MPI für Informatik / Computational Biology and Applied Algorithmics |
|Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients.|
|Authors:||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|
|Date of Publication (YYYY-MM-DD):||2009|
|Title of Journal:||Hepatology|
|Issue / Number:||6|
|Intended Educational Use:||No|
|Abstract / Description:||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.).
|Last Change of the Resource (YYYY-MM-DD):||2009-12-21|
|External Publication Status:||published|
|Communicated by:||Thomas Lengauer|
|Affiliations:||MPI für Informatik/Computational Biology and Applied Algorithmics|
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