Preventive and therapeutic effects of a super-multivalent sialylated filamentous bacteriophage against the influenza virus.

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Course and complications of influenza A in seniors over 65 years of age.

OBJECTIVES: Influenza A and B viruses cause epidemics every year, with approximately 3-5 million serious cases and about 290,000 to 650,000 deaths worldwide. Most patients die from bacterial complications of influenza. The aim of our study was to describe the clinical pictures of influenza and the development of the complications in seniors over 65 years of age, who were treated in University Hospital Pilsen. The course of the disease and changes in laboratory parameters were evaluated with regard to the method of treatment performed. METHODS: A descriptive retrospective study was performed. Clinical and laboratory data of seniors with the diagnosis of influenza were extracted from electronic medical records and later analysed. The data were processed with Excel 2016 and Statistica. RESULTS: A collection of 261 seniors, of whom 218 were hospitalized and 43 treated in an outpatient setting, has been studied. Patients who later developed complications had elevated values of CRP, procalcitonin, urea, and creatinine. The antiviral drug oseltamivir was administered to 226 of 261 seniors. Forty-seven seniors (18.0%) died from influenza and its complications (severe pneumonia with acute respiratory insufficiency or heart failure). CONCLUSIONS: The course of influenza in seniors was usually more severe and required hospitalization along with antiviral treatment. The mortality rate in the monitored group exceeded 18%. Annual timely vaccination, but also other preventive measures, and maybe considering other risk groups are methods to prevent severe or even fatal cases of influenza.

Evaluation of the bioavailability of a Tamiflu taste-masking pediatric formulation using a juvenile pig model and LC-MS/MS.

Aim: To improve the palatability and increase compliance in pediatric patients, different taste-masking technologies have been evaluated to support the NIH Pediatric Formulation Initiative.Methods: This bioavailability approach combined a juvenile porcine model which represented the pediatric population, and an advanced UHPLCMS/MS method. Juvenile pigs were administered with either commercial Tamiflu or its taste-masking formulation and plasma samples were obtained from 0 to 48 h. The mass spectrometer was operated in positive mode with electrospray ionization.Results: The bioavailability profiles were not significantly different between the two formulations which demonstrated that taste-masking by forming an ionic complex was a promising approach for formulation modification.Conclusion: The pre-clinical study revealed a promising model platform for developing and screening taste-masking formulations.

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Clinical analysis of influenza in the neonatal intensive care unit.

BACKGROUND: The aim was to investigate the clinical characteristics, treatment and prognosis of neonatal influenza. METHODS: The clinical data of 21 neonates who were diagnosed with influenza and admitted to the neonatal intensive care unit of Henan Provincial Children's Hospital, China, between January 2023 and January 2024 were retrospectively analyzed. RESULTS: A total of 21 patients were admitted, including 14 with influenza A and 7 with influenza B. Eighteen of these patients were reported to have been exposed to family members with respiratory symptoms before hospitalization. Among all the patients' mothers, only 1 received the influenza vaccine during pregnancy. Fifteen newborns had fever, 13 appetite loss, 10 cough, 9 shortness of breath, 9 nasal obstruction, 3 runny nose, 3 vomiting, 2 severe wheezing, 2 choking, 2 diarrhea, 1 bloating, and 1 sputum in the throat. The pulmonary auscultation sounds were coarse in 19 neonates, weak in 2, moist rales were appreciated in 5 and wheezing in 4 of them. The peripheral total white blood cell count was normal in 18 patients and elevated in 3. The C-reactive protein level was normal in all subjects, and the procalcitonin level was elevated in 1. Nineteen patients had pneumonia on chest imaging. All patients were treated with oseltamivir and finally recovered. CONCLUSION: Influenza A is the most common type of neonatal influenza. The clinical symptoms are atypical, and fever is the main symptom. Treatment with oseltamivir is safe and effective, and the prognosis is mostly favorable.

Occurrence and environmental fate of anti-influenza drugs in a subcatchment of the Yodo River Basin, Japan.

Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)-the active ingredient of Xofluza, an increasingly popular anti-influenza drug-and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogKd values for the rates of sorption of BALM (0.5-1.6) and BAL (1.8-3.1) on river sediment were higher than those of conventional drugs (-0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90-99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments.

UPLC-PDA factorial design assisted method for simultaneous determination of oseltamivir, dexamethasone, and remdesivir in human plasma.

A green and simple UPLC method was developed and optimized, adopting a factorial design for simultaneous determination of oseltamivir phosphate and remdesivir with dexamethasone as a co-administered drug in human plasma and using daclatasvir dihydrochloride as an internal standard within 5 min. The separation was established on UPLC column BEH C18 1.7 µm (2.1 × 100.0 mm) connected to UPLC pre-column BEH 1.7 µm (2.1 × 5.0 mm) at 50 °C with an injection volume of 10 µL. The photodiode array detector (PDA) was set at three wavelengths of 220, 315, and 245 nm for oseltamivir phosphate, the internal standard, and both dexamethasone and remdesivir, respectively. The mobile phase consisted of methanol and ammonium acetate solution (40 mM) adjusted to pH 4 in a ratio of 61.5:38.5 (v/v) with a flow rate of 0.25 mL min-1. The calibration curves were linear over 500.0-5000.0 ng mL-1 for oseltamivir phosphate, over 10.0-500.0 ng mL-1 and 500.0-5000.0 ng mL-1 for dexamethasone, and over 20.0-500 ng mL-1 and 500.0-5000.0 ng mL-1 for remdesivir. The Gibbs free energy and Van't Hoff plots were used to investigate the effect of column oven temperatures on retention times. Fluoride-EDTA anticoagulant showed inhibition activity on the esterase enzyme in plasma. The proposed method was validated according to the M10 ICH, FDA, and EMA's bioanalytical guidelines. According to Eco-score, GAPI, and AGREE criteria, the proposed method was considered acceptable green.

Whole-Genome Analysis of the Influenza A(H1N1)pdm09 Viruses Isolated from Influenza-like Illness Outpatients in Myanmar and Community-Acquired Oseltamivir-Resistant Strains Present from 2015 to 2019.

In this study, we describe the genetic characteristics of influenza A(H1N1)pdm09 strains detected in Myanmar from 2015 to 2019. Whole genomes from 60 A(H1N1)pdm09 virus isolates were amplified using real-time polymerase chain reaction and successfully sequenced using the Illumina iSeq100 platforms. Eight individual phylogenetic trees were retrieved for each segment along with those of the World Health Organization (WHO)-recommended Southern Hemisphere vaccine strains for the respective years. A(H1N1)pdm09 viruses from 2015 were found to belong to clade 6B, those from 2016 to 6B.1, 2017 to 6B.1A, and 2019 to 6B.1A.5a, and were genetically distinct from the Southern Hemisphere vaccine strains for the respective seasons, A/California/7/2009 and A/Michigan/45/2015. We observed one virus with intra-subtype reassortment, collected in the 2015 season. Importantly, three viruses possessed the H275Y substitution in the neuraminidase protein, appearing to be community-acquired without the prior administration of neuraminidase inhibitors. These viruses exhibited highly reduced susceptibility to oseltamivir and peramivir. This study demonstrates the importance of monitoring genetic variations in influenza viruses that will contribute to the selection of global influenza vaccines.

Antivirals for treatment of severe influenza: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023, that enrolled hospitalised patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. Pairs of coauthors independently extracted data on study characteristics, patient characteristics, antiviral characteristics, and outcomes, with discrepancies resolved by discussion or by a third coauthor. Key outcomes of interest were time to alleviation of symptoms, duration of hospitalisation, admission to intensive care unit, progression to invasive mechanical ventilation, duration of mechanical ventilation, mortality, hospital discharge destination, emergence of antiviral resistance, adverse events, adverse events related to treatments, and serious adverse events. We conducted frequentist network meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This study is registered with PROSPERO, CRD42023456650. FINDINGS: Of 11 878 records identified by our search, eight trials with 1424 participants (mean age 36-60 years for trials that reported mean or median age; 43-78% male patients) were included in this systematic review, of which six were included in the network meta-analysis. The effects of oseltamivir, peramivir, or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza were of very low certainty. Compared with placebo or standard care, we found low certainty evidence that duration of hospitalisation for seasonal influenza was reduced with oseltamivir (mean difference -1·63 days, 95% CI -2·81 to -0·45) and peramivir (-1·73 days, -3·33 to -0·13). Compared with standard care, there was little or no difference in time to alleviation of symptoms with oseltamivir (0·34 days, -0·86 to 1·54; low certainty evidence) or peramivir (-0·05 days, -0·69 to 0·59; low certainty evidence). There were no differences in adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir (very low certainty evidence). Uncertainty remains about the effects of antivirals on other outcomes for patients with severe influenza. Due to the small number of eligible trials, we could not test for publication bias. INTERPRETATION: In hospitalised patients with severe influenza, oseltamivir and peramivir might reduce duration of hospitalisation compared with standard care or placebo, although the certainty of evidence is low. The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials. FUNDING: World Health Organization.

Comparison of the Effectiveness of Baloxavir and Oseltamivir in Outpatients With Influenza B.

This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382.

Characteristics and outcome of influenza-associated encephalopathy/encephalitis among children in China.

BACKGROUND: Influenza-Associated Encephalopathy/Encephalitis (IAE) is characterized by high incidence and poor prognosis. The aim of this study is to describe the clinical features and outcomes of IAE in pediatric patients. METHODS: We performed a retrospective review of hospitalized cases of laboratory-confirmed influenza infection between January 2018 and December 2021. Demographic, clinical, imaging, treatment and outcome data were collected. Statistical analysis was performed using SPSS software. RESULTS: Of 446 children hospitalized with influenza, 71 cases were identified with a diagnosis of IAE. The median age was 3 years and 46 (64.8 %) were younger than 5 years. Only one patient was vaccinated for seasonal influenza. 46 (64.8 %) patients had abnormal electroencephalogram examination and 47 (66.2 %) had abnormal brain MRI or CT findings. 68 (95.8 %) patients were treated with oseltamivir/peramivir. 12 (16.9 %) patients suffered mortality. Non-survivors were more likely to have lower Glasgow coma score (median 7), longer duration of fever (median 3 days), with underlying medical conditions (P = 0.006), and complications including sepsis (P = 0.003), shock (P < 0.001), respiratory failure (P = 0.006), acute renal failure (P = 0.001), myocardial damage (P < 0.001), coagulation disorders (P = 0.03), electrolyte disturbance (P = 0.001) and hyperlactacidemia (P = 0.003). Non-survivors had higher percentages of corticosteroids (P = 0.003) and immunoglobulin (P = 0.003) treatments compared to survivors. CONCLUSIONS: Children with IAE have a high mortality rate. Lower Glasgow coma score, longer duration of fever, with underlying medical conditions and complications pose a great risk to poor prognosis. Influenza vaccination is recommended to all eligible children.

Synergistic activity of an RNA polymerase PA-PB1 interaction inhibitor with oseltamivir against human and avian influenza viruses in cell culture and in ovo.

In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.

Factors Associated With Nonprescription of Oseltamivir for Infant Influenza Over 9 Seasons.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends oseltamivir phosphate for children <2 years old with confirmed or suspected influenza as they are at high risk for complications. We analyzed infant characteristics associated with nonprescription of oseltamivir over 9 years. METHODS: We conducted a retrospective electronic health record (EHR) review of infants <12 months old born between January 1, 2012 and December 31, 2019 within the University of Pittsburgh Medical Center health system in Southwestern Pennsylvania who had >2 well-child visits during their first year. Infants with a confirmed positive test for influenza were included in the analysis. Factors associated with infant oseltamivir nonprescription were assessed using multivariable logistic regression. RESULTS: Of 457 infants with confirmed influenza, 86% were prescribed oseltamivir. The proportion of infants prescribed oseltamivir increased from an average of 64.6% during the 2012-2016 influenza seasons to 90.4% during the 2016-2020 influenza seasons. Infants were more likely to not be prescribed oseltamivir if they experienced >2 days of influenza symptoms (odds ratio (OR): 9.4, 95% CI: 4.8, 18.7, P < .001), were diagnosed during the 2012-2016 influenza seasons (OR: 4.2, 95% CI: 1.8, 9.5, P < .001), tested positive for influenza via a multiplex/reverse transcriptase polymerase chain reaction test (OR: 6.7, 95% CI: 2.7, 16.3, P < .001; OR: 2.7, 95% CI: 1.1, 7.1; P = .04), or did not have a fever at point-of-care (OR: 2.3, 95% CI: 1.2, 4.6, P = .01). CONCLUSION: Adherence to CDC influenza antiviral treatment guidelines for infants is high and improved over time. However, the provision of targeted education to providers may further improve oseltamivir prescribing practices for high-risk children <12 months of age.

Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases.

The unexpected emergence of oseltamivir-resistant A(H1N1) viruses in 2008 was facilitated in part by the establishment of permissive secondary neuraminidase (NA) substitutions that compensated for the fitness loss due to the NA-H275Y resistance substitution. These viruses were replaced in 2009 by oseltamivir-susceptible A(H1N1)pdm09 influenza viruses. Genetic analysis and screening of A(H1N1)pdm09 viruses circulating in Germany between 2009 and 2024 were conducted to identify any potentially synergistic or resistance-associated NA substitutions. Selected viruses were then subjected to further characterization in vitro. In the NA gene of circulating A(H1N1)pdm09 viruses, two secondary substitutions, NA-V241I and NA-N369K, were identified. These substitutions demonstrated a stable lineage in phylogenetic analysis since the 2010-2011 influenza season. The data indicate a slight increase in viral NA bearing two additional potentially synergistic substitutions, NA-I223V and NA-S247N, in the 2023-2024 season, which both result in a slight reduction in susceptibility to NA inhibitors. The accumulation of secondary synergistic substitutions in the NA of A(H1N1)pdm09 viruses increases the probability of the emergence of antiviral-resistant viruses. Therefore, it is crucial to closely monitor the evolution of circulating influenza viruses and to develop additional antiviral drugs against different target proteins.

Influenza in Pregnancy: Maternal, Obstetric, and Fetal Implications, Diagnosis, and Management.

Influenza(flu) in pregnancy is associated with higher rates of hospitalization, ICU admission, and death and with increased odds of congenital anomalies and stillbirth, but not preterm birth. Clinical manifestations of flu in pregnancy are the same as nonpregnant patients. Pregnant individuals with flu-like symptoms or flu exposure should be treated with antivirals. Diagnostic testing is not needed. Oseltamivir is the mainstay of treatment(and prophylaxis), and when given within 48 hours of symptom onset, it decreases morbidity and mortality. Influenza is associated with worse maternal, obstetric, and neonatal outcomes. These risks are mitigated by early oseltamivir treatment and maternal vaccination; hence the recommendation for universal vaccination in pregnancy.

Evaluating the Public Health and Health Economic Impacts of Baloxavir Marboxil and Oseltamivir for Influenza Pandemic Control in China: A Cost-Effectiveness Analysis Using a Linked Dynamic Transmission-Economic Evaluation Model.

BACKGROUND: Pandemic influenza poses a recurring threat to public health. Antiviral drugs are vital in combating influenza pandemics. Baloxavir marboxil (BXM) is a novel agent that provides clinical and public health benefits in influenza treatment. METHODS: We constructed a linked dynamic transmission-economic evaluation model combining a modified susceptible-exposed-infected-recovered (SEIR) model and a decision tree model to evaluate the cost-effectiveness of adding BXM to oseltamivir in China's influenza pandemic scenario. The cost-effectiveness was evaluated for the general population from the Chinese healthcare system perspective, although the users of BXM and oseltamivir were influenza-infected persons. The SEIR model simulated the transmission dynamics, dividing the population into four compartments: susceptible, exposed, infected, and recovered, while the decision tree model assessed disease severity and costs. We utilized data from clinical trials and observational studies in the literature to parameterize the models. Costs were based on 2021 CN¥ and not discounted due to a short time-frame of one year in the model. One-way, two-way, and probabilistic sensitivity analyses were also conducted. RESULTS: The integrated model demonstrated that adding BXM to treatment choices reduced the cumulative incidence of infection from 49.49% to 43.26% and increased quality-adjusted life years (QALYs) by 0.00021 per person compared with oseltamivir alone in the base-case scenario. The intervention also amounted to a positive net monetary benefit of CN¥77.85 per person at the willingness to pay of CN¥80,976 per QALY. Sensitivity analysis confirmed the robustness of these findings, with consistent results across varied key parameters and assumptions. CONCLUSIONS: Adding BXM to treatment choices instead of only treating with oseltamivir for influenza pandemic control in China appears to be cost-effective compared with oseltamivir alone. The dual-agent strategy not only enhances population health outcomes and conserves resources, but also mitigates influenza transmission and alleviates healthcare burden.

Considerations when treating influenza infections with oseltamivir.

INTRODUCTION: Since the coronavirus disease 2019-mandated social distancing policy has been lifted worldwide, the circulation of influenza is expected to resume. Currently, oseltamivir is approved as the first-line agent for influenza prevention and treatment. AREAS COVERED: This paper reviews the updated evidence in the pharmacology, resistance mechanisms, clinical pharmacy management, and real-world data on oseltamivir for influenza. EXPERT OPINION: Oseltamivir is an oral prodrug of oseltamivir carboxylate, an influenza A and B neuraminidase inhibitor. Recently, the therapeutic efficacy of oseltamivir has been demonstrated in several trials. Oseltamivir is generally well-tolerated but may lead to neuropsychiatric events and bleeding. Oseltamivir-resistant influenza virus has been associated with the H275Y mutation in the influenza A(H1N1)pdm09 virus, while most strains are still sensitive to oseltamivir. Dose adjustment for oseltamivir should be based on creatinine clearance and body weight in pediatric patients with renal failure. According to real-world data from Nanfang Hospital, the annual number of patients prescribed oseltamivir declined from 35,711 in 2019 to 8,971 in 2020, with marked increases in 2022 (20,213) and 2023 (18,071). Among the 206 inpatients, children aged < 6 years who were treated with oseltamivir had the shortest duration to defervescence.

Genotypic and phenotypic susceptibility of emerging avian influenza A viruses to neuraminidase and cap-dependent endonuclease inhibitors.

Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor (baloxavir) were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC50s 3- to 4-fold lower than for other subtypes (median IC50: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC50 increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC50 and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC50 (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.

A cost-effectiveness analysis of reduced viral transmission with baloxavir marboxil versus oseltamivir or no treatment for seasonal and pandemic influenza management in the United Kingdom.

BACKGROUND: Baloxavir marboxil is an oral, single-dose, cap-dependent endonuclease inhibitor that reduces the duration of influenza symptoms and rapidly stops viral shedding. We developed a susceptible, exposed, infected, recovered (SEIR) model to inform a cost-effectiveness model (CEM) of baloxavir versus oseltamivir or no antiviral treatment in the UK. RESEARCH DESIGN AND METHODS: The SEIR model estimated the attack rates among otherwise healthy and high-risk individuals in seasonal and pandemic settings. The CEM assumed that a proportion of infected patients would receive antiviral treatment. Results were reported at the population level (per 10,000 at risk of infection). RESULTS: The SEIR model estimated greater reductions in infections with baloxavir. In a seasonal setting, baloxavir provided incremental cost-effectiveness ratios (ICERs) of £1884 per quality-adjusted life-year (QALY) gained versus oseltamivir and a dominant cost-effectiveness position versus no antiviral treatment in the total population; ICERs of £2574/QALY versus oseltamivir and £128/QALY versus no antiviral treatment were seen in the high-risk population. Baloxavir was also cost-effective versus oseltamivir or no antiviral treatment and reduced population-level health system occupancy concerns during a pandemic. CONCLUSION: Baloxavir treatment resulted in the fewest influenza cases and was cost-effective versus oseltamivir or no antiviral treatment from a UK National Health Service perspective.

Baloxavir marboxil ('baloxavir') is a prescription medicine for people who become ill with influenza (or 'the flu') that can reduce how long flu symptoms last and the likelihood of complications from the flu that may require going to the hospital. Baloxavir can also reduce the amount and duration of virus shed by infected individuals thus potentially slow or stop the flu from spreading to healthy people. We studied differences in reducing predicted flu infections between baloxavir and another flu treatment, known as oseltamivir, or no flu treatment at all. Treatment with baloxavir resulted in fewer flu infections in the UK population than oseltamivir or no treatment. We then studied how these differences might affect costs between baloxavir and oseltamivir or no treatment at a population level in the UK. Overall, in the majority of scenarios explored in the model, baloxavir was cost-effective as an antiviral treatment for people with the flu in the UK.