Abstract

Background. To compare the effectiveness of oseltamivir for treatment of influenza A and influenza B, we conducted a prospective, multicenter study of the 2003–2004 and 2004–2005 influenza seasons. The study included 3351 patients in whom influenza had been diagnosed by use of an antigen detection test kit.

Methods. Oseltamivir was administered to 1818 patients with influenza A and 1485 patients with influenza B. No anti-influenza drugs were administered to 21 patients with influenza A or to 27 patients with influenza B. Patients receiving oseltamivir therapy were divided into 4 groups according to the time between the onset of fever (temperature, ⩾37.5°C) and administration of the first dose of oseltamivir (0–12 h, 13–24 h, 25–36 h, and 37–48 h). The patients were also divided into 4 subgroups on the basis of age (0–6 years, 7–15 years, 16–64 years, and >64 years). Virus isolation was performed after completion of oseltamivir therapy for 44 patients with influenza A and 31 patients with influenza B.

Results. The duration of fever was significantly shorter for patients with influenza A and B who were treated with oseltamivir than for patients who were not treated with an anti-influenza drug (P < .001 for both). The time until the patient became afebrile after the initial administration of oseltamivir and the duration of fever were significantly longer for patients with influenza B than for patients with influenza A for the 0–12 h, 13–24 h, 25–36 h, and 37–48 h groups (P < .001) and for all age groups (P < .001). After 4–6 days of oseltamivir therapy, the influenza B virus reisolation rate (51.6%) was significantly higher than the influenza A virus reisolation rate (15.9%) (P < .001).

Conclusion. Oseltamivir is less effective for influenza B than for influenza A with regard to duration of fever and virus persistence, irrespective of patient age or the timing of administration of the first dose.

Oseltamivir, an oral neuraminidase inhibitor, has become widely prescribed in Japan for the treatment of influenza [1, 2]. The clinical effectiveness of oseltamivir for the treatment of influenza A has been well documented, but its efficacy for influenza B has not been fully investigated because of a lack of patients with influenza B [3–10]. Recently, we reported that oseltamivir was possibly less effective against influenza B than against influenza A on the basis of an analysis of the duration of fever, which was measured in days [1]. In this study, we analyzed a large number of patients with influenza A and patients with influenza B, including both children and adults, whose diagnoses were made using antigen detection test kits [11–14] and who were treated with oseltamivir. The duration of fever was measured in hours, to compare the effectiveness of oseltamivir against influenza A and influenza B. Virus isolation after administration of oseltamivir was also performed to compare the viral persistence of influenza A virus and influenza B virus. We report a longer duration of fever and longer virus persistence in patients with influenza B than in those with influenza A.

Methods

Study procedures. Family doctors, pediatricians, and physicians at 36 clinics that belong to the Influenza Study Group of the Japan Physicians Association participated in the study. Patients were enrolled from 6 December 2003 through 11 April 2005. Patients who reported to 1 of these 36 clinics throughout Japan with influenza-like illness (manifesting such symptoms as a body temperature ⩾37.5°C, upper respiratory tract symptoms, and systemic symptoms) received a diagnosis of influenza A or B based on the results of commercial antigen detection kits. Among the patients with influenza confirmed by antigen detection kits, those who received oseltamivir within 48 h after onset of symptoms or who did not receive an anti-influenza drug were registered in this study after providing informed consent. For patients with influenza, the decision on whether to administer oseltamivir was left to the discretion of the clinician, who considered the background and characteristics of the patient, such as the presence of other existing diseases, the patient's age, and the patient's preference.

Specimens from throat swabs, nasal swabs, or nasal aspirates were subjected to antigen detection and virus isolation. Commercial antigen detection kits based on immunochromatography (Capilia FluA,B [Tauns and Nippon Becton Dickinson] [15, 17, 18], Espline Influenza A&B-N [Fujirebio] [15, 16, 18], RapidTesta FLU AB [Daiichi Pure Chemicals] [19], and Poctem Influenza A/B [Sysmex] [15, 18]) were mainly used. Another kit based on an EIA (Influ A-B Quick "SEIKEN" [Denka Seiken] [17]) was also used. The reported sensitivities and specificities of the commercial antigen detection kits for influenza A by several studies in Japan were as follows: 96%–98% and 93.9%–100%, respectively, for Capilia FluA,B; 95.4%–96.8% and 97.6%–100%, respectively, for Espline Influenza A&B-N; 82.8% and 97.0%, respectively, for Influ AB Quick "SEIKEN"; 86%–95% and 100%, respectively, for Poctem Influenza A/B; and 83.2%–98% and 96%–98.5%, respectively, for RapidTesta FLU AB. For influenza B, the sensitivities and specificities were as follows: 86% and 98%, respectively, for Capilia FluA,B; 88.1%–91.2% and 97.6%–100%, respectively, for Espline Influenza A&B-N; 87% and 100%, respectively, for Poctem Influenza A/B; and 82.7%–88% and 97.7%, respectively, for RapidTesta FLU AB [15–19]. No significant difference in specificity has been reported for influenza A and influenza B. Virus isolation was performed using throat swabs, nasal swabs, or nasal aspirates by standard methods using Madin-Darby canine kidney cells.

Oseltamivir (75 mg for adults and for children who weighed ⩾37.5 kg and 2 mg/kg for children who weighed <37.5 kg) was administered orally twice per day for 5 days. Patients took the initial dose of oseltamivir at the clinic or at home and entered the time of the initial administration of the oseltamivir dose on a questionnaire that had been provided.

Age, sex, vaccination status, results of the antigen detection test kit, and the highest body temperature during the course of the disease were recorded for all patients. The date and time of the onset of fever, the date and time of administration of oseltamivir, and the resolution of fever were recorded by the physician, patient, or an attending family member. The first time that a patient reported a fever (temperature, ⩾37.5°C) was defined as the time of onset. Patients were asked to measure body temperature at least 3 times per day (8:00 A.M., 2:00 P.M., and 8:00 P.M.); the time at which a body temperature of <37.5°C was attained was defined the time that the patient became afebrile.

All data were collected using an internet-based protocol in which participating physicians sent their data to a central computer system based on a Pentium workstation running a Structured Query Language (SQL) database and on a Web server located in a secure room at the Gifu City Medical Association. All participating doctors were given an identification number and password and were able to access the computer system via the Internet to enter data into the SQL database [1, 20]. The time from the initial administration of oseltamivir to the resolution of fever and the duration of fever between the onset and resolution were calculated automatically in the SQL database.

Statistical analysis. Student's t test was used for between-group comparisons of the time to onset of fever and the duration of fever. The χ2 test was also used to compare between-group differences in the percentage of cases of isolated virus, both before and after oseltamivir therapy. A P value of <.05 was considered to be statistically significant.

Results

Patient characteristics. A total of 3351 patients were enrolled (1818 patients with influenza A who were treated with oseltamivir, 1485 patients with influenza B who were treated with oseltamivir, 21 patients with influenza A who did not receive treatment with an anti-influenza drug, and 27 patients with influenza B who did not receive treatment with an anti-influenza drug). The demographic characteristics of the patients are summarized in table 1. No significant between-group differences were found for the ratio of female subjects to male subjects or for vaccination status. The peak body temperature was significantly higher in patients with influenza A than in patients with influenza B for both groups of oseltamivir recipients (39.0°C ± 0.7°C and 38.8°C ± 0.6°C, respectively; P < .001). The commercial antigen detection kits used were Capilia FluA,B in 2762 cases, Espline Influenza A&B-N in 324 cases, Influ AB Quick"SEIKEN" in 132 cases, Poctem Influenza A/B in 47 cases, RapidTesta FLU AB in 22 cases, and other kits in 64 cases.

Table 1

Characteristics of patients in a comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B.

Table 1

Characteristics of patients in a comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B.

The rate of compliance with the prescribed oseltamivir regimen was very high. Some patients discontinued the use of oseltamivir if influenza symptoms abated in <5 days. Minor adverse reactions were observed in 19 patients with influenza A and 15 patients with influenza B. No severe adverse reactions were reported.

Duration of fever from the onset. The durations of fever after onset are shown in table 1. The duration of fever from its onset was significantly shorter in both patients with influenza A and those with influenza B who were treated with oseltamivir than in those who were not treated with an anti-influenza drug (for patients with influenza A, 47.9 ± 26.0 and 82.4 ± 36.0 h, respectively [P < .001]; for patients with influenza B, 65.4 ± 32.8 and 78.3 ± 41.9 h, respectively [P < .001]). Among oseltamivir recipients, the duration of fever was significantly longer for patients with influenza B than for patients with influenza A (65.4 ± 32.8 and 47.9 ± 26.0 h, respectively; P < .001).

Analysis for the time from onset to the start of treatment. The patients who received oseltamivir were categorized into 4 groups on the basis of the time from onset of fever to the start of treatment (0–12 h, 13–24 h, 25–36 h, and 37–48 h after onset). The duration of fever starting from the time at which the first dose of oseltamivir was administered is listed in table 2. The duration of fever from the first administration tended to be shorter in patients who started taking medication 25–36 h after onset than in patients started medication at 0–12, 13–24, or 37–48 h after onset, both for patients with influenza A and for those with influenza B. The duration of fever from the time at which the first dose of oseltamivir was administered was significantly longer for patients with influenza B than for patients with influenza A in all 4 categories (P < .001).

Table 2

Duration of fever after administration of the first dose of oseltamivir for patients with influenza A or influenza B, by time to administration of the first dose after the onset of fever.

Table 2

Duration of fever after administration of the first dose of oseltamivir for patients with influenza A or influenza B, by time to administration of the first dose after the onset of fever.

The duration of fever from onset was similar (table 3). The duration of fever in patients with influenza A and influenza B was significantly shorter in patients who received medication ⩽12 h after the onset of symptoms (37.6 ± 25.9 h and 53.1 ± 31.2 h for patients with influenza A and those with influenza B, respectively) than in patients who commenced treatment 13–24, 25–36, or 37–48 h after onset . The duration of fever was significantly longer in patients with influenza B than in patients with influenza A in all categories (P < .001).

Table 3

Duration of fever for patients with influenza A and those with influenza B, by time to the first administration of oseltamivir after the onset of fever.

Table 3

Duration of fever for patients with influenza A and those with influenza B, by time to the first administration of oseltamivir after the onset of fever.

Analysis by age. The patients who received oseltamivir were categorized into 4 groups on the basis of age (0–6, 7–15, 16–64, and >64 years). The duration of fever from the time that the first dose of oseltamivir was administered and the duration of fever from onset are listed by age in tables table 4 and table 5, respectively. The duration of fever from the time at which the first dose was administered was significantly shorter for patients with influenza A aged 7–15 years than for those aged 0–6, 16–64, and >64 years (P < .001). The duration of fever from onset was also significantly shorter for patients with influenza B aged 7–15 years than for those aged 0–6 or >64 years (P < .001). The duration of fever from the time that the first dose of oseltamivir was administered was significantly shorter for patients with influenza A than for patients with influenza B in all age groups (P < .001).

Table 4

Duration of fever after administration of the first dose of oseltamivir for influenza A or influenza B, by patient age.

Table 4

Duration of fever after administration of the first dose of oseltamivir for influenza A or influenza B, by patient age.

Table 5

Duration of fever for influenza A and influenza B, by patient age.

Table 5

Duration of fever for influenza A and influenza B, by patient age.

The duration of fever from onset was significantly shorter for patients with influenza A aged 7–15 years than for those aged 0–6, 16–64, or >64 years (P < .01, P < .001 and P < .001, respectively). The duration of fever from the onset was significantly shorter for patients with influenza B aged 7–15 years than for those aged 0–6, 16–64, or >64 years (P < .001, P < .01 and P < .001, respectively). Furthermore, the duration of fever from onset was significantly shorter for patients with influenza A than for those with influenza B in all age groups (P < .001).

Virus isolation before and after oseltamivir therapy. To confirm the reliability of our diagnosis using the rapid antigen detection kits, the specimens obtained from 181 patients with influenza A and 212 patients with influenza B were subjected to virus isolation. Influenza A virus was isolated in 150 of 181 patients with influenza A, and influenza B virus was isolated 184 of 212 patients with influenza B before they commenced oseltamivir therapy. There was no significant difference in the rate of virus isolation between patients with influenza A and those with influenza B.

Among the patients who had positive virus isolation test results before the initial administration of oseltamivir, 44 with influenza A and 31 with influenza B again underwent virus isolation tests 4–6 days (mean ± SD, 4.9 ± 0.7 days) after the initial dose of oseltamivir was administered. The compliance rate of these 44 patients was almost 100% until the clinical visit for the second virus isolation. The results of the reisolation tests are listed in table 6. Of the 44 influenza A virus–positive patients (42 of whom were infected with A/H3N2, and 2 of whom were infected with A/H1N1), a virus was reisolated in 7 (15.9%; 6 with A/H3N2, and 1 with A/H1N1). The influenza B virus was isolated in 31 patient samples before oseltamivir therapy was initiated and was reisolated from samples from 16 patients (51.6%). These results revealed that the influenza B virus persisted at a present significantly higher rate than the influenza A virus at 4–6 days after the first dose of oseltamivir was administered.

Table 6

The results of virus isolation tests before and after oseltamivir therapy.

Table 6

The results of virus isolation tests before and after oseltamivir therapy.

Discussion

An increased benefit associated with the early administration of oral oseltamivir has been reported. A report by Aoki et al. [9] included 958 laboratory-confirmed influenza cases (944 cases of influenza A, 6 cases of influenza B, and 8 cases of influenza A and B); however, the number of patients with influenza B was too small to reveal a significant finding. We have reported an increased benefit associated with the early administration of oseltamivir for influenza B, as was previously shown for influenza A and for amantadine therapy for influenza A in the 2002–2003 influenza season, with 1479 patients with influenza A and 684 patients with influenza B. In this study, we examined the time course, in hours, from the onset of fever to the initial administration of oseltamivir and to the resolution of fever in 1818 patients with influenza A and 1485 patients with influenza B who were treated with oseltamivir in the 2003–2004 and the 2004–2005 influenza seasons. An increased benefit from the early administration of oseltamivir was again demonstrated. Interestingly, the time from the initial administration of oseltamivir to the resolution of fever was quite comparable among the 4 groups with regard to the time from onset to the start of treatment (i.e., 0–12, 13–24, 25–36, and 37–48 h after onset) (table 2). Because a similar clinical course was seen in most patients after the initial administration of oseltamivir, these results indicate that inhibiting the increase of infected cells in the host is important for quickly reducing symptoms (table 3) and accelerating recovery from illness.

We also reported previously that, in an analysis of duration of fever calculated in days in the 2002–2003 influenza season, oseltamivir therapy was possibly less beneficial for influenza B than for influenza A. In this study, both the duration of fever from receipt of the first dose of oseltamivir and the duration from the onset of fever were significantly longer in patients with influenza B than in patients with influenza A. This tendency was consistently observed in all age groups. The results of this study confirmed that oseltamivir therapy is less beneficial for influenza B than for influenza A. There is a limit to the findings of our study in that it was performed in a general practice setting and not in the context of a rigorous clinical protocol. However, this limitation should not be sufficient to invalidate our findings.

After oseltamivir therapy, the influenza B virus was isolated from the patients more frequently than was the influenza A virus (table 6). Culture and enzymatic assay studies of the in vitro antiviral activity of oseltamivir against laboratory strains of influenza virus have suggested that the influenza B virus was less susceptible than the influenza A virus to oseltamivir [21–23]. These in vitro results may be relevant to our results, which revealed more frequent isolation of influenza B virus than influenza A virus after oseltamivir therapy. Furthermore, these findings may explain our finding that oseltamivir is less effective against influenza B than against influenza A in a clinical setting. In patients with influenza B, it may be necessary to develop a more suitable oseltamivir medication regimen (e.g., use of a different dosage or a change in the number of frequency of administration). We are currently performing a study of virus isolation before and after receipt of oseltamivir treatment using a much larger patient group, to clarify the relationship between susceptibility to oseltamivir and viral persistence.

The duration of fever was significantly shorter in patients with influenza A and influenza B aged 7–15 years than in such patients in the other age groups. It is not clear whether age itself is an important factor or whether the dosage of oseltamivir given to children aged <7 years or adults aged ⩾16 years may be insufficient to effectively inhibit virus replication. It may be also necessary to develop a more suitable medication regimen that takes into consideration patient age. Further investigation should address this issue.

The Influenza Study Group of the Japan Physicians Association

Hideo Kanazawa, Hiroaki Tomori, Ietaka Sato, Ken-ichi Doniwa, Ken-ichi Kawamura, Ken Takayasu, Kiyomitsu Miyachi, Kunio Kondou, Makiko Fujikawa, Masayuki Nakano, Midori Yoshimura, Mitsuhiro Kamei, Naohisa Mise, Naoki Kawai, Nobuo Hirotsu, Norio Iwaki, Osame Tanaka, Osamu Kunishima, Satoru Mitsuoka, Satsuki Tomita, Seio Tamai, Shigeo Kato, Shinro Matsuura, Taizo Tsuchimoto, Takashi Kawashima, Takashi Kimura, Takatoshi Hanajima, Takeshi Makino, Takeshi Shigematsu, Tetsunari Maeda, Toku Takahashi, Tomoyuki Harada, Toru Nagai, Toshio Kawada, Tuyoshi Okayama, and Yoshihide Ishida.

Acknowledgments

We thank Yoshio Goto for his support in this study.

Potential conflicts of interest. All authors: no conflicts.

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These 2 authors contributed equally to this article.

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