Abstract
The clinical progression of chronic hepatitis B (HBV) and C (HCV) is highly variable and not fully explained by virological factors alone. This narrative review explores the role of allostatic load, defined as the cumulative physiological burden of chronic stress, as a host factor that may contribute to this heterogeneity by influencing immune dysregulation, hepatic inflammation, and clinical outcomes. We conducted a narrative synthesis of English-language studies identified through PubMed, Web of Science, Scopus, PsycINFO, and gray literature. We included studies (cross-sectional, case-control, cohort studies, clinical trials, implementation studies, and policy documents) that employed any measure of psychosocial stress (validated psychometric scales/biomarkers/clinical diagnoses) and hepatitis-related clinical or virologic outcomes. Preclinical studies that described biological mechanisms were also included. Given significant heterogeneity, findings were summarized thematically. Chronic stress disrupts hepatic immune homeostasis through neuroendocrine pathways, including the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system activation, leading to Kupffer cell activation, pro-inflammatory cytokine release, and impaired antiviral immunity. Psychosocial stress and depression are associated with reduced adherence to antiviral therapy, particularly in HCV, and may influence disease flares and fibrosis progression. Structural and social determinants of health, such as poverty, trauma, adverse childhood experiences, and incarceration, impact allostatic load and create barriers to care, exacerbating health disparities in vulnerable populations. Allostatic load offers a biopsychosocial framework for HBV/HCV, but clinical evidence remains limited and heterogeneous, with a more established link in HCV. Future research should prioritize prospective studies using standardized stress biomarkers and evaluate integrated care models that address mental health and structural barriers to improve outcomes and achieve health equity.