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: In addition to the I38 substitutions, E23K/G, A37T, and E199G substitutions were identified in the PA subunit that affect BXA susceptibility by less than 10-fold.
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.
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: 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.
Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors.
Introduction: E31K is associated with increased replication of egg-passaged viruses, while the impact of E23K is unknown.
Introduction: Additionally, 2 PAN changes were identified in nonviable replicate passages (viral RNA could be recovered, but virus titers were below detection limits), including E23K in CA/04 and E31K in PR/8 (data not shown).
Introduction: However, E23K was identified in one influenza A virus-infected patient in a phase 2 clinical trial of a similar compound (S-033188/baloxavir marboxil), suggesting that it may play a role in endonuclease inhibitor resistance (T.
Introduction: However, in replicate assays that showed reduced viral replication capacity upon passage (CA/04 at P15 and PR/8 at P4) (data not shown), viruses were isolated that
Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.
Result: Collectively, treatment-emergent monitoring in the phase 2 study identified I38T or I38F substitutions in A/H1N1 viruses as conferring more than 10-fold reductions in BXA susceptibility, whereas E23K had a significant but lesser impact.
Result: Susceptibility testing revealed that rgA/WSN/33 (H1N1) with the single substitution I38T, I38F or E23K showed FCs of 27.24, 10.61 and 4.74-fold, respectively, whereas the rgB/Maryland/1/59 with G548R mutation did not impact BXA sensitivity (Table 1).
Result: This extensive sequencing resulted in the detection of the E23K change in PA of A/H1N1pdm virus for one patient.
Table: E23K|mgd
Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil.
Discussion: In the Phase II clinical trial of baloxavir efficacy in adults aged 20-64 years, PA I38T, I38F, and E23K substitutions were detected in A(H1N1)pdm09 viruses and a PA G548R substitution was detected in a B virus.
Discussion: In vitro studies have revealed that influenza A(H1N1) viruses with the PA I38T, I38F, or E23K substitutions show 27.2, 10.6, and 4.7-fold higher EC50 values, respectively, whereas the PA G548R substitution in influenza B virus does not affect baloxavir susceptibility.
IV mutation literature information.
PMID: 
2021
Influenza and other respiratory viruses
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