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Efficacy of Oseltamivir Therapy in Ferrets Inoculated with Different Clades of H5N1 Influenza Virus

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 20 October 2006/ Returned for modification 28 November 2006/ Accepted 30 January 2007

Highly pathogenic H5N1 influenza viruses have infected an increasing number of humans in Asia, with high mortality rates and the emergence of multiple distinguishable clades. It is not known whether antiviral drugs that are effective against contemporary human influenza viruses will be effective against systemically replicating viruses, such as these pathogens. Therefore, we evaluated the use of the neuraminidase (NA) inhibitor oseltamivir for early postexposure prophylaxis and for treatment in ferrets exposed to representatives of two clades of H5N1 virus with markedly different pathogenicities in ferrets. Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir (5 mg/kg of body weight/day) given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when it was initiated 24 h after virus inoculation. For the treatment of ferrets inoculated with the less pathogenic A/Turkey/15/06 (H5N1) virus, 10 mg/kg/day of oseltamivir was sufficient to reduce the lethargy of the animals, significantly inhibit inflammation in the upper respiratory tract, and block virus spread to the internal organs. Importantly, all ferrets that survived the initial infection were rechallenged with homologous virus after 21 days and were completely protected from infection. Direct sequencing of the NA or HA1 gene segments in viruses isolated from ferret after treatment showed no amino acid substitutions known to cause drug resistance in conserved residues. Thus, early oseltamivir treatment is crucial for protection against highly pathogenic H5N1 viruses and the higher dose may be needed for the treatment of more virulent viruses.

Published ahead of print on 12 February 2007.

This article has been cited by other articles:

• Writing Committee of the Second World Health Organ, (2008). Update on Avian Influenza A (H5N1) Virus Infection in Humans. NEJM 358: 261-273 [Full Text]