initiation. To accomplish this, data collected on body weight changes and cardiometabolic risk indicators from virally-suppressed men and women enrolled in the CCS who switched to or added an INSTI to ART will be compared to those remaining on non-INSTI ART and to co-enrolled at-risk HIV(-) controls over a 5-year period. In addition, metabolomic and inflammatory profiles linked to INSTI weight gain will be combined with cardiometabolic risk indicators using integrative community detection and differential network analysis bioinformatics tools to determine sex-specific metabolic signatures associated with an increased risk of cardiometabolic disease. This study will provide new pathophysiologic insights into INSTI- induced weight gain and may shift the paradigm for ART treatment guidelines by informing individualized treatment strategies on use of these agents in high-risk patients.