Mutations in influenza A virus during amantadine-oseltamivir combination therapy

Article type: Research Article

Authors: Shiraishi, Kyoko^; | Mitamura, Keiko | Ozawa, Makoto^; | Kakugawa, Satoshi | Kiso, Maki | Sakai-Tagawa, Yuko | Sugaya, Norio | Kawaoka, Yoshihiro^{; ; ;}

Affiliations: Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan | Oozora Taiyou Clinic, Tokyo, Japan | Department of Pediatrics, Eiju General Hospital, Tokyo, Japan | International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan | Department of Pathobiological Sciences, University of Wisconsin, Madison, WI, USA | Department of Pediatrics, Keiyu Hospital, Tokyo, Japan | Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan

Note: [] Correspondence: Yoshihiro Kawaoka, DVM, PhD, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel.: +81 3 5449 5310; Fax: +81 3 5449 5408; E-mail: kawaoka@ims.u-tokyo.ac.jp

Abstract: Although two classes of antiviral drugs, M2 ion channel blockers and neuraminidase (NA) inhibitors, are available to combat seasonal H1N1 and H3N2, and highly pathogenic avian (e.g., H5N1) influenza, the emergence and spread of drug-resistant viruses is of great concern. Animal studies suggest that combination chemotherapy with M2 and NA inhibitors may be an effective option to reduce the emergence of drug-resistant viruses. In this study, we evaluated the antiviral susceptibility of clinical isolates from immunocompetent children infected with a seasonal influenza A virus and treated with a combination of amantadine and oseltamivir. We found that amantadine-resistant viruses emerged during this combination treatment. While viruses with mutations known to confer oseltamivir resistance were not detected, we found viruses with mutations in NA that reduced sialidase activity and viruses with hemagglutinin mutations. These findings suggest that while the amantadine-oseltamivir combination is an effective therapeutic option for influenza, drug-resistant viruses do appear with this combination therapy.

Keywords: Influenza A virus, combination therapy, drug-resistant mutants

DOI: 10.3233/JPI-2010-0256

Journal: Journal of Pediatric Infectious Diseases, vol. 5, no. 3, pp. 243-248, 2010