Antiviral therapy of chronic hepatitis B: can we clear the virus and prevent drug resistance?

Antiviral therapy of chronic HBV infection remains a clinical challenge. Once this infection has been-established, the viral genome persists for life, either as an integrated genome or as episomal covalently closed circular DNA (cccDNA). The latter is the source of renewed viral replication in case of immune depression or after antiviral drug withdrawal. The mechanisms of clearance of infected cells involve CD8+ cell-mediated cytolytic and non-cytolytic pathways. Antiviral therapy, using nucleoside analogues that inhibit the viral polymerase, induces a slow depletion of intrahepatic cccDNA. The persistence of low-grade viral replication under antiviral therapy may then lead to the selection of drug-resistant mutants. New assays have been developed to study the functional consequences of these polymerase mutations in terms of replication capacity and drug susceptibility. Together with the development of new HBV polymerase inhibitors and novel immunostimulatory approaches, this should lead to the design and evaluation of rational treatment combinations for a better control of viral replication and prevention of drug resistance.