New treatments to reach functional cure: Virological approaches

Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (pegIFN-α) or any of the five approved nucleos(t)ide analogues (NA). If viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NA, i.e. entecavir and tenofovir, HBsAg loss is achieved by PEG-IFN-α and/or NA in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NA or a combination of NA and PEG-IFN-α have not provided a dramatic increase in the rate of "functional cure". Because of this and the need of long-term NA administration, there is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, in order to define new targets and develop novel drugs. This includes the direct inhibition of several HBV life cycle steps by either entry inhibitors, drugs targeting cccDNA, siRNA targeting viral transcripts, capsid assembly modulators, and approaches targeting the secretion of viral envelope proteins. The addition of one or several new drugs to current therapies should offer the prospect of a markedly improved response to treatments and an increased rate of functional cure. This should lead to a reduced risk of antiviral drug resistance, and to a decreased incidence of cirrhosis and hepatocellular carcinoma (HCC). In this chapter, we review investigational and early clinical efforts regarding the identification and characterization of antiviral targets that are being evaluated for the development of innovative DAA concepts for chronic HBV infections.