Hepatitis B core-related antigen: A novel and promising surrogate biomarker to guide anti-hepatitis B virus therapy

The current requirement for biomarkers to detect hepatitis B virus (HBV) infection is polarized. One is a fully-automated and highly sensitive measurement system; the other is a simple system for point-of-care testing (POCT) in resource-limited areas. Hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular DNA and serum HBV DNA. Even in patients with undetectable serum HBV DNA or HBsAg loss, HBcrAg may remain detectable. Decreased HBcrAg levels are associated with reduction of the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B. Recently, a fully-automated, novel high-sensitivity HBcrAg assay (iTACT-HBcrAg, cut-off value: 2.1 logIU/mL) has been developed. This attractive assay has been released in Japan very recently. iTACT-HBcrAg can be useful for monitoring HBV reactivation and prediction of HCC occurrence, as an alternative to HBV DNA. Moreover, monitoring HBcrAg may be suitable for determining the therapeutic effectiveness of approved drugs and novel drugs under development. Presently, international guidelines recommend anti-HBV prophylaxis for pregnant women with high viral loads to prevent mother-to-child transmission of HBV. However, >95% of HBV-infected individuals live in countries where HBV DNA quantification is not available. Worldwide elimination of HBV needs the scaling-up of examination and medication services in resource-limited areas. Based on this situation, a rapid and easy HBcrAg assay as a POCT is valuable. This review provides the latest information regarding the clinical use of a new surrogate marker, HBcrAg, in HBV management, based on iTACT-HBcrAg or POCT, and introduces novel agents targeting HBV RNA/protein.

Novel biomarkers for the management of chronic hepatitis B

Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.