AAC Accepts, published online ahead of print on 15 December 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01032-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Robust Antiviral Efficacy upon Administration of a Nucleoside Analog to Hepatitis C Virus-Infected Chimpanzees

Steven S. Carroll^*, Steven Ludmerer, Larry Handt, Kenneth Koeplinger, Nanyan Rena Zhang, Donald Graham, Mary-Ellen Davies, Malcolm MacCoss, Daria Hazuda, and David B. Olsen

Antiviral Research Department, Laboratory Animal Resources, Department of Drug Metabolism, Vaccines Biologics Research, Merck Research Laboratories, West Point, PA, 19486; And Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ, 07065

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with increased incidence of liver fibrosis, cirrhosis and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated interferon and ribavirin which result in a sustained viral response in 40-60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase (RdRp). A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon with an EC₅₀ of 0.3 µM (EC₉₀ = 1.3 µM). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose- and time-dependent decreases in plasma viral load. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log₁₀ IU/mL, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log₁₀, and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV Taqman assay (20 IU/mL). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least twelve days after dosing ended. The results demonstrate a robust antiviral effect on administration of MK-0608 to HCV-infected chimpanzees.