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Antimicrob. Agents Chemother. doi:10.1128/AAC.01317-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The HCV replicon presents a higher barrier to resistance to nucleoside analogs than to non-nucleoside polymerase or protease inhibitors

^* To whom correspondence should be addressed. Email: isabel.najera{at}roche.com.

	Abstract

Specific inhibitors of HCV replication that target the NS3/4A protease (e.g. VX-950) or the NS5B polymerase (e.g. R1479/R1626, PSI-6130/R7128, NM107/NM283, HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and non-nucleoside inhibitors during clinical trials, and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine if nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and non-nucleoside inhibitors.

Treatment of replicon cells at 10X and 15X the EC₅₀ with nucleoside inhibitors resulted in clearance of the replicon while treatment with a non-nucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than for non-nucleoside or protease inhibitors. Furthermore, the combination of a non-nucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.