title: Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012-2013.
abstract: Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. 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 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012-2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.
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: Instituto Nacional de Saúde, Av. Padre Cruz, 1649-016 Lisboa, Portugal; Faculdade de Farmácia, Universidade de Lisboa, Portugal. Electronic address: h.rebelo.andrade@insa.min-saude.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Rebelo-de-Andrade
authors.affiliation: Instituto Nacional de Saúde, Av. Padre Cruz, 1649-016 Lisboa, Portugal; Faculdade de Farmácia, Universidade de Lisboa, Portugal. Electronic address: vanessa.correia@insa.min-saude.pt.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Correia
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: Global Influenza Programme, World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland. Electronic address: rdragerdayal@gmail.com.
authors.forename: Renu
authors.initials: R
authors.lastname: Drager-Dayal
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.lastname: Gregory
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
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authors.lastname: Gubareva
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: tkage@nih.go.jp.
authors.forename: Tsutomu
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authors.affiliation: Public Health England Colindale, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Electronic address: Angie.Lackenby@phe.gov.uk.
authors.forename: Angie
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authors.affiliation: Public Health Laboratory Centre, 382 Nam Cheong Street, Shek Kip Mei, Kowloon, Hong Kong, China. Electronic address: janicelo@dh.gov.hk.
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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: todagiri@nih.go.jp.
authors.forename: Takato
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authors.lastname: Odagiri
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, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. Electronic address: emitaka@nih.go.jp.
authors.forename: Emi
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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: mtashiro@nih.go.jp.
authors.forename: Masato
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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: ro_phls1@dh.gov.hk.
authors.forename: Sun
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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.
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mesh_terms: D000146:Acids, Carbocyclic; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D053139:Oseltamivir / Q000627:therapeutic use; D011714:Pyrans; D012794:Sialic Acids; D053243:Zanamivir / Q000031:analogs & derivatives / Q000627:therapeutic use
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; Normalization using fold-change data; Oseltamivir