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In February 2013, a patient hospitalized with pneumonia and acute respiratory distress syndrome (ARDS) was confirmed to be infected with a rare subtype of H7N9 avian influenza A virus (A/Shanghai/1/2013) [1]. Since then, a total of 132 laboratory-confirmed human H7N9 infections have been reported in eastern China and Taiwan, resulting in a 28% mortality rate (as of 30 May 2013) [2, 3]. No human H7N9 cases have been reported in other countries. The virus did not spread efficiently among humans, but limited, nonsustained human-to-human transmission could not be excluded in a few family clusters [4]. Viruses of the H7N9 subtype had not been previously isolated from humans, and infections with low-pathogenic avian influenza viruses have not been associated with severe infection or death. This is important because current seasonal influenza vaccines contain only H1N1 and H3N2 influenza A antigens, and all population groups are immunologically naive to both H7 and N9 surface antigens. The presence of H7 surface antigen is also troubling as highly pathogenic viruses of this HA subtype were shown to infect humans and 1 fatal case was reported [5]. Although vaccines are the most effective option for controlling influenza infections, none are available for prevention of H7N9 infections [6]. Human influenza H7N9 viruses are resistant to adamantanes as they harbor an S31N amino acid substitution in the M2; thus, neuraminidase (NA) inhibitors (NAIs) are the only option for control of H7N9 influenza infections [1]. The NAI oseltamivir is recommended for treatment of human H7N9 infections [4, 7]. Challenges in H7N9 antiviral treatment include the development of ARDS as a common complication in patients hospitalized with pneumonia [1, 8] as well as limited clinical experience and knowledge about the effectiveness of oseltamivir on human H7N9 infections. Moreover, human H7N9 viruses with NAI resistance-associated mutations (R152K and R292K, N2 numbering) were reported during treatment, emphasizing that the emergence of drug-resistant viruses should be monitored [1, 9]. Mouse models are well established for evaluating viral pathogenesis and the efficacy of antiviral drugs, as mice and humans develop similar changes in the respiratory tract, with the predominant involvement of the lower airway in mice [10]. Whereas pathological changes caused by human H7N9 viruses in mice have been reported recently [11–13], ARDS was not described, and therapeutic strategies have not been fully explored. Here we evaluate the susceptibility of a panel of N9 influenza viruses to NAIs in vitro, establish the pathogenicity of A/Anhui/1/2013 (H7N9) in BALB/c mice, and examine the efficacy of oseltamivir treatment against lethal H7N9 virus challenge.

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.