Urgent scientific issues to be solved in clinical trials of capsid assembly modulator combined with nucleos(t)ide analogues for the treatment of chronic hepatitis B / 临床肝胆病杂志

ABSTRACT

Chronic hepatitis B virus (HBV) infection is the main cause of viral hepatitis, liver cirrhosis, and primary liver cancer. At present, nucleos(t)ide analogues (NUC) and pegylated interferon α used in clinical practice cannot directly target covalently closed circular DNA, and it is difficult to achieve clinical cure of chronic hepatitis B patients; therefore, it is urgently needed to develop direct-acting antiviral agents targeting all stages of the HBV replication cycle. Capsid assembly modulator (CpAM) targets the assembly of viral capsids through various mechanisms, thereby exerting a direct-acting antiviral effect. Its combination with NUC should have a good synergistic antiviral effect, but the results of existing clinical trials have shown that chronic hepatitis B patients who received a limited course of antiviral therapy with CpAM and NUC all experienced off-therapy viral rebound. Based on the mechanism of action of these two types of drugs, this article provides a reasonable explanation for the above clinical trial results and points out that a longer course of antiviral therapy with CpAM and NUC may be needed in the future clinical trials with safe drug withdrawal as the end point of observation, so as to deplete or silence the pool of covalently closed circular DNA and increase the possibility of safe drug withdrawal in CHB patients. In addition, further studies are needed to explore antiviral therapeutic strategies with a combination of multiple targets.