Antiviral Resistance in A(H7N9) viruses

Abstract

Human infections with H7N9 avian influenza virus have raised concerns for an emerging pandemic influenza. Clinically, antiviral treatment with neuraminidase (NA) inhibitors reduced viral load in the throat swabs and improved clinical outcome in many H7N9 patients, even when treatment started 48 hours after illness onset. Persistent high viral load in spite of antiviral therapy was associated with adverse clinical outcome including the dependence on extracorporeal membrane oxygenation. An R292K mutation that confers significant resistance (>1,000 fold reduced sensitivity) to oseltamivir and peramivir and moderate resistance to zanamivir (>100 fold) has been reported in four out of more than 370 human H7N9 infections to date. The transmission potential of a human influenza A H7N9 isolate with a NAR292K mutation was evaluated in the ferret model followed by genotyping assay to monitor the stability of the mutation in vivo. Both the H7N9 wild-type and the R292K variants transmitted at comparable efficiency to the direct or respiratory droplet contact ferrets. Genotyping assay identified the wild-type genotype gained dominance over the R292K mutant in inoculated or infected ferrets, suggesting H7N9 virus with the R292K mutation may transmit among ferrets but is not stably maintained in vivo. The emergence of the R292K NA inhibitor resistant variants should be closely monitored in H7N9 patients and would render the treatment with oseltamivir and peramivir ineffective, but i.v. zanamivir may remain a therapeutic option.