Cumulative viral evolutionary changes in chronic hepatitis B virus infection precedes hepatitis B e antigen seroconversion.


Journal Article

OBJECTIVE: To examine viral evolutionary changes and their relationship to hepatitis B e antigen (HBeAg) seroconversion. DESIGN: A matched case-control study of HBeAg seroconverters (n = 8) and non-seroconverters (n = 7) with adequate stored sera before seroconversion was performed. Nested PCR, cloning and sequencing of hepatitis B virus (HBV) precore/core gene was performed. Sequences were aligned using Clustal X2.0, followed by construction of phylogenetic trees using Pebble 1.0. Viral diversity, evolutionary rates and positive selection were then analysed. RESULTS: Baseline HBV quasispecies viral diversity was identical in seroconverters and non-seroconverters 10 years before seroconversion but started to increase approximately 3 years later. Concurrently, precore stop codon (PSC) mutations appeared. Some 2 years later, HBV-DNA declined, together with a dramatic reduction in HBeAg titres. Just before HBeAg seroconversion, seroconverters had HBV-DNA levels 2 log lower (p = 0.008), HBeAg titres 310-fold smaller (p = 0.02), PSC mutations > 25% (p < 0.001), viral evolution 8.1-fold higher (p = 0.01) and viral diversity 2.9-fold higher (p < 0.001), compared to non-seroconverters, with a 9.3-fold higher viral diversity than baseline (p = 0.011). Phylogenetic trees in seroconverters showed clustering of separate time points and longer branch lengths than non-seroconverters (p = 0.01). Positive selection was detected in five of eight seroconverters but none in non-seroconverters (p = 0.026). There was significant negative correlation between viral diversity (rs = -0.60, p < 0.001) and HBV-DNA or HBeAg (rs = -0.58, p = 0.006) levels; and positive correlation with PSC mutations (rs = 0.38, p = 0.009). Over time, the significant positive correlation was viral diversity (rs = 0.65, p < 0.001), while negative correlation was HBV-DNA (rs = -0.627, p < 0.001) and HBeAg levels (rs = -0.512, p =0.015). CONCLUSIONS: Cumulative viral evolutionary changes that precede HBeAg seroconversion provide insights into this event that may have implications for therapy.

Full Text

Cited Authors

  • Cheng, Y; Guindon, S; Rodrigo, A; Wee, LY; Inoue, M; Thompson, AJV; Locarnini, S; Lim, SG

Published Date

  • September 2013

Published In

Volume / Issue

  • 62 / 9

Start / End Page

  • 1347 - 1355

PubMed ID

  • 23242209

Pubmed Central ID

  • 23242209

Electronic International Standard Serial Number (EISSN)

  • 1468-3288

International Standard Serial Number (ISSN)

  • 0017-5749

Digital Object Identifier (DOI)

  • 10.1136/gutjnl-2012-302408


  • eng