New antiviral agents for the therapy of chronic hepatitis B virus infection

The development of new antiviral strategies for the treatment of chronic he patitis B remains a major goal since hepatitis virus (HBV) is resistant to interferon treatment as well as to new nucleoside analogs. HBV is a small D NA virus that replicates its genome via a reverse transcription step. The v iral polymerase has been the main viral target that was studied to design n ew antiviral treatments. Active research has led to the discovery of new nu cleoside analogs that are potent inhibitors of the viral reverse transcript ase. Among them, lamivudine has also proven antiviral efficacy in clinical trials with a sustained inhibition of viral replication. However, due to th e kinetics of viral clearance, long-term antiviral therapy is necessary to eradicate viral infection. These prolonged regimens are associated with the emergence of drug-resistant strains that harbor mutations in the viral pol ymerase gene within-the conserved B and C domains. New approaches using com binations of nucleoside analogs or other strategies, such as immune interve ntion (DNA vaccine, stimulation of the TH1 response) or gene therapy (antis ense oligonucleotides, dominant negative mutants), should therefore be eval uated in animal models to optimize the current antiviral protocols.