Toward a Cure for Hepatitis B Virus Infection: Combination Therapy Involving Viral Suppression and Immune Modulation and Long-term Outcome

Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, the approved therapeutic regimens include nucleos(t)ide analogues (NAs) and either interferon or pegylated interferon. NA therapy is generally safe and well tolerated, but the rate of posttreatment virologic relapse is high, making NA treatment a lifetime commitment. The benefits of pegylated interferon treatment include a finite duration, more-durable response and absence of viral resistance. However, sustained response to interferon alone is achieved only in a minority of patients, and side effects are common, which limit its clinical use. Given that HBV covalently closed circular DNA and the integrated HBV genome persist stably in the nuclei of infected hepatocytes, elimination (complete cure) of HBV is rarely achieved. After completion of treatment, sustained HBV surface antigen loss, with or without seroconversion to HBV surface antibody positivity (ie, functional cure), is therefore recommended as the ideal end point for anti-HBV treatment, despite the lack of complete eradication of HBV. Theoretically, combination of antiviral agents with differential mechanisms of actions on HBV, including viral suppression combined with immune modulation (as occurs during treatment with NA plus pegylated interferon), is an encouraging strategy to treat chronic hepatitis B. Recent studies have confirmed certain virological and serological advantages of simultaneous administration of NA and pegylated interferon (de novo combination therapy) or addition of pegylated interferon to ongoing NA therapy (sequential combination therapy) over monotherapy. Few data exist, however, on the long-term outcomes of patients receiving combination therapy. This review summarizes current combination therapy developed to cure chronic HBV infection.