Functionally cured chronic hepatitis B: A cure-related occult HBV infection state

Occult HBV infection (OBI) is characterized by the presence of replication-competent hepatitis B virus (HBV) DNA (covalently closed circular DNA [cccDNA] and/or relaxed circular DNA [rcDNA]) in the liver and/or HBV DNA in the blood, despite negative hepatitis B surface antigen (HBsAg) serology. The potential risks associated with OBI include HBV blood transmission, diagnostic challenges, and viral reactivation under immunosuppressive therapy. Some patients with OBI may face a higher risk of liver fibrosis compared to those who have achieved complete clearance of the virus. Functional cure is defined as the clearance of HBsAg, with or without hepatitis B surface antibody (anti-HBs) seroconversion, and undetectable serum HBV DNA after finite therapy. It has been recommended as the optimal goal of antiviral treatment for chronic hepatitis B (CHB) by major guidelines. We highlight that patients achieving functional cure represent a distinct form of cure-related OBI, with unique virological features and potential clinical implications. Furthermore, although direct epidemiological evidence remains limited, accumulating studies have demonstrated that OBI cases with undetectable HBV DNA and negative HBsAg serology retain the potential for transfusion transmission. Accordingly, the transfusion-related risk associated with functional cure should not be overlooked. Here, we discuss the definition, virological and immunological basis, prevalence, diagnosis, and clinical significance of OBI, highlighting its link to cccDNA persistence and immune suppression of viral replication. Finally, we emphasize regular follow-up to mitigate the risks of transfusion-related transmission, HBV reactivation, and disease progression. Further research is warranted to elucidate the viral and immune status of functionally cured patients, thereby optimizing treatment strategies and ensuring blood safety.