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Pillay D, Zambon M. Antiviral drug resistance.  BMJ. 1998;317:660-6629728000Google ScholarCrossref
De Clercq E. Antiviral drugs in current clinical use.  J Clin Virol. 2004;30:115-13315125867Google ScholarCrossref
Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.  J Antimicrob Chemother. 2005;55:(suppl 1)  i5-i2115709056Google ScholarCrossref
 Roche. Factsheet Tamiflu. December 2005. http://www.roche.com/med_mbtamiflu05e.pdfAccessed July 1, 2006
Kiso M, Mitamura K, Sakai-Tagawa Y.  et al.  Resistant influenza A viruses in children treated with oseltamivir: descriptive study.  Lancet. 2004;364:759-76515337401Google ScholarCrossref
Le QM, Kiso M, Someya K.  et al.  Avian flu: isolation of drug-resistant H5N1 virus [published correction appears in Nature. 2005;438:754].  Nature. 2005;437:110816228009Google ScholarCrossref
de Jong MD, Tran TT, Truong HK.  et al.  Oseltamivir resistance during treatment of influenza A (H5N1) infection.  N Engl J Med. 2005;353:2667-267216371632Google ScholarCrossref
Treanor JJ. Influenza virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier/Churchill Livingstone; 2005:2060-2085
Colman PM, Hoyne PA, Lawrence MC. Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase.  J Virol. 1993;67:2972-29808497041Google Scholar
Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus.  J Infect Dis. 1998;178:1257-12629780244Google ScholarCrossref
Gubareva LV. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors.  Virus Res. 2004;103:199-20315163510Google ScholarCrossref
McKimm-Breschkin JL. Resistance of influenza viruses to neuraminidase inhibitors—a review.  Antiviral Res. 2000;47:1-1710930642Google ScholarCrossref
Whitley RJ, Hayden FG, Reisinger KS.  et al.  Oral oseltamivir treatment of influenza in children.  Pediatr Infect Dis J. 2001;20:127-13311224828Google ScholarCrossref
Carr J, Ives J, Kelly L.  et al.  Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo.  Antiviral Res. 2002;54:79-8812062393Google ScholarCrossref
Herlocher ML, Carr J, Ives J.  et al.  Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets.  Antiviral Res. 2002;54:99-11112062395Google ScholarCrossref
Ives JA, Carr JA, Mendel DB.  et al.  The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo.  Antiviral Res. 2002;55:307-31712103431Google ScholarCrossref
Herlocher ML, Truscon R, Elias S.  et al.  Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets.  J Infect Dis. 2004;190:1627-163015478068Google ScholarCrossref
Mishin VP, Hayden FG, Gubareva LV. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors.  Antimicrob Agents Chemother. 2005;49:4515-452016251290Google ScholarCrossref
Hatakeyama S, Sakai-Tagawa Y, Kiso M.  et al.  Enhanced expression of an α2,6-linked sialic acid on MDCK cells improves isolation of human influenza viruses and evaluation of their sensitivity to a neuraminidase inhibitor.  J Clin Microbiol. 2005;43:4139-414616081961Google ScholarCrossref
Gubareva LV, Kaiser L, Matrosovich MN, Soo-Hoo Y, Hayden FG. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir.  J Infect Dis. 2001;183:523-53111170976Google ScholarCrossref
Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB.Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC).  Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [published correction appears in MMWR Morb Mortal Wkly Rep. 2005; 54:750].  MMWR Recomm Rep. 2005;54((RR-8)):1-4016086456Google Scholar
Burmeister WP, Ruigrok RW, Cusack S. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid.  EMBO J. 1992;11:49-561740114Google Scholar
McKimm-Breschkin J, Trivedi T, Hampson A.  et al.  Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir.  Antimicrob Agents Chemother. 2003;47:2264-227212821478Google ScholarCrossref
Moscona A. Neuraminidase inhibitors for influenza.  N Engl J Med. 2005;353:1363-137316192481Google ScholarCrossref
Monto AS, McKimm-Breschkin JL, Macken C.  et al.  Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.  Antimicrob Agents Chemother. 2006;50:2395-240216801417Google ScholarCrossref
World Health Organization.  Use of influenza antivirals during 2003-2004 and monitoring of neuraminidase inhibitor resistance.  Wkly Epidemiol Rec. 2005;80:15615918290Google Scholar
Oo C, Hill G, Dorr A, Liu B, Boellner S, Ward P. Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1-5 years.  Eur J Clin Pharmacol. 2003;59:411-41512910331Google ScholarCrossref
Cass LM, Brown J, Pickford M.  et al.  Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers.  Clin Pharmacokinet. 1999;36:(suppl 1)  21-3110429837Google ScholarCrossref
Original Contribution
April 4, 2007

Emergence of Influenza B Viruses With Reduced Sensitivity to Neuraminidase Inhibitors

Author Affiliations

Author Affiliations: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science (Drs Hatakeyama, Ito, Kiso, and Kawaoka), Department of Infectious Diseases, Graduate School of Medicine (Drs Hatakeyama and Koike), and International Research Center for Infectious Diseases, Institute of Medical Science (Dr Kawaoka), University of Tokyo, Tokyo, Japan; Department of Pediatrics, Keiyu Hospital, Kanagawa, Japan (Dr Sugaya); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama (Drs Ito, Kiso, and Kawaoka); Zama Children's Clinic, Kanagawa (Dr Yamazaki); Department of Pediatrics, Isehara Kyodo Hospital, Kanagawa (Drs Ichikawa and Kimura); Kawasaki City Institute of Public Health, Kanagawa (Mr Shimizu); Yokohama City Institute of Health, Kanagawa (Ms Kawakami); Department of Pediatrics, Eiju General Hospital, Tokyo (Dr Mitamura); and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison (Dr Kawaoka).

JAMA. 2007;297(13):1435-1442. doi:10.1001/jama.297.13.1435

Context Very little is known about the frequency of generation and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Furthermore, transmission of resistant virus, whether influenza A or B, has not been recognized to date.

Objective To assess the prevalence and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors.

Design, Setting, and Patients Investigation of the neuraminidase inhibitor sensitivity of influenza B isolates from 74 children before and after oseltamivir therapy and from 348 untreated patients with influenza (including 66 adults) seen at 4 community hospitals in Japan during the 2004-2005 influenza season. Four hundred twenty-two viruses from untreated patients and 74 samples from patients after oseltamivir therapy were analyzed.

Main Outcome Measure Sialidase inhibition assay was used to test the drug sensitivities of influenza B viruses. The neuraminidase and hemagglutinin genes of viruses showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations that have the potential to confer reduced sensitivity to these drugs.

Results In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses.

Conclusions In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.