The Role of Hepatitis B Core-Related Antigen

Abstract

Hepatitis B virus (HBV) cannot be completely eliminated from infected hepatocytes due to the existence of intrahepatic covalently closed circular DNA (cccDNA). Serological biomarkers reflect intrahepatic viral replicative activity as non-invasive alternatives to liver biopsy. Hepatitis B core-related antigen (HBcrAg) is a novel biomarker that has an important role in chronic hepatitis B (CHB), because it correlates with serum HBV DNA and intrahepatic cccDNA. In clinical cases with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with promising outcomes for CHB patients. HBcrAg can predict spontaneous or treatment-induced hepatitis B envelope antigen (HBeAg) seroconversion, persistent responses before and after cessation of nucleos(t)ide analogues, potential HBV reactivation, HBV reinfection after liver transplantation, and risk of hepatocellular carcinoma progression or recurrence. In this review, the clinical applications of HBcrAg in CHB patients based on its virological features are described. Furthermore, new potential therapeutic anti-HBV agents that affect intrahepatic cccDNA are under development, and the monitoring of HBcrAg might be useful to judge therapeutic effects. In conclusion, HBcrAg might be a suitable surrogate marker beyond other HBV markers to predict the disease progression and treatment responses of CHB patients.

Keywords: HBV DNA; chronic hepatitis B (CHB); covalently closed circular DNA (cccDNA); hepatitis B core-related antigen (HBcrAg); hepatitis B virus (HBV).

Figure 1

Schematic representation of the Hepatitis B virus (HBV) lifecycle, from HBV entry into hepatocytes to release from hepatocytes. (a) The c covalently closed circular DNA (ccDNA) is present as minichromosomes of 5 to 50 in one hepatocyte. A portion of the incompletely circularized double stranded DNA, which has been reverse transcribed and synthesized, is transferred again into the nucleus. It is recycled as cccDNA to maintain the stock amount of cccDNA [6]. HBcrAg is produced from cccDNA. (b) Hepatitis B core-related antigen (HBcrAg) is a denatured mixture consisting of hepatitis B envelope antigen (HBeAg), hepatitis B core antigen (HBcAg), and 22-kDa precore protein (p22cr) coded with the precore/core region [32,33,34]. HBeAg: Information about replication status of the virus; p22cr: Empty virus particle; HBcAg: Undetectable protein in blood because it is always part of a complex. These three different types of antigen proteins are translated by the mRNA of transcriptional products of cccDNA, which itself is generated by the HBV replication process in hepatocytes [36]. By serologic testing, HBeAg, p22cr, and HBcAg can be measured as HBcrAg all together [33,35]. Abbreviations: HBV, hepatitis B virus; cccDNA, covalently closed circular DNA; HBcrAg, hepatitis B core-related antigen; HBeAg, hepatitis B envelope antigen; HBcAg, hepatitis B core antigen; p22cr, 22-kDa precore protein.