Community Transmission of Oseltamivir-Resistant A(H1N1)pdm09 Influenza
N Engl J Med 2011; 365:2541-2542December 29, 2011
Article
To the Editor:
Oseltamivir-resistant prepandemic seasonal influenza A (H1N1) viruses with a H275Y neuraminidase substitution spread globally in 2008,1 reducing the effectiveness of oseltamivir.2 Although oseltamivir-resistant pandemic 2009 A (H1N1) viruses, now known as A(H1N1)pdm09, have been detected in persons receiving oseltamivir treatment, they have been detected in less than 1% of untreated patients in the community, and transmission has been documented only in closed settings or settings involving close contact with infected persons.3,4
We identified sustained community transmission of oseltamivir-resistant A(H1N1)pdm09 viruses in Australia. Reverse-transcriptase-polymerase-chain-reaction-positive A(H1N1)pdm09 viruses were obtained from 182 patients in emergency departments, intensive care units, and general practitioners' offices in the Hunter New England region of New South Wales, Australia, between May and August 2011.
Viruses were analyzed for oseltamivir resistance. A total of 29 A(H1N1)pdm09 viruses (16%) contained the H275Y neuraminidase substitution responsible for oseltamivir resistance, and all were resistant to the adamantine class of antiviral agents. Culture was attempted for all specimens and yielded 90 isolates, of which 15 contained the H275Y substitution. A fluorescence-based neuraminidase inhibition assay5 of the H275Y isolates showed that the IC50 value (the concentration of drug required to inhibit neuraminidase activity by 50%) was 513 times higher for oseltamivir and 80 times higher for peramivir than the IC50 values associated with wild-type strains. However, these isolates remained fully sensitive to zanamivir. The frequency of H275Y variants was 4 in 50 viruses in June (8%), 20 in 85 viruses in July (24%), and 4 in 45 viruses in August (9%). Hemagglutinin and neuraminidase sequence analysis (Global Initiative on Sharing All Influenza Data accession numbers, EPI334765-334790 and 335634-335637) showed that the resistant strains were closely related (99.9 to 100% hemagglutinin nucleotide similarity and 99.6 to 100% neuraminidase nucleotide similarity), suggesting the spread of a single variant.
Most patients lived within a 50-km (31-mi) radius of Newcastle, the seventh largest city in Australia, and three patients lived 90, 150, and 490 km (56, 93, and 304 mi) away. Two genetically related strains were detected elsewhere in the state, including in Sydney.
An ethics waiver was granted and authorized under the New South Wales Public Health Act of 2010 for an urgent public health investigation. Hospital records and interviews with patients and general practitioners revealed that only 1 of the 29 patients with resistant influenza had received oseltamivir before the influenza specimen collection (Table 1Table 1Characteristics of Patients with Oseltamivir-Resistant Influenza in the Hunter New England Health District, According to Hospital Records and Responses from Interviews with Patients and General Practitioners.). The ages were similar among the 29 patients with oseltamivir-resistant influenza (median, 31 years; range, 4 months to 62 years) and the 153 patients with sensitivity to oseltamivir (median, 29 years; range, 1 month to 74 years). Five patients with oseltamivir-resistant influenza were children younger than 5 years of age. The resistant viruses remained antigenically similar to the vaccine strain, including those from 3 patients who received the 2011 influenza vaccine (Table 1). Four households had 2 affected patients each, and 2 other patients shared a short car journey. The remaining patients had no known epidemiologic link with the other patients with oseltamivir-resistant influenza described here.
As winter approaches in the Northern Hemisphere, it remains important to ensure that A(H1N1)pdm09 strains from early in the season are analyzed rapidly for any indication that this transmissible oseltamivir-resistant variant has spread.
Aeron C. Hurt, Ph.D.
World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, North Melbourne, VIC, Australia
aeron.hurt@influenzacentre.orgKate Hardie, M.P.H.
Hunter New England Population Health, Newcastle, NSW, Australia
Noelene J. Wilson, B.Med.Sc.
Hunter Area Pathology Service, Newcastle, NSW, Australia
Yi-Mo Deng, Ph.D.
WHO Collaborating Centre for Reference and Research on Influenza, North Melbourne, VIC, Australia
Maggi Osbourn, B.N., Grad.Dip.Legal Studies, B.N., Grad.Dip.Legal Studies
Hunter New England Population Health, Newcastle, NSW, Australia
Nicole Gehrig, B.Sc.
Hunter Area Pathology Service, Newcastle, NSW, Australia
Anne Kelso, Ph.D.
WHO Collaborating Centre for Reference and Research on Influenza, North Melbourne, VIC, Australia
Supported by a grant from the Australian Government Department of Health and Ageing to the Melbourne WHO Collaborating Centre for Reference and Research on Influenza. Members of the investigational team are listed in the Supplementary Appendix, available with the full text of this letter at NEJM.org.
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