New biomarkers of chronic hepatitis B

Abstract

Since HBsAg, HBeAg and HBV DNA have been standardized and used as viral markers for chronic hepatitis B infection for many decades, their profiles are well characterized in the natural history and treatment of the disease. These existing markers have been proven to be useful in the disease outcome prognostication and treatment efficacy. With the profound viral suppressive effects from nucleos(t)ide analogues (NA), their roles are rather limited in reflecting the cccDNA content. In addition, there are also lacks of reliable markers to predicting viral rebound after cessation of long-term NA therapy. In the recent years, measurements of two novel HBV markers have been actively explored, with the aim of providing better correlations with regard to the disease activity and treatment outcome. They are hepatitis B core-related antigen (HBcrAg) and HBV RNA. HBcrAg is a composite measurement of three viral proteins from pre-core/core gene transcription. They are HBcAg, HBeAg and p22cr. It has been found that HBcrAg has a strong correlation with cccDNA level in the liver even in patients with undetectable serum HBV DNA. In addition, it has significance in different scenarios of HBV disease including its reduction in levels during treatment, rates of HBeAg seroconversion, HBsAg seroclearance, development of cirrhosis and HCC, and HBV reactivations from cessation of treatment and from occult HBV infected patients undergoing immunosuppressive therapy. HBV RNA is another new HBV marker being actively investigated. Pregenomic HBV RNA acts as the template for reverse transcription to relaxed circular DNA after encapsidation. HBV RNA is therefore present in all HBV patients. Under normal circumstance, serum HBV RNA levels are lower than that of serum HBV DNA. It has been shown to have good correlations with HBV DNA and cccDNA. The reduction of HBV RNA was shown to predict HBeAg seroconversion in patients receiving Peg-IFN and/ or NA. Novel treatments targeting HBV RNA knockdown had shown decrease in HBV RNA levels. In addition, detectable HBV RNA was associated with a higher chance of HBV relapse after cessation of the NA treatment. The development of measurements of these two new markers would provide more informative resources for clinicians to have better disease prognostication and management for HBV patients.