Abstract
BackgroundResistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility.MethodsThe NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0–15) and zanamivir (days 15–25 and 70–80).ResultsCompared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6–69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin.ConclusionsReduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines the importance of close monitoring of treated patients especially those immunocompromised.
Highlights
Oseltamivir is considered to be the drug of choice for treatment of patients with pandemic influenza, whereas zanamivir is usually restricted to patients with suspected oseltamivir resistant strains.Until recently, a low frequency of resistance to neuraminidase inhibitors (NAIs) was reported among seasonal as well as A(H5N1) influenza viruses, most often in drug treated and/or immunosuppressed patients [1,2,3]
Natural resistance to oseltamivir in seasonal H1N1 viruses associated with the mutation H275Y in the NA emerged in 2007 in Europe and became predominant worldwide within a year [8,9]
We report here the selection of the H275Y and I223R mutations in the NA in an immunocompromised patient with sustained H1N1pdm09 virus shedding successively treated by one course of oseltamivir and two courses of zanamivir
Summary
A low frequency of resistance to neuraminidase inhibitors (NAIs) was reported among seasonal as well as A(H5N1) influenza viruses, most often in drug treated and/or immunosuppressed patients [1,2,3]. The H275Y substitution in the neuraminidase (NA) of the N1 subtype is the most commonly observed mutation associated with oseltamivir resistance. Natural resistance to oseltamivir in seasonal H1N1 viruses associated with the mutation H275Y in the NA emerged in 2007 in Europe and became predominant worldwide within a year [8,9]. Oseltamivir resistant variants were rarely reported among pandemic A(H1N1) 2009 (H1N1pdm09) influenza viruses: by October 5, 2011, a total of 605 cases have been identified worldwide (18 cases in France) with a high proportion in immunocompromised and/or oseltamivir treated patients [13]. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility
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