Existence of hepatitis C virus NS5B variants naturally resistant to non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients.
OBJECTIVE
To characterize the effect of hepatitis C virus (HCV) polymerase intrinsic genetic heterogeneity on the inhibitory activity of nucleoside and non-nucleoside HCV polymerase inhibitors.


METHODS
The sensitivity of genotype (GT) 1 HCV NS5B clinical isolates from treatment-naive patients to nucleoside and non-nucleoside polymerase inhibitors was assessed. The genetic diversity at the population level, as well as that of their quasispecies, was correlated with the observed reduced sensitivity to inhibitors.


RESULTS
R1479 and NM107 (nucleoside analogues that have entered Phase 2 clinical trials as prodrugs R1626 and NM283, respectively) were similarly active across the tested clinical isolates. Resistance mutations to nucleoside analogues were not observed in any of the isolates. However, the activity of the non-nucleoside thumb II inhibitor NNI-1, palm I inhibitors NNI-2 and NNI-3, and palm II inhibitor HCV-796 was reduced across different isolates. This reduction in inhibitory activity for non-nucleoside inhibitors (NNIs) was, in most cases, correlated with the existence of known NNI resistance mutations in the NS5B polymerase population of the clinical isolates, as detected by population sequencing. Resistance mutations to NNIs were also observed at a low frequency within the clinical isolates' viral quasispecies that allowed for their rapid selection upon drug selective pressure.


CONCLUSIONS
The higher frequency of known NNI resistance mutations or polymorphisms known to affect their antiviral potency when compared with the lack of detection of resistance mutations to the nucleoside analogues suggests a potential for primary reduced responsiveness as well as faster development of clinically significant resistance.
Le Pogam
Sophie
S
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Seshaadri
Amritha
A
Kosaka
Alan
A
Chiu
Sophie
S
Kang
Hyunsoon
H
Hu
Steven
S
Rajyaguru
Sonal
S
Symons
Julian
J
Cammack
Nick
N
Nájera
Isabel
I
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D003562:Cytidine; D011741:Pyrimidine Nucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C506207:valopicitabine; C508950:4'-azidocytidine