Functional cure of hepatitis B requires silencing covalently closed circular and integrated hepatitis B virus DNA

Chronic hepatitis B virus (HBV) infection remains a major global health problem. Hepatitis B surface antigen (HBsAg) loss has been accepted as the definition of a functional HBV cure. Recent studies found that while covalently closed circular DNA (cccDNA) is the predominant source of HBsAg in hepatitis B e antigen–positive (HBeAg-positive) patients, integrated HBV DNA (iDNA) is the main source in HBeAg-negative patients. Consequently, achieving a functional HBV cure will require not only silencing of cccDNA but also iDNA. Assays that distinguish the source of HBsAg are needed to evaluate emerging therapies. In this issue of the JCI, Grudda et al. developed a PCR-based assay that differentiated the source of HBsAg and explored the contributing sources of HBsAg in patients on nucleos(t)ide analog antivirals. These findings provide a tool for understanding the contribution of iDNA in HBV infection and may guide therapies toward a functional HBV cure.