Impaired Intrahepatic Hepatitis B Virus Productivity Contributes to Low Viremia in Most HBeAg-Negative Patients

Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding the mechanisms of viral decay and how these processes are thwarted in patients with chronic hepatitis B, according to the authors of a study reported in the September 2007 issue of Gastroenterology.

The German researchers analyzed liver biopsies from 119 treatment-naive patients with chronic HBV infection, of whom 42 were hepatitis B "e" antigen (HBeAg) positive and 77 were HBeAg negative. HBV transcriptional and replicative activity were assessed.

Results

• Compared with HBeAg positive patients, HBeAg negative
individuals had:

- significantly lower median serum HBV DNA levels (-4 log);
- lower HBV DNA levels in the liver (-2 log);
- lower levels of HBV cccDNA (-1 log).

• Despite a good correlation between amounts of progeny virions (virus particles) in the liver and serum HBV DNA in all patients, cccDNA levels did not correspond to serum titers in HBeAg negative individuals.

• Analysis of HBV RNA transcripts showed that impaired virion productivity in HBeAg negative individuals was due to lower steady-state levels of pregenomic RNA produced per cccDNA.

• PreS/S RNA levels and serum HBsAg concentrations did not differ between HBeAg positive and HBeAg negative patients after controlling for cccDNA content, showing that subviral particle production was not impaired in HBeAg negative patients and correlated with cccDNA levels.

• Although the majority of HBeAg negative individuals harbored cccDNA with common precore and/or basal core promoter mutations, occurrence of these variants was not responsible for reduced viral replication.

• Instead, replacement of wild-type (non-mutated) cccDNA with core promoter mutants re-established high virion productivity.

Conclusion

Based on these findings, the study authors concluded, "Lower viremia in HBeAg negative individuals is not only due to lower cccDNA content but also to impaired virion productivity, which can arise without emergence of HBeAg variants and without affecting HBsAg production."

10/16/07

Reference
T Volz, M Lutgehetmann, P Wachtler, and others. Impaired Intrahepatic Hepatitis B Virus Productivity Contributes to Low Viremia in Most HBeAg-Negative Patients. Gastroenterology 133(3): 843-852. September 2007.