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Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment‐naïve patients
Author(s) -
Kuntzen Thomas,
Timm Joerg,
Berical Andrew,
Len Niall,
Berlin Aaron M.,
Young Sarah K.,
Lee Bongshin,
Heckerman David,
Carlson Jonathan,
Reyor Laura L.,
Kleyman Marianna,
McMahon Cory M.,
Birch Christopher,
Schulze zur Wiesch Julian,
Ledlie Timothy,
Koehrsen Michael,
Kodira Chinnappa,
Roberts Andrew D.,
Lauer Georg M.,
Rosen Hugo R.,
Bihl Florian,
Cerny Andreas,
Spengler Ulrich,
Liu Zhimin,
Kim Arthur Y.,
Xing Yanming,
Schneidewind Arne,
Madey Margaret A.,
Fleckenstein Jaquelyn F.,
Park Vicki M.,
Galagan James E.,
Nusbaum Chad,
Walker Bruce D.,
LakeBakaar Gerond V.,
Daar Eric S.,
Jacobson Ira M.,
Gomperts Edward D.,
Edlin Brian R.,
Donfield Sharyne M.,
Chung Raymond T.,
Talal Andrew H.,
Marion Tony,
Birren Bruce W.,
Henn Matthew R.,
Allen Todd M.
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22549
Subject(s) - viral quasispecies , telaprevir , virology , boceprevir , biology , resistance mutation , population , ns5b , hepatitis c virus , viral replication , viral load , drug resistance , genotype , viral evolution , virus , mutation , hepacivirus , genetics , ribavirin , polymerase chain reaction , medicine , gene , reverse transcriptase , genome , environmental health
Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000‐fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro . Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment‐naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT‐C) in the population, we analyzed HCV genome sequences from 507 treatment‐naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication‐competent, drug‐resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo . Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN‐191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG‐021541; and to the NS4A antagonist ACH‐806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug‐resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo . Conclusion: Naturally occurring dominant STAT‐C resistance mutations are common in treatment‐naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin. (H EPATOLOGY 2008;48:1769–1778.)