The scientific basis of combination therapy for chronic hepatitis B functional cure

Functional cure of chronic hepatitis B (CHB) or hepatitis B surface antigen (HBsAg) loss after 24 weeks of therapy is now the goal of treatment but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories those that reduce viral replication, antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleotide analogs and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, a rationale exists for using combinations of all three therapy types. Monitoring during therapy is essential to predict HBsAg loss and understand the mechanisms of HBsAg loss using viral and immunological biomarkers and, in selected cases, intrahepatic sampling. The various paths to a functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.