Clinical value of HBcrAg


Serum levels of HBcrAg refect the amount of HBV cccDNA in hepatocytes, only measurable by liver biopsy. Wong et al1 showed at baseline strong positive correlations (p <0.001) between serum HBcrAg concentrations and

  • levels of serum HBV DNA
  • intrahepatic total HBV DNA
  • intrahepatic cccDNA

Later on, Suzuki et al2 reported signifcant positive correlations (p <0.001) between serum HBcrAg concentrations and levels of serum HBV DNA and intrahepatic cccDNA. Especially in 31 patients that were HBV-DNA negative of which 20 had detectable HBcrAg levels, there was a statistically signifcant correlation between HBcrAg and cccDNA.

From a monitoring perspective, the study by Wong et al1 also showed that 26 out of 36 patients that were assessed for histological improvement showed a signifcantly greater reduction in HBV cccDNA and HBcrAg levels compared to patients with no or little improvement. Furthermore they noted that low baseline levels predict a more favourable treatment response.

On the other hand, studies from 20103 and 20134-6 indicate that higher levels of HBcrAg are associated with a higher risk of developing hepatocellular carcinoma (HCC), and an increased risk of both re-activation of hepatitis and recurrence of HCC.

Clinical relevance

With the introduction of the LUMIPULSE G system in Europe, HBcrAg-trials are being conducted in European populations. In these initial studies HBcrAg levels were evaluated in the natural history of HBV infection and measured in the stages of immune-tolerance, immune-clearance, HBeAg-negative hepatitis and HBeAg-negative inactive carriers.

These studies show that the HBcrAg levels vary signifcantly depending on these diferent phases of infection. Therefore HBcrAg may help to distinguish between inactive carriers and those with active disease and in that way decide who requires a closer monitoring.

So far, a small set of samples with follow-up data on clinical events also showed that patients with a lower level of HBcrAg had a signifcantly lower chance of experiencing a clinical event such as HBV reactivation or initiation of antiviral therapy.

Next steps

The diferent fndings known today on correlations with HBV DNA and HBsAg coincide with the conclusion of other studies that HBcrAg may serve as a valuable marker for viral replication and refect the transcriptional activity of intrapetic cccDNA.

Larger and prospective studies are needed especially including samples with more follow-up data and samples of patients undergoing treatment.


  1. Wong DK, et al. Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection. J Clin Microbiol 2007 Dec;45(12): 3942-7.
  2. Suzuki F, et al. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 2009 Jan;81(1): 27-33.
  3. Hosaka T, et al. HBcrAg is a predictor of post-treatment recurrence of hepatocellular carcinoma during antiviral therapy. Liver Int. 2010 Nov;30(10):1461-70.
  4. Kumada T, et al. Efect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis. J Hepatol. 2013 Mar;58(3): 427-33.
  5. Morita S, et al. Characteristics and prediction of hepatitis B e-antigen negative hepatitis following seroconversion in patients with chronic hepatitis B. Hepatol Res. 2014 Oct;44(10): E45-53.
  6. Matsuzaki T, et al. Signifcance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation. J Gastroenterol Hepatol. 2013 Jul;28(7): 1217-22.

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