Metabolic Mechanisms of INSTI-Associated Weight Gain: A Multi-Omics Study in Male People with HIV.

BACKGROUND: Integrase Strand Transfer Inhibitors (INSTI) are recommended as first-line antiretroviral therapy (ART) for HIV infection, yet are frequently associated with excessive weight gain. METHODS: We conducted a multi-omics study on male people with HIV (PWH). A total of 64 male PWH were enrolled and stratified based on their therapeutic history and weight changes over the first year (G1 receiving INSTI with weight gain ≥ 5%; G2 switching to INSTI with weight gain ≥ 5%; and G3 switching to INSTI without weight gain). INSTI-based regimens included bictegravir-, elvitegravir-, and dolutegravir-containing combinations. 26 healthy male controls were also included. Plasma untargeted metabolomics and proteomics were analyzed longitudinally. Machine learning models were employed to integrate multi-omics data and identify predictive biomarkers. RESULTS: Metabolomic analysis revealed that switching to INSTI induced a generalized hypometabolic state, characterized by a universal decline in thyroxine and an increase in N-acetylputrescine across all switching groups, independent of weight outcomes. In contrast, proteomic profiling identified distinct molecular drivers specific to the weight-gain groups. Random forest modeling identified transthyretin (TTR) as the top predictive biomarker among pre-INSTI multi-omics features. CONCLUSION: Our integrated multi-omics approach reveals that INSTI-based regimens induce universal metabolic changes. The change of thyroxine and the predictability of TTR in multi-omic studies show the critical role of thyroxine metabolism in INSTI-associated weight gain.