Correlation of HBcrAg with Intrahepatic Hepatitis B Virus Total DNA and Covalently Closed Circular DNA in HBeAg-Positive Chronic Hepatitis B Patients

Abstract

The purpose of this study was to explore the correlations of serum hepatitis B core-related antigen (HBcrAg) with intrahepatic Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and HBV total DNA in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. Serum HBcrAg and other parameters, including HBV DNA, HBV RNA, HBeAg, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were quantitatively measured at baseline and follow-up time points. Intrahepatic HBV cccDNA and total DNA were quantitatively detected at baseline and 96 weeks. Grading of liver necroinflammation and staging of hepatic fibrosis were assessed at baseline and 96 weeks. Correlations between serum HBcrAg and other parameters were analyzed by Pearson's correlation analysis. The results showed that pretreatment HBcrAg correlated significantly with HBV total DNA levels (r = 0.328, P = 0.003) in 82 CHB patients, and, after removing three outliers, with intrahepatic HBV cccDNA (r = 0.323, P = 0.004; n = 79). Serum HBcrAg correlated better with HBV cccDNA in patients with lower levels of serum HBV DNA (stratified by 7 log IU/ml of HBV DNA; r = 0.656, P = 0.003 versus r = -0.02, P = 0.866). Significant inverse correlations were found between HBcrAg and grade of liver necroinflammation (r = -0.245, P = 0.037), stage of hepatic fibrosis (r = -0.360, P = 0.002) at baseline. Serum HBcrAg presented significant correlation with intrahepatic HBV cccDNA in patients with HBeAg seroconversion at 96 weeks (r = 0.622, P = 0.006). The decrease in HBcrAg showed significant correlation with the decrease in HBV cccDNA after 96-week NA therapy (r = 0.282, P = 0.043). Serum HBcrAg also correlated significantly with other serum markers at baseline and 96 weeks of NA therapy. In conclusion, baseline HBcrAg and its decreased value were significantly correlated with the corresponding intrahepatic HBV cccDNA.

Keywords: HBV RNA; chronic hepatitis B; covalently closed circular DNA; hepatitis B core-related antigen; nucleos(t)ide analogues.

FIG 1

Dynamic changes of HBcrAg levels from baseline to 96 weeks in CHB patients who received NA therapy, stratified by virological response (A) and HBeAg seroconversion (B) at 96 weeks. *, P < 0.05; VR+, virological response (HBV DNA < 20 IU/ml); VR−, without virological response; SC+, HBeAg seroconversion; SC−, without HBeAg seroconversion.

FIG 2

Correlation between HBcrAg and HBV total DNA (A), intrahepatic HBV cccDNA (B), intrahepatic HBV cccDNA (after removing three outliers) (C), HBV total DNA (after removing three outliers) (D), intrahepatic HBV cccDNA (with HBV DNA of <7 log U/ml) (E), intrahepatic HBV cccDNA (with HBV DNA of ≥7 log U/ml) (F). cccDNA, covalently closed circular DNA; HBV total DNA, hepatitis B virus total DNA; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBcrAg, hepatitis B core-related antigen.

FIG 3

Correlation between HBcrAg and serum HBV RNA (A), HBV DNA (B), HBeAg (C), HBsAg (D), the grade of liver necroinflammation (E), and stage of hepatic fibrosis (F) in HBeAg-positive CHB patients at baseline. HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBcrAg, hepatitis B core-related antigen.