CommentaryAre novel combination therapies needed for chronic hepatitis B?

The treatment of chronic hepatitis B remains limited to monotherapy with pegInterferon-alpha or one of 5 different nucleoside analogues (NUC). While viral suppression can be achieved in approximately 95% of patients with new-generation NUCs, the rate of HBeAg seroconversion ranges from only 20% with NUCs to 30% with pegInterferon-alpha. HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NUCs or a combination of NUC and pegInterferon-alpha have been unsuccessful. This situation has led researchers to investigate a number of steps in the HBV replication cycle as potential targets for new antiviral drugs. Novel targets and compounds could readily be evaluated in in vitro and in vivo models of HBV infection. The addition of one or more new drugs to the current regimen should offer the prospect of markedly improving the response to therapy, reducing the future burden of drug resistance, cirrhosis and hepatocellular carcinoma.

► HBV infection is characterized by the persistence of a viral minichromosome (cccDNA). ► Viral suppression is achieved in the majority of patients with current treatments. ► cccDNA eradication is currently not possible with antiviral therapy. ► The new treatment endpoints are HBsAg clearance and/or immune control of infection. ► Novel viral and host targets are required to develop true combination therapy.