Virological and clinical outcomes in outpatients treated with baloxavir or neuraminidase inhibitors for A(H3N2) influenza: A multicenter study of the 2022-2023 season.

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.

In vitro neuraminidase inhibitory concentrations (IC50) of four neuraminidase inhibitors in the Japanese 2022-23 season: Comparison with the 2010-11 to 2019-20 seasons.

To assess the extent of susceptibility to the four neuraminidase inhibitors (NAIs) approved in Japan of the epidemic viruses in the 2022-23 influenza season in Japan, we measured the 50 % inhibitory concentration (IC50) of oseltamivir, zanamivir, peramivir, and laninamivir in influenza virus isolates from patients. 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 IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Virus isolates, one A(H1N1)pdm09 and 74 A(H3N2), were measured in the 2022-23 season. The geometric mean IC50s of the 74 A(H3N2) isolated prior to treatment were 0.78 nM, 0.66 nM, 2.08 nM, and 2.85 nM for oseltamivir, peramivir, zanamivir, and laninamivir, respectively, comparable to those of the previous ten studied seasons. No A(H3N2) with highly reduced sensitivity to any of the NAIs was found in the 2022-23 season prior to or after drug administration. These results indicate that the sensitivity to these four commonly used NAIs has been maintained, at least for A(H3N2), in the 2022-23 influenza season in Japan, after the 2020-21 and 2021-22 seasons when the prevalence of influenza was extremely low.

Duration of fever and other symptoms after the inhalation of laninamivir octanoate hydrate: A study of the 2017/18 and 2018/19 seasons and comparison with the 2011/12 to 2016/17 Japanese influenza seasons.

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.

Susceptibility of epidemic viruses to neuraminidase inhibitors and treatment-emergent resistance in the Japanese 2019-20 influenza season.

OBJECTIVES: To investigate the susceptibility of epidemic influenza viruses to neuraminidase inhibitors (NAIs) and the emergence of resistant viruses after treatment, a prospective, observational study was done in the 2019-20 Japanese influenza season. METHODS: Influenza viruses were isolated before and twice after treatment, the first at day 5 and the second at day 10. The 50% inhibitory concentrations (IC50s) to oseltamivir, zanamivir, peramivir, and laninamivir were measured and compared with those of 2010-11 to 2018-19 seasons. NA amino acid sequences were analyzed by next generation sequencing (NGS). RESULTS: The IC50 geometric means of the NAIs for 128 A(H1N1)pdm09, 2 A(H3N2), and 33 B were comparable to those of the previous seasons. Only 2 (1.6%) A(H1N1)pdm09 with significantly high IC50 to oseltamivir were found pretreatment. No A(H3N2) or B had resistance. Treatment-emergent oseltamivir resistance was found in 2 among 33 oseltamivir-treated A(H1N1)pdm09, only at the second follow-up. The NGS indicated a rapid increase in the proportion of H275Y to wild type, from 0% to almost 100% between days 5 and 10. CONCLUSIONS: These results suggest the continued effectiveness of these NAIs for epidemic influenza in Japan. Treatment-emergent resistant H275Y A(H1N1)pdm09 viruses were detected after oseltamivir treatment, rapidly replacing the wild type.

Virological and clinical outcomes in outpatients treated with baloxavir or oseltamivir: A Japanese multicenter study in the 2019-2020 influenza season.

Although the virological and clinical efficacies of baloxavir for influenza and the post-treatment emergence of variant viruses have been reported in clinical trials, its efficacies have not been fully investigated in clinical settings. This prospective, observational investigator-initiated study was conducted during the 2019-2020 Japanese influenza season. In outpatients receiving baloxavir or oseltamivir, nasopharyngeal samples were obtained on day 1 before treatment and on the scheduled days 5 and 10 after treatment. RT-PCR and sequencing were performed to detect polymerase acidic protein (PA) E23X/I38X and neuraminidase (NA) H275Y variants in clinical and cultivated samples. Fever and illness-related symptoms were recorded using self-reporting diaries. Overall, 116 outpatients, 76 treated with baloxavir (34 under 12 years) and 40 with oseltamivir (32 under 12 years), were eligible. Of these, 91 were infected with A (H1N1)pdm09 (78.4%), of which 58 received baloxavir and 33 received oseltamivir. PA variants were detected in clinical (1.7%, 1/58; 3.8%, 1/26 for children under 12 years) and isolated (3.4%, 2/58; 3.8%, 1/26 for children under 12 years) samples obtained on day 5 after baloxavir treatment, but not on day 10. The isolation frequencies of A (H1N1)pdm09 on days 5 and 10 after baloxavir treatment were 5.2% (3/58) and 0.0% (0/58), respectively. Of the three viruses isolated on day 5, two (66.7%, 2/3) were PA I38 T/F variants with reduced baloxavir susceptibility. The isolation frequencies of A (H1N1)pdm09 on days 5 and 10 after oseltamivir treatment were 30.3% (10/33) and 6.1% (2/33), respectively. Only the two viruses isolated on day 10 were NA H275Y variants. The median duration of fever in baloxavir and oseltamivir recipients was 22.3 and 27.5 h, respectively. No patients with PA or NA variants showed prolonged durations of fever. Baloxavir was virologically effective for influenza in the clinical setting of the 2019-2020 Japanese season. Variant emergence after baloxavir treatment was limited to the early post-treatment stage.

Improvement of respiratory symptoms and health-related quality of life with peramivir in influenza patients with chronic respiratory disease: Additional outcomes of a randomized, open-label study.

BACKGROUND: To compare peramivir 300 mg single-dose, peramivir 600 mg repeat-dose, and oseltamivir effects on health-related quality of life, including respiratory symptoms and general conditions, time to symptom alleviation, time to fever resolution, incidence of exacerbations, and virus titer, in influenza patients with chronic respiratory disease. METHODS: We report additional outcomes from a 2-week, multicenter, randomized, open-label study in Japan (UMIN000030118). Influenza patients with chronic respiratory disease received intravenous peramivir (300 mg single-dose [n = 66], 600 mg repeat-dose [600 mg/d of 2 consecutive days; n = 70]) or oral oseltamivir (75 mg twice daily, 5 days; n = 72). The principal endpoint of this analysis was change from baseline to Day 14 at each time point in Chronic Obstructive Pulmonary Disease Assessment Test (CAT) scores. RESULTS: Both peramivir regimens reduced total CAT score at Day 3 more than oseltamivir (peramivir 600 mg vs oseltamivir, P = .0032; peramivir 300 mg vs oseltamivir, P = .0203). Cough/phlegm CAT scores were most improved with peramivir 600 mg. Median time to alleviation of three respiratory symptoms was longer with peramivir 600 mg (68.9 hours) than with peramivir 300 mg (50.6 hours, hazard ratio [HR] 1.57; P = .0191) and shorter with peramivir 300 mg than oseltamivir (78.8 hours, HR 0.62; P = .0141). Alleviation of seven influenza symptoms and fever resolution was shortest with peramivir 300 mg. CONCLUSIONS: Rapid improvement in CAT score, including cough, and shorter time to alleviation of respiratory symptoms associated with peramivir is of potential benefit to patients with chronic respiratory disease.

Effect of peramivir on respiratory symptom improvement in patients with influenza virus infection and pre-existing chronic respiratory disease: Findings of a randomized, open-label study.

BACKGROUND: The efficacy of neuraminidase inhibitors on improvement of respiratory symptoms triggered by influenza in patients with pre-existing chronic respiratory diseases is unknown. METHODS: This 2-week, randomized, open-label study evaluated intravenous peramivir 600 mg on two consecutive days (peramivir-repeat), peramivir 300 mg single dose (peramivir-single), and oral oseltamivir 75 mg twice daily for 5 days in patients with confirmed influenza and chronic respiratory diseases. Patients recorded symptom scores daily. The primary endpoint of cumulative area of time vs symptoms (CATVS) was expressed as an index value of area under the curve vs time of the total score of cough, sore throat, and nasal congestion from baseline to 2 weeks. RESULTS: Of 214 randomized patients, 209 (56% female, 77% aged <65 years, 94% outpatients, 91% bronchial asthma, 62% influenza A) received ≥1 dose of study drug. Mean (standard deviation) CATVS was similar for peramivir-repeat (782.78 [487.17]) vs peramivir-single (717.35 [347.55]; P = .4371), and for peramivir-repeat vs oseltamivir (856.34 [404.99]; P = 1.00). However, CATVS was significantly shorter for peramivir-single vs oseltamivir, with an estimated treatment difference (TD) of -145.07 (95% confidence interval: -284.57, -5.56; P = .0416). In subgroup analyses, CATVS was significantly shorter for peramivir-single vs oseltamivir among patients with influenza A (TD: -206.31 [-383.86, -28.76]; P = .0231), bronchial asthma (TD: -156.57 [-300.22, -12.92]; P = .0328), baseline respiratory severity score <5 (TD: -265.32 [-470.42, -60.21]; P = .0120), and age <65 (TD: -184.30 [-345.08, -23.52]; P = .0249). CONCLUSIONS: In patients with chronic respiratory diseases, peramivir-single was not significantly different from peramivir-repeat and was more effective than oseltamivir at alleviating respiratory symptoms.

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2018-19 season: Comparison with the 2010-11 to 2017-18 seasons.

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 (IC50) 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 IC50 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 IC50s 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.

Duration of fever and PA/I38X-substituted virus emergence in patients treated with baloxavir in the 2018-2019 influenza season.

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.

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2017-18 season: Comparison with the 2010-11 to 2016-17 seasons.

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 (IC50) 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 IC50 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 IC50s 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.