ABSTRACT
The neuraminidase (NA) inhibitor (NAI) oseltamivir (OST) is the most widely used influenza antiviral drug. Several NA amino acid substitutions are reported to reduce viral susceptibility to OST in in vitro assays. However, whether there is a correlation between the level of reduction in susceptibility in vitro and the efficacy of OST against these viruses in vivo is not well understood. In this study, a ferret model was utilised to evaluate OST efficacy against circulating influenza A and B viruses with a range of in vitro generated 50% inhibitory concentrations (IC50) values for OST. OST efficacy against an A(H1N1)pdm09 and an A(H1N1)pdm09 virus with the H275Y substitution in neuraminidase was also tested in the macaque model. The results from this study showed that OST had a significant impact on virological parameters compared to placebo treatment of ferrets infected with wild-type influenza A viruses with normal IC50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC50 values. Differing pathogenicity of the viruses made evaluation of clinical parameters difficult, although some effect of OST in reducing clinical signs was observed with influenza A(H1N1) and A(H1N1)pdm09 (H275Y) viruses. Viral titres in macaques were too low to draw conclusive results. Analysis of the ferret data revealed a correlation between IC50 and OST efficacy in reducing viral shedding but highlighted that the current WHO guidelines/criteria for defining normal, reduced or highly reduced inhibition in influenza B viruses based on in vitro data are not well aligned with the low in vivo OST efficacy observed for both wild-type influenza B viruses and those with reduced OST susceptibility.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza A Virus, H3N2 Subtype , Influenza B virus , Orthomyxoviridae Infections , Oseltamivir , Animals , Female , Male , Amino Acid Substitution , Disease Models, Animal , Drug Evaluation, Preclinical , Ferrets , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/metabolism , Influenza B virus/genetics , Influenza B virus/metabolism , Macaca fascicularis , Macrolides , Mutation, Missense , Neuraminidase/genetics , Neuraminidase/metabolism , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Oseltamivir/pharmacologyABSTRACT
Influenza A and B viruses cause significant morbidity and mortality worldwide each year. The neuraminidase inhibitors (NAIs) are the most commonly used class of influenza antiviral drugs for the treatment of infected patients. In vitro studies have shown that influenza B viruses are significantly less susceptible to oseltamivir and other neuraminidase inhibitors compared with influenza A viruses. Following analysis of published clinical studies, we show that oseltamivir does appear to have lower effectiveness in patients infected with influenza B virus compared with influenza A infected patients, but due to insufficient studies on zanamivir, laninamivir or peramivir, it was not possible to conclude the relative effectiveness of these drugs against influenza A virus compared with B virus.