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Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus
Elena A. Govorkova, Natalia A. Ilyushina, David A. Boltz, Alan Douglas, Neziha Yilmaz, and Robert G. Webster*
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA; The D. I. Ivanovsky Institute of Virology, Moscow, 123098, Russia; National Institute for Medical Research, Mill Hill, London NW7 1AA, UK; Virology and NIC of Turkey Refik Saydam Hygiene Institute, Ankara, Turkey; Department of Pathology, University of Tennessee, Memphis, TN 38105, USA
* To whom correspondence should be addressed. Email: robert.webster@stjude.org<SCRIPT type=text/javascript><!-- var u = "robert.webster", d = "stjude.org"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT> . <!-- null -->
Abstract
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 post-exposure prophylaxis and for treatment in ferrets exposed to representatives of two clades of H5N1 virus with markedly different pathogenicity to ferrets. Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir 5 mg/kg/day given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when 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 re-challenged 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 that higher dose may be needed for the treatment of more virulent viruses.
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Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus
Elena A. Govorkova, Natalia A. Ilyushina, David A. Boltz, Alan Douglas, Neziha Yilmaz, and Robert G. Webster*
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA; The D. I. Ivanovsky Institute of Virology, Moscow, 123098, Russia; National Institute for Medical Research, Mill Hill, London NW7 1AA, UK; Virology and NIC of Turkey Refik Saydam Hygiene Institute, Ankara, Turkey; Department of Pathology, University of Tennessee, Memphis, TN 38105, USA
* To whom correspondence should be addressed. Email: robert.webster@stjude.org<SCRIPT type=text/javascript><!-- var u = "robert.webster", d = "stjude.org"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT> . <!-- null -->
Abstract
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 post-exposure prophylaxis and for treatment in ferrets exposed to representatives of two clades of H5N1 virus with markedly different pathogenicity to ferrets. Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir 5 mg/kg/day given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when 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 re-challenged 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 that higher dose may be needed for the treatment of more virulent viruses.
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