Baloxavir safety and clinical and virologic outcomes in influenza virus-infected pediatric patients by age group: age-based pooled analysis of two pediatric studies conducted in Japan.

BACKGROUND: Anti-influenza treatment is important for children and is recommended in many countries. This study assessed safety, clinical, and virologic outcomes of baloxavir marboxil (baloxavir) treatment in children based on age and influenza virus type/subtype. METHODS: This was a post hoc pooled analysis of two open-label non-controlled studies of a single weight-based oral dose of baloxavir (day 1) in influenza virus-infected Japanese patients aged < 6 years (n = 56) and ≥ 6 to < 12 years (n = 81). Safety, time to illness alleviation (TTIA), time to resolution of fever (TTRF), recurrence of influenza illness symptoms and fever (after day 4), virus titer, and outcomes by polymerase acidic protein variants at position I38 (PA/I38X) were evaluated. RESULTS: Adverse events were reported in 39.0 and 39.5% of patients < 6 years and ≥ 6 to < 12 years, respectively. Median (95% confidence interval) TTIA was 43.2 (36.3-68.4) and 45.4 (38.9-61.0) hours, and TTRF was 32.2 (26.8-37.8) and 20.7 (19.2-23.8) hours, for patients < 6 years and ≥ 6 to < 12 years, respectively. Symptom and fever recurrence was more common in patients < 6 years with influenza B (54.5 and 50.0%, respectively) compared with older patients (0 and 25.0%, respectively). Virus titers declined (day 2) for both age groups. Transient virus titer increase and PA/I38X-variants were more common for patients < 6 years. CONCLUSIONS: The safety and effectiveness of single-dose baloxavir were observed in children across all age groups and influenza virus types. Higher rates of fever recurrence and transient virus titer increase were observed in children < 6 years. TRIAL REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information JapicCTI-163,417 (registered 02 November 2016) and JapicCTI-173,811 (registered 15 December 2017).

Early Fever Resolution in Early Childhood Influenza Treated with Baloxavir Marboxil: A Retrospective Study Compared to Those with Oseltamivir.

Background and Objectives: Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor prescribed for influenza treatment. Unlike neuraminidase inhibitors like oseltamivir, which impair viral release from infected host cells, baloxavir blocks influenza virus proliferation by inhibiting viral mRNA transcription. This study aimed to compare the effectiveness of baloxavir and oseltamivir for the treatment of early childhood influenza. Materials and Methods: Of 1410 patients diagnosed with influenza between 2015 and 2018 at a Japanese primary care outpatient clinic, 1111 pediatric patients aged 0-6 years who were treated with baloxavir (n = 555) or oseltamivir (n = 556) were enrolled retrospectively. The following clinical factors were compared between patients treated with baloxavir and oseltamivir: age, sex, time from fever onset to drug administration (<24 h or 24-48 h), time from drug administration to fever reduction, influenza type (A or B), and influenza vaccination before disease onset. The duration of the fever, which was used as an index of clinical effectiveness, was compared using the log-rank test. Clinical factors associated with fever duration were determined using multivariate logistic regression analysis. Results: Median age (3.0 vs. 2.5 years), influenza type A (99% vs. 47%), median duration from drug administration to fever resolution (1 day vs. 2 days), and influenza vaccination (done, 41% vs. not done, 65%) were significantly different between the baloxavir and oseltamivir groups (p < 0.001). The number of patients with a fever duration of one day was 553 (99.6%) in the baloxavir group and 6 (1.1%) in the oseltamivir group (p < 0.001). Baloxavir use was only significantly associated with fever duration in the multivariate analysis (odds ratio 50,201, p < 0.001). Apparent adverse effects were not observed in the baloxavir-treated group. Conclusions: Baloxavir treatment resulted in a shorter fever duration than oseltamivir treatment in early childhood influenza.

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. METHODS: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. RESULTS: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively. CONCLUSIONS: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. METHODS: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. RESULTS: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). CONCLUSIONS: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. CLINICAL TRIALS REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN000038159).

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

Clinical and virological outcomes with baloxavir compared with oseltamivir in pediatric patients aged 6 to < 12 years with influenza: an open-label, randomized, active-controlled trial protocol.

BACKGROUND: Children with influenza virus infections are prone to complications and are common sources of influenza transmission. Baloxavir marboxil inhibits cap-dependent endonuclease and was approved for influenza treatment in adolescent, adult, and pediatric patients in Japan. The miniSTONE-2 study included pediatric patients with influenza (1 to < 12 years) and demonstrated similar median times to alleviation of signs and symptoms of influenza with a single dose of baloxavir granules (weight < 20 kg: 2 mg/kg, ≥ 20 kg: 40 mg) and oseltamivir. Although the baloxavir dose in miniSTONE-2 was higher than the Japanese-approved dose, baloxavir exposure in miniSTONE-2 was similar to Japanese pediatric patients who receive the Japanese-approved dose. This study will be the first randomized active-controlled study in pediatric patients with influenza using the Japanese-approved dose of baloxavir. METHODS: This is a multicenter, open-label, randomized, active-controlled trial in which 200 Japanese subjects aged 6 to < 12 years with influenza virus infection are randomly allocated (2:1) to a single dose of baloxavir at the approved dose in Japan (weight ≥ 10 to < 20 kg: 10 mg, ≥ 20 to < 40 kg: 20 mg, ≥ 40 kg: 40 mg) or oseltamivir twice daily for 5 days. The primary clinical endpoint is the time to illness alleviation of influenza, from administration of baloxavir or oseltamivir until the following criteria were met and sustained for at least 21.5 h (24 h-10%): cough and nasal discharge/nasal congestion rated as absent or mild axillary body temperature < 37.5 °C. The primary analysis population is the intention-to-treat infected population, which includes all pediatric subjects who receive at least one dose of study drug and have confirmed influenza virus infection by reverse transcription-polymerase chain reaction. The safety population includes all subjects who receive at least one dose of study drug. DISCUSSION: No comparative studies have been conducted to confirm the efficacy and safety of baloxavir versus a comparator in pediatric patients with influenza infection in Japan. The outcomes from this trial will provide evidence on the efficacy and safety of baloxavir as an antiviral treatment option for Japanese pediatric patients with influenza infection. Trial registration Japan Registry of Clinical Trials: jRCTs011200011. Registered November 2020. ( https://rctportal.niph.go.jp/en/ ).

Baloxavir treatment of oseltamivir-resistant influenza A/H1pdm09 in two immunocompromised patients.

Few treatment options are available for oseltamivir-resistant influenza. It has been proposed that baloxavir can be effective in this setting due to its distinct mechanism of action but clinical experience is lacking for immunocompromised patients. We report two such cases treated with baloxavir after failure of oseltamivir and detection of oseltamivir resistance mutations. Baloxavir/zanamivir combination therapy was effective in one patient, but persistent viral shedding was noted with baloxavir monotherapy in the other patient.

Association of baloxavir marboxil prescription with subsequent medical resource utilization among school-aged children with influenza.

PURPOSE: Baloxavir marboxil is a novel antiviral agent for influenza, introduced into clinical practice in 2018. A concern remains about the variant virus with reduced susceptibility after baloxavir exposure and its clinical consequences such as healthcare-seeking behavior. METHODS: Using a healthcare database in Japan, we compared the medical resource use following baloxavir and neuraminidase inhibitors (NAIs) treatment among children aged 7-15 years. The study period was from December 2018 to March 2019. The primary endpoint was the composite of hospitalization, laboratory and radiological tests, and antibiotic use over 1-9 days of antiviral treatment. As exploratory analyses, secondary outcomes being each single component of the primary composite were assessed and subgroup analyses comparing baloxavir with each NAI were done. RESULTS: Data from 115 867 prescriptions in 115 238 children were analyzed (median age: 10 years; severe influenza risk in 26%; baloxavir accounting for 43%). Overall, baloxavir use did not increase subsequent medical resource utilization in the composite endpoint (adjusted odds ratio [aOR]: 1.04; 95% confidence interval [CI]: 0.99-1.09; P = 0.14), as were likelihoods of other secondary outcomes. In the subgroup analysis, baloxavir use was associated with higher medical resource use than oseltamivir (aOR: 1.21; 95% CI: 1.13-1.31; P < 0.001) and lower resource use than zanamivir (aOR: 0.93; 95% CI 0.86-1.00; P = 0.040). CONCLUSIONS: Based on a single-year experience in Japan, prescribing baloxavir rather than NAIs did not increase medical resource utilization within 9 days of treatment, except in one exploratory comparison with oseltamivir.

A Case of an Increase in Prothrombin Time-International Normalized Ratio by Interaction Between Warfarin and Baloxavir Marboxil in a Patient on Implantable Ventricular Assist Device.

BACKGROUND: Baloxavir marboxil (BM) is a novel drug with a cap-dependent endonuclease inhibitory action for influenza A or B; it is highly safe and requires just a single oral dose. Patients with severe heart failure use implantable ventricular assist device (iVAD) until transplantation, but they have an increased risk of thrombosis development. Their warfarin is administered based on point-of-care testing (POCT) with a strict control of prothrombin time-international normalized ratio (PT-INR). CASE REPORT: Here, we report a case of a patient with iVAD whose PT-INR was significantly increased from the target range after BM administration. The patient was a 45-year-old man and transplanted with iVAD; warfarin treatment was started when his PT-INR target range was 3.0-3.5. At home, he frequently self-measured PT-INR by POCT and precisely controlled the warfarin dose. He had a fever, was diagnosed with influenza A and was administered BM 40 mg. Thereafter, his PT-INR continued to increase, reaching 4.8 on day 12 of BM administration, exceeding his target range; warfarin was skipped for 1 day. In this case, based on the history of BM administration and clinical course, the increase in PT-INR could be due to BM. Considering the interaction between warfarin and BM, we suspected a possibility of competition for protein-binding sites. Increased PT-INR in the patient was detected early by POCT and thus severe bleeding was avoided. CONCLUSION: Strict monitoring of PT-INR when using BM in patients taking warfarin is of clinical importance.

Open-label study of the safety, pharmacokinetics, and effectiveness of a 2 mg/kg dose of baloxavir marboxil 2% granules in children <20 kg with influenza.

INTRODUCTION: Baloxavir marboxil is an oral anti-influenza drug with demonstrated safety and efficacy in pediatric patients when a 2% granules formulation is administered at 1 mg/kg. This study assessed safety, effectiveness, and pharmacokinetics of a higher dose (2 mg/kg) of baloxavir marboxil 2% granules in pediatric patients weighing <20 kg. METHODS: This multicenter, open-label, noncontrolled study was conducted at 15 sites in Japan (January 2019-March 2020; JapicCTI-194577). Patients aged <12 years with confirmed influenza received a single oral dose of baloxavir marboxil at 2 mg/kg if body weight was <10 kg or 20 mg if ≥ 10 to <20 kg. Safety, pharmacokinetics, effectiveness (time to illness alleviation [TTIA] of influenza; time to resolution of fever; virus titer), and polymerase acidic protein (PA) substituted viruses were assessed over 22 days. RESULTS: 45 patients, all aged ≤6 years, were enrolled. Adverse events were reported in 24 (53.3%) patients, most commonly nasopharyngitis, diarrhea, and upper respiratory tract infection. Median (95% confidence interval [CI]) TTIA was 37.8 (27.5-46.7) hours; median (95% CI) time to resolution of fever was 22.0 (20.2-28.6) hours. A >4 log decrease in mean viral titer occurred at day 2 and a subsequent temporary 1-2 log increase in patients with influenza A(H3N2) and B. Treatment-emergent PA/I38X-substituted virus was detected in 16/39 (41.0%) patients, but no prolonged TTIA or time to resolution of fever was associated with its presence. CONCLUSIONS: Baloxavir granules administered at 2 mg/kg in children <20 kg were well tolerated, with symptom alleviation similar to 1 mg/kg.

Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus.

BACKGROUND: Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses. METHODS: In this study, we examined the efficacy of baloxavir marboxil in nude mice that were immunologically deficient. RESULTS: Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment. CONCLUSIONS: Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected.

Detection of Variants With Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018-2019 Influenza Season.

During the 2018-2019 influenza seasons, we detected reduced baloxavir marboxil (baloxavir) susceptible variants with I38S or I38T amino acid substitutions on the PA subunit of influenza virus ribonucleic acid polymerase in 7 of 18 baloxavi-treated children and found that virus titer rebounded in some of these children with variants. We also found fever durations to be similar between patients with or without the variants, but the patients with variants shed the virus 3 days longer and took longer to improve clinical symptoms than those without variants. The emergence of these variants should be monitored during future influenza seasons.

Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil.

Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.

Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza.

Baloxavir marboxil (formerly S-033188) is a prodrug of baloxavir acid (S-033447) and inhibits cap-dependent endonuclease, an essential protein involved in the initiation of viral transcription by cleaving capped mRNA bound to PB2. Its adverse event profile is comparable to oseltamivir but is still vulnerable to resistance. The single-dose baloxavir marboxil is an appealing antiviral regimen for the treatment of influenza among outpatients when compared with longer, twice-daily regimens of oral and inhaled neuraminidase inhibitors. This review focuses on the mode of action, antiviral activity, pharmacokinetics, clinical indications, and safety profiles of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes.

BACKGROUND: We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza. METHODS: This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1-11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration. RESULTS: Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9-62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer). CONCLUSIONS: A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children. CLINICAL TRIALS REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417).

Influenza management with new therapies.

PURPOSE OF REVIEW: Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting. RECENT FINDINGS: Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group. SUMMARY: Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.

Early combination treatment with baloxavir and peramivir for hospitalized adults with influenza A in Yokohama, Japan.

Baloxavir marboxil is a new anti-influenza drug, but data on the clinical efficacy of a combination treatment of baloxavir and peramivir is scarce. We conducted a single-center retrospective analysis comparing the mortality of a combination of baloxavir and peramivir (B & P, n = 10) and peramivir without baloxavir (P-mono, n = 132) in hospitalized adults with influenza A between 2011 and 2019 in Yokohama City, Japan. Sequencing analysis was conducted in the B & P group to check the I38 mutation in polymerase acidic protein which is associated with baloxavir resistance. The 30-day mortality rates were 0 (0%) in the B & P group and 6 (4.5%) in the P-mono group, respectively, which was not statistically significant. The I38 mutation was not detected before and after the combination treatment. A combination treatment of baloxavir and peramivir might be more effective than peramivir without baloxavir and prevent the emergence of baloxavir resistance in hospitalized adults with influenza A.

Baloxavir for the treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir.

BACKGROUND: Seasonal influenza causes significant morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. In this population, influenza virus can replicate for prolonged periods, despite neuraminidase inhibitor treatment, leading to resistance and treatment failure. Baloxavir targets the influenza polymerase and may be an effective treatment option in these patients. METHODS: We used baloxavir to treat five allogeneic SCT recipients that were still symptomatic and shedding influenza virus after completing one or more treatment courses of oseltamivir and characterized the viral isolates before and during treatment. RESULTS: Two patients were infected with influenza A/H1pdm09 carrying a neuraminidase variant (H275Y) linked to oseltamivir resistance. Both these two patients were successfully treated with baloxavir. Of the three patients infected with wild-type influenza virus, two cleared the virus after baloxavir treatment, while the third patient developed the polymerase I38T variant linked to baloxavir resistance. CONCLUSIONS: Our data suggest that baloxavir treatment can be effective in treating neuraminidase inhibitor-resistant influenza in profoundly immunocompromised patients. Randomized clinical trials are needed to define the role of baloxavir alone and combined with oseltamivir for the treatment of influenza in SCT recipients and other immunocompromised populations.

Preparing for the 2019-2020 influenza season.

Although the 2017-2018 influenza season had very high rates of influenza-associated illness, the 2018-2019 influenza season was comparable to previous seasons. Influenza A was the most commonly identified type worldwide, although variations in influenza A subtype prevalence existed. Influenza vaccination remains the single most effective way to prevent influenza-associated illness. A novel influenza antiviral, baloxavir, has demonstrated promising results; however, concerns about development of resistance exist.

A Comparison of the Frequency of Prescription and Pharmacy Revisits between Baloxavir Marboxil and Neuraminidase Inhibitors in Influenza-Infected Pediatric Patients during the 2019-2020 Influenza Season.

The novel anti-influenza virus agent baloxavir marboxil is a selective inhibitor of an influenza cap-dependent endonuclease. Although a single oral dose in tablet form of baloxavir marboxil is expected to improve drug compliance and rapidly reduce viral titers for pediatric patients with influenza, there is a concern that baloxavir marboxil-resistant influenza A variants could be generated. In this study, we investigated the frequency of prescription and pharmacy revisits for baloxavir marboxil at an outpatient clinic compared with that of neuraminidase inhibitors in pediatric patients with influenza. A total of 475 pediatric patients who were infected with the influenza virus visited the pharmacy between December 2019 and March 2020. Baloxavir marboxil (n = 149), oseltamivir (n = 161) and laninamivir (n = 162) were mainly prescribed and only a few patients were treated with peramivir (n = 2) or zanamivir (n = 1). Baloxavir marboxil-, oseltamivir- and laninamivir-treated pediatric patients were enrolled, and a log-rank test showed that the revisits of pediatric patients who were taking baloxavir marboxil was lower than those for oseltamivir (p < 0.001). Moreover, Cox proportional hazards models also revealed that baloxavir marboxil decreased the risk of revisits in comparison to oseltamivir (hazard ratio 0.28, 95% confidence interval 0.11-0.70, p = 0.006), while no difference was found between laninamivir and baloxavir marboxil. Although there is a need to acquire appropriate and relevant information concerning resistant viruses, our results suggest that baloxavir marboxil may be a useful drug for treating pediatric patients with influenza infections.