Early findings of oseltamivir-resistant pandemic (H1N1) 2009 influenza A viruses in Taiwan

In this study, we investigated the frequency of oseltamivir resistance in pandemic (H1N1) 2009 influenza A viruses in Taiwan and characterized the resistant viruses. From May 2009 to January 2010, 1187 pandemic H1N1 virus-positive cases in Taiwan were tested for the H275Y substitution in the neuraminidase (NA) gene that confers resistance to oseltamivir. Among them, eight hospitalized cases were found to be infected with virus encoding the H275Y substitution in their original specimens collected after oseltamivir treatment. The epidemiologic investigation indicated that each of the cases occurred sporadically and there was no evidence of further transmission. We monitored the variation of amino acid residues at position 275 of the NA gene in a series of specimens taken at various time-points and observed that viruses encoding the H275Y substitution differ in their fitness in vivo and in MDCK cells. Phylogenetic analysis indicated that the hemagglutinin (HA) sequences of oseltamivir-resistant pandemic H1N1 viruses exhibited greater diversity than the NA sequences and progressive changes of the HA genes from clade A1 into A2 and from there into clade A3 were observed. The resistant viruses seemed to occur in combination with diverse HA genes and a dominant NA gene. Enzymatic analysis of the viruses revealed that the ratio of NA/HA activities in oseltamivir-resistant viruses was reduced considerably compared to those in wild-type ones.