Evolutionary analysis of pre S/S mutations in HBeAg-negative chronic hepatitis B with HBsAg <100 IU/ml

Abstract

Background: Hepatitis B surface antigen (HBsAg) and viral load are important clinical indicators for patients with chronic hepatitis B (CHB) infection treated with antiviral therapy. Few studies have evaluated viral sequence biomarkers predicting the risk of hepatocellular carcinoma (HCC) in the stage, which show a low serological response (HBsAg <100 IU/ml) and high viral levels (HBV DNA >2,000 IU/ml). Additionally, point mutations within the pre S/S regions of HBsAg have frequently been reported to be associated with diagnostic failure, vaccine escape and immunotherapy escape. However, the prevalence of escape mutations with low levels of HBsAg (<100 IU/ml) in inactive HBsAg carriers has not been systematically studied within the past decade. Methods: This study aims to determine the trend of the biological prevalence of escape mutations within the pre S/S regions of special model of inactive CHB infection. Increased diversity over the complete HBV genome at baseline was associated with evolutionary characteristics. We used Sanger sequencing, quantitative HBV serology (HBeAg and HBsAg) and liver function index (aspartate alanine aminotransferase, ALT; alanine aminotransferase, AST) to identify whether HBV genome sequences are associated with the serological response to long-term host immunity in special inactive CHB infection.Results: Compared to HBV in HCC, HBV sequencing analysis of 28 LR/RA CHB patients with genotypes B and C showed higher genetic diversity among four ORFs, but the two groups presented similar selective pressure. Seven positive selection sites in the pre-S1 region are potentially associated with immune evasion. These mutations in the pre-S/S region might be associated with the HCC phenotype of low HBsAg expression, with the P region possibly impacting high viral loads.Conclusion: According to the results of this study, LR/RA CHB is characterized by not only genetic diversity but also positive evolutionary pressure within the pre-S/S regions. Increased viral diversity across the HBV genome is also associated with low levels of HBsAg. In conclusion, the cumulative evolutionary changes in the HBV pre-S/S regions that facilitate immune evasion should be monitored individually. Due to the similarity of evolutionary characteristics in HCC, low serological responses and high viremia may be associated with the risk of HCC.

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