title: Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014.
abstract: Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 10,641 viruses collected by WHO-recognized National Influenza Centres between May 2013 and May 2014 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. In addition, neuraminidase (NA) sequence data, available from the WHO CCs and from sequence databases (n=3206), were screened for amino acid substitutions associated with reduced NAI susceptibility. Ninety-five per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 2% (n=172) showed highly reduced inhibition (HRI) against at least one of the four NAIs, commonly oseltamivir, while 0.3% (n=32) showed reduced inhibition (RI). Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=169), A(H3N2) with NA E119V (n=1), B/Victoria-lineage with NA E117G (n=1) and B/Yamagata-lineage with NA H273Y (n=1); amino acid position numbering is A subtype and B type specific. Although approximately 98% of circulating viruses tested during the 2013-2014 period were sensitive to all four NAIs, a large community cluster of A(H1N1)pdm09 viruses with the NA H275Y substitution from patients with no previous exposure to antivirals was detected in Hokkaido, Japan. Significant numbers of A(H1N1)pdm09 NA H275Y viruses were also detected in China and the United States: phylogenetic analyses showed that the Chinese viruses were similar to those from Japan, while the United States viruses clustered separately from those of the Hokkaido outbreak, indicative of multiple resistance-emergence events. Consequently, global surveillance of influenza antiviral susceptibility should be continued from a public health perspective.
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. Electronic address: emitaka@nih.go.jp.
authors.forename: Emi
authors.initials: E
authors.lastname: Takashita
authors.affiliation: National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address: adam.meijer@rivm.nl.
authors.forename: Adam
authors.initials: A
authors.lastname: Meijer
authors.affiliation: Public Health England Colindale, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Electronic address: Angie.Lackenby@phe.gov.uk.
authors.forename: Angie
authors.initials: A
authors.lastname: Lackenby
authors.affiliation: World Health Organization Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, 1600 Clifton RD NE, MS-G16 Atlanta, GA, United States. Electronic address: LGubareva@CDC.gov.
authors.forename: Larisa
authors.initials: L
authors.lastname: Gubareva
authors.affiliation: Instituto Nacional de Saúde, Av. Padre Cruz, 1649-016 Lisboa, Portugal; Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: h.rebelo.andrade@insa.min-saude.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Rebelo-de-Andrade
authors.affiliation: Global Influenza Programme, World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland. Electronic address: besselaart@who.int.
authors.forename: Terry
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authors.lastname: Besselaar
authors.affiliation: World Health Organization Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, 1600 Clifton RD NE, MS-G16 Atlanta, GA, United States. Electronic address: agf1@cdc.gov.
authors.forename: Alicia
authors.initials: A
authors.lastname: Fry
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Electronic address: vgregor@nimr.mrc.ac.uk.
authors.forename: Vicky
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authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, VIDRL, At the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: leah.leang@influenzacentre.org.
authors.forename: Sook-Kwan
authors.initials: SK
authors.lastname: Leang
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Changping District, Beijing 102206, China. Electronic address: huangweijuan@cnic.org.cn.
authors.forename: Weijuan
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authors.lastname: Huang
authors.affiliation: Public Health Laboratory Centre, 382 Nam Cheong Street, Shek Kip Mei, Kowloon, Hong Kong, China. Electronic address: janicelo@dh.gov.hk.
authors.forename: Janice
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authors.affiliation: Division of Communicable Diseases, Health Security, & Environment, World Health Organization Regional Office for Europe, UN City, Marmorvej 51, DK-2100 Copenhagen Ø, Denmark. Electronic address: PDM@euro.who.int.
authors.forename: Dmitriy
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authors.lastname: Pereyaslov
authors.affiliation: Respiratory Viruses Laboratory/IOC, FIOCRUZ, Av Brasil, 4365 Rio de Janeiro, Brazil. Electronic address: mmsiq@ioc.fiocruz.br.
authors.forename: Marilda M
authors.initials: MM
authors.lastname: Siqueira
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Changping District, Beijing 102206, China. Electronic address: dayanwang@cnic.org.cn.
authors.forename: Dayan
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authors.lastname: Wang
authors.affiliation: Public Health Laboratory Centre, 382 Nam Cheong Street, Shek Kip Mei, Kowloon, Hong Kong, China. Electronic address: so_phls10@dh.gov.hk.
authors.forename: Gannon C
authors.initials: GC
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authors.affiliation: Global Influenza Programme, World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland. Electronic address: zhangw@who.int.
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authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Electronic address: rdaniel@nimr.mrc.ac.uk.
authors.forename: Rod S
authors.initials: RS
authors.lastname: Daniels
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, VIDRL, At the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; University of Melbourne, Melbourne School of Population and Global Health, Melbourne, VIC 3010, Australia. Electronic address: Aeron.Hurt@influenzacentre.org.
authors.forename: Aeron C
authors.initials: AC
authors.lastname: Hurt
authors.affiliation: World Health Organization Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. Electronic address: mtashiro2@gmail.com.
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mesh_terms: D000146:Acids, Carbocyclic; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D002681:China / Q000453:epidemiology; D003517:Cyclopentanes / Q000494:pharmacology; D004196:Disease Outbreaks / Q000706:statistics & numerical data; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005060:Europe / Q000453:epidemiology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics; D009981:Influenza B virus / Q000187:drug effects* / Q000235:genetics; D020128:Inhibitory Concentration 50; D007564:Japan / Q000453:epidemiology; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D053139:Oseltamivir / Q000494:pharmacology; D010802:Phylogeny; D011714:Pyrans; D012794:Sialic Acids; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D014944:World Health Organization; D053243:Zanamivir / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D053139:Oseltamivir; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir; C414210:peramivir
keywords: Antiviral resistance; Global analysis; Influenza virus; Neuraminidase inhibitors; Oseltamivir; Reduced susceptibility