Hepatitis B virus vaccination, while effective in reducing incident chronic hepatitis B in endemic regions, will not have the desired impact on the rates of end-stage liver disease in chronically infected persons. A large reservoir of chronic infection remains and needs to be managed effectively. Over three decades, interferon alpha (IFNα), and nucleoside analogue therapies have reduced the morbidity and mortality associated with chronic hepatitis B by suppressing viral replication and retarding the progression to cirrhosis and the development of hepatocellular carcinoma (HCC). The preferential preservation of covalently closed circular (cccDNA) and capsid reverse transcriptase-cccDNA interactions during nucleoside analogue therapy currently prevent cure; the majority of patients require continuous maintenance suppressive therapy. In selected patients nucleoside analogues may be stopped. New targets for drug therapy need to be directed at inhibiting intracellular HBV replication, transcription and translation pathways to enhance the likelihood of a cure in the host. Such cures for chronic hepatitis B infection will require several synergistic therapies to achieve either complete eradication of replicative intermediates from the host (cure), or more probably, a functional cure defined as loss of hepatitis B surface antigen. Hampering such development is the lack of a proven serological surrogate for cccDNA to evaluate treatment efficacy. This review outlines the pathophysiology of the virus, the host immunological responses and current therapies. Understanding the interactions between HBV and the host remains fundamental to guide correct sequencing and combinations of treatment with either host or viral-targeting agents to achieve higher rates of cur
