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

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.

Fig 1. Flow of participants through the study.

A total of 1,635 patients were enrolled. Patients identified with undifferentiated type/subtype (n = 72), more than 1 type/subtype virus (n = 1), no record of temperature (n = 135), and no fever throughout the observation period (n = 59) were excluded. A total of 1,368 patients were analyzed.

Fig 2. Variation of type/subtype of influenza virus in each NAI treatment group and selection of NAIs by season.

A: Proportion of type/subtype of influenza virus in each NAI treatment group. B: Proportion of each NAI treatment group by season. NAI, neuraminidase inhibitors.

Fig 3. The comparison of fever duration by the four NAIs by type/subtype group.

A: A/H1N1pdm09 group. B: A/H3N2 group. C: influenza B group. Left: Boxplots of fever duration for the four NAIs tested by ANOVA. The bold line is the average, while the box shows the interquartile range. P-value at the bottom was obtained from ANOVA. Right: Kaplan-Meyer method of fever duration. Black line: oseltamivir, red line: zanamivir, green line: laninamivir, and blue line: peramivir. P-value from log-rank analysis is indicated in the graph. The group with a sample size <5 was excluded from analysis. OS: oseltamivir, ZA: zanamivir, LA: laninamivir, PE: peramivir, NAI: neuraminidase inhibitor.

Fig 4. Temperature curve of the patients infected with influenza A/H1N1pdm09 with the H275Y mutation.

Patients in cases 1–5 received oseltamivir. The patient in case 6 received laninamivir and that in case 7 received zanamivir. Fever duration is shown in the right upper field in each box.

Fig 5. Fever duration comparison between A/H1N1pdm09 oseltamivir-resistant and oseltamivir-sensitive patient groups aged 0 to 5 years.

Left: Boxplots of t-test for the average fever duration. The bold line is the average value; the box shows the interquartile range. Right: Kaplan-Meier method for fever duration. Black line: oseltamivir-sensitive; red line: oseltamivir-resistant.