Higher Baseline Viral Diversity Correlates With Lower Hbsag Decline Following Pegylated Interferon-Alpha Therapy In Patients With Hbeag-Positive Chronic Hepatitis B

Background: Viral diversity seems to predict treatment outcomes in certain viral infections. The aim of this study was to evaluate the association between baseline intra-patient viral diversity and hepatitis B surface antigen (HBsAg) decline following PEGylated interferon-alpha (Peg-IFN-alpha) therapy.Patients and methods: Twenty-six HBeAg-positive patients who were treated with Peg-IFN-alpha were enrolled. Nested polymerase chain reaction (PCR), cloning, and sequencing of the hepatitis B virus S gene were performed on baseline samples, and normalized Shannon entropy (Sn) was calculated as a measure of small hepatitis B surface protein (SHBs) diversity. Multiple regression analysis was used to estimate the association between baseline Sn and HBsAg decline.Results: Of the 26 patients enrolled in the study, 65.4% were male and 61.5% were infected with hepatitis B virus genotype B. The median HBsAg level at baseline was 4.5 log(10)IU/mL (interquartile range: 4.1-4.9) and declined to 3.0 log(10)IU/mL (interquartile range: 1.7-3.9) after 48 weeks of Peg-IFN-alpha treatment. In models adjusted for baseline alanine aminotransferase (ALT) and HBsAg, the adjusted coefficients (95% CI) for Delta HBsAg and relative percentage HBsAg decrease were -1.3 (-2.5, -0.2) log(10)IU/mL for higher SHBs diversity (Sn >= 0.58) patients and -26.4% (-50.2%, -2.5%) for lower diversity (Sn<0.58) patients. Further analysis showed that the "a" determinant upstream flanking region and the first loop of the "a" determinant (nucleotides 341-359, 371-389, and 381-399) were the main sources of higher SHBs diversity.Conclusion: Baseline intra-patient SHBs diversity was inverse to HBsAg decline in HBeAg-positive chronic hepatitis B (CHB) patients receiving Peg-IFN-alpha monotherapy. Also, more sequence variations within the "a" determinant upstream flanking region and the first loop of the "a" determinant were the main sources of the higher SHBs diversity.