Mechanisms and management of pegylated interferon-α toxicity in chronic hepatitis B

Pegylated interferon-α (PegIFN-α) is a cornerstone immunomodulatory therapy with the potential to achieve a functional cure for chronic hepatitis B (CHB). However, its clinical application is constrained by a high frequency of multisystem adverse reactions, which often lead to dose modifications or treatment discontinuation. These toxicities are not ancillary effects but rather direct consequences of the drug's therapeutic mechanism, arising from a broad and often dysregulated systemic immune activation. This review systematically delineates the clinical spectrum of these reactions and provides a unified framework for their underlying host immunopathological mechanisms. We dissect the interconnected network of host factors including cytokine-driven inflammation, hematopoietic suppression, loss of immune tolerance, and neuro-immune axis disruption that mediate common toxicities such as flu-like syndrome, cytopenias, autoimmunity, and neuropsychiatric symptoms. A focused analysis of ocular vascular injury is included. By synthesizing recent evidence, we discuss predictive biomarkers and contemporary management strategies designed to navigate this therapeutic dichotomy. Finally, we outline future directions for developing safer, mechanism-informed, and host-directed personalized therapies for CHB.