Metabolomic Profile of Weight Gain of People Living with HIV Treated with Integrase Strand Transfer Inhibitor Regimens Reveals Dysregulated Lipid Metabolism and Mitochondrial Dysfunction

<b>Background/Objectives</b>: Excessive weight gain is a growing concern among people living with HIV (PWH) receiving integrase strand transfer inhibitor (INSTI)-based regimens as first-line antiretroviral therapy (ART), as it may contribute to multimorbidity. The mechanisms driving weight gain in INSTI users are not fully understood but are thought to be multifactorial. This study examines the plasma metabolome associated with weight gain in PWH on INSTI-based regimens. <b>Methods</b>: We conducted a nested case-control study within the randomized clinical trial MICTLAN (NCT06629480). Sixty-six participants were randomized to receive INSTI-based regimens, either bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), and followed for 18 months. Weight gain >10% relative to baseline was considered a primary endpoint and used as a criterium to categorize cases (n = 28) and controls (n = 38). Anthropometric and clinical measurements, plasma insulin, and metabolomic profiles were assessed at baseline and 18 months post-ART. Plasma untargeted metabolomics was performed using liquid chromatography-mass spectrometry (LC-MS/MS) to identify metabolomic changes linked to weight gain. Bioinformatic tools, including Partial Least Squares Discriminant Analysis (PLS-DA), volcano plots, and KEGG pathway enrichment analysis, were used to analyze plasma metabolomes and identify significant differential metabolites. <b>Results</b>: Weight gain at 18 months in PWH on INSTI-based ART was associated with insulin resistance, as measured by HOMA-IR (OR 3.23; 95% CI 1.14-9.10; <i>p</i> = 0.023), and visceral adipose tissue thickness > 4 cm (OR 4.50; 95% CI 1.60-13.03; 9.10; <i>p</i> = 0.004), and hypertriglyceridemia (OR 3.9; 95% CI 1.38-10.94; <i>p</i> = 0.008). Baseline HIV RNA viral load >50,000 copies/mL (OR 8.05; 95% CI 2.65-24.43; <i>p</i> = 0.0002) was identified as a baseline predictor of weight gain (aOR 6.58 (1.83-23.58); <i>p</i> = 0.004). In addition, accumulation of circulating medium-chain acylcarnitines, indicative of mitochondrial dysfunction, and insulin resistance were linked to weight gain in PWH on INSTI-based regimens after 18 months of therapy. <b>Conclusions</b>: This metabolomic study identified metabolites reflecting mitochondrial dysfunction, dysregulated lipid metabolism, and altered amino acid metabolism as key mechanisms underlying insulin resistance and weight gain in PWH on INSTI-based ART.