(A) HBV infection during adulthood results in an acute, often severe phase of liver inflammation that is self-limited in the vast majority (95%) of cases and results in life-long cellular and humoral immunity. Immunity is protective but not sterilizing, as HBV can reactivate from cccDNA if the patients become immunosuppressed. (B) HBV infection in early life results in persistent, life-long infection, currently affecting more than 254 million people worldwide. Phases with normal alanine aminotransferase levels (HBeAg⁺ or HBeAg^– infection) alternate with phases of increased alanine aminotransferase levels (HBeAg⁺ or HBeAg^– hepatitis). Whereas both the acute and the chronic forms of HBV infection can be prevented by prophylactic HBsAg vaccination, there is no curative treatment for most patients once they acquired chronic HBV infection. Current treatment with nucleos(t)ide analogs suppresses HBV replication and reduces the risk of liver fibrosis and carcinoma but does not eliminate HBV cccDNA, and treatment with pegylated IFN-α rarely results in HBsAg loss. Of note, HBsAg can be produced from both cccDNA and from integrated, nonreplicating HBV DNA sequences. The latter are thought to be the dominant source of serum HBsAg in HBeAg^– patients. Loss of HBsAg with or without detectable anti-HBs is called functional HBV cure, if it persists for more than 24 weeks without concomitant therapy. Adapted from Gastroenterology with permission (16).