Abstract
Glutathione (GSH), the most abundant intracellular non-protein thiol, is a central regulator F redox homeostasis, immune function, and mitochondrial integrity. In human immunodeficiency virus (HIV) infection, persistent oxidative stress and impaired precursor availability result in sustained glutathione deficiency, contributing to immune dysfunction, inflammation, and disease progression despite effective antiretroviral therapy. This redox imbalance is further exacerbated in HIV-tuberculosis co-infection, where compounded inflammatory and metabolic stress increases susceptibility to opportunistic infections and treatment-related complications. This review examines the efficacy and safety of glutathione supplementation and precursor-based strategies in HIV infection and HIV-tuberculosis co-infection. Evidence from mechanistic studies, clinical trials, and translational research suggests that glutathione repletion, achieved through direct supplementation or precursor approaches such as N-acetylcysteine, Glycine and N-acetylcysteine (GlyNAC), and cysteine-rich dietary interventions, can restore intracellular thiol balance, improve immune cell function, enhance mitochondrial performance, and reduce systemic oxidative stress. These interventions have shown consistent safety and tolerability across diverse populations, including individuals receiving complex antiretroviral and antitubercular regimens, with gastrointestinal discomfort being the most commonly reported adverse effect and serious toxicities remaining rare. Despite encouraging findings, translation into routine clinical practice remains limited by methodological heterogeneity, short study durations, and lack of standardized biomarkers and long-term outcome data. Future research should prioritize rigorously designed trials incorporating mechanistic endpoints, standardized redox measurements, and clinically meaningful outcomes. Collectively, the available evidence supports glutathione-centered strategies as promising adjuncts to existing HIV and tuberculosis treatment paradigms, warranting further investigation to define their role in improving immune resilience and long-term clinical outcomes.