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Antimicrobial Agents and Chemotherapy, November 2008, p. 3889-3897, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice{triangledown}

Natalia A. Ilyushina,1,2 Alan Hay,3 Neziha Yilmaz,4 Adrianus C. M. Boon,1 Robert G. Webster,1,5 and Elena A. Govorkova1*

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794,1 The D. I. Ivanovsky Institute of Virology, Moscow 123098, Russia,2 National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom,3 Virology and NIC of Turkey Refik Saydam Hygiene Institute, Ankara, Turkey,4 Department of Pathology, University of Tennessee, Memphis, Tennessee 381055

Received 7 December 2007/ Returned for modification 28 January 2008/ Accepted 21 July 2008

We studied the effects of a neuraminidase inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses. In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (50% inhibitory concentration [IC50] = 0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC50 = 5.5 nM). In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg of body weight/day), ribavirin (37.5, 55, or 75 mg/kg/day), or the combination of both drugs for 8 days, starting 4 h before virus inoculation. Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo. Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations. The combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 1 mg/kg/day and the combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 10 mg/kg/day were synergistic against A/Vietnam/1203/04 and A/Turkey/15/06 viruses, respectively. These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01). Importantly, we observed clear differences between the efficacies of the drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for the protection of mice against A/Vietnam/1203/04 virus. Our preliminary results suggest that oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy, depending on the H5N1 virus and the concentrations used.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678. Phone: (901) 595-2243. Fax: (901) 595-8559. E-mail: elena.govorkova{at}stjude.org

{triangledown} Published ahead of print on 25 August 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3889-3897, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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