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Different specimen types are used for influenza diagnosis but comparative data for viral loads from different swab types are limited. We compared influenza viral loads (determined by quantitative reverse transcription polymerase chain reaction [RT-PCR]) in 93 paired midturbinate and nasopharyngeal swab aliquots from influenza infected patients enrolled in a phase 3 randomized-controlled study with the objective of maximizing the number of swabs available for sequence analysis. Midturbinate swabs yielded a 53% lower viral load versus nasopharyngeal swabs, and this difference was similar for influenza A and B. These data suggest that nasopharyngeal swabs might be preferred in diagnostic settings when obtaining higher viral load is important., Competing Interests: C. B. has received consulting fees as a contractor for F. Hoffmann‐La Roche Ltd. during the execution of this work. L. K. and S. W. are employees of, and own stocks in, F. Hoffmann‐La Roche Ltd., (© 2024 F.Hoffmann‐La Roche Ltd. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

In a post-hoc analysis of the phase 3 BLOCKSTONE study (JapicCTI-184180), we investigated household transmission of baloxavir-resistant (PA/I38X) influenza viruses. Using baloxavir resistance rates from prior clinical trials and the rate of influenza transmission observed in the study, the predicted number of PA/I38X transmission events was 4.8, assuming wild type and PA/I38X viruses were equally transmissible. However, no PA/I38X viruses were observed. These results suggest a low potential for baloxavir-resistant influenza virus transmission from treated to untreated individuals, potentially due to reduced viral/transmission fitness for PA/I38X viruses and/or low viral titres at the time when resistant viruses arise., (© 2023 F. Hoffmann-La Roche Ltd. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Influenza antivirals are important tools in our fight against annual influenza epidemics and future influenza pandemics. Combinations of antivirals may reduce the likelihood of drug resistance and improve clinical outcomes. Previously, two hospitalised immunocompromised influenza patients, who received a combination of a neuraminidase inhibitor and baloxavir marboxil, shed influenza viruses resistant to both drugs. Here-in, the replicative fitness of one of these A(H1N1)pdm09 virus isolates with dual resistance mutations (NA-H275Y and PA-I38T) was similar to wild type virus (WT) in vitro, but reduced in the upper respiratory tracts of challenged ferrets. The dual-mutant virus transmitted well between ferrets in an airborne transmission model, but was outcompeted by the WT when the two viruses were co-administered. These results indicate the dual-mutant virus had a moderate loss of viral fitness compared to the WT virus, suggesting that while person-to-person transmission of the dual-resistant virus may be possible, widespread community transmission is unlikely., (© 2022. The Author(s).)

Background: Neuraminidase inhibitors (NAIs) are considered the standard of care for hospitalised patients with influenza. We aimed to test whether combining the cap-dependent endonuclease inhibitor baloxavir marboxil (hereafter baloxavir) with standard-of-care NAIs would result in improved clinical outcomes compared with NAI monotherapy in hospitalised patients with severe influenza., Methods: We did a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Patients aged 12 years or older who were hospitalised with laboratory-confirmed influenza (by RT-PCR or a rapid test) and had a National Early Warning Score 2 (NEWS2) of 4 or greater were included. Recruitment took place in 124 centres across 25 countries. Using a permuted-block method and an interactive response system, patients were randomly assigned (2:1) to receive either baloxavir plus NAIs (hereafter the baloxavir group) or placebo plus NAIs (hereafter the control group). Participants, investigators, and those assessing outcomes were masked to group assignment. Baloxavir was administered orally on day 1 and day 4 (40 mg for bodyweight <80 kg, or 80 mg for ≥80 kg), and on day 7 if no clinical improvement had occurred by day 5. The NAIs included in this study were oseltamivir, zanamivir, and peramivir, which were selected and administered according to local standard practice. The primary endpoint was time to clinical improvement, defined as time to a NEWS2 of 2 or lower for 24 h or hospital discharge, whichever came first, based on daily assessments over the study duration of 35 days. Secondary endpoints included safety analyses. The modified intention-to-treat infected (mITTI) population (ie, all patients who were randomly assigned to treatment, received a dose of study drug, and were RT-PCR-positive for influenza at any timepoint according to the treatment assigned at randomisation) was used in all efficacy analyses. The safety population (ie, all patients who received at least one dose of study treatment, according to the treatment received) was used in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03684044., Findings: Overall, 366 patients were enrolled between Jan 8, 2019, and March 16, 2020, of whom 241 were assigned to the baloxavir group and 125 to the control group. The mITTI population comprised 322 patients, 208 in the baloxivir group and 114 in the control group. In total, 280 (87%) of these patients had influenza A infections. Median time to clinical improvement was 97·5 h (95% CI 75·9 to 117·2) in the baloxavir group and 100·2 h (75·9 to 144·4) in the control group (median difference -2·7 h [95% CI -53·4 to 25·9], p=0·467). Baloxavir plus NAI was well tolerated, and no new safety signals were observed; serious adverse events occurred in 29 (12%) of 239 patients in the baloxavir group versus 19 (15%) of 124 patients in the control group, of which one was considered related to treatment (orthostatic hypotension in a patient in the control group). Overall, four deaths (2%) occurred in the baloxavir group and seven (6%) in the control group; none were considered related to treatment., Interpretation: Combining baloxavir with NAIs did not result in superior clinical outcomes compared with NAIs alone. The combination of baloxavir plus NAI was well tolerated. The findings suggest that combination antivirals would not be routinely indicated in clinical practice for hospitalised patients with severe influenza., Funding: F Hoffmann-La Roche and the Biomedical Advanced Research and Development Authority., Competing Interests: Declaration of interests DK has received advisory fees from F Hoffmann-La Roche, Sanofi Pasteur, and GlaxoSmithKline, and a clinical trials grant from F Hoffmann-La Roche and GlaxoSmithKline. MGI received research support, paid to Northwestern University, from AiCuris, Janssen, and Shire; he is a paid consultant for Adagio, AlloVir, Celltrion, Cidara, Genentech, F Hoffmann-La Roche, Janssen, Shionogi, and Viracor Eurofins, and he is a paid member of data monitoring and safety boards for Janssen, Merck, SAB Biotherapeutics, Sequiris, Takeda, and Vitaeris. J-PM has received advisory fees from F Hoffmann-La Roche, AM-Pharma, and AKPA; lecture fees from Fresenius, MSD, Astellas, and Estor; and clinical trial grants from AKPA and Biomérieux. NL has previously received honoraria for consultancy work and speaking in educational programmes from Shionogi, Janssen, Sanofi Pasteur, Gilead Sciences Canada, F Hoffmann-La Roche, Genentech, and CIDARA Therapeutics, and travel support from Shionogi, Sanofi Pasteur, F Hoffmann-La Roche, and Genentech. LK, NC, AA, BC, and SWill are employees of Roche Products. SWild is an employee of F Hoffmann-La Roche. TW has received honoraria for consultancy work and speaking in educational programmes from AstraZeneca, Basilea, Biotest, Bayer, Boehringer Ingelheim, Berlin Chemie, GlaxoSmithKline, Infectopharm, Johnson & Johnson, MSD, Novartis, Pfizer, F Hoffmann-La Roche, and Sanofi Aventis. TS has received lecture fees from AstraZeneca, Boehringer Ingelheim, Sanofi Pasteur, Novartis, KYORIN Pharmaceutical, and Daiichi Sankyo. DSH, NZ, and JHH have nothing to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Baloxavir marboxil (BXM) is an approved drug that selectively targets cap-dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 in the PA subunit were identified as a major pathway for reduced susceptibility to baloxavir acid (BXA), the active form of BXM. Additionally, substitutions found at positions E23, A37, and E199 in the PA subunit impact BXA susceptibility by less than 10-fold., Methods: We comprehensively evaluated the impact of novel amino acid substitutions identified in PA, PB1, and PB2 subunits in BXM clinical trials and influenza sequence databases by means of drug susceptibility and replicative capacity., Results: PA/I38N in A(H1N1)pdm09 and PA/I38R in A(H3N2) were newly identified as treatment-emergent substitutions in the CAPSTONE-2 study. The I38N substitution conferred reduced susceptibility by 24-fold, whereas replicative capacity of the I38N-substituted virus was impaired compared with the wild-type. The I38R-substituted virus was not viable in cell culture. All other mutations assessed in this extensive study did not significantly affect BXA susceptibility (< 2.4-fold change)., Conclusion: These results provide additional information on the impact of amino acid substitutions in the trimeric viral polymerase complex to BXA susceptibility and will further support influenza surveillance., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: Baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. We assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza., Methods: MiniSTONE-2 (Clinicaltrials.gov: NCT03629184) was a double-blind, randomized, active controlled trial enrolling children 1-<12 years old with a clinical diagnosis of influenza. Children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. The primary endpoint was incidence, severity and timing of adverse events (AEs); efficacy was a secondary endpoint., Results: In total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. Characteristics of participants were similar between treatment groups. Overall, 122 AEs were reported in 84 (48.6%) children. Incidence of AEs was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). The most common AEs were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. No deaths, serious AEs or hospitalizations were reported. Median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6-163.2) hours with baloxavir versus 150.0 (115.0-165.7) hours with oseltamivir., Conclusions: Oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. Baloxavir provides a new therapeutic option with a simple oral dosing regimen.