Discussion: The PA-I38T mutation was described to be associated with reduced IAV susceptibility to BXA and IAV variants harboring an I38T, I38F, or I38M substitution showed reduced BXA susceptibility during phase 2 and phase 3 trials, respectively.
The active form of the influenza cap-snatching endonuclease inhibitor baloxavir marboxil is a tight binding inhibitor.
PMID: 33647314
2021
The Journal of biological chemistry
Introduction: In a recent trial, I38T/M/F substitutions appeared in 9.7% of patients receiving BXM.
Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir.
Result: As an internal quality control, a pair of A (H3N2) viruses was included in each test; their genomes were nearly identical, except substitution I38M in PA protein.
Result: However, the median pimodivir IC50 for the PA-I38M control virus was somewhat lower (5.77 vs 7.11 nM, p < 0.0001).
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: PA I38T/M/F substitutions reduce its antiviral efficacy.
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
Introduction: Influenza surveillance studies conducted in Japan during the 2018-19 influenza season confirmed treatment-emergence of PA/I38T and PA/I38M variants in A(H3N2)-infected subjects.
Result: Additionally, PA/I38T-, I38T/I-, and I38M-substituted A(H3N2) viruses were detected from 10, 2, and 1 BXM-treated subject, respectively, and PA/I38T-substituted type B viruses were detected from 1 BXM-treated patient.
Result: Resistance monitoring in phase 2 (T0821) and pediatric (T0822 [Japic CTI-163417]) trials revealed treatment-emergent I38T/F/M substitutions in PA, which confer reduced susceptibility to BXA (Table 1 and Tabl
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.
PMID: 32253432
2020
The Journal of infectious diseases
Abstract: 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.
Abstract: 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.
Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts.
PMID: 32640124
2020
The New England journal of medicine
Abstract: In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively.
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.
PMID: 32526195
2020
The Lancet. Infectious diseases
Abstract: Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
Baloxavir Marboxil 2% Granules in Japanese Children With Influenza: An Open-label Phase 3 Study.
PMID: 32433222
2020
The Pediatric infectious disease journal
Abstract: Polymerase acidic protein/I38T/M-substituted viruses were detected in 5 children infected with influenza A, but none with influenza B.
Method: The baseline characteristics of children with emergence of PA/I38T/M substitutions were presented.
Result: An increase in infectious virus around day 4 or 6 was observed in children with influenza B and in children with PA/I38T/M-substituted viruses, respectively (Figure, Supplemental Digital Content 7A, http://links.lww.com/INF/D974).
Result: Fever recurrence after day 4 was seen in 3 of 5 children with PA/I38T/M-substituted influenza A, 1 of 10 children with unsubstituted influenza A and 7 of 12 children with influenza B (Figur
Rapid detection of an I38T amino acid substitution in influenza polymerase acidic subunit associated with reduced susceptibility to baloxavir marboxil.
PMID: 32064779
2020
Influenza and other respiratory viruses
Introduction: Moreover, in a phase III clinical trial, PA I38T and I38M substitutions were detected after exposure to the drug in 9.7% of 370 influenza A(H3N2) viruses.4 Patients infected with mutant influenza viruses carrying PA I38T or I38F exhibited prolonged viral shedding, and the median time to alleviation of symptoms was longer in baloxavir recipients infected with viruses with PA I38T or I38M substitutions than in those without substitutions.3, 4 In a pediatric study, PA I38T and I38M substitutions emerged in 18 (23.4%) of 77 influenza A(H3N2) viruses.3 .
IV mutation literature information.
PMID: 
2021
Frontiers in microbiology
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