부산대학교 도서관

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. Author summary: Oseltamivir (Tamiflu) is an antiviral widely used for the treatment of infection due to influenza viruses and is especially useful for the treatment of severely ill high-risk patients. Antiviral resistance to oseltamivir is of concern as it can undermine the utility of the drug. Influenza viruses can become less susceptible to oseltamivir due to amino acid substitutions that arise in the viral surface protein, neuraminidase (NA). During influenza surveillance, to monitor for resistance, laboratory experiments are carried out to measure viral susceptibility to oseltamivir, whereby the quantity of drug needed to inhibit NA enzyme action is measured. However, how well these laboratory measurements predict resistance of viruses to oseltamivir in a clinical setting is not well understood. In this study, 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. A key finding from our analysis was that oseltamivir had reduced efficacy in reducing viral shedding against wild-type influenza B viruses compared to wild-type influenza A viruses, which has implications on how data from influenza B viruses with reduced susceptibility are currently being interpreted. [ABSTRACT FROM AUTHOR]