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Antimicrobial Agents and Chemotherapy, December 2004, p. 4784-4792, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4784-4792.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Combination of a Hepatitis C Virus NS3-NS4A Protease Inhibitor and Alpha Interferon Synergistically Inhibits Viral RNA Replication and Facilitates Viral RNA Clearance in Replicon Cells

Kai Lin, Ann D. Kwong, and Chao Lin*

Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts

Received 14 April 2004/ Returned for modification 9 June 2004/ Accepted 5 August 2004

The present standard of care for hepatitis C virus (HCV) infection is pegylated alpha interferon (IFN-{alpha}) in combination with ribavirin. However, specific antivirals such as HCV NS3-NS4A protease inhibitors are now in clinical development, and these agents can potentially be used in combination with the present treatments. Therefore, it is important to investigate the potential benefits or adverse effects of these new combinations by using available in vitro HCV culture systems first. In the present study we demonstrate that the combination of a specific HCV NS3-NS4A protease inhibitor and IFN-{alpha} synergistically inhibits HCV RNA replication in replicon cells, with little or no increase in cytotoxicity. Furthermore, the benefit of the combination was sustained over time, such that a greater than 3-log reduction in HCV RNA levels was achieved following 9 days of treatment. The viral RNA appeared to be cleared from the replicon cells after 14 days of treatment, and no viral RNA rebound was observed upon withdrawal of the inhibitors. In each case, the antiviral effects obtained with higher concentrations of either the protease inhibitor alone or IFN-{alpha} alone can be achieved by a combination of both agents at lower concentrations, which may potentially reduce the risk of possible adverse effects associated with high doses of either agent.

* Corresponding author. Mailing address: Vertex Pharmaceuticals Incorporated, 130 Waverly St., Cambridge, MA 02139. Phone: (617) 444-6202. Fax: (617) 444-6210. E-mail: chao_lin{at}vrtx.com.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4784-4792, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4784-4792.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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