Functional cure for chronic hepatitis B: A state of immune control over cccDNA persistence

Functional (clinical) cure is considered a desirable therapeutic endpoint of antiviral therapy for chronic hepatitis B (CHB). Recent studies have detected transcriptionally active covalently closed circular DNA (cccDNA) and integrated hepatitis B virus (HBV) DNA (iDNA) in the liver tissue of patients who achieved functional cure. More than that, a small subset of these patients even showed positive staining for hepatitis B surface antigen (HBsAg) in hepatocytes. Notably, compared to uncured patients, functionally cured patients demonstrate significantly restored HBV-specific immune responses. Based on these findings, it is clear that although cccDNA or iDNA are not completely cleared in certain functionally cured patients, the circulating viral markers are largely undetectable, even with the sensitive measuring methods that are routinely used. This is because, virologically, the residual viral genomic DNA in functionally cured patients is often genetically or epigenetically modified or undergoes post-transcriptional splicing and editing that prevents viral protein expression and productive replication. More importantly, the restored host immune responses further suppress viral protein production and HBV DNA replication to undetectable levels in peripheral blood. Thus, this form of functional cure for CHB might be described more accurately as an "undetectable" state of circulating virologic markers under the control of a restored host immune response against HBV infection. This resembles occult HBV infection to some extent, as replicative forms of HBV DNA-such as relaxed circular DNA and/or cccDNA-persist in the liver, accompanied by a risk of reactivation. As a result, consolidation therapy following serum HBsAg loss and continued follow-up monitoring after discontinuation of treatment become crucial. This review provides a comprehensive overview of the status of CHB patients who achieved functional cure, explains its underlying reasons, and assesses its relevance to clinical treatment and practice.