The Kynurenine/Tryptophan Ratio as a Clinical Metabolomic Biomarker in Adults Living with HIV: A Systematic Review

Introduction: Persistent immune activation and chronic inflammation remain defining features of HIV infection despite effective antiretroviral therapy (ART). The kynurenine-to-tryptophan (K/T) ratio, a surrogate marker of indoleamine-2,3-dioxygenase-1 (IDO1) activity, has emerged as a promising metabolomic biomarker linking immune dysregulation with clinical outcomes. However, its overall clinical significance across the spectrum of HIV infection has not been comprehensively synthesized. This systematic review evaluated the evidence supporting the K/T ratio as a clinical metabolomic biomarker in adults living with HIV.

Methods: A systematic review was conducted according to PRISMA 2020 guidelines through June 2026. Original studies evaluating plasma or serum kynurenine, tryptophan, or the K/T ratio in adults with HIV were included. Cohort, case-control, cross-sectional, and clinical studies were considered. Methodological quality was assessed using the Newcastle–Ottawa Scale and the Joanna Briggs Institute Critical Appraisal Checklist.

Results: Eighteen studies comprising more than 3,500 participants from 12 countries met the inclusion criteria. Across all studies, the K/T ratio was consistently elevated in people living with HIV compared with seronegative controls. Higher K/T ratios were associated with lower CD4⁺ T-cell counts, higher plasma viral loads, microbial translocation markers (lipopolysaccharide and soluble CD14), and increased inflammatory cytokines, including IL-6 and TNF-α. Although ART significantly reduced K/T values, complete normalization was uncommon, indicating persistent immunometabolic dysfunction despite viral suppression. Elevated K/T ratios were further associated with delayed immune reconstitution, increased mortality, cardiovascular disease progression, liver fibrosis, HIV-associated neurocognitive disorders, depressive symptoms, and immune reconstitution inflammatory syndrome.

Conclusions: The K/T ratio is a robust clinical metabolomic biomarker that reflects persistent IDO1-mediated immune dysfunction in HIV. Its consistent association with disease progression, chronic inflammation, and multiple HIV-related comorbidities highlights its potential for clinical risk stratification and precision medicine.