Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo

Abstract

Oseltamivir phosphate (Tamiflu, Ro 64-0796) is the first orally administered neuraminidase (NA) inhibitor approved for use in treatment and prevention of influenza virus infection in man. Oseltamivir phosphate is the pro-drug of the active metabolite oseltamivir carboxylate (Ro 64-0802). Extensive monitoring throughout the oseltamivir development programme has identified a very low incidence of patients who have carried drug-resistant virus. The predominant mutation seen is the substitution of arginine for lysine at position 292 of the viral NA. The fitness of clinically isolated influenza virus A/Sydney/5/97 (H3N2) carrying this mutation was markedly reduced in animal models of influenza virus infection. The infectivity and replicative abilities of R292K mutant virus were reduced by at least 2 logs in a mouse model of influenza infection and by 2 and 4 logs, respectively, in the ferret model. Pathogenicity of R292K influenza virus A/Sydney/5/97 was reduced in ferrets as measured by inflammatory and febrile responses at least in parallel to the decrease in replicative ability. The data indicate that the R292K NA mutation compromises viral fitness such that virus carrying this mutation is unlikely to be of significant clinical consequence in man.