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Reduced Effectiveness of Oseltamivir in Children Infected With Oseltamivir-resistant Influenza A (H1N1) Viruses With His275Tyr Mutation

Saito, Reiko MD, PhD*; Sato, Isamu MD, PhD; Suzuki, Yasushi MSc*; Baranovich, Tatiana MD, PhD*; Matsuda, Ryu MD; Ishitani, Nobuo MD, PhD§; Dapat, Clyde MSc*; Dapat, Isolde Caperig BSc*; Zaraket, Hassan PhD*; Oguma, Taeko MD*; Suzuki, Hiroshi MD, PhD*

The Pediatric Infectious Disease Journal: October 2010 - Volume 29 - Issue 10 - p 898-904
doi: 10.1097/INF.0b013e3181de9d24
Original Studies

Background: Little is known about whether neuraminidase inhibitors are effective for children infected with oseltamivir-resistant influenza A(H1N1) viruses.

Methods: Children aged 15 years and younger having influenza-like illness and who visited outpatient clinics within 48 hours of fever onset were enrolled from 2006–2007 to 2008–2009 influenza seasons in Japan. Patients received oseltamivir, zanamivir, or no treatment after screening by a rapid antigen test. Nasopharyngeal swabs were collected before antiviral therapy and were used for virus isolation. Oseltamivir resistance was determined by detection of the H275Y mutation in neuraminidase, and susceptibility test using neuraminidase inhibition assay. Daily body temperature was evaluated according to drug type and susceptibility by univariate and multivariate analyses.

Results: Of 1647 patients screened, 238 oseltamivir-resistant H1N1 cases (87 oseltamivir-treated, 64 zanamivir-treated, and 87 nontreated) and 110 oseltamivir-susceptible cases (60 oseltamivir-treated and 50 nontreated) were evaluated. In oseltamivir-resistant cases, fever on days 4 to 5 after the start of treatment was significantly higher in oseltamivir-treated and nontreated than in zanamivir-treated patients (P < 0.05). In oseltamivir-susceptible cases, fever was significantly lower in oseltamivir-treated than nontreated on days 3 to 6 (P < 0.01). Similar findings were obtained for duration of the fever and proportion of recurrent fever. Reduced effectiveness of oseltamivir was more prominent in children 0 to 6 years old than in those 7 to 15 years old. Multiple logistic regression analysis showed that lower age, nontreatment, and oseltamivir treatment of oseltamivir-resistant patients were factors associated with the duration of the longer fever.

Conclusions: Infection with oseltamivir-resistant viruses significantly reduced the effectiveness of oseltamivir, and this tendency was more apparent in younger children.


From the *Department of Public Health, Niigata University, Graduate School of Medical and Dental Sciences, Niigata City, Niigata Prefecture, Japan; †Yoiko Pediatric Clinic, Niigata City, Niigata Prefecture, Japan; ‡Matsuda Pediatric Clinic, Kurayoshi City, Tottori Prefecture, Japan; and §Ishitani Pediatric Clinic, Tottori City, Tottori Prefecture, Japan

Accepted for publication March 19, 2010.

Hassan Zaraket is currently at Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN.

Supported by grants-in-aid from the Ministry of Health, Labor and Welfare in Japan (Kourou-kaken).

Address for correspondence: Reiko Saito, MD, PhD, Department of Public Health, Niigata University, Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-Ku, Niigata City, Niigata Prefecture, 951-8510, Japan. E-mail:

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© 2010 Lippincott Williams & Wilkins, Inc.