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Entecavir allows an unexpectedly high residual replication of HBV mutants resistant to lamivudine.
Antivir. Ther. (Lond.) 20, 779-787 (2016)
BACKGROUND: Entecavir is an efficient inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT) and widely used for therapy of chronic hepatitis B. Entecavir treatment of HBV patients with Lamivudine-resistant viral strains, however, often fails, but the mechanism of cross-resistance development is not fully understood. METHODS: Using nonlinear regression models, dose response curves of cloned HBV strains from patients pre-treated with RT inhibitors were established in human hepatoma cell lines after transfection with HBV genomes containing HBV polymerase genes from patient isolates. 50% and 90% inhibitory concentrations (IC50, IC90) and antiviral resistance factors (RF50 and RF90) were calculated. RESULTS: The Entecavir dose-response curve of Lamivudine-resistant HBV RT mutants rtM204 for the replication of HBV decreased less than expected with increasing drug dose. Remarkably, due to the flat dose-response curves, RF90 values against Entecavir of samples with rtM204 substitutions were up to 30 times higher than their RF50 values. CONCLUSIONS: The unexpectedly high IC90 indicates a strong residual replication capacity of Lamivudine-resistant HBV rtM204 variants under Entecavir therapy, although IC50 values are initially within the therapeutic range of Entecavir. This characteristic favors rapid selection of additional mutants with overt resistance against Entecavir. Thus, the current phenotypic resistance assays should include determination of IC90.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Hepatitis-b-virus; Dna-synthesis; Phenotypic Assays; Drug-resistance; In-vitro; Susceptibility; Inhibition; Encapsidation; Polymerase; Mutation
Language
english
Publication Year
2016
Prepublished in Year
2015
HGF-reported in Year
2015
ISSN (print) / ISBN
1359-6535
e-ISSN
2040-2058
Journal
Antiviral Therapy
Quellenangaben
Volume: 20,
Issue: 8,
Pages: 779-787
Publisher
International Medical Press
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
PSP Element(s)
G-502700-003
DOI
10.3851/IMP2928
WOS ID
WOS:000370915600001
PubMed ID
25560463
Erfassungsdatum
2015-12-31