title: Drug susceptibility surveillance of influenza viruses circulating in the United States in 2011-2012: application of the WHO antiviral working group criteria.
abstract: BACKGROUND
  Assessing susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) is primarily done in NA inhibition (NI) assays, supplemented by NA sequence analysis. However, two factors present challenges for NI assay data interpretation: lack of established IC50 values indicative of clinically relevant resistance and insufficient harmonization of NI testing methodologies among surveillance laboratories. In 2012, the WHO working group on influenza antiviral susceptibility (WHO-AVWG) developed criteria to facilitate consistent interpretation and reporting of NI assay data.
  
  
  METHODS
  The WHO-AVWG classification criteria were applied in interpreting NI assay data for two FDA-licensed NAIs, oseltamivir and zanamivir, for viruses collected in the United States during the 2011-2012 winter season.
  
  
  RESULTS
  All A (H1N1)pdm09 viruses (n = 449) exhibited normal inhibition by oseltamivir and zanamivir, with the exception of eight viruses (1·8%) with highly reduced inhibition by oseltamivir, which carried the H275Y marker of oseltamivir resistance. A (H3N2) viruses (n = 978) exhibited normal inhibition by both NAIs, except for one virus with highly reduced inhibition by zanamivir due to the cell culture-selected NA change, Q136K. Type B viruses (n = 343) exhibited normal inhibition by both drugs, except for an isolate with reduced inhibition by both NAIs that had the cell culture-selected A200T substitution.
  
  
  CONCLUSIONS
  WHO-AVWG classification criteria allowed the detection of viruses carrying the established oseltamivir resistance marker, as well as viruses whose susceptibility was altered during propagation. These criteria were consistent with statistical-based criteria for detecting outliers and will be useful in harmonizing NI assay data among surveillance laboratories worldwide and in establishing laboratory correlates of clinically relevant resistance.
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Okomo-Adhiambo
authors.forename: Ha T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Anwar
authors.initials: A
authors.lastname: Abd Elal
authors.forename: Katrina
authors.initials: K
authors.lastname: Sleeman
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Fry
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Gubareva
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D062665:Epidemiological Monitoring; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D053139:Oseltamivir / Q000494:pharmacology; D014481:United States; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D053243:Zanamivir / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D053243:Zanamivir
keywords: Influenza; neuraminidase inhibition; oseltamivir; zanamivir