Novel serum biomarkers for response to nucleoside/nucleotide analogue therapy in patients with chronic hepatitis B—a literature review

According to the World Health Organization (WHO), 296 million people were living with chronic hepatitis B virus (HBV) infection in 2019, with about 1.5 million new infections each year. In 2019, HBV caused approximately 820,000 deaths, mostly from complications of cirrhosis and hepatocellular carcinoma (primary liver cancer). Large gaps in HBV detection and treatment continue to exist, with approximately 10% of chronically infected individuals diagnosed worldwide and only 2% of these receiving treatment. The current approach in the treatment of chronic hepatitis B (CHB) is with nucleoside/nucleotide analogues (NUCs), which successfully suppress viral replication but do not lead to a complete cure, defined as HBV surface antigen (HBsAg) seroclearance in combination with undetectable HBV DNA, 24 weeks after stopping NUCs therapy. Given the low rate of HBsAg seroclearance during long-term treatment with NUCs, HBsAg formation is considered to be independent of viral replication. The sources of HBsAg production are 1) covalently closed circular DNA (ccc DNA) in the hepatocyte nucleus and 2) HBV DNA sequences integrated into the hepatocyte genome. In view of this, it is considered that new serum biomarkers are needed to better assess the course of the disease since routine biomarkers, such as HBV DNA load, used in monitoring chronic HBV infection do not provide sufficient information regarding HBV activity. Quantitative analysis of HBsAg (qHBsAg), HBV RNA, and HBcrAg, which have been proposed as surrogate markers of HBV activity, is discussed. Literature analysis of publications related to the novel surrogate markers showed promising results for qHBsAg, HBV RNA, and HBcrAg. Given the information that new serum biomarkers provide for patients on long-term NUC therapy, it is being discussed that, in order to achieve a 'functional cure', a combination of agents, including an antiviral agent, an HBsAg-suppressing agent, and an immunomodulator for enhancing the immune response, will be needed. They should be safe, with a limited duration of treatment, and affordable.