Need of the hour: A promising biomarker for the effective monitoring of hepatitis B infections

Chronic hepatitis B (CHB) is a viral disease that can progressively cause severe liver damage, ultimately leading to cirrhosis or hepatocellular carcinoma (an aggressive cancer of the liver). While anti-viral therapy has been successful in considerably decreasing the viral load, completely eliminating the virus continues to remain a challenge. This is because the hepatitis B virus has the unique ability to insert its genetic material into the host liver cell genome. Using this mechanism, HBV can remain inactive in its carriers and presents a risk of subsequent re-infection. And thus, continuous monitoring of HBV carriers is encouraged.

A good strategy for this is the assessment of viral antigens that can predict the viral load as serum biomarkers. In this context, the presence of a protein called “hepatitis B e-antigen” (HBeAg) often indicates an active infection with a rapidly multiplying viral population. Conversely, an HBeAg-negative status implicates minimal viral replication or a dormant (slow) infection. Thus, the loss of HBeAg or development of antibodies against this antigen is considered as a sign of recovery. While HBeAg along with HB surface antigen (HBsAg) as well as HBV DNA and RNA (viral genetic material) have been traditionally used to track disease progression, these markers often do not reliably predict treatment response and disease severity, highlighting the need for more robust biomarkers.

An alternative way to monitor HBV infections is by looking at “hepatitis B core-related antigen” (HBcrAg), an important structural component of the virus that has recently been in the limelight for its potential role as a biomarker. Preliminary evidence also suggests its correlation with the aforementioned viral antigens. Still, whether it can accurately predict changes in the levels of viral antigens and histology (changes in the liver tissue), as the disease progresses and in response to therapy, remains less understood.

To find out more, researchers from China, on behalf of the HepB-Related Fibrosis Assessment Research Group, probed deeper into the potential of HBcrAg as an alternative marker in the monitoring of CHB disease. In a multicenter study, they revealed new insights into the use of HBcrAg levels in CHB. Lead author of the study, Dr. Hong Zhao, explains, “We aimed to investigate the correlations between HBcrAg and virological and histological variables before and after 78 weeks of antiviral therapy in CHB patients, both HBeAg-positive and negative, and to identify the predictors for HBeAg loss in HBeAg positive patients.” Their paper was made available online on 17^th March 2021 and, on 20^th May 2021, was published in Volume 134 Issue 10 of Chinese Medical Journal.

The researchers investigated patients with CHB who had not received treatment previously. The patients were subjected to 78 weeks of entecavir therapy, an anti-viral treatment, followed by a paired liver biopsy at the end of treatment. The researchers graded Inflammation of the liver using a modified histology activity index and assessed fibrosis (scarring of damaged liver tissue) using the Ishak fibrosis score (also called the F score). Viral antigens were quantified using immuno-assays.

They found that, of the 145 patients who underwent a biopsy, 93 were HBeAg positive and 52 were HBeAg-negative. Prior to the treatment, HBeAg-positive patients had higher levels of HBcrAg along with HBV DNA, HBsAg, and alanine aminotransferase (a liver enzyme whose high levels indicate damage) than HBeAg-negative patients. Notably, HBeAg-positive patients showed a greater decline in HBcrAg levels of than HBeAg-negative patients, which strongly correlated with a decrease in HBV DNA and HBsAg. A decline in HBcrAg was also associated with a decrease in inflammation in HBeAg-positive patients, although this association was weak. Further, HBeAg loss was associated with a greater reduction in HBcrAg. Upon analysis, the researchers found that HBcrAg was the only predictor of HBeAg loss following treatment.

Thus, HBcrAg is a robust and independent serum biomarker that can accurately predict the viral load in CHB and reflects response to anti-viral treatments in an effective manner. In addition, it may also be useful to distinguish between patients with active infections and those who are simply carriers.

Dr. Zhou explains the clinical implications of their study, “As a marker for the number of infected hepatocytes, HBcrAg may reflect both viral replication and viral protein production. In addition, a decline in HBcrAg can be used to predict HBeAg loss after antiviral therapy. HBcrAg may thus become a practical clinical marker, given its extensive and reliable application.” 

These findings pave the way for a reliable monitoring method of CHB, which can aid clinical decisions and, hopefully, improve the lives of patients with HBV infections.

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Reference

Title of original paper: Hepatitis B core-related antigen reflects viral replication and protein production in chronic hepatitis B patients

Journal: Chinese Medical Journal

DOI: https://doi.org/10.1097/CM9.0000000000001418