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J Pediatr Infect Dis 2010; 05(03): 243-248
DOI: 10.3233/JPI-2010-0256
Georg Thieme Verlag KG Stuttgart – New York

Mutations in influenza A virus during amantadine-oseltamivir combination therapy

Kyoko Shiraishi
a   Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
b   Oozora Taiyou Clinic, Tokyo, Japan
,
Keiko Mitamura
c   Department of Pediatrics, Eiju General Hospital, Tokyo, Japan
,
Makoto Ozawa
d   International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
e   Department of Pathobiological Sciences, University of Wisconsin, Madison, WI, USA
,
Satoshi Kakugawa
a   Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
,
Maki Kiso
a   Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
,
Yuko Sakai-Tagawa
a   Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
,
Norio Sugaya
f   Department of Pediatrics, Keiyu Hospital, Tokyo, Japan
,
Yoshihiro Kawaoka
a   Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
d   International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
e   Department of Pathobiological Sciences, University of Wisconsin, Madison, WI, USA
g   Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan
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Publikationsverlauf

11. September 2009

11. Februar 2010

Publikationsdatum:
28. Juli 2015 (online)

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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