Getting to HBV cure: the promising paths forward

Chronic hepatitis B virus (HBV) infection is a global public health burden estimated to impact nearly 300 million people worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve due to the persistence of the covalently closed circular DNA, HBV DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain the level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing towards clinical development. The future of HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs, and discusses the limitations and unanswered questions on the journey to HBV cure.