Hepatitis B Core-Related Antigen Reflects Viral Replication and Protein Production in Chronic Hepatitis B Patients
Chronic hepatitis B (CHB) is a significant global health issue, affecting approximately 260 million people worldwide. A substantial proportion of these individuals, ranging from 15% to 40%, may develop severe complications such as cirrhosis and hepatocellular carcinoma (HCC). Antiviral therapy has been shown to achieve virological response, hepatitis B e antigen (HBeAg) loss or seroconversion, histological improvement, and ideally, hepatitis B surface antigen (HBsAg) loss or seroconversion. However, the complete eradication of hepatitis B virus (HBV) from infected hepatocytes remains challenging due to the persistence of intrahepatic covalently closed circular DNA (cccDNA).
Hepatitis B core-related antigen (HBcrAg) has emerged as a promising virological marker for monitoring CHB. HBcrAg is encoded by the precore/core region and comprises three proteins: HBeAg, hepatitis B core antigen (HBcAg), and a 22,000 Da precore protein (p22cr). HBcrAg has been utilized as a surrogate marker for other virological agents and has shown potential in predicting antiviral efficacy, the risk of HBV reactivation in occult HBV infections under immunosuppressive therapies, the risk of HCC development, and post-operative HCC recurrence.
This study aimed to investigate the correlations between HBcrAg and antiviral efficacy, as well as virological and histological variables, in CHB patients. The research involved 145 treatment-naïve CHB patients from mainland China who underwent liver biopsy and received entecavir (ETV) therapy for 78 weeks, with a paired liver biopsy conducted at the end of the treatment period. The patients were categorized into HBeAg-positive and HBeAg-negative groups, and correlations between HBcrAg and various virological and histological markers were analyzed.
At baseline, HBeAg-positive patients exhibited higher median HBcrAg levels (7.4 log10 U/mL) compared to HBeAg-negative patients (5.3 log10 U/mL). The decline in HBcrAg after 78 weeks of therapy was also more pronounced in HBeAg-positive patients (median decline of 1.6 log10 U/mL) than in HBeAg-negative patients (median decline of 0.9 log10 U/mL). These findings suggest that HBcrAg levels are higher in patients with more active viral replication, which is typically associated with HBeAg-positive status.
The study found significant correlations between HBcrAg and HBV DNA at baseline in both HBeAg-positive (r = 0.641) and HBeAg-negative patients (r = 0.616). In HBeAg-positive patients, HBcrAg also correlated with HBsAg (r = 0.495) but not with anti-hepatitis B virus core antibody (anti-HBc). Weak correlations were observed between HBcrAg and histological activity index (HAI) (r = 0.232) and Ishak fibrosis score (r = -0.292) in HBeAg-positive patients. At 78 weeks, significant correlations were only found between HBcrAg and anti-HBc in both HBeAg-positive (r = -0.263) and HBeAg-negative patients (r = -0.291).
The decline in HBcrAg (ΔHBcrAg) was significantly correlated with reductions in HBV DNA (r = 0.366 in HBeAg-positive and r = 0.626 in HBeAg-negative patients) and HBsAg (r = 0.526 in HBeAg-positive and r = 0.289 in HBeAg-negative patients). Additionally, ΔHBcrAg correlated with reduced HAI in HBeAg-positive patients (r = 0.329). Patients who achieved HBeAg loss (n = 29) showed a larger reduction in HBcrAg (median decline of 2.3 log10 U/mL) compared to those who did not (median decline of 1.3 log10 U/mL). Multivariate analysis identified ΔHBcrAg as an independent predictor of HBeAg loss (P = 0.005).
The study also highlighted the role of HBcrAg as a surrogate marker for intrahepatic cccDNA and its transcriptional activity. Previous research has demonstrated strong correlations between HBcrAg and intrahepatic cccDNA, as well as its transcriptional activity. This study’s findings align with these observations, suggesting that HBcrAg levels reflect viral replication and protein production.
Despite the significant correlations observed, the study noted limitations. HBcrAg was only measured at baseline and 78 weeks, lacking serial data at fixed time points during antiviral therapy. This limitation prevents a comprehensive understanding of the dynamic changes in HBcrAg levels during treatment. Additionally, the study did not explore whether HBcrAg levels or the degree of change during therapy, rather than the degree of change between baseline and 78 weeks, could predict HBeAg loss.
In conclusion, HBcrAg serves as a valuable marker for monitoring viral replication and protein production in CHB patients. The study demonstrated significant correlations between HBcrAg and HBV DNA, HBsAg, and histological markers, particularly in HBeAg-positive patients. The decline in HBcrAg was identified as a predictor of HBeAg loss, highlighting its potential utility in clinical practice. Further research is needed to explore the dynamic changes in HBcrAg levels during antiviral therapy and to validate its predictive value for HBeAg loss and other clinical outcomes.
doi.org/10.1097/CM9.0000000000001418
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