Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice

J Infect Dis. 2005 Aug 15;192(4):665-72. doi: 10.1086/432008. Epub 2005 Jul 15.

Abstract

Control of highly pathogenic avian H5N1 influenza viruses is a major public-health concern. Antiviral drugs could be the only option early in the pandemic.METHODS. BALB/c mice were given oseltamivir (0.1, 1, or 10 mg/kg/day) twice daily by oral gavage; the first dose was given 4 h before inoculation with H5N1 A/Vietnam/1203/04 (VN1203/04) virus. Five- and 8-day regimens were evaluated.RESULTS. Oseltamivir produced a dose-dependent antiviral effect against VN1203/04 in vivo (P<.01). The 5-day regimen at 10 mg/kg/day protected 50% of mice; deaths in this treatment group were delayed and indicated the replication of residual virus after the completion of treatment. Eight-day regimens improved oseltamivir efficacy, and dosages of 1 and 10 mg/kg/day significantly reduced virus titers in organs and provided 60% and 80% survival rates, respectively (P<.05). Overall, the efficacy of the 5- and 8-day regimens differed significantly (death hazard ratio, 2.658; P<.01). The new H5N1 antigenic variant VN1203/04 was more pathogenic in mice than was A/HK/156/97 virus, and a prolonged and higher-dose oseltamivir regimen may be required for the most beneficial antiviral effect.CONCLUSIONS. Oseltamivir prophylaxis is efficacious against lethal challenge with VN1203/04 virus in mice. Viral virulence may affect the antiviral treatment schedule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetamides / administration & dosage*
  • Animals
  • Antiviral Agents / administration & dosage*
  • Brain / virology
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Guanidines
  • Influenza A virus / drug effects*
  • Influenza A virus / pathogenicity*
  • Inhibitory Concentration 50
  • Lung / virology
  • Mice
  • Mice, Inbred BALB C
  • Orthomyxoviridae Infections / drug therapy*
  • Oseltamivir
  • Pyrans
  • Sialic Acids / pharmacology
  • Virulence
  • Virus Replication / drug effects
  • Zanamivir

Substances

  • Acetamides
  • Antiviral Agents
  • Guanidines
  • Pyrans
  • Sialic Acids
  • Oseltamivir
  • Zanamivir