Method: Influenza A PR/8 (H1N1), ZX/1109 (H1N1), the PR/8-R292K mutant (H1N1, oseltamivir-resistant, recombinant strain), the PR/8-I38T mutant (H1N1, baloxavir-resistant, recombinant strain), A/WSN/33 (H1N1), HK/68 (H3N2), and influenza B/Lee/40 were propagated in 8- to 10-day-old embryonated chicken eggs or MDCK cells for 3 days at 37 C.
Result: Except for compound 21B1 showing no activity against the A/Hong Kong/8/68 (HK/68, H3N2) strain, these compounds were active against a variety of influenza A virus strains, including HK/68 (H3N2), A/WSN/33 (H1N1), A/LiaoNing-ZhenXing/1109/2010 (ZX/1109, H1N1, natural isolate oseltamivir-resistant), the PR/8-R292K mutant (H1N1, recombinant oseltamivir-resistant), the PR/8-I38T mutant (H1N1, recombinant baloxavir-resistant), and influenza B/Lee/40 virus strains (Table 1).
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 for the treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir.
Abstract: 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.
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.
Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.
PMID: 32064779
2020
Influenza and other respiratory viruses
Abstract: In vitro studies have revealed that an I38T substitution in the polymerase acidic subunit (PA) is associated with reduced susceptibility of influenza viruses to baloxavir.
Abstract: METHODS: Three assays were developed based on RNase H2-dependent PCR (rhPCR) and named A/H1pdm PA_I38T rhPCR, A/H3 PA_I38T rhPCR, and B PA_I38T rhPCR.
Abstract: OBJECTIVES: Development of a rapid and simple method for monitoring influenza A(H1N1)pdm09, A(H3N2), and B viruses possessing the I38T substitution in PA.
Introduction: In Japan, two approaches have been developed to monitor the emergence of baloxa
Detection of Variants With Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018-2019 Influenza Season.
PMID: 32034420
2020
The Journal of infectious diseases
Abstract: 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.
Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018.
Abstract: PA gene sequence data, available from public databases (n = 13523), were screened for amino acid substitutions associated with reduced susceptibility to baloxavir (PA E23G/K/R, PA A36V, PA A37T, PA I38F/M/T/L, PA E119D, PA E199G): 11 (0.08%) viruses possessed such substitutions.
Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes.
Abstract: 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).
Abstract: 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.
Abstract: 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).|m
Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse.
PMID: 31526451
2019
The Journal of general virology
Abstract: A PA-I38T mutation has also been detected in viruses recovered from humans treated with BXM and is responsible for the reduction in susceptibility to BXM.
Abstract: A mutated virus with PA-I38T was less susceptible to BXM than viruses with PA-N675D or without mutation.
Abstract: These mutations were the substitution of isoleucine with threonine at position 38 (PA-I38T) and that of asparagine with aspartic acid at position 675 in PA (PA-N675D).
IV mutation literature information.
PMID: 
2020
Molecules (Basel, Switzerland)
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