Abstract

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, yet metabolic 
syndrome (MetS) emerged as a critical comorbidity in people living with HIV (PLHIV), affecting 20–54% of this 
population compared to 10–25% in the general population. The complex interplayed between viral pathogenesis, 
immune dysregulation, chronic inflammation, and drug-induced metabolic perturbations necessitates advanced 
molecular profiling to elucidate underlying mechanisms and identify therapeutic targets. This narrative review 
critically examined the application of metabolomics in characterizing ART-associated MetS, focusing on mechanistic 
insights, biomarker discovery, and clinical translation. A comprehensive literature search was conducted using 
PubMed, Embase, and Web of Science databases (2015–2025), prioritizing metabolomics studies, clinical trials, and 
mechanistic investigations. Current evidence demonstrated profound alterations in lipid metabolism, particularly 
increased ceramides, diacylglycerols, and altered sphingolipid profiles, alongside perturbations in branched-chain 
amino acid catabolism, tricarboxylic acid cycle intermediates, and bile acid homeostasis. Integrase strand transfered 
inhibitors and protease inhibitors exhibit distinct metabolomic signatures, with the former associated with weight 
gain through alterations in hypothalamic neuropeptide regulation and adipogenesis pathways. Despite significant 
advances, metabolomics-guided personalized ART selection remained limited by small cohort sizes, heterogeneous 
analytical platforms, and insufficient longitudinal validation. Future research must prioritize standardized multi
omics integration, mechanistic validation studies, and biomarker-driven clinical trials to translate metabolomic 
discoveries into precision medicine approaches that mitigate metabolic complications while maintaining virological 
efficacy in PLHIV.