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Analysis of Hepatitis B Virus Haplotype Diversity Detects Striking Sequence Conservation Across Genotypes and Chronic Disease Phase
Author(s) -
Wagner Josef,
Yuen Lilly,
Littlejohn Margaret,
Sozzi Vitina,
Jackson Kathy,
Suri Vithika,
Tan Susanna,
Feierbach Becket,
Gaggar Anuj,
Marcellin Patrick,
Buti Ferret Maria,
Janssen Harry L.A.,
Gane Ed,
Chan Henry L.Y.,
Colledge Danni,
Rosenberg Gillian,
Bayliss Julianne,
Howden Benjamin P,
Locarnini Stephen A.,
Wong Darren,
Thompson Alexander T.,
Revill Peter A.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31516
Subject(s) - haplotype , genotype , biology , hbeag , hepatitis b virus , virology , genetics , hepatitis b , immunology , gene , virus , hbsag
Background and Aims We conducted haplotype analysis of complete hepatitis B virus (HBV) genomes following deep sequencing from 368 patients across multiple phases of chronic hepatitis B (CHB) infection from four major genotypes (A‐D), analyzing 4,110 haplotypes to identify viral variants associated with treatment outcome and disease progression. Approach and Results Between 18.2% and 41.8% of nucleotides and between 5.9% and 34.3% of amino acids were 100% conserved in all genotypes and phases examined, depending on the region analyzed. Hepatitis B e antigen (HBeAg) loss by week 192 was associated with different haplotype populations at baseline. Haplotype populations differed across the HBV genome and CHB history, this being most pronounced in the precore/core gene. Mean number of haplotypes (frequency) per patient was higher in immune‐active, HBeAg‐positive chronic hepatitis phase 2 (11.8) and HBeAg‐negative chronic hepatitis phase 4 (16.2) compared to subjects in the “immune‐tolerant,” HBeAg‐positive chronic infection phase 1 (4.3, P < 0.0001). Haplotype frequency was lowest in genotype B (6.2, P < 0.0001) compared to the other genotypes (A = 11.8, C = 11.8, D = 13.6). Haplotype genetic diversity increased over the course of CHB history, being lowest in phase 1, increasing in phase 2, and highest in phase 4 in all genotypes except genotype C. HBeAg loss by week 192 of tenofovir therapy was associated with different haplotype populations at baseline. Conclusions Despite a degree of HBV haplotype diversity and heterogeneity across the phases of CHB natural history, highly conserved sequences in key genes and regulatory regions were identified in multiple HBV genotypes that should be further investigated as targets for antiviral therapies and predictors of treatment response.