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Introduction: Large scale investigation of the clinical effectiveness of neuraminidase inhibitors for circulating influenza viruses are important along with the surveillance of virus susceptibility in vitro., Methods: The duration of fever and other influenza symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2017/18 and 2018/19 influenza seasons and compared with the results of the previous six seasons., Results: Influenza A(H1N1)pdm09, A(H3N2), and B were found in 14, 45, and 52 patients in the 2017/18 season and in 22, 62, and 0 in the 2018/19 season, respectively. The median duration of fever for B was significantly longer than for A(H1N1)pdm09 and A(H3N2) in the 2017/18 season (p = 0.0461) and for A(H3N2) than for A(H1N1)pdm09 in the 2018/19 season (p = 0.0290). However, the differences were subtle in both seasons for other symptoms, with no significant differences in their median duration in comparison of the circulating types/subtypes. Over the eight seasons with the previous six seasons added, the median durations of fever were consistently longer for B than for A, but the relation between the A subtypes was inconsistent. The median durations of fever were comparable over the eight seasons for the virus types/subtypes, as were the median durations of other symptoms. The percentage of febrile patients decreased in a similar pattern over the eight seasons for each type/subtype., Conclusions: The results confirmed that laninamivir has continued to be clinically effective against all types/subtypes of influenza viruses, with no safety issues., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the epidemic viruses in the 2018-19 Japanese influenza season, we measured the 50% inhibitory concentration (IC 50 ) of four NAIs, oseltamivir, zanamivir, peramivir, and laninamivir, for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2017-18 seasons. Viral isolation was done with specimens obtained prior to and after treatment, and the type/subtype was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Virus isolates, 51 A(H1N1)pdm09, 125 A(H3N2), and one B, were measured in the 2018-19 season and the geometric mean IC 50 s of the four NAIs were quite comparable to the previous eight studied seasons. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2018-19 season prior to drug administration, although such A(H1N1)pdm09 were found in two, two, and two samples in the 2010-11, 2013-14, and 2015-16 seasons, respectively. No isolates with highly reduced sensitivity to the four NAIs were found for A(H3N2) or B through the 2010-11 to 2018-19 seasons. Among 18 samples with A(H1N1)pdm09 virus isolated after NAI administration, highly reduced sensitivity to oseltamivir and peramivir was detected from one of the five patients treated with oseltamivir. These results suggest that the sensitivity to the four commonly used NAIs has been maintained, although viruses with highly reduced sensitivity to oseltamivir and peramivir have emerged in some adult patients treated with oseltamivir., Competing Interests: Declaration of Competing Interest This study was supported by Daiichi-Sankyo Co. H. Ikematsu have previously received honoraria from Daiichi Sankyo Co., Ltd for medical advice and lectures., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Duration of fever and virus persistence after baloxavir administration were investigated in 81 outpatients, 16 with A(H1N1)pdm09 and 65 with A(H3N2) in the Japanese 2018-2019 influenza season. Only eight cases of A(H3N2) viruses were detected post-dose. PA/I38T-substituted viruses were detected in four (6.2%) of 65 A(H3N2) patients, at days 3 and 4, constituting 50% (4/8) of A(H3N2) detected post-dose. The median duration of fever was 26.0 h for A(H1N1)pdm09 and 20.3 h for A(H3N2). The median duration of fever for patients with PA/I38T-substituted viruses was 22.0 h, without significant difference to that of the patients in whom the mutated virus was not detected. Emergence of PA/I38T-substituted viruses after treatment with baloxavir was confirmed, but no significant prolongation of fever was observed in the four patients with PA/I38T-substituted virus emergence., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The authors alone are responsible for the content in and writing of the paper., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the viruses epidemic in the 2017-18 Japanese influenza season, we measured the 50% inhibitory concentration (IC 50 ) for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2016-17 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 237 virus isolates, 50 A(H1N1)pdm09, 92 A(H3N2), and 95 B were measured. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2017-18 season. No isolates with highly reduced sensitivity to the four NAIs have been found for A(H3N2) or B from the 2010-11 to 2017-18 seasons. The geometric mean IC 50 s of the four NAIs were quite consistent during the eight studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2016/17 influenza season and the results were compared with those of the 2011/12 to 2015/16 seasons. A total of 1278 patients were evaluated for the duration of fever and symptoms in the six studied seasons. In the 2016/17 season, the influenza types/subtypes of the patients were 6 A (H1N1)pdm09 (2.9%), 183 A (H3N2) (87.6%), and 20 B (9.6%). The respective median durations of fever for A (H1N1)pdm09, A (H3N2), and B were 38.0, 33.0, and 38.5 h, without significant difference (p = 0.9201), and the median durations of symptoms were 86.5, 73.0, and 99.0 h, with significant difference (p = 0.0342). The median durations of fever and symptoms after laninamivir inhalation were quite consistent for the six studied seasons for A (H1N1)pdm09, A (H3N2), and B, without any significant differences. The percentage of patients with unresolved fever patients displayed a similar pattern through the six studied seasons for all these virus types. There was no significant difference in the duration of fever or symptoms between the Victoria and Yamagata lineages in the 2016/17 season and those of the previous studied seasons. Over the seasons tested, ten adverse drug reactions (ADRs) were reported from 1341 patients. The most frequent ADR was diarrhea and all ADRs were self-resolving and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A (H1N1)pdm09, A (H3N2), and B, with no safety issues., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2016-17 Japanese influenza season, we measured the 50% inhibitory concentration (IC 50 ) of these NAIs for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2015-16 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 276 virus isolates, 6 A (H1N1)pdm09 (2.2%), 249 A (H3N2) (90.2%), and 21 B (7.6%), had the IC 50 measured for the four NAIs. B isolates included 11 (52.4%), 9 (42.9%), and one (4.8%) of the Victoria, Yamagata, and undetermined strains, respectively. No A (H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2016-17 season. No isolate with highly reduced sensitivity to the four NAIs have been found for A (H3N2) or B from the 2010-11 to 2016-17 seasons. No significant trend of increase or decrease was found in the geometric mean IC 50 s of the four NAIs during the seven studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained and that any change in the effectiveness of these NAIs would be minute. Common usage of NAIs for patient treatment has not been a driving force in the selection of NAI resistant viruses., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2015/16 influenza season, and the results were compared with those of the 2011/12 to 2014/15 seasons. A total of 1068 patients were evaluated for the duration of fever and symptoms in the five studied seasons. The influenza types/subtypes were 125 A(H1N1)pdm09 (62.2%), 17 A(H3N2) (8.5%), and 59 B (29.4%) in the 2015/16 season. The median durations of fever were 40.0, 41.0, and 47.0 h, and the median durations of symptoms were 87.0, 76.0, and 93.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively, with no significant difference. The median durations of fever were 52.0 and 46.0 h and the median durations of symptoms 93.0 and 88.0 h for the Victoria and Yamagata B lineages, respectively, with no significant difference. Fever resolution after laninamivir inhalation by the A(H1N1)pdm09 patients was similar in the 2013/14 and 2015/16 seasons. Fever resolution after laninamivir inhalation was similar in all comparisons of the 2011/12 to 2015/16 seasons for both A(H3N2) and B, with no significant difference among the five seasons. Over the seasons tested, eight adverse drug reactions (ADRs) were reported for 1128 patients. The most frequent ADR was diarrhea, and all ADRs were resolved and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A(H1N1)pdm09, A(H3N2), and B, with no safety issues., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2015-2016 influenza season in Japan, we measured the 50% inhibitory concentration (IC 50 ) of NAIs for influenza virus isolates and compared them with the results from the 2010-11 to 2014-15 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Influenza viruses were isolated: 210 influenza A(H1N1)pdm09 (67.3%), 20 A(H3N2) (6.4%), and 82 B (26.3%), and for the Victoria and Yamagata lineages the numbers were 53 (64.6%) and 28 (34.1%), respectively, with one unknown. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM). No isolate showed a very high IC50 for A(H3N2) or B. The ratios of geometric mean IC50 of the 2015-2016 influenza season to those of the 2010-2011 to 2014-2015 influenza seasons ranged from 0.62 to 1.78 for A(H1N1) pdm09. The range was 0.73-1.35 for A(H3N2) and 0.48-1.12 for B. No significant trend of increase or decrease in IC50 was found for any of the four NAIs. Although some isolates showed highly reduced sensitivity to oseltamivir among the A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2), and B viruses are susceptible to all four NAIs, with no trend toward decreased sensitivity., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The duration of fever and other symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2014-2015 influenza season and the results were compared with those of the previous three seasons, 2011-2012 to 2013-2014. From these four seasons, the data of 636 influenza A(H3N2) and 128 influenza B patients was available for analysis. No significant difference was found in their baseline characteristics. The median duration of fever for all A(H3N2) patients ranged from 32.0 to 41.0 h. The duration of fever in the 2014-2015 season was significantly shorter than that in the 2012-2013 and 2013-2014 seasons (p = 0.0204 and 0.0391, respectively), but the differences were within nine hours. The median duration of symptoms for A(H3N2) ranged from 80.0 to 89.0 h, with no significant difference among the four seasons (p = 0.2222). The median duration of fever for B patients ranged from 43.0 to 50.0 h, with no significant difference among the four seasons. The duration of the symptoms for B varied by season, but no significant difference was found among the four seasons. Over the four seasons, 44 adverse events were reported from among 921 patients, with all resolving without treatment. These results indicate the continuing effectiveness of laninamivir against influenza A(H3N2) and B, with no safety issues. It is unlikely that the clinical use of laninamivir has caused viral resistance in the currently epidemic viruses., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

To assess the extent of viral resistance to the four neuraminidase inhibitors (NAIs), we measured their 50% inhibitory concentration (IC50) for influenza virus isolates from the 2014-2015 influenza season for comparison with those circulating in the 2010-2011 to 2013-2014 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. IC50 was measured for 200 influenza A(H3N2) and 19 influenza B in the 2014-2015 season, and no virus with highly reduced sensitivity to the four NAIs was detected. The ratios of the geometric means of the A(H3N2) IC50s of 2014-2015 to those of the 2010-2011, 2011-2012, 2012-2013, and 2013-2014 seasons ranged from 0.72 to 1.05, 0.82 to 1.22, 0.69 to 1.00, and 0.70 to 1.03, respectively. The ratios of the geometric mean of the B IC50s to the previous four seasons ranged from 0.59 to 1.28, 0.66 to 1.34, 0.84 to 1.21, and 1.06 to 1.47, respectively. There was no trend in the change of the IC50s for A(H3N2) or B. Significant differences were found in some seasons, but the differences in the IC50s were all less than two fold. These results show change in the geometric mean IC50 by season but with no trend, which indicates that the influence of viral mutation on the effectiveness of these NAIs was minute for A(H3N2) and B over the past five seasons., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The clinical outcome of laninamivir octanoate hydrate (laninamivir) in the Japanese 2013-2014 influenza season was investigated. A total of 235 patients were enrolled, of whom 222 were evaluated for the duration of fever and other symptoms. The types/subtypes were 101 A(H1N1)pdm09 (45.5%), 37 A(H3N2) (16.7%), and 84 B (37.8%). The median durations of fever were 32.0, 41.0, and 50.0 h, and the median durations of symptoms were 74.5, 85.0, and 95.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively. The differences among the three groups were not statistically significant. There was no significant difference in the duration of fever or symptoms between patients under 10 and 10 years or over. The median durations of fever were 46.0 and 58.0 h and the median durations of symptoms were 95.0 and 77.0 h for the Yamagata and Victoria lineages, respectively. The virus positive rates at day 5 were significantly different at 31.5% (28/89), 12.1% (4/33), and 34.7% (26/75) for the three type/subtypes, respectively. The virus positive rates for A(H1N1)pdm09 and B were significantly higher for the patients under 10 years than for the patients 10 years or older. (p = 0.0379 and 0.0320, respectively). No significant increase was found between the IC(50) of days 1 and 5. No adverse drug reactions associated with laninamivir were reported. These results indicate the continuing clinical utility of laninamivir against influenza, irrespective of the virus type/subtype or lineage, and that it is unlikely that the clinical use of laninamivir will lead to selection of resistant virus., (Copyright © 2015. Published by Elsevier Ltd.)

To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of neuraminidase inhibitors (NAIs) for the influenza virus isolates in the 2013-2014 influenza season and compared the results to those of the 2010-2011 to 2012-2013 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 327 influenza viruses were isolated: 172 influenza A(H1N1)pdm09 (52.6%), 49 A(H3N2) (15.0%), and 106 B (32.4%). Numbers of Victoria and Yamagata lineage isolates were 36 and 70, respectively. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC50 for A(H3N2) or B. The IC50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010-2011 season (P < 0.05). The IC50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012-2013 season (P < 0.001). The IC50 of the NAIs for B except for oseltamivir were significantly lower than those of the 2012-2013 season (P < 0.001). Although there are some isolates that show highly reduced sensitivity to oseltamivir among A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2) and B viruses are susceptible to all four NAIs with no trend toward decreased sensitivity., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu(®)), zanamivir (Relenza(®)), laninamivir octanoate (Inavir(®)), and peramivir (Rapiacta(®)) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each NAI for influenza virus isolates in the 2012-2013 influenza season and compared the results to those of the 2010-2011 and 2011-2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC50 values for A(H3N2) and B were similar to those of the 2010-2011 and 2011-2012 seasons. No isolate showed an increased IC50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase at present., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012-2013 influenza season for comparison with that of the Japanese 2011-2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older (p < 0.0001). No significant change in IC50 value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Laninamivir octanoate hydrate (laninamivir) is a long-acting, single inhalation neuraminidase inhibitor that was approved in Japan in 2010 for the treatment of influenza A and B virus infection. We investigated the duration of fever and other symptoms after the initiation of laninamivir in the Japanese 2011-2012 influenza season. Virus isolation was done and the 50% inhibitory concentration (IC₅₀) was measured for the virus isolates at days 1 and 5. For 211 patients (A(H3N2): 190, B: 21), the median durations of fever of A(H3N2) and B patients were 33.0 and 50.0 h, respectively (p = 0.0989). Fever was resolved within 72 h after inhalation by 89.7% of the A(H3N2) patients and by 81.0% of the patients with B. The median durations of symptoms for A(H3N2) and B patients were 89.0 and 94.0 h, respectively (p = 0.5809). On day 5, the influenza virus-positive rates for A(H3N2) and B patients were significantly different: 25.8% (40/155) and 70.6% (12/17), respectively (p < 0.0001). No significant change in IC₅₀ value was found between day 1 and day 5 for any of the four tested neuraminidase inhibitors, and no IC₅₀ value exceeded 50 nM. The incidence of adverse drug reactions was 1.3% (3/234), with no serious reactions reported. These results show that laninamivir was effective for the treatment of both influenza A(H3N2) and B in this study, with no safety issues. The clinical effectiveness of laninamivir for A(H3N2) was superior to that for B., (Copyright © 2013. Published by Elsevier Ltd.)

The neuraminidase inhibitors oseltamivir phosphate (Tamiflu®), zanamivir (Relenza®), laninamivir octanoate (Inavir®), and peramivir (Rapiacta®) have been available for the treatment of influenza in Japan since 2010. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC₅₀) of each drug for influenza virus isolates from the 2011-2012 influenza season. Specimens were obtained from patients prior to treatment. Viral isolation was done using Madine-Darby canine kidney cells, and the type and subtype of influenza A(H1N1)pdm09, A(H3N2), or influenza B were determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate. The lineage of influenza B virus was determined by direct sequencing of the hemagglutinin gene. Influenza A(H3N2) and influenza B viruses were isolated in 283 and 42 patients, respectively, while no influenza A(H1N1)pdm09 virus was isolated. No isolate showed an IC₅₀ value exceeding 50 nM for any of the neuraminidase inhibitors. IC50 values for A(H3N2) were similar between the 2010-2011 and 2011-2012 seasons. In contrast, the IC₅₀ values for influenza B viruses in the 2011-2012 season to the four drugs were significantly lower than those found in the 2010-2011 season. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC₅₀ values to increase in Japan at present., (Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Disease. Published by Elsevier Ltd. All rights reserved.)

Comparison of the viral persistence of pandemic H1N1 (H1N1pdm) and seasonal H1N1 with or without H275Y mutation after oseltamivir therapy has not been adequately done. Virus was isolated before and on days 4-6 from the start of oseltamivir treatment for 158 cases of seasonal (2007-2008 and 2008-2009 seasons) or pandemic (2009-2010 season) H1N1 influenza. Sequence analysis was done for each season and NA inhibition assay (IC(50)) was done in the 2009-2010 season. H275Y mutation before therapy was 0% in the 2007-2008 and 2009-2010 seasons, but 100% in the 2008-2009 season. Fever and other symptoms were noticeably prolonged after oseltamivir therapy for children with H275Y mutated seasonal H1N1 (2008-2009 season), but not in patients with seasonal H1N1 without mutation (2007-2008) or H1N1pdm (2009-2010). The viral persistence rate was significantly higher for patients 15 years or younger than for those 16 years and older with H275Y mutated seasonal H1N1 (46.2% and 10.5%, respectively) or with H1N1pdm (43.3% and 11.5%, respectively). The H275Y mutation emerged after oseltamivir treatment in 2.4% (2/82) of all patients with H1N1pdm. In two children, the H275Y mutation emerged after therapy and the IC(50) increased more than 200 fold; however, the prolongation of fever was not so prominent. In conclusion, oseltamivir was effective for fever and other clinical symptoms; however, the virus persisted longer than expected after treatment in H1N1pdm influenza-infected children in the 2009-2010 season, similar to seasonal H1N1 with H275Y mutation in the 2008-2009 season.

The clinical symptoms and effectiveness of neuraminidase inhibitors (NAI) have not been adequately compared among pandemic H1N1 2009 patients, seasonal H1N1 patients, and patients with H1N1 with the H275Y mutation. The data of 68 seasonal H1N1 patients in 2007-2008, 193 seasonal H1N1 patients in 2008-2009, and 361 pandemic H1N1 2009 patients diagnosed by PCR who received an NAI were analyzed. The duration of fever (body temperature ≥ 37.5 ºC) after the first dose of NAI and from onset was calculated. The H275Y neuraminidase mutation status was determined for 166 patients. Significantly lower mean age (18.4 ± 13.2 years) and a higher percentage of teenagers (53.7%) were found for pandemic 2009 influenza than for seasonal influenza (P < 0.001). The peak body temperature was equivalent (mean, 39.0 ºC) in the three seasons, and the frequency of symptoms was the same or lower for pandemic influenza compared with seasonal H1N1. None of the 34 analyzed pandemic H1N1 virus isolates contained the H275Y mutation, which was commonly detected in the 2008-2009 season. The duration of fever after the start of oseltamivir therapy was significantly shorter for patients with pandemic (23.0 ± 11.6 h) than with seasonal H1N1 in both the 2008-2009 (49.7 ± 32.3 h) and 2007-2008 seasons (32.0 ± 18.9 h). The mean duration of fever after the first dose of zanamivir was not different among the three seasons (26.9-31.5 h). Clinical symptoms were the same or somewhat milder, and oseltamivir was more effective, for pandemic 2009 than for seasonal H1N1 influenza with or without H275Y mutation.

A retrospective study of the 2003-2004, 2004-2005, and 2005-2006 influenza seasons was done to investigate the effectiveness of amantadine and oseltamivir for treating influenza A. Commercial antigen detection kits were used for diagnosis and data were collected from 44 clinics throughout Japan, using an Internet-based system. Oseltamivir was administered to 2775 patients and amantadine to 781 patients. The durations of fever, from the time of the first drug administration and from the onset of fever, were calculated for each patient. In the 2005-2006 season, the duration of fever from the first drug administration was longer for patients who received amantadine than for those who received oseltamivir when the patients were grouped by the time from onset of fever to the start of treatment (P < 0.001 for groups administered at 0-12, 13-24, 25-36 h from the onset) and by patient age (P < 0.001 for under 16 years and P < 0.05 for 16-64 years). Mean values of duration of fever from the first drug administration were 31.3 h, 31.3 h, and 31.9 h for oseltamivir therapy, and 33.3 h, 42.7 h, and 53.3 h for amantadine therapy, in the 2003-2004, 2004-2005, and 2005-2006 seasons, respectively. Reduction in the effectiveness of amantadine over the three influenza seasons were also observed in each age group of 0-6, 7-15, and 16-64 years. The studied season was an independent factor associated with the effectiveness of amantadine by multiple regression analysis. In conclusion, the effectiveness of oseltamivir did not change, but the effectiveness of amantadine was progressively reduced over the three influenza seasons.