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Neuraminidase Inhibitor Susceptibility Testing in Human Influenza Viruses: A Laboratory Surveillance Perspective

By Margaret Okomo-Adhiambo, Katrina Sleeman, Kristina Ballenger, Ha T. Nguyen, Vasiliy P. Mishin, Tiffany G. Sheu, James Smagala, Yan Li, Alexander I. Klimov and Larisa V. Gubareva


Neuraminidase inhibitors (NAIs) are vital in managing seasonal and pandemic influenza infections. NAI susceptibilities of virus isolates (n = 5540) collected during the 2008–2009 influenza season were assessed in the chemiluminescent neuraminidase inhibition (NI) assay. Box-and-whisker plot analyses of log-transformed IC50s were performed for each virus type/subtype and NAI to identify outliers which were characterized based on a statistical cutoff of IC50 >3 interquartile ranges (IQR) from the 75th percentile. Among 1533 seasonal H1N1 viruses tested, 1431 (93.3%) were outliers for oseltamivir; they all harbored the H275Y mutation in the neuraminidase (NA) and were reported as oseltamivir-resistant. Only 15 (0.7%) of pandemic 2009 H1N1 viruses tested (n = 2259) were resistant to oseltamivir. All influenza A(H3N2) (n = 834) and B (n = 914) viruses were sensitive to oseltamivir, except for one A(H3N2) and one B virus, with D151V and D197E (D198E in N2 numbering) mutations in the NA, respectively. All viruses tested were sensitive to zanamivir, except for six seasonal A(H1N1) and several A(H3N2) outliers (n = 22) which exhibited cell culture induced mutations at residue D151 of the NA. A subset of viruses (n = 1058) tested for peramivir were sensitive to the drug, with exception of H275Y variants that exhibited reduced susceptibility to this NAI. This study summarizes baseline susceptibility patterns of seasonal and pandemic influenza viruses, and seeks to contribute towards criteria for defining NAI resistance

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  1. (2003). Assaying susceptibility of avian and other influenza A viruses to zanamivir: comparison of fluorescent and chemiluminescent neuraminidase assays. Avian Dis.
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  3. (2006). Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob. Agents Chemother.
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  5. (2000). Development of a sensitive chemiluminescent neuraminidase assay for the determination of influenza virus susceptibility to zanamivir.
  6. (2009). Dynamics of antiviral-resistant influenza viruses in the Netherlands, 2005-2008. Antiviral Res.
  7. (2008). Effectiveness of oseltamivir treatment among children with influenza A or B virus infections during four successive winters in
  8. (2008). Emergence of resistance to oseltamivir among influenza A(H1N1) viruses
  9. Evaluation of a rapid molecular algorithm for detection of pandemic influenza A (H1N1) 2009 virus and screening for a key oseltamivir resistance (H275Y) substitution in neuraminidase.
  10. (2003). Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the neuraminidase inhibitor susceptibility network.
  11. (1979). Fluorometric assay of neuraminidase with a sodium (4-methylumbelliferyl-alpha-D-N-acetylneuraminate) substrate.
  12. (2010). Host cell selection of influenza neuraminidase variants: implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Res.
  13. (2005). Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet.
  14. (2008). Influenza activity - United States and worldwide, 2007-08 season.
  15. (2008). influenza activity - United States,
  16. (2009). influenza activity - United States, September 28, 2008-April 4, 2009, and composition of the 2009-10 influenza vaccine.
  17. (2007). Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A infection in children.
  18. (2008). Medical management of influenza infection.
  19. (2000). Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors.
  20. (2008). Mutations of neuraminidase implicated in neuraminidase inhibitors resistance.
  21. (2006). Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient. Antimicrob. Agents Chemother.
  22. (2010). Neuraminidase Receptor Binding Variants of Human Influenza A(H3N2) Viruses due to Substitution of Aspartic acid 151 in the Catalytic Site - Role in Virus Attachment?
  23. (2003). Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob. Agents Chemother.
  24. (2007). Oseltamivir-resistant influenza virus A
  25. (2007). Oseltamivir-resistant influenza viruses A
  26. (2009). Pyrosequencing as a tool to detect molecular markers of resistance to neuraminidase inhibitors in seasonal influenza A viruses. Antiviral Res.
  27. (2005). Sensitivity of influenza viruses to zanamivir and oseltamivir: a study performed on viruses circulating in France prior to the introduction of neuraminidase inhibitors in clinical practice. Antiviral Res.
  28. (1993). Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus
  29. (2008). Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob. Agents Chemother.
  30. (1996). Surveillance for neuraminidase-inhibitor-resistant influenza viruses in
  31. (2004). Surveillance of influenza isolates for susceptibility to neuraminidase inhibitors during the 2000-2002 influenza seasons. Virus Res.
  32. (2007). Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.
  33. (2005). Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob. Agents Chemother.
  34. (2004). Susceptibility of human influenza viruses from Australasia and South East Asia to the neuraminidase inhibitors zanamivir and oseltamivir. Antiviral Res.
  35. (2009). swine influenza A (H1N1) infections--California and Texas,
  36. The detection of oseltamivir-resistant pandemic influenza A/H1N1 2009 viruses using a real-time RT-PCR assay.
  37. (2008). Widespread oseltamivir resistance in influenza A viruses (H1N1),
  38. (2009). Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation.