http://orcid.org/0000-0002-8953-5962
Figures
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).
Citation: Mawatari M, Saito R, Hibino A, Kondo H, Yagami R, Odagiri T, et al. (2019) Effectiveness of four types of neuraminidase inhibitors approved in Japan for the treatment of influenza. PLoS ONE 14(11): e0224683. https://doi.org/10.1371/journal.pone.0224683
Editor: Victor C. Huber, University of South Dakota, UNITED STATES
Received: June 3, 2019; Accepted: October 18, 2019; Published: November 7, 2019
Copyright: © 2019 Mawatari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
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.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RS received research grants from Shionogi & Co., LTD., Daiichi Sankyo Co., LTD., Chugai Pharmaceutical Co., Ltd., and GlaxoSmithKline K.K. This does not alter our adherence to PLOS ONE policies on sharing data materials.
Introduction
Influenza causes morbidity and mortality in humans worldwide, with high socioeconomic burden. In Japan, it is estimated that 10–15 million people are infected with influenza, which is equivalent to more than 10% of the total population [1]. Neuraminidase inhibitors (NAIs) are effective for the prevention and treatment of influenza. The four NAIs, oseltamivir (Tamiflu®, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan), zanamivir (Relenza®, GlaxoSmithKline plc, London, United Kingdom), laninamivir (Inavir®, Daiichi Sankyo Co., Ltd., Tokyo, Japan), and peramivir (Rapiacta®, Shionogi & Co., Ltd., Osaka, Japan) are available for clinical use in Japan [2]. These NAIs are prescribed to seven to eight million influenza-infected outpatients and inpatients annually [2].
Neuraminidase is an enzyme on the surface of the virus that is needed to release progeny virions from the host cells [3]. NAIs inhibit the viral neuraminidase, resulting in the blockage of viral replication and transmission. Past reports showed that in patients who received oseltamivir for influenza infections, fever was alleviated approximately one day earlier than in those who did not [4–6]. Similar effect of zanamivir was also reported [7, 8]. Laninamivir and peramivir are exclusively used in Japan; therefore, information on these drugs is limited [2]. The outstanding feature in Japan is that the four drugs can be prescribed to outpatients who are covered by health insurance [2]. Thus, clinicians can decide which drugs to prescribe depending on the patient’s situation and consent. Another peculiar situation is that, oseltamivir has not been recommended for teenagers’ use since 2005 until 2018 due to suspected associations with abnormal behaviors [2].
In 2007–2008, the spread of influenza A/H1N1, which has an amino acid mutation at position 275 histidine to tyrosine (H275Y) in neuraminidase protein (which confers resistance to oseltamivir and peramivir), occurred globally [9]. Patients who were infected with these viruses had prolonged fever following treatment with oseltamivir [10–14]. However, after the circulation of influenza A/H1N1pdm09 began in 2009, only the sporadic outbreaks of oseltamivir-resistance viruses were reported [2, 9, 15–17]. Therefore, limited reports are available regarding the clinical outcome of H275Y mutated A/H1N1 pdm09 virus [18, 19].
In the present study, we evaluated various factors influencing fever duration in patients who received one of the four NAIs against laboratory confirmed influenza infections, at outpatient clinics. Moreover, we evaluated the effectiveness of oseltamivir on H275Y mutated A/H1N1pdm09 virus compared to sensitive viruses.
Materials and methods
Study design and patients
An observational study was conducted in 8 clinics in 6 prefectures (Niigata, Gunma, Tokyo, Chiba, Kyoto, and Nagasaki) in Japan through 4 influenza seasons, from 2012–2013 to 2015–2016. Patients, otherwise healthy, aged 0 to 19 years who presented at outpatient clinics within 48 hours after the onset of influenza-like symptoms (such as fever, sore throat, cough, sneeze, or general fatigue) were screened by influenza rapid diagnostic test (RDT) kits. All patients who tested positive for influenza A or B were enrolled in the study. After obtaining written informed consent from the patients or their guardians, the clinicians prescribed one of the four NAIs. Selection of the drugs was left to the discretion of the clinicians and patients. The drugs were prescribed as standard of care with no intervention from the study authors. Drug dosages followed the standard prescription course recommended in Japan. Oseltamivir was administered orally for 5 days (2×75 mg/day for adults and children weighing ≥37.5 kg and 2 mg/kg/day for children weighing <37.5 kg). Zanamivir was administered by inhalation daily for 5 days (2×10 mg/day for adults and children ≥5 years old). Laninamivir was administered by inhalation (adults and children aged ≥10 years, as a single dose of 40 mg; and to children <10 years old, as a single dose of 20 mg). Peramivir was intravenously infused once (adults at a dose of 300 mg; children at 10 mg based on 1 kg body weight to a maximum of 600 mg, over a period of 15–30 min) [2].
Clinicians recorded patients’ age, sex, vaccination status, time from disease onset to the first clinic visit, body temperature at the clinic visit, and prescribed NAIs. Patients or guardians recorded the patients’ body temperature 3 times daily (morning, noon, and evening) until defervescence (<37.5 °C), for a maximum of 8 days at home.
The exclusion criteria from the analysis were as follows: patients identified with undifferentiated type/subtype; samples were positive for two or more influenza type/subtype; patients did not record their own temperature at home; or body temperature was <37.5 °C throughout the observation period.
Ethical approval for the study was obtained from the Ethics Committee at Niigata University (#1347).
Detection of influenza virus
Nasopharyngeal swabs or nasal discharges were obtained from the patients at the first clinic visit and stored into virus transport media. Samples were kept frozen at -20 °C until transport to Niigata University for further viral examinations. Specimens were inoculated onto Madin-Darby canine kidney cells [19, 20]. Samples with a positive cytopathic effect were typed and subtyped using the cycling probe real-time polymerase chain reaction (PCR) method, which can identify influenza A/H1N1pdm09, A/H3N2, B/Victoria, or B/Yamagata [20]. The assay can simultaneously detect the presence of H275Y mutation in neuraminidase protein for A/H1N1pdm09 viruses [21]. In addition, susceptibility testing of A/H1N1pdm09 influenza viruses was performed using the neuraminidase inhibition assay as previously reported, against oseltamivir, zanamivir, laninamivir, and peramivir, using 2′-(4-methylumbelliferyl)-a-D-N-acetylneuraminic acid (MUNANA) to validate the results of the cycling probe real-time PCR assay [22]. The value was determined by the 50% inhibitory concentration (IC50) [22].
Evaluation of fever duration
Fever duration was measured in hours, from the start of treatment until the patient reached the first point of 3 consecutive measurements <37.5 °C. If the patient had recurrent fever after 3 consecutive measurements <37.5 °C, the fever duration continued to be measured until final defervescence (regardless of the afebrile period), to prevent the influence of antipyretics. Usage of antipyretics was recorded in the patients’ home records, but this information was not used in this study because it did not affect the analyses.
Statistical analysis
Demographic details such as sex, age, body temperature at the clinic visit, time from onset to the first clinic visit, and vaccination status were extracted from patients’ records. Each variable was tabulated by NAI groups (oseltamivir, zanamivir, laninamivir, and peramivir) and by type/subtype. For our analysis, the B/Victoria and B/Yamagata groups in the influenza B virus group were integrated into one group. For univariate analysis, analysis of variance (ANOVA) was used to compare the average of continuous variables. Fisher’s exact test was used to examine categorical variables. To estimate the bias of selecting NAIs by virus type/subtype and season, we calculated both the proportion of each virus for each treatment group as well as the proportion of each treatment group for each season. The average fever duration was evaluated by t-test if the category was two. ANOVA was used if categories were three and higher, and Bonferroni corrected t-test was employed as a post-hoc test between each pair. Categories used for evaluation were as follows: type/subtype (A/H1N1pdm09, A/H3N2, or B), age groups (0 to 5, 6 to 9, or 10 to 19 years), body temperature at clinic visit (<38.5 °C or ≥38.5 °C), time from onset to the first clinic visit (0–24 hours, or 24–48 hours), vaccination status (vaccinated or unvaccinated), and prescribed NAIs (oseltamivir, zanamivir, laninamivir, or peramivir). In addition, Kaplan-Meier method was employed to evaluate the alleviation of fever, and statistically tested by a log-rank test. Any subset with a sample size <5 was excluded from the Kaplan-Meier method analysis.
For multivariable analysis, we used Cox proportional-hazard model to evaluate the duration of fever from the first dose of the NAI to fever alleviation <37.5 °C. To assess the hazard ratio (HR), fever duration (hours) was set as the dependent variable. The following were the independent variables: NAIs treatment (zanamivir, laninamivir, or peramivir based on oseltamivir), type/subtype (A/H3N2, or B based on A/H1N1pdm09), age group (6 to 9 years, or 10 to 19 years, compared with 0 to 5 years), vaccination status (vaccinated compared with unvaccinated), time from the onset to the clinic visit (24–48 hours compared with 0–24 hours), and body temperature at the clinic visit (continuous variables).
Additionally, we conducted a sub-group analysis based on age group, in order to evaluate the relationship between a younger age and the low effectiveness of laninamivir, which is a single dose inhalation drug. ANOVA was used for this analysis.
We performed further analysis to compare fever duration after oseltamivir treatment between the H275Y mutated (oseltamivir-resistant) A/H1N1pdm09 group and the oseltamivir-sensitive group. Since the patients with H275Y mutated virus treated by oseltamivir were all aged 5 or younger, this sub-group analysis was done for those in that age group.
P values <0.05 were considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [23].
Results
Patients’ characteristics
A total of 1,635 patients were enrolled. After excluding patients that did not meet the inclusion criteria, a total of 1,368 patients, through consecutive four influenza seasons from 2012–2013 to 2015–2016, were analyzed (Fig 1). Among them, 297 (21.7%), 683 (49.9%), and 388 (28.4%) were diagnosed with A/H1N1pdm09, A/H3N2, and B, respectively (Table 1). Influenza B was further divided into Victoria (n = 133) and Yamagata (n = 255), but they were aggregated into one group in our analysis. Most of the patients (74.3%) were aged <10 years. About half (48.8%) had body temperature of ≥38.5 °C at the first clinic visit. The vast majority of the patients (74.2%) visited the clinic within 24 hours after the onset of symptoms. Slightly over half of the patients (56.3%) had received influenza vaccine in preparation for the influenza season. Roughly half of the patients (54.5%) were treated with oseltamivir. Others were prescribed with laninamivir (26.7%), zanamivir (16.2%), and peramivir (2.6%).
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.
Baseline characteristics were further stratified by influenza types/subtypes and treatment groups. For A/H1N1pdm09, the average age for oseltamivir treatment group (6.2 ± 7.3 years) was younger than that for zanamivir (10.1 ± 2.7) and laninamivir (9.3 ± 2.2 years) treatment groups (Table 2). In Japan, oseltamivir was not recommended for use among teenagers because of the possibility of abnormal behaviors [2]. The average age for the peramivir treatment group (6.0 ± 4.4 years) was the lowest, because this drug was more used for younger children when oral or inhalation medication was difficult. Although the number of patients in the peramivir group was low and the statistical power was lacking, we retained the peramivir treatment group in our analysis because the clinical effectiveness of peramivir in outpatients has rarely been reported [24, 25]. The patient characteristics for influenza A/H3N2 and B were similar to those for A/H1N1pdm09, for all categories.
The proportion of various types/subtypes of influenza virus in each NAI treatment group is shown in Fig 2A. Among all treatment groups, the A/H3N2 group had the highest proportion of the influenza virus (47–69%). The influenza B proportion was higher in the zanamivir (33%) or laninamivir (36%) treatment groups than in the oseltamivir (24%) or peramivir (23%) treatment groups. In Japan, Kawai et al. reported that the fever duration for zanamivir was shorter than for oseltamivir in influenza B patients [26]. Therefore, Japanese physicians may prescribe zanamivir more frequently for influenza B than for influenza A.
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.
Throughout all seasons, the oseltamivir treatment group had the highest proportion (42–68%) (Fig 2B).
Univariate analyses of fever duration by the different characteristics
ANOVA and Bonferroni corrected t-test showed that the average duration of fever was significantly longer for influenza B than for A/H1N1pdm09 and A/H3N2 (p<0.001) (Table 3 and S1 Fig). The fever duration for the A/H1N1pdm09 group was longer than that for the A/H3N2 group (p = 0.028). Patients aged 0 to 5 years had longer fever duration than those aged 10 to 19 years (p<0.001). Patients with body temperature ≥38.5 °C at the clinic visit showed longer fever duration than those with temperature <38.5 °C (p = 0.004). Patients who visited within 24 hours of the onset of symptoms, compared to those who visited 24–48 hours after, had longer fever duration (p<0.001); the unvaccinated group had longer duration than the vaccinated (p = 0.029). However, no significant difference was seen among the four NAI groups.
Univariate analysis of fever duration for four NAIs by each type/subtype
When stratified by type and subtype, the average fever duration for A/H1N1pdm09 (p = 0.549), A/H3N2 (p = 0.520), and influenza B (p = 0.275) was similar among the four NAIs (Fig 3). The results of the Kaplan-Meier method supported the ANOVA results (Fig 3).
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.
Multivariable analysis of fever duration
We conducted multivariable analysis using Cox-proportional hazard model to evaluate factors associated with the alleviation of fever. HR <1 indicated prolonged fever alleviation for the variable. Treatment (laninamivir [HR = 0.78, p = 0.006] compared to oseltamivir); type/subtype (B [HR = 0.58, p<0.001] compared to A/H1N1pdm09 infection); and higher body temperature at the clinic visit (HR = 0.88, p<0.001) were significantly associated with longer fever duration (Table 4). However, compared to age 0 to 5 years, increasing age (6 to 9 years [HR = 1.31, p<0.001] and 10 to 19 years [HR = 1.67, p<0.001]) showed shorter fever alleviation durations. No association was shown with vaccination status and time from the onset to clinic.
Sub-group analysis of fever duration for four NAIs by age group
In the 0 to 5 years age group, the average fever duration for laninamivir (75.8 hours) was longer than that for oseltamivir (42.2 hours) (p = 0.028) (Table 5). In the 6 to 9 years age group, the average fever duration for laninamivir (42.9 hours) tended to be longer than that for oseltamivir (37.3 hours), but the difference was not significant (p = 0.120). In the 10 to 19 years age group, the average fever duration for four NAIs was not significantly different.
Fever duration after oseltamivir treatment for H275Y mutated A/H1N1pdm09 virus infection
We detected seven cases of A/H1N1pdm09 with H275Y mutation in neuraminidase protein, which conferred resistance to oseltamivir and peramivir. The IC50 value against oseltamivir for these 7 isolates ranged from 291.77 to 395.24 nM (S1 Table). Five cases were treated with oseltamivir, one with laninamivir, and another with zanamivir (Fig 4). In patients who were treated with laninamivir or zanamivir, fever was alleviated within 48 hours. Fever in 2 (40%) of the patients that were treated with oseltamivir was also alleviated within 48 hours; however, the remaining 3 patients (60%) had prolonged fever, which continued for more than 100 hours. In oseltamivir-treated patients who were infected with A/H1N1pdm09, the average fever duration was longer in patients (0–5 years) infected with oseltamivir-resistant viruses (n = 5, 89 ± 47 hours) than oseltamivir-sensitive viruses (n = 111, 40 ± 27 hours, p<0.001); (Fig 5). However, the log-rank test for Kaplan-Meier method was marginally significant (p = 0.067). We did not carry out multivariable analysis for this sub-group due to the small sample size of H275Y cases.
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.
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.
Discussion
In this study we compared the clinical effectiveness of four NAIs (for children and adults aged <20 years) against laboratory confirmed influenza A/H1N1pdm09, A/H3N2, and B. We found that influenza B infections, laninamivir treatment, younger age (0–5 years), and higher body temperature at clinic visit were associated with longer fever duration after the commencement of treatment, in multivariable analysis. We also found that fever duration in young children (0–5 years) infected with H275Y mutated influenza A/H1N1pdm09 virus and treated with oseltamivir was prolonged, compared to those with oseltamivir-sensitive virus infections. Our results revealed important information regarding the clinical effectiveness, especially of laninamivir and peramivir that are licensed for outpatients only in Japan, and also regarding oseltamivir-resistant viruses for which only limited clinical information is available.
Our results also showed that fever alleviation in influenza B infections was delayed roughly by half a day (~ 12 hours) compared to influenza A. Multivariable analysis also showed that influenza B infections was an independent risk factor for prolonged fever regardless of the treatment used among patients aged <20 years. In several studies, longer fever duration for influenza B, ranging from 13 to 36 hours after NAI treatment, have been reported [4, 5, 27, 28]. The reason for poor outcomes for influenza B than for influenza A remains unclear. Influenza B is reported to have a lower susceptibility to NAIs than does influenza A (2 to 16-fold changes) [29]. The virus re-isolation rate is significantly higher for influenza B than for influenza A after 4–6 days of oseltamivir therapy [30]. These might have caused the prolonged fever duration in patients with influenza B.
In our study, laninamivir treated group had significantly longer fever duration (HR, 0.78, p<0.01) compared to oseltamivir group in multivariable analysis. Laninamivir is a single dose, long-acting drug that is administered by inhalation, while oseltamivir and zanamivir are administered twice daily for 5 days. Ishiguro et al. reported that fever duration in laninamivir-treated influenza A or B infections was longer compared to oseltamivir or peramivir-treated infections among outpatients aged 0–18 years using Cox-proportional hazard model [24]. Koseki et al. reported that the frequency of biphasic fever was significantly higher in laninamivir-treated patients than in zanamivir-treated patients, although the fever duration for zanamivir and laninamivir was not significantly different among patients aged 5 to 18 years [31]. Hikita et al. reported that the median fever duration after treatment with laninamivir of 3 days, was significantly longer by 1 day for peramivir in influenza B-infected patients aged 5 to 18 years (P <0.01) [32]. Sugaya et al. reported a significantly shorter fever duration (0.75 to 1.10 day) in patients administerd peramivir than in those administered laninamivir (P<0.05) among influenza A/H3N2 or A/H1N1pdm09 infections [33]. Ishiguro et al. suggested the possibility that an inadequate inhalation of the single dose laninamivir influenced the longer fever duration in patients aged 5 to 9 years than those treated with other NAIs [24]. Koseki et al. also suggested that incomplete inhalation of the single dose of laninamivir, especially in young children, could explain the increase in frequency of biphasic fever in the laninamivir treated group compared with zanamivir treated group [31]. Our study also showed that the average fever duration was longer in laninamivir treated group than in those who were treated by oseltamivir among the younger age. This might have been caused by inadequate inhalation in the younger age group. Nevertheless, variable results have been reported for the four NAIs [24, 25, 34–36]. Therefore, there is need for continuing evaluation of the clinical effects of the four NAIs.
Our study showed that a younger age was a factor of prolonged fever. Past studies repeatedly showed that younger children had longer fever duration than older children or adults [5, 24, 31, 37, 38]. Prolonged fever in young children may be due to the longer virus shedding in younger patients than older patients [33, 39]. It is also known that fever is often prolonged in immunocompromised patients who shed virus longer than immunocompetent patients [40]. Prolonged viral shedding in children could have resulted from low immunity due to the less experience of infections [24, 41].
Patients with higher body temperature at the clinic visit had longer fever duration in this study. Kawai et al. reported similar results that patients with high peak body temperature had longer fever duration [42]. Kaiser et al. reported that viral titers correlated positively with symptoms and temperature, and that cytokine level, for such as interleukin 6 and tumor necrosis factor alpha, also correlated positively with temperature [43]. Prolonged fever caused by high body temperature at the clinic visit may have resulted from higher viral titer and higher cytokine levels.
In univariate analysis, unvaccinated status was associated with prolonger fever, but this was not significant in multivariable analysis. Tochino et al. reported longer fever duration among vaccinated than among unvaccinated patients in univariate but not in multivariable analysis [44]. In this previous study, the vaccinated patients were younger; therefore, being younger vaccinated patients might have led to the longer fever duration. In our study, unvaccinated patients were older than the vaccinated patients (8.9 versus 7.7 years, p<0.01); however, the unvaccinated patients had higher temperature at the clinic visit that might have resulted in the prolonger fever duration shown in univariate analysis (38.5 versus 38.3 °C, p<0.01) that was offset in multivariable analysis. As suggested by Tochino et al., differences in medical care-seeking behavior may exist in vaccinated patients with low grade fever and/or mild symptoms who did not go to the hospital.
Current study showed that the fever duration was longer in the oseltamivir-resistant group than in the oseltamivir-sensitive group among influenza A/H1N1pdm09-infected patients. Several studies reported that when patients were treated with oseltamivir, oseltamivir-resistant former influenza A/H1N1 circulating during 2007–2008 demonstrated prolonged fever compared to oseltamivir-sensitive influenza [12, 13, 45]. The Influenza Resistance Information Study showed that viral RNA was detected for longer periods in patients infected with oseltamivir-resistant influenza A/H1N1pdm09 and A/H3N2 viruses, although these patients exhibited a shorter duration of symptoms compared to those infected with oseltamivir-sensitive influenza [15]. We previously reported five cases of oseltamivir and peramivir-resistant influenza A/H1N1pdm09 in 2015/2016 season [19]. In all these patients, following treatment with oseltamivir or peramivir, the fever subsided within 48 hours of the start of treatment [19]. Only the two child cases from the previous report were included in the current study. In the former A/H1N1 infection, younger children showed prolonged fever duration, which was not reported among the adults [45]. Exclusion of adult patients in this study may have led to the prolonged fever duration in the H275Y cases.
Our study has some limitations. Because this was an observational study, the selection of NAIs was left to the physician’s discretion. The sample size of patients receiving peramivir was not large, hence accurate statistical analysis could not be conducted; thus, caution is necessary when interpreting the results. Because peramivir is an injectable drug, it is easy to administer to patients who cannot take oral medicines or inhalants, such as seriously ill patients or young infants. Moreover, because oseltamivir is not recommended for use in those aged 10 to 19 years (because of abnormal behavior) by the order of the Ministry of Health, Labor, and Welfare [2], this skewed our patients’ age to the younger side, in the oseltamivir treatment group than that in the zanamivir or laninamivir groups. Since zanamivir- and laninamivir-treated patients had similar mean age, the results between zanamivir and laninamivir were comparable. Nevertheless, we used the multivariable analysis to adjust for those age differences. The viral load and severity of illness data were not evaluated in this study. We collected the second samples after 3–7 days of the first visit to measure viral load shift by the treatment, but the number of samples are too less, compared to those who clinical records were obtained. Thus, we decided not to include viral load analysis in this study, but in the future study. For the diseases severity, our sample size was too small to evaluate the frequency of severity such as admission rates or mortality with enough statistical power on study group that was otherwise healthy outpatients, so we excluded it from our analysis. In the comparison between oseltamivir-resistant and oseltamivir-sensitive influenza, the sample size of oseltamivir-resistant influenza patients was also limited.
In conclusion, laninamivir treatment showed longer fever durations among the four NAIs. Fever duration was prolonged in children treated with oseltamivir for A/H1N1pdm09 harboring H275Y mutation. Thus, our study can serve as comparative evidence to assess the clinical effectiveness of another class of drug (cap-dependent endonuclease inhibitor) recently approved in Japan and United States [46], which can be an effective therapeutic option when administered alone or in combination [47].
Supporting information
S1 Fig. Univariate analysis of the fever duration by each characteristic.
A: Type/subtype (A1: A/H1N1pdm09; A3: A/H3N2; B: influenza B), B: Age group. C: Body temperature at the clinic visit. D: Time from disease onset to the first clinic visit. E: Vaccine status. F: Treatment (OS: oseltamivir, ZA: zanamivir, LA: laninamivir, PE: peramivir). Left: Boxplots of ANOVA or t test of the average fever duration. Bold line is the mean; the box shows the interquartile range. Right: Kaplan-Meier method of analysis for the fever duration.
https://doi.org/10.1371/journal.pone.0224683.s001
(PDF)
S1 Table. The 50% inhibitory concentrations and administered medications in patients infected with H275Y mutated influenza A/H1N1pdm09 virus.
https://doi.org/10.1371/journal.pone.0224683.s002
(XLSX)
Acknowledgments
The membership for Japanese Influenza Collaborative Study Group are as follows: Dr. Shinji Kimura in Hokkaido; Dr. Isamu Sato, Dr. Yoshinari Tanabe, Dr. Taketo Otsuka, Dr. Minoru Okazaki in Niigata; Dr. Takashi Kawashima in Gunma, Dr. Tadashi Saito, Dr. Haruo Kuroki in Chiba; Dr. Jin Takasaki, Dr. Nobuyoshi Kobayashi in Tokyo; Dr. Naoki Koudo, Dr. Shigeyoshi Hibi, Dr. Satoshi Ikushima, Dr. Fumihiro Fujiwara, and Dr. Kentaro Tsunamoto in Kyoto; Dr. Takao Yoshiwara in Osaka; Dr. Tetsuo Hashida in Hyogo; Dr. Hironori Masaki, Dr. Norichika Asoh, Dr. Yoshiko Tsuchihashi, Dr. Yutaka Shirahige, Dr. Reiki Kuroki, Dr. Kazuhiko Hoshino, Dr. Satoshi Degawa, and Dr. Yasuhiko Ono in Nagasaki; and Dr. Tomoko Makiya and Dr. Hirotsune Hamabata in Okinawa.
References
- 1. Murakami Y, Hashimoto S, Kawado M, Ohta A, Taniguchi K, Sunagawa T, et al. Estimated number of patients with influenza A(H1)pdm09, or other viral types, from 2010 to 2014 in Japan. PLoS One. 2016;11: e0146520. Epub 2016/01/20. pmid:26784031.
- 2. Zaraket H, Saito R. Japanese surveillance systems and treatment for influenza. Current Treat Options Infect Dis. 2016;8: 311–328. Epub 2016/12/31. pmid:28035195.
- 3. McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Resp Viruses. 2013;7 Suppl 1: 25–36. Epub 2013/01/04. pmid:23279894.
- 4. Kawai N, Ikematsu H, Iwaki N, Maeda T, Satoh I, Hirotsu N, et al. A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: a Japanese multicenter study of the 2003–2004 and 2004–2005 influenza seasons. Clin Infect Dis. 2006;43: 439–444. Epub 2006/07/14. pmid:16838232.
- 5. Sato M, Saito R, Sato I, Tanabe N, Shobugawa Y, Sasaki A, et al. Effectiveness of oseltamivir treatment among children with influenza A or B virus infections during four successive winters in Niigata City, Japan. Tohoku J Exp Med. 2008;214: 113–120. Epub 2008/02/21. pmid:18285668.
- 6. Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. 2015;385(9979): 1729–1737. Epub 2015/02/03. pmid:25640810.
- 7. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet. 2006;367(9507):303–313. Epub 2006/01/31. pmid:16443037.
- 8. Sugaya N, Tamura D, Yamazaki M, Ichikawa M, Kawakami C, Kawaoka Y, et al. Comparison of the clinical effectiveness of oseltamivir and zanamivir against influenza virus infection in children. Clin Infect Dis. 2008;47(3): 339–345. Epub 2008/06/28. pmid:18582202.
- 9. Hurt AC. The epidemiology and spread of drug resistant human influenza viruses. Curr Opin Virol. 2014;8: 22–29. Epub 2014/05/29. pmid:24866471.
- 10. Baranovich T, Saito R, Suzuki Y, Zaraket H, Dapat C, Caperig-Dapat I, et al. Emergence of H274Y oseltamivir-resistant A(H1N1) influenza viruses in Japan during the 2008–2009 season. J Clin Virol. 2010;47(1): 23–28. Epub 2009/12/08. pmid:19962344.
- 11. Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007–08. Emerg Infect Dis. 2009;15(2): 155–162. Epub 2009/02/06. pmid:19193257.
- 12. Matsuzaki Y, Mizuta K, Aoki Y, Suto A, Abiko C, Sanjoh K, et al. A two-year survey of the oseltamivir-resistant influenza A(H1N1) virus in Yamagata, Japan and the clinical effectiveness of oseltamivir and zanamivir. Virol J. 2010;7:53. Epub 2010/03/06. pmid:20202225.
- 13. Saito R, Sato I, Suzuki Y, Baranovich T, Matsuda R, Ishitani N, et al. Reduced effectiveness of oseltamivir in children infected with oseltamivir-resistant influenza A (H1N1) viruses with His275Tyr mutation. Pediatr Infect Dis J. 2010;29(10): 898–904. Epub 2010/05/06. pmid:20442686.
- 14. Sugaya N, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob Agents Chemother. 2010;54(6): 2575–2582. pmid:20368393
- 15. Lina B, Boucher C, Osterhaus A, Monto AS, Schutten M, Whitley RJ, et al. Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study. Influenza Other Resp Viruses. 2018;12(2): 267–278. Epub 2017/12/22. pmid:29265727.
- 16. Wang B, Taylor J, Ratnamohan M, McPhie K, Kesson A, Dixit R, et al. Frequency of oseltamivir resistance in Sydney, during the Newcastle outbreak of community transmitted oseltamivir-resistant influenza A(H1N1)pdm09 virus, Australia, June to August 2011. Eurosurveillance. 2012;17(27): 20210. Epub 2012/07/14. pmid:22790606.
- 17. Takashita E, Ejima M, Itoh R, Miura M, Ohnishi A, Nishimura H, et al. A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013. Eurosurveillance. 2014;19(1): 4–9.
- 18. Kakuya F, Kinebuchi T, Fujiyasu H, Tanaka R, Okubo H, Kano H. Clinical findings in 10 children with H275Y influenza A(H1N1)pdm09 virus infection. Pediatr Int. 2015;57(5): 888–892. pmid:25865177
- 19. Hibino A, Kondo H, Masaki H, Tanabe Y, Sato I, Takemae N, et al. Community- and hospital-acquired infections with oseltamivir- and peramivir-resistant influenza A(H1N1)pdm09 viruses during the 2015–2016 season in Japan. Virus Genes. 2017;53(1):89–94. Epub 2016/10/08. pmid:27714496.
- 20. Dapat IC, Dapat C, Baranovich T, Suzuki Y, Kondo H, Shobugawa Y, et al. Genetic characterization of human influenza viruses in the pandemic (2009–2010) and post-pandemic (2010–2011) periods in Japan. PLoS One. 2012;7(6):e36455. pmid:22761651
- 21. Suzuki Y, Saito R, Sato I, Zaraket H, Nishikawa M, Tamura T, et al. Identification of oseltamivir resistance among pandemic and seasonal influenza A (H1N1) viruses by an His275Tyr genotyping assay using the cycling probe method. J Clin Microbiol. 2011;49(1): 125–130. Epub 2010/11/19. pmid:21084523.
- 22. Zaraket H, Kondo H, Hibino A, Yagami R, Odagiri T, Takemae N, et al. Full genome characterization of human influenza A/H3N2 isolates from Asian countries reveals a rare amantadine resistance-conferring mutation and novel PB1-F2 polymorphisms. Front Microbiol. 2016;7: 262. pmid:27014195
- 23. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3): 452–458. Epub 2012/12/05. pmid:23208313.
- 24. Ishiguro N, Koseki N, Kaiho M, Ariga T, Kikuta H, Oba K, et al. Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014–2015 to 2016–2017 influenza seasons in Japan. J Infect Chemother. 2018;24(6):449–457. Epub 2018/03/01. pmid:29487035.
- 25. Shobugawa Y, Saito R, Sato I, Kawashima T, Dapat C, Dapat IC, et al. Clinical effectiveness of neuraminidase inhibitors-oseltamivir, zanamivir, laninamivir, and peramivir-for treatment of influenza A(H3N2) and A(H1N1)pdm09 infection: an observational study in the 2010–2011 influenza season in Japan. J Infect Chemother. 2012;18(6):858–864. pmid:22644080
- 26. Kawai N, Ikematsu H, Iwaki N, Maeda T, Kawashima T, Hirotsu N, et al. Comparison of the effectiveness of Zanamivir and Oseltamivir against influenza A/H1N1, A/H3N2, and B. Clin Infect Dis. 2009;48(7):996–997. Epub 2009/03/06. pmid:19260819.
- 27. Sugaya N, Mitamura K, Yamazaki M, Tamura D, Ichikawa M, Kimura K, et al. Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A infection in children. Clin Infect Dis. 2007;44(2): 197–202. pmid:17173216
- 28. Kondo H, Shobugawa Y, Hibino A, Yagami R, Dapat C, Okazaki M, et al. Influenza Virus Shedding in Laninamivir-Treated Children upon Returning to School. Tohoku J Exp Med. 2016;238(2):113–121. pmid:26806610
- 29. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase inhibitors. Antiviral Res. 2002;54(3):143–147. Epub 2002/06/14. pmid:12062387.
- 30. Burnham AJ, Baranovich T, Govorkova EA. Neuraminidase inhibitors for influenza B virus infection: efficacy and resistance. Antivir Res. 2013;100(2):520–534. Epub 2013/09/10. pmid:24013000.
- 31. Koseki N, Kaiho M, Kikuta H, Oba K, Togashi T, Ariga T, et al. Comparison of the clinical effectiveness of zanamivir and laninamivir octanoate for children with influenza A (H3N2) and B in the 2011–2012 season. Influenza Other Resp Viruses. 2014;8(2):151–158.
- 32. Hikita T, Hikita H, Hikita F, Hikita N, Hikita S. Clinical effectiveness of peramivir in comparison with other neuraminidase inhibitors in pediatric influenza patients. Int J pediatr. 2012;2012: 834181. Epub 2012/04/21. pmid:22518184.
- 33. Sugaya N, Sakai-Tagawa Y, Bamba M, Yasuhara R, Yamazaki M, Kawakami C, et al. Comparison between virus shedding and fever duration after treating children with pandemic A H1N1/09 and children with A H3N2 with a neuraminidase inhibitor. Antivir Ther. 2015;20(1): 49–55. Epub 2014/05/17. pmid:24832015.
- 34. Yoshi N, Tocino Y, Fujioka M, Kureya Y, Asai K, Kimura T, et al. Comparison of the clinical courses of patients with influenza after neuraminidase inhibitors treatment: A postcard survey of the 2013–2014 influenza season in Osaka. Osaka City Med J. 2016;62(2): 29–38. Epub 2016/12/01. pmid:30550708.
- 35. Hirotsu N, Saisho Y, Hasegawa T, Shishido T. Clinical and virologic effects of four neuraminidase inhibitors in influenza A virus-infected children (aged 4–12 years): an open-label, randomized study in Japan. Expert Rev Anti Infect Ther. 2018;16(2):173–182. Epub 2017/12/30. pmid:29284320.
- 36. Takemoto Y, Asai T, Ikezoe I, Yano T, Ichikawa M, Miyagawa S, et al. Clinical effects of oseltamivir, zanamivir, laninamivir and peramivir on seasonal influenza infection in outpatients in Japan during the winter of 2012–2013. Chemotherapy. 2013;59(5):373–378. pmid:24821568
- 37. Kawai N, Ikematsu H, Iwaki N, Satoh I, Kawashima T, Maeda T, et al. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002–2003 influenza season. Clin Infect Dis. 2005;40(9):1309–1316. Epub 2005/04/13. pmid:15825034.
- 38. Suzuki E, Ichihara K. The course of fever following influenza virus infection in children treated with oseltamivir. J Med Virol. 2008;80(6):1065–1071. Epub 2008/04/23. pmid:18428131.
- 39. Li CC, Wang L, Eng HL, You HL, Chang LS, Tang KS, et al. Correlation of pandemic (H1N1) 2009 viral load with disease severity and prolonged viral shedding in children. Emerg Infect Dis. 2010;16(8):1265–1272. Epub 2010/08/04. pmid:20678321.
- 40. Leekha S, Zitterkopf NL, Espy MJ, Smith TF, Thompson RL, Sampathkumar P. Duration of influenza A virus shedding in hospitalized patients and implications for infection control. Infect Control Hosp Epidemiol. 2007;28(9):1071–1076. Epub 2007/10/13. pmid:17932829.
- 41. Munoz FM. Influenza virus infection in infancy and early childhood. Paediatr Respir Rev. 2003;4(2):99–104. Epub 2003/05/22. pmid:12758046.
- 42. Kawai N, Ikematsu H, Iwaki N, Maeda T, Kanazawa H, Kawashima T, et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infection. 2008;56(1):51–57. https://doi.org/10.1016/j.jinf.2007.09.002.
- 43. Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol. 2001;64(3):262–268. Epub 2001/06/26. pmid:11424113.
- 44. Tochino Y, Fujioka M, Sakazaki H, Ikuno Y, Tochino R, Yoshii N, et al. Current usage and effectiveness of influenza medications and factors regarding the time taken to alleviate fever based on postcard questionnaire survey. J Gen Fam Med. 2017;18(6):386–392. Epub 2017/12/22. pmid:29264069.
- 45. Kawai N, Ikematsu H, Iwaki N, Kondou K, Hirotsu N, Kawashima T, et al. Clinical effectiveness of oseltamivir for influenza A(H1N1) virus with H274Y neuraminidase mutation. J Infection. 2009;59(3):207–212. Epub 2009/07/22. pmid:19619898.
- 46. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir Marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913–923. Epub 2018/09/06. pmid:30184455.
- 47. Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019;32(2):176–186. Epub 2019/02/07. pmid:30724789.