Temporal changes in plasma metabolic signatures to predict immune response of antiretroviral therapy among people living with HIV

Abstract Antiretroviral therapy (ART) is an effective treatment for people living with HIV (PLHIVs), requiring an extended period to achieve immune reconstitution. Metabolic alterations induced by ART are crucial for predicting long‐term therapeutic responses, yet comprehensive investigation through large‐scale clinical studies is still lacking. Here, we collected plasma samples from 108 PLHIVs to the untargeted plasma metabolomics study, based on the longitudinal metabolomics design. Cross‐sectional analyzes were performed at pre‐ and post‐ART to explore the metabolic transformation induced by the therapy. Subsequently, delta values between pre‐ and post‐ART measurements were calculated to quantify metabolic alterations. Then, the optimal set of metabolic traits and clinical signatures were further identified and applied to construct random forest model for predicting the future therapeutic responses to ART. We found distinct ART‐induced metabolic transformation among PLHIVs. After confounder‐adjustments, five metabolites exhibited significant associations with future immune response: tetracosatetraenoic acid (24:4n‐6) (pre‐ART) (odds ratio [OR]: 0.978, 95% confidence interval [CI]: 0.955~0.997), 1‐(3,4‐dihydroxyphenyl)−5‐hydroxy‐3‐decanone (pre‐ART) (OR: 1.298, 95% CI: 1.061~1.727), beta‐PC‐M6 (change) (OR: 0.967, 95% CI: 0.938~0.993), d ‐Galactaro‐1,4‐lactone (change) (OR: 1.032, 95% CI: 1.007~1.063), Annuionone C (change) (OR: 1.100, 95% CI: 1.030~1.190). The addition of plasma metabolites to clinical markers accurately predicted immune response to ART with an area under curve of 0.91. Notably, most disrupted metabolites were significantly correlated with blood lipids, suggesting that metabolic transformation might contribute to dyslipidemia among PLHIVs. This study highlights the distinct metabolic transformation post‐ART among PLHIVs and reveals the potential role of metabolic transformation as key determinants of ART efficacy.