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Hepatitis B virus genome diversity in adolescents: Tenofovir disoproxil fumarate treatment effect and HBeAg serocon version
Author(s) -
Combet Christophe,
Bhardwaj Neeru,
Hedskog Charlotte,
Podlaha Ondrej,
Gaggar Anuj,
Murray Karen F.,
Mo Hongmei,
Svarovskaia Evguenia,
Zoulim Fabien
Publication year - 2021
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.13547
Subject(s) - seroconversion , viral load , hbeag , population , placebo , hepatitis b virus , virology , medicine , immunology , biology , gastroenterology , virus , hbsag , alternative medicine , environmental health , pathology
Abstract More systematic analysis of hepatitis B virus (HBV) genome diversity, linked with tenofovir disoproxil fumarate (TDF) treatment and HBeAg seroconversion, are needed. GS‐US‐174–0115 was a double‐blind, placebo‐controlled, Phase 3, 192‐week clinical trial that evaluated TDF in adolescents with chronic hepatitis B (CHB). HBV full‐genome deep sequencing was performed using Illumina MiSeq at baseline (BL; n = 85), Week 8 (W8; n = 80), Week 72 (W72; PBO only, n = 42), and treatment‐free follow‐up (TDF only, n = 25). The viral diversity was calculated using Shannon entropy and population nucleotide diversity with a 2% variant cutoff. Our data showed (i) a higher viral diversity in the X region at baseline than the core/polymerase/surface regions, (ii) higher core/surface viral diversity at baseline for patients with seroconversion, (iii) an expected reduction in viral diversity after 8 weeks of TDF treatment, and (iv) a drop in viral diversity at W72 for patients receiving placebo with a seroconversion ( n = 7). The higher viral diversity in X was associated with higher baseline alanine aminotransferase (ALT) levels ( p < .001). Patients with greater reduction of diversity at W8 of TDF treatment had higher baseline ALT levels. For placebo patients who seroconverted, the drop in viral diversity at W72 ( p = .04) coincided with reduction of serum HBV DNA (average change from baseline = −4.10 log10 copies/ml) and unique combinations of variants were enriched in a patient's viral population post seroconversion. The basal core promoter (BCP) variants, A1762T and G1764A, and the pC variant, G1896A, were most often enriched at or after seroconversion.