Emergence of Oseltamivir-Resistant H7N9 Influenza Viruses in Immunosuppressed Cynomolgus Macaques

• Published in: The Journal of infectious diseases Vol. 216; no. 5; pp. 582 - 593
• Main Authors: Kiso, Maki, Iwatsuki-Horimoto, Kiyoko, Yamayoshi, Seiya, Uraki, Ryuta, Ito, Mutsumi, Nakajima, Noriko, Yamada, Shinya, Imai, Masaki, Kawakami, Eiryo, Tomita, Yuriko, Fukuyama, Satoshi, Itoh, Yasushi, Ogasawara, Kazumasa, Lopes, Tiago J. S., Watanabe, Tokiko, Moncla, Louise H., Hasegawa, Hideki, Friedrich, Thomas C., Neumann, Gabriele, Kawaoka, Yoshihiro
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.09.2017
• Subjects: Animals; Antiviral Agents - therapeutic use; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Viral; Female; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; High-Throughput Nucleotide Sequencing; Immunocompromised Host; Influenza A Virus, H7N9 Subtype - drug effects; Influenza A Virus, H7N9 Subtype - physiology; Macaca fascicularis - virology; Male; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - veterinary; Orthomyxoviridae Infections - virology; Oseltamivir - therapeutic use; Virus Replication; VIRUSES; immunosuppression; nonhuman primates; Influenza virus; oseltamivir resistance
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jix296

Antiviral compounds (eg, the neuraminidase inhibitor oseltamivir) are invaluable for the treatment of individuals infected with influenza A viruses of the H7N9 subtype (A[H7N9]), which have infected and killed hundreds of persons. However, oseltamivir treatment often leads to the emergence of resistant viruses in immunocompromised individuals. To better understand the emergence and properties of oseltamivir-resistant A(H7N9) viruses in immunosuppressed individuals, we infected immunosuppressed cynomolgus macaques with an A(H7N9) virus and treated them with oseltamivir. Disease severity and mortality were higher in immunosuppressed than in immunocompetent animals. Oseltamivir treatment at 2 different doses reduced A(H7N9) viral titers in infected animals, but even high-dose oseltamivir did not block viral replication sufficiently to suppress the emergence of resistant variants. Some resistant variants were not appreciably attenuated in cultured cells, but an oseltamivir-resistant A(H7N9) virus did not transmit among ferrets. These findings are useful for the control of A(H7N9) virus infections in clinical settings.