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


CONCLUSIONS
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.
Kuntzen
Thomas
T
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. t.kuntzen@gmx.de
Timm
Joerg
J
Berical
Andrew
A
Lennon
Niall
N
Berlin
Aaron M
AM
Young
Sarah K
SK
Lee
Bongshin
B
Heckerman
David
D
Carlson
Jonathan
J
Reyor
Laura L
LL
Kleyman
Marianna
M
McMahon
Cory M
CM
Birch
Christopher
C
Schulze Zur Wiesch
Julian
J
Ledlie
Timothy
T
Koehrsen
Michael
M
Kodira
Chinnappa
C
Roberts
Andrew D
AD
Lauer
Georg M
GM
Rosen
Hugo R
HR
Bihl
Florian
F
Cerny
Andreas
A
Spengler
Ulrich
U
Liu
Zhimin
Z
Kim
Arthur Y
AY
Xing
Yanming
Y
Schneidewind
Arne
A
Madey
Margaret A
MA
Fleckenstein
Jaquelyn F
JF
Park
Vicki M
VM
Galagan
James E
JE
Nusbaum
Chad
C
Walker
Bruce D
BD
Lake-Bakaar
Gerond V
GV
Daar
Eric S
ES
Jacobson
Ira M
IM
Gomperts
Edward D
ED
Edlin
Brian R
BR
Donfield
Sharyne M
SM
Chung
Raymond T
RT
Talal
Andrew H
AH
Marion
Tony
T
Birren
Bruce W
BW
Henn
Matthew R
MR
Allen
Todd M
TM
D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D047028:Macrocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009154:Mutation / Q000235:genetics*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010670:Phenylthiourea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010802:Phylogeny; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002219:Carbamates; D047028:Macrocyclic Compounds; D009842:Oligopeptides; D010670:Phenylthiourea; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C530651:1-(4-pentyloxy-3-trifluoromethylphenyl)-3-(pyridine-3-carbonyl)thiourea; C479555:BILN 2061; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C510133:SCH6; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase