Universität zu Köln

Geipel, Andreas, Seiz, Pia L., Niekamp, Hauke, Neumann-Fraune, Maria, Zhang, Ke, Kaiser, Rolf, Protzer, Ulrike ORCID: 0000-0002-9421-1911, Gerlich, Wolfram H. and Glebe, Dieter (2015). Entecavir allows an unexpectedly high residual replication of HBV mutants resistant to lamivudine. Antivir. Ther., 20 (8). S. 779 - 788. LONDON: INT MEDICAL PRESS LTD. ISSN 1359-6535

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Abstract

Background: Entecavir is an efficient inhibitor of 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 non-linear 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 and IC90) and corresponding 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 30x 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 favours rapid selection of additional mutants with overt resistance against entecavir. Thus, the current phenotypic resistance assays should include determination of IC90.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Geipel, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Seiz, Pia L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niekamp, Hauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumann-Fraune, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Ke UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaiser, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Protzer, Ulrike UNSPECIFIED orcid.org/0000-0002-9421-1911 UNSPECIFIED Gerlich, Wolfram H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Glebe, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-415161
DOI:	10.3851/IMP2928
Journal or Publication Title:	Antivir. Ther.
Volume:	20
Number:	8
Page Range:	S. 779 - 788
Date:	2015
Publisher:	INT MEDICAL PRESS LTD
Place of Publication:	LONDON
ISSN:	1359-6535
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATITIS-B-VIRUS; PHENOTYPIC ASSAYS; DNA-SYNTHESIS; SUSCEPTIBILITY; INHIBITION; ENCAPSIDATION; POLYMERASE; MUTATION; PROTEIN; DOMAIN Multiple languages Infectious Diseases; Pharmacology & Pharmacy; Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41516