Metabolomic Signatures of Insulin Resistance and Visceral Adiposity Changes in HIV-infected Adults on Newer Line Antiretroviral Therapy

Despite dramatic improvements in HIV-related morbidity and mortality3 since the introduction of combination antiretroviral therapy (ART), metabolic complications including insulin resistance (IR),4,5 adipose tissue changes,6-8 and cardiovascular disease (CVD)11,12 remain significant concerns in HIV-infected adults on ART. The association between ART and HIV-associated changes in body composition13 as well as IR has been documented.6-8,14 However, appreciable data is still lacking in potential biomarkers which may predict the development of poor metabolic outcomes. Metabolomics provides the ability to identify and quantify small molecules present in both disease and non- disease states, thereby distinguishing particular clusters of metabolites which could potentially serve as novel clinical biomarkers.18 Several non-HIV studies have shown a positive association of intermediary metabolites such as acylcarnitines (ACs) and branched chain amino acids (BCAAs) with IR,19-24 associations of BCAAs with obesity, and associations of phospholipids (PLs) and abnormal fatty acid synthesis with obesity.25-27 However, few studies have used targeted metabolomics to assess the association between these metabolites (ACs, PLs, BCAAs) and visceral adiposity or IR in HIV-infected adults29 – particularly those on newer line ART - or explored whether these associations are different compared to an HIV-uninfected population. We will leverage the highly established research infrastructure within the AIDS Clinical Trials Group (ACTG) 5260s, Multicenter AIDS Cohort Study (MACS), and Women's Interagency HIV Study (WIHS) cohorts, utilizing repository specimens to study metabolomic signatures of central adiposity and IR in HIV-infected and -uninfected adults. ACTG A5257 (parent study of A5260s) was a randomized trial comparing atazanavir/ritonavir, darunavir/ritonavir and raltegravir-based ART. Well-characterized longitudinal data up to 96 weeks on the outcomes for this proposal have already b