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

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $603,222

## Abstract

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 ins...

## Key facts

- **NIH application ID:** 10257594
- **Project number:** 1R01DK125246-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jessica Alejandra Alvarez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $603,222
- **Award type:** 1
- **Project period:** 2021-03-02 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257594

## Citation

> US National Institutes of Health, RePORTER application 10257594, SPPACE INSTI Study:  Sex-specific Predictors, Pathways, And Cardiometabolic Effects of Weight Gain Associated with Integrase Strand-Transfer Inhibitors (1R01DK125246-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10257594. Licensed CC0.

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