Reducing HBV antigen levels per se may not restore virus-specific T-cell responses.

Successful CHB therapies may combine antivirals and immune-stimulating agents.

Future combination therapies for CHB should include T-cell vaccines.

Drugs aiding the intrahepatic cross-presentation of HBV antigens may also work.

Combination therapies require strong industrial and academic collaborations.

Hepatitis B virus (HBV) causes either acute or chronic liver diseases. Chronic hepatitis B (CHB) often progresses to the development of cirrhosis and hepatocellular carcinoma. As HBV is extremely noncytopathic, immunological events play a key role in the infection outcome. Indeed, adaptive immune responses trigger viral clearance during acute infection and viral persistence reflects the failure to generate and maintain such responses. Current therapies for patients with CHB rely on direct-acting antivirals (DAAs) that suppress viral replication without eradicating HBV from the liver. Cure of CHB may well require combining these and forthcoming DAAs with immune-stimulating approaches of different nature and function. Here, we review the relative potential of these combination therapies.

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