Reduced effectiveness of oseltamivir in children infected with oseltamivir-resistant influenza A (H1N1) viruses with His275Tyr mutation.
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.
Saito
Reiko
R
Department of Public Health, Niigata University, Graduate School of Medical and Dental Sciences, Niigata City, Niigata Prefecture, Japan. jasmine@med.niigata-u.ac.jp
Sato
Isamu
I
Suzuki
Yasushi
Y
Baranovich
Tatiana
T
Matsuda
Ryu
R
Ishitani
Nobuo
N
Dapat
Clyde
C
Dapat
Isolde Caperig
IC
Zaraket
Hassan
H
Oguma
Taeko
T
Suzuki
Hiroshi
H
D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D005334:Fever / Q000175:diagnosis; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D007564:Japan; D008297:Male; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D009305:Nasopharynx / Q000821:virology; D009439:Neuraminidase; D053139:Oseltamivir / Q000627:therapeutic use*; D016896:Treatment Outcome; D014764:Viral Proteins; D053243:Zanamivir / Q000627:therapeutic use
D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D053243:Zanamivir