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

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.