Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil.
PMID: 33099886
2021
Influenza and other respiratory viruses
Result: Assessment of novel PA/I38X substitutions detected in clinical trials.
Discussion: While in vitro results of the replicative capacity of I38X mutant viruses from different studies vary, further investigation of potential compensatory mutations that could recover the fitness cost of I38T substitution will be needed.
Multiple polymerase acidic (PA) I38X substitutions in influenza A(H1N1)pdm09 virus permit polymerase activity and cause reduced baloxavir inhibition.
PMID: 33351916
2021
The Journal of antimicrobial chemotherapy
Abstract: METHODS: Influenza A(H1N1)pdm09 viral polymerase complexes containing all 19 I38X AA substitutions were reconstituted in HEK293T cells in a mini-replicon assay.
Baloxavir-oseltamivir combination therapy inhibits the emergence of resistant substitutions in influenza A virus PA gene in a mouse model.
Abstract: Baloxavir marboxil (BXM) treatment-emergent polymerase acid (PA) I38X amino acid substitution (AAS) in the resistant variants of influenza viruses raise concerns regarding their emergence and spread.
Abstract: Deep sequencing analysis revealed that 67% (n = 4/6) of the population treated with BXM single therapy (1 or 5 mg/kg) possessed the treatment-emergent PA-I38X AAS variants (I38T, I38S, and I38V).
Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.
PMID: 31309975
2020
The Journal of infectious diseases
Abstract: CONCLUSIONS: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound.
Abstract: METHODS: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.
Abstract: Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively.
Abstract: RESULTS: Viruses containing
Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes.
Discussion: Consequently, a follow-up pediatric study was conducted during the 2018-2019 season to assess whether a higher dose (2 mg/kg) might reduce PA/I38X-substituted virus emergence (JapicCTI-194577).
Discussion: Further study is required to assess whether alter
Discussion: The possibility that the association between the emergence of PA/I38X variants and prolongation of symptom alleviation requires additional investigation, including data on innate and acquired cellular immune responses before and at the time of variant emergence.
Discussion: We speculate that despite subinhibitory baloxavir concentration for PA/I38X-substituted viruses, patients with higher baseline antibody titers were better able to control replication and reduce the risk of variant emergence.
Baloxavir Marboxil 2% Granules in Japanese Children With Influenza: An Open-label Phase 3 Study.
PMID: 32433222
2020
The Pediatric infectious disease journal
Discussion: In children with fever resolution before day 4, fever recurrence was observed in approximately 60% of children with PA/I38X-substituted virus or influenza B after day 4, although fever resolved again during the 14-day observation period (Figure, Supplemental Digital Content 7B, http://links.lww.com/INF/D974).
Discussion: The PA/I38X-substituted A(H3N2) wa
Discussion: The previous pediatric study reported that children with PA/I38X-substituted viruses showed transient increases and prolongation of infectious virus detection.
Discussion: Treatment-emergent PA/I38X-substituted viruses with reduced susceptibility to baloxavir were detected in the previous adult and pediatric phase 3 studies.
IV mutation literature information.
PMID: 
2021
Influenza and other respiratory viruses
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