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Author, Editor(s)
Author(s):
Susser, Simone
Welsch, Christoph
Wang, Yalan
Zettler, Markus
Domingues, Francisco S.
Karey, Ursula
Hughes, Eric
Ralston, Robert
Tong, Xiao
Herrmann, Eva
Zeuzem, Stefan
Sarrazin, Christoph		dblp
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Not MPG Author(s):
Susser, Simone
Wang, Yalan
Zettler, Markus
Karey, Ursula
Hughes, Eric
Ralston, Robert
Tong, Xiao
Herrmann, Eva
Zeuzem, Stefan
Sarrazin, Christoph

BibTeX cite key*:

Susser2009

Title

Title*:

Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients.

Journal

Journal Title*:

Hepatology
Journal's URL:


Download URL
for the article:

http://dx.doi.org/10.1002/hep.23192
Language:

English

Publisher

Publisher's
Name:

John Wiley & Sons
Publisher's URL:


Publisher's
Address:

Chichester
ISSN:

0270-9139

Vol, No, pp, Date

Volume*:

50
Number:

6

Publishing Date:

August 2009

Pages*:

1709-1718
Number of
VG Pages:


Page Start:


Page End:


Sequence Number:


DOI:

10.1002/hep.23192

Note, Abstract, ©

Note:


(LaTeX) Abstract:

Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS) 3/4A protease inhibitor that is currently being evaluated in combination with peginterferon alfa-2b and ribavirin in phase 3 studies. The clinical resistance profile of boceprevir is not characterized in detail so far. The NS3 protease domain of viral RNA was cloned from HCV genotype 1-infected patients (n = 22). A mean number of 47 clones were sequenced before, at the end, and after treatment with 400 mg boceprevir twice or three times daily for 14 days for genotypic, phenotypic, and viral fitness analysis. At the end of treatment, a wild-type an NS3 protease sequence was observed with a mean frequency of 85.9\%. In the remaining isolates, five previously observed resistance mutations (V36M/A, T54A/S, R155K/T, A156S, V170A) and one mutation (V55A) with unknown resistance to boceprevir were detected either alone or in combination. Phenotypic analysis in the HCV replicon assay showed low (V36G, T54S, R155L; 3.8- to 5.5-fold 50\% inhibitory concentration [IC(50)]), medium (V55A, R155K, V170A, T54A, A156S; 6.8- to 17.7-fold IC(50)) and high level (A156T; >120-fold IC(50)) resistance to boceprevir. The overall frequency of resistant mutations and the level of resistance increased with greater declines in mean maximum HCV RNA levels. Two weeks after the end of treatment, the frequency of resistant variants declined and the number of wild-type isolates increased to 95.5\%. With the exception of V36 and V170 variants all resistant mutations declined by more than 50\%. Mathematical modeling revealed impaired replicative fitness for all single mutations, whereas for combined mutations a relative increase of replication efficiency was suggested. Conclusion: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross-resistance to telaprevir. (HEPATOLOGY 2009.).

URL for the Abstract:


Categories,
Keywords:


HyperLinks / References / URLs:


Copyright Message:


Personal Comments:


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Access Level:

Internal

Correlation
MPG Unit:
Max-Planck-Institut für Informatik
MPG Subunit:
Computational Biology and Applied Algorithmics
Appearance:
MPII WWW Server, MPII FTP Server, MPG publications list, university publications list, working group publication list, Fachbeirat, VG Wort


BibTeX Entry:

@ARTICLE{Susser2009,
AUTHOR = {Susser, Simone and Welsch, Christoph and Wang, Yalan and Zettler, Markus and Domingues, Francisco S. and Karey, Ursula and Hughes, Eric and Ralston, Robert and Tong, Xiao and Herrmann, Eva and Zeuzem, Stefan and Sarrazin, Christoph},
 TITLE = {Characterization of resistance to the protease inhibitor boceprevir in hepatitis {C} virus-infected patients.},
 JOURNAL = {Hepatology},
 PUBLISHER = {John Wiley & Sons},
 YEAR = {2009},
 NUMBER = {6},
 VOLUME = {50},
 PAGES = {1709--1718},
 ADDRESS = {Chichester},
 MONTH = {August},
 ISBN = {0270-9139},
 DOI = {10.1002/hep.23192},
}

Entry last modified by Anja Becker, 03/12/2010
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Editor(s)
[Library]		Created
12/21/2009 13:54:43
Revision
1.
0.


Editor
Anja Becker
Francisco S. Domingues


Edit Date
12.03.2010 13:21:00
12/21/2009 01:54:43 PM