Progression and status of antiviral monitoring in patients with chronic hepatitis B: From HBsAg to HBV RNA

Abstract

As alternative indexes of hepatitis B virus (HBV), covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and peripheral blood RNA known as pgRNA, have been advocated as novel serum markers for prediction of prognosis and treatment response in chronic hepatitis B (CHB). Since the availability of commercial quantitative assays of HBsAg in 2011, HBsAg has been widely used for predicting treatment response of patients with CHB. Patients who received interferon therapy have shown a sharper reduction of HBsAg level than those who received nucleoside drug (NAs) therapy. Upon peginterferon treatment, sustained responders have presented a larger reduction of HBsAg level than the non-responders. An absence of HBsAg decline, together with < 2log reduction in HBV DNA at week 12, can serve as a stopping rule in HBsAg-negative patients infected with genotype D HBV. A sharp reduction of HBsAg titer in the NAs therapy is a predictor of HBsAg clearance in long-term treatment. HBcrAg, which consists of three species of related proteins sharing an identical 149 amino acid sequence, including HbcAg, hepatitis B e antigen (HBeAg), and a truncated 22-kDa precore protein, is still detectable in situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved. Therefore, HBcrAg remains a measurable serum marker to correlate with cccDNA in this situation. The decline in HBcrAg has been observed with NAs therapy and the pattern of decline might provide prognostic information on the risk of HBV post-treatment reactivation. Peripheral blood RNA, which is known as pgRNA, directly derives from cccDNA and reflects intrahepatic cccDNA level. Quantitative pgRNA has been suggested to be helpful in CHB management. However, commercial quantitative assays are lacking. Additionally, the use of simultaneous and continuous clearance of HBV RNA and HBV DNA in serum has been suggested to be a safe stopping rule of NAs therapy for patients with CHB. However, clinical studies of large sample sizes are needed to prove the feasibility and significance of using serum HBV RNA as the assessment standard of antiviral therapy in CHB and the safety of the stopping rule in clinics.

Keywords: Hepatitis B core-related antigen, Response prediction, Chronic hepatitis B, Interferon, Nucleos(t)ide analogs, Hepatitis B surface antigen, Progenome RNA

Core tip: As the surrogate biomarkers of intrahepatic viral replicative activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HbcrAg), and serum hepatitis B virus (HBV) RNA levels have been advocated as novel serum markers for treatment response in chronic hepatitis B. Currently, quantitative HBsAg has been widely used for predicting treatment response of chronic hepatitis B. HBcrAg can predict the risk of post-treatment reactivation of HBV as it is detectable in patients whose HBV DNA levels are undetectable or HBsAg loss is achieved. Serum HBV RNA may be useful in monitoring drug withdrawal, but clinical studies with large sample sizes remain necessary to further determine this capability.