A two-year survey of the oseltamivir-resistant influenza A(H1N1) virus in Yamagata, Japan and the clinical effectiveness of oseltamivir and zanamivir.
BACKGROUND
Oseltamivir is the preferred antiviral drug for influenza, but oseltamivir-resistant A(H1N1) viruses have circulated worldwide since the 2007-2008 influenza season. We aimed to determine the rate of oseltamivir resistance among A(H1N1) isolates from Yamagata, Japan, to compare the virological characteristics between isolates from the 2007-2008 and 2008-2009 seasons, and to evaluate the clinical effectiveness of oseltamivir.


RESULTS
Oseltamivir resistance, determined by detecting the H275Y mutation in the neuraminidase (NA) gene, was observed in 2.5% (2 of 79) and 100% (77 of 77) of isolates from the 2007-2008 and 2008-2009 seasons, respectively. Antigenic analysis suggested that antigenically different variants of A(H1N1) viruses circulated in the 2008-2009 season. Growth testing demonstrated that the ability of the 2008-2009 isolates to replicate in MDCK cells was similar to those of the oseltamivir-susceptible isolates from the 2007-2008 season. A phylogenetic analysis revealed that two oseltamivir-resistant viruses isolated in the 2007-2008 season were closely related to other oseltamivir-susceptible viruses in Yamagata but were different from oseltamivir-resistant viruses isolated in Europe and North America in the 2007-2008 season. The oseltamivir-resistant viruses isolated in Japan in the 2008-2009 season were phylogenetically similar to oseltamivir-resistant isolates from Europe and North America during the 2007-2008 season. Furthermore, the median duration of fever after the start of oseltamivir treatment was significantly longer in oseltamivir-resistant cases (2 days; range 1-6 days) than in oseltamivir-susceptible cases (1.5 days: range 1-2 days) (P = 0.0356).


CONCLUSIONS
Oseltamivir-resistant A(H1N1) isolates from Yamagata in the 2007-2008 season might have acquired resistance through the use of oseltamivir, and the 2008-2009 oseltamivir-resistant isolates might have been introduced into Japan and circulated throughout the country. Influenza surveillance to monitor oseltamivir-resistance would aid clinicians in determining an effective antiviral treatment strategy.
Matsuzaki
Yoko
Y
Course of Clinical Nursing, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan. matuzaki@med.id.yamagata-u.ac.jp
Mizuta
Katsumi
K
Aoki
Yoko
Y
Suto
Asuka
A
Abiko
Chieko
C
Sanjoh
Kanako
K
Sugawara
Kanetsu
K
Takashita
Emi
E
Itagaki
Tsutomu
T
Katsushima
Yuriko
Y
Ujike
Makoto
M
Obuchi
Masatsugu
M
Odagiri
Takato
T
Tashiro
Masato
M
D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002675:Child, Preschool; D004285:Dogs; D024882:Drug Resistance, Viral; D006801:Humans; D007223:Infant; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology*; D007564:Japan; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use*; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D014764:Viral Proteins / Q000235:genetics; D014774:Virulence; D053243:Zanamivir / Q000627:therapeutic use*
D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D053243:Zanamivir