The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to Nucleoside Analogs than to

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Antimicrobial Agents and Chemotherapy, May 2008, p. 1604-1612, Vol. 52, No. 5

0066-4804/08/$08.00+0 doi:10.1128/AAC.01317-07

The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to

Nucleoside Analogs than to Nonnucleoside Polymerase or Protease Inhibitors

F. McCown, Sonal Rajyaguru, Sophie Le Pogam, Samir Ali, Wen-Rong Jiang,

Hyunsoon Kang, n Symons, Nick Cammack, and Isabel Najera*

Department of HCV Biology, Virology Disease Biology Area, Roche Palo Alto LLC,

3431 Hillview Ave., Palo Alto, California 94304

Received 11 October 2007/ Returned for modification 28 November 2007/ Accepted

11 February 2008

Specific inhibitors of hepatitis C virus (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, and 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 nonnucleoside inhibitors during

clinical trials and the lack of selection of resistance to the nucleoside

inhibitors, we used the replicon system to determine whether nucleoside

inhibitors demonstrate a higher genetic barrier to resistance than protease and

nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors

at 10 and 15 times the 50% effective concentration resulted in clearance of the

replicon, while treatment with a nonnucleoside 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 to nonnucleoside or

protease inhibitors. Furthermore, the combination of a nonnucleoside or protease

inhibitor with a nucleoside polymerase inhibitor could have a clear clinical

benefit through the delay of resistance emergence.

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* Corresponding author. Mailing address: Department of HCV Biology, Virology

Disease Biology Area, Roche Palo Alto LLC, 3431 Hillview Ave, Palo Alto, CA

94304. Phone: (650) 855-5134. Fax: (650) 354-7554. E-mail:

isabel.najera@...

Published ahead of print on 19 February 2008.

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