New hepatitis B drug development disillusions: time to reset?

After more than 5 years of intense preclinical and clinical research, the development of new hepatitis B virus (HBV) drugs appears to be stalling. The main reasons for this are the major limitations of the developmental path, including the use of inappropriate endpoints for clinical development, the standards for efficacy and approval being too strict (functional cure after short finite treatment duration), expecting compounds to do what they cannot do because of their known targets and mechanisms of action, and hoping that one size will fit all, despite the fact that HBV infection is heterogeneous. A functional HBV cure cannot be easily attained with only a few weeks or months of treatment with the classes of compounds that are currently in development. Therefore, researchers, drug developers, and regulators need to establish a new consensus about endpoints that are both clinically relevant and achievable, and redefine the objectives, timelines, and pathways of new HBV drug development.