This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, K. Articles by Lin, C. Search for Related Content PubMed PubMed Citation Articles by Lin, K. Articles by Lin, C.

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

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-) 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- 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- 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.

This article has been cited by other articles:

• Wyles, D. L., Kaihara, K. A., Schooley, R. T. (2008). Synergy of a Hepatitis C Virus (HCV) NS4A Antagonist in Combination with HCV Protease and Polymerase Inhibitors. Antimicrob. Agents Chemother. 52: 1862-1864 [Abstract] [Full Text]  
• Wyles, D. L., Kaihara, K. A., Vaida, F., Schooley, R. T. (2007). Synergy of Small Molecular Inhibitors of Hepatitis C Virus Replication Directed at Multiple Viral Targets. J. Virol. 81: 3005-3008 [Abstract] [Full Text]  
• Dahari, H., Ribeiro, R. M., Rice, C. M., Perelson, A. S. (2007). Mathematical Modeling of Subgenomic Hepatitis C Virus Replication in Huh-7 Cells. J. Virol. 81: 750-760 [Abstract] [Full Text]  
• Ma, S., Boerner, J. E., TiongYip, C., Weidmann, B., Ryder, N. S., Cooreman, M. P., Lin, K. (2006). NIM811, a Cyclophilin Inhibitor, Exhibits Potent In Vitro Activity against Hepatitis C Virus Alone or in Combination with Alpha Interferon.. Antimicrob. Agents Chemother. 50: 2976-2982 [Abstract] [Full Text]  
• Lin, K., Perni, R. B., Kwong, A. D., Lin, C. (2006). VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells.. Antimicrob. Agents Chemother. 50: 1813-1822 [Abstract] [Full Text]  
• Perni, R. B., Almquist, S. J., Byrn, R. A., Chandorkar, G., Chaturvedi, P. R., Courtney, L. F., Decker, C. J., Dinehart, K., Gates, C. A., Harbeson, S. L., Heiser, A., Kalkeri, G., Kolaczkowski, E., Lin, K., Luong, Y.-P., Rao, B. G., Taylor, W. P., Thomson, J. A., Tung, R. D., Wei, Y., Kwong, A. D., Lin, C. (2006). Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease. Antimicrob. Agents Chemother. 50: 899-909 [Abstract] [Full Text]  
• Malcolm, B. A., Liu, R., Lahser, F., Agrawal, S., Belanger, B., Butkiewicz, N., Chase, R., Gheyas, F., Hart, A., Hesk, D., Ingravallo, P., Jiang, C., Kong, R., Lu, J., Pichardo, J., Prongay, A., Skelton, A., Tong, X., Venkatraman, S., Xia, E., Girijavallabhan, V., Njoroge, F. G. (2006). SCH 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease, Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Alpha Interferon in Replicon Cells. Antimicrob. Agents Chemother. 50: 1013-1020 [Abstract] [Full Text]  
• Lin, C., Gates, C. A., Rao, B. G., Brennan, D. L., Fulghum, J. R., Luong, Y.-P., Frantz, J. D., Lin, K., Ma, S., Wei, Y.-Y., Perni, R. B., Kwong, A. D. (2005). In Vitro Studies of Cross-resistance Mutations against Two Hepatitis C Virus Serine Protease Inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 280: 36784-36791 [Abstract] [Full Text]  
• Lindenbach, B. D., Evans, M. J., Syder, A. J., Wolk, B., Tellinghuisen, T. L., Liu, C. C., Maruyama, T., Hynes, R. O., Burton, D. R., McKeating, J. A., Rice, C. M. (2005). Complete Replication of Hepatitis C Virus in Cell Culture. Science 309: 623-626 [Abstract] [Full Text]