INTRAHEPATIC AND SERUM MARKERS OF HEPATITIS B VIRUS AS PREDICTORS OF RESPONSE TO PEGYLATED INTERFERON THERAPY

Effective predictors of treatment response to pegylated interferon (PEG-IFN) in patients with chronic hepatitis B (CHB) are currently limited. This research was aimed at studying the predictive roles of intrahepatic and serum markers of hepatitis B virus (HBV) in patients with HBeAg-positive (group 1) and HBeAg-negative CHB (group 2) receiving standard course of 48-week PEG-IFN therapy and followed up for at least 24 weeks. Intrahepatic cccDNA and intrahepatic viral antigens, including HBsAg and HBcAg were assessed in paired pre- and post-treatment liver specimens. Kinetics of quantitative serum markers, including HBsAg and HBcrAg in response to therapy was also examined. In addition, pre-existing HBV mutations in the EnhII/BCP/PC and Pre-S/S regions at baseline were determined by Sanger sequencing and Next Generation Sequencing (NGS). The results showed that group 1 had significantly higher baseline intrahepatic and serum markers compared with group 2. Baseline quantitative HBcrAg correlated with cccDNA levels in both groups. In contrast, quantitative HBsAg correlated with cccDNA levels only in group 1 but not in group 2. However, changes in HBsAg and HBcrAg levels during therapy were correlated with the reduction of cccDNA in both groups. Generally, responders had more rapid decline of both serum markers during therapy compared with non-responders. In group 1, patients infected with HBV mutants in the EnhII/BCP/PC region had significantly lower response rates compared with those infected with wild-type strains. The decline in the expression of intrahepatic HBsAg, but not HBcAg, was associated with treatment response. In conclusion, serum HBcrAg represented a better surrogate marker of intrahepatic cccDNA compared with serum HBsAg. Monitoring both serum markers during PEG-IFN therapy may help identify patients with high and low probability of achieving response. NGS could accurately identify pre-treatment viral mutants that might be associated with treatment outcome.