Advances in the immunological basis and therapeutic strategies for functional cure of chronic hepatitis B

Chronic hepatitis B (CHB) is a leading cause of cirrhosis and hepatocellular carcinoma.Although nucleos(t)ide analogues and pegylated interferon-α suppress viral replication and induce sustained responses in some patients, functional cure remains uncommon.It is characterized by sustained hepatitis B surface antigen loss, with or without antibody to hepatitis B surface antigen seroconversion, and undetectable hepatitis B virus (HBV) DNA after treatment cessation.This endpoint should also be accompanied by normalization of serum alanine aminotransferase levels and improvement in liver histology.Persistent HBV covalently closed circular DNA and integrated HBV DNA sustain antigen production, while prolonged antigen exposure impairs host antiviral immunity.Together, these processes create a major barrier to functional cure.Chronic antigenic stimulation exhausts HBV-specific T cells, impairs B-cell function, reinforces hepatic immune tolerance, and disrupts innate immunity, metabolism, epigenetic regulation, and the gut-liver axis.Accordingly, functional cure will probably require both a reduced viral antigen burden and antiviral immune restoration.Combination strategies integrating novel antiviral agents with pegylated interferon-α, therapeutic vaccines, immune checkpoint inhibitors, or innate immune agonists have therefore become a major therapeutic focus.This review summarizes the immunopathological mechanisms underlying functional cure of CHB, strategies for antiviral immune restoration, as well as recent advances in biomarker development and patient stratification.It highlights the interactions among persistent antigen exposure, immune exhaustion, and hepatic immune tolerance, with particular emphasis on the roles of antigen reduction, antiviral immune restoration, and precise patient stratification in promoting functional cure.This review aims to deepen understanding of the immunological basis of functional cure in CHB and inform the optimization of combination therapies and the development of individualized treatment strategies.4 / 80