Effectiveness of four types of neuraminidase inhibitors approved in Japan for the treatment of influenza

PLoS One. 2019 Nov 7;14(11):e0224683. doi: 10.1371/journal.pone.0224683. eCollection 2019.

Abstract

Background: Neuraminidase inhibitors (NAIs) effectively treat influenza. The clinical effectiveness of four NAIs (oseltamivir, zanamivir, laninamivir, and peramivir) was evaluated against influenza A/H1N1pdm09, A/H3N2, and B viruses. Additionally, fever duration in patients infected with oseltamivir-resistant influenza A/H1N1pdm09 with the H275Y mutation was evaluated.

Methods: Patients aged <20 years who visited outpatient clinics in Japan with influenza-like illnesses were enrolled during 4 influenza seasons from 2012/2013 to 2015/2016. After obtaining informed consent, patients who tested positive for influenza with rapid tests received one of the four NAIs. Patients recorded their body temperature daily for 8 days from the first visit. The influenza strain was identified using real-time polymerase chain reaction. Univariate and multivariable analyses were used to evaluate factors influencing fever duration. In children aged ≤5 years treated with oseltamivir, fever duration in oseltamivir-resistant A/H1N1pdm09-infected patients was compared to that in oseltamivir-sensitive A/H1N1pdm09-infected patients.

Results: Of the 1,368 patients analyzed, 297 (21.7%), 683 (49.9%), and 388 (28.4%) were infected with influenza A/H1N1pdm09, A/H3N2, and B, respectively. In multivariable analysis factors associated with significantly prolonged fever duration included: treatment with laninamivir (hazard ratio [HR]: 0.78, p = 0.006, compared to oseltamivir), influenza B (HR: 0.58, p<0.001, compared to influenza A/H1N1pdm09), and a higher body temperature at the clinic visit (HR: 0.87 per degree Celsius, p<0.001). Increasing age was associated with a significantly shorter duration of fever (HR: 1.31 for 6-9 years old, p<0.001; and HR: 1.65 for 10-19 years old, p<0.001, respectively, compared to 0-5 years old). Following treatment with oseltamivir, fever duration was significantly longer for oseltamivir-resistant A/H1N1pdm09-infected patients (n = 5) than for oseltamivir-sensitive A/H1N1pdm09 infected patients (n = 111) (mean, 89 versus 40 hours, p<0.001).

Conclusions: Our results revealed characteristic information on the effectiveness of the four NAIs and also on oseltamivir-resistant viruses that may affect patients' clinical care.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Drug Approval
  • Enzyme Inhibitors / therapeutic use*
  • Fever / complications
  • Humans
  • Infant
  • Infant, Newborn
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza, Human / complications
  • Influenza, Human / drug therapy*
  • Japan
  • Multivariate Analysis
  • Mutation / genetics
  • Neuraminidase / antagonists & inhibitors*
  • Oseltamivir / therapeutic use
  • Proportional Hazards Models
  • Seasons
  • Temperature
  • Treatment Outcome
  • Young Adult

Substances

  • Enzyme Inhibitors
  • Oseltamivir
  • Neuraminidase

Grants and funding

RS was supported by JSPS Core-to-core Program, B.Asia-Africa Science Platforms, Kakenhi (Grants-in-Aid for Scientific Research), sourced from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from Japan Agency for Medical Research and Development (AMED) (15fm0108009h0001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.