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Hepatology DOI:10.1002/hep.22549

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

Publication TypeJournal Article
Year of Publication2008
AuthorsKuntzen, T, Timm, J, Berical, A, Lennon, N, Berlin, AM, Young, SK, Lee, B, Heckerman, D, Carlson, J, Reyor, LL, Kleyman, M, McMahon, CM, Birch, C, Wiesch, JSchulze Zu, Ledlie, T, Koehrsen, M, Kodira, C, Roberts, AD, Lauer, GM, Rosen, HR, Bihl, F, Cerny, A, Spengler, U, Liu, Z, Kim, AY, Xing, Y, Schneidewind, A, Madey, MA, Fleckenstein, JF, Park, VM, Galagan, JE, Nusbaum, C, Walker, BD, Lake-Bakaar, GV, Daar, ES, Jacobson, IM, Gomperts, ED, Edlin, BR, Donfield, SM, Chung, RT, Talal, AH, Marion, T, Birren, BW, Henn, MR, Allen, TM
JournalHepatology
Volume48
Issue6
Pages1769-78
Date Published2008 Dec
ISSN1527-3350
KeywordsAntiviral Agents, Carbamates, Cohort Studies, Drug Resistance, Viral, Female, Genetic Testing, Hepacivirus, Hepatitis C, Humans, Macrocyclic Compounds, Male, Mutation, Oligopeptides, Phenylthiourea, Phylogeny, Proline, Protease Inhibitors, Quinolines, Thiazoles, Viral Load, Viral Nonstructural Proteins
Abstract

UNLABELLED: Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in 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.

URLhttp://dx.doi.org/10.1002/hep.22549
DOI10.1002/hep.22549
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/19026009?dopt=Abstract

Alternate JournalHepatology
PubMed ID19026009
PubMed Central IDPMC2645896
Grant ListAI048216 / AI / NIAID NIH HHS / United States
AI066316 / AI / NIAID NIH HHS / United States
U19-AI666345 / AI / NIAID NIH HHS / United States
R01 AI067926-01 / AI / NIAID NIH HHS / United States
U19 AI066345-010005 / AI / NIAID NIH HHS / United States
R01 AI067926 / AI / NIAID NIH HHS / United States
U19 AI048216 / AI / NIAID NIH HHS / United States
R01 HD41224 / HD / NICHD NIH HHS / United States
U19 AI066316-010001 / AI / NIAID NIH HHS / United States
U19 AI066345 / AI / NIAID NIH HHS / United States
R01 HD041224 / HD / NICHD NIH HHS / United States
HHSN266200400001C / AO / NIAID NIH HHS / United States
R01 HD041224-04 / HD / NICHD NIH HHS / United States
R01-AI067926-01 / AI / NIAID NIH HHS / United States
HHSN266200400001C / / PHS HHS / United States
U19 AI066316 / AI / NIAID NIH HHS / United States