Interferon-Associated Inflammation and Galectin-9 Predict Risk of Non-AIDS Events and Mortality in Treated HIV

People with HIV (PWH) receiving suppressive antiretroviral therapy (ART) remain at increased risk of severe non-AIDS events (SNAEs) and premature death, but the biological mechanisms that precede these outcomes remain poorly defined. We performed a nested case-control study within CoRIS, a nationwide prospective cohort of 17,906 ART-naive PWH, to identify inflammatory and transcriptional signatures associated with subsequent SNAEs and mortality during suppressive ART. Plasma obtained two years after ART initiation from 187 participants (92 cases and 95 matched controls) underwent high-dimensional proteomic profiling of 326 inflammation-related proteins and RNA sequencing of paired peripheral blood mononuclear cells (PBMCs). Proteomic screening identified 33 differentially expressed proteins in participants who later developed SNAEs, with marked heterogeneity across clinical phenotypes. By contrast, transcriptomic analyses showed consistent enrichment of type I interferon-stimulated genes among individuals who subsequently developed SNAEs or died during follow-up. Among circulating proteins, galectin-9 (LGALS9) showed the most consistent association with adverse outcomes. Orthogonal measurement by ELISA confirmed the reproducibility of LGALS9, whereas other candidates showed weaker or context-dependent associations. We then sought external validation in CNICS using a case-cohort study of ART-suppressed PWH across eight US sites, in which 922 participants with available plasma were randomly sampled from 9,430 eligible individuals and followed longitudinally for non-accidental mortality; 103 deaths occurred over a median follow-up of 9 years. In this independent cohort, higher LGALS9 plasma levels showed a clear graded association with shorter time to death. These findings identify galectin-9 and interferon-linked immune activation as reproducible features of the inflammatory milieu that precedes major non-AIDS outcomes in treated HIV, and support LGALS9 as a prognostic biomarker for risk stratification and outcome-focused validation.