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.
Highlights
Infection with influenza viruses results in a highly contagious respiratory disease that causes substantial global morbidity and mortality [1]
Influenza viruses can become less susceptible to oseltamivir due to amino acid substitutions that arise in the viral surface protein, neuraminidase (NA)
We developed an animal model to evaluate this relationship between laboratory data and clinical efficacy in more detail and demonstrated that in vivo efficacy of oseltamivir is lower against viruses that show reduced inhibition by oseltamivir in laboratory testing
Summary
Infection with influenza viruses results in a highly contagious respiratory disease that causes substantial global morbidity and mortality [1]. The only exception was during the 2007–2009, when a former seasonal influenza A(H1N1) virus with the H275Y NA amino acid substitution circulated world-wide and led to guideline changes against the use of OST [18, 19]. The emergence of this virus underscored the importance of maintaining regular surveillance of influenza viruses to monitor antiviral susceptibility [10,11,12,13, 20]. While community outbreaks have occurred since 2009 with H275Y A (H1N1)pdm viruses [23, 24], the overall prevalence of H275Y in this subtype has generally remained low
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