R01DK125246

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

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, TNF) 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 the switch to or addition of INSTIs.
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 pathophysiological insights into INSTI-induced weight gain and may shift the paradigm for ART treatment guidelines by informing individualized treatment strategies on the use of these agents in high-risk patients.

Emory University

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Atlanta, Georgia 303082012 United States

Single Zip Code

High Priority HIV/AIDS Research within the Mission of the NIDDK (R01 Clinical Trial Optional) (PAS-18-698)

Amendment Since initial award the total obligations have increased 577% from $613,961 to $4,154,622.