The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment but not off-treatment viral suppression. Loss of hepatitis B surface antigen (HBsAg), the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this endpoint is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication.