Novel circulating markers for hepatitis B virus infection

Abstract

Studies on natural history of chronic hepatitis B disease have revealed the clinical importance of measuring HBsAg, HBeAg and HBV DNA levels. Their profiles are also characterized in patients receiving treatment of the disease. They are proven to be useful in the disease outcome prognostication and treatment efficacy. However, it has been shown that their roles are rather limited in reflecting the cccDNA content especially in the situations where there is profound viral suppression under nucleos(t)ide analogues (NA) therapy. In recent years, measurements of two novel HBV markers have been actively investigated, with the aim of providing better correlations with regard to the disease activity and treatment outcome. The two upcoming ones are hepatitis B core-related antigens (HBcrAg) and HBV RNA. Measurement of HBcrAg levels indeed is a composite detection of three viral proteins from pre-core/core gene transcription, namely HBcAg, HBeAg and p22cr. It has been found that HBcrAg has a good correlation with intrahepatic cccDNA level in patients with or without undetectable serum HBV DNA. Furthermore, measuring HBcrAg is of clinical relevance in different scenarios of HBV disease including the levels with respect to 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. Therefore, HBV RNA would be present in all HBV patients. Serum absolute HBV RNA levels are usually 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 has also been shown to predict HBeAg seroconversion in patients receiving Peg-IFN and/ or NA. Novel treatments targeting HBV RNA knockdown result in good reduction of HBV RNA levels. Detectable HBV RNA is associated with a higher chance of HBV relapse after cessation of the NA treatment. It is expected that the development of measurements of these two new markers would provide more informative resources for clinicians for better disease prognostication and management for HBV patients.