Abstract

Functional cure of chronic hepatitis B defined as sustained HBsAg loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of HBV persistence has enabled the identification of novel treatment targets, drug discovery and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogues will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new non-invasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response.