title: Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.
abstract: Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.
authors.affiliation: University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. asmonto@umich.edu
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Monto
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McKimm-Breschkin
authors.forename: Catherine
authors.initials: C
authors.lastname: Macken
authors.forename: Alan W
authors.initials: AW
authors.lastname: Hampson
authors.forename: Alan
authors.initials: A
authors.lastname: Hay
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimov
authors.forename: Masato
authors.initials: M
authors.lastname: Tashiro
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.forename: Michelle
authors.initials: M
authors.lastname: Aymard
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hayden
authors.forename: Maria
authors.initials: M
authors.lastname: Zambon
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014943:Global Health; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D009981:Influenza B virus / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009975:Orthomyxoviridae / Q000187:drug effects*; D011159:Population Surveillance; D011714:Pyrans / Q000494:pharmacology / Q000627:therapeutic use*; D012794:Sialic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D014944:World Health Organization; D053243:Zanamivir
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir