Influenza polymerase inhibitor resistance: Assessment of the current state of the art - A report of the isirv Antiviral group

Ison, Michael G.; Hayden, Frederick G.; Hay, Alan J.; Gubareva, Larisa V.; Govorkova, Elena A.; Takashita, Emi; McKimm-Breschkin, Jennifer L.

doi:10.1016/j.antiviral.2021.105158

Cited by 30 publications

(29 citation statements)

References 137 publications

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“…The orally administered PAI baloxavir marboxil (baloxavir) is the first in a new class of drugs targeting the cap-dependent endonuclease activity of the influenza PA protein. This antiviral was approved in Japan and the United States in 2018 and is now approved in several countries ( Beigel and Hayden, 2021 ; Ison et al, 2021 ). Antiviral usage against influenza differs among countries, with the highest usage per capita being reported in Japan ( Table S1 ).…”

Section: Introductionmentioning

confidence: 99%

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

et al. 2022

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“…The two clinically approved classes of influenza antivirals are the neuraminidase (NA) inhibitors (NAIs), which target the viral NA protein and inhibit virus budding, and a polymerase acidic protein (PA) endonuclease inhibitor that targets the PA protein and viral transcription. Four NAIs have been approved in various countries [ 1 ], whereas only one endonuclease inhibitor (baloxavir marboxil, BXM) is currently clinically available [ 2 ]. Viral resistance can arise during treatment with either type of agent.…”

Section: Introductionmentioning

confidence: 99%

“…Viral resistance can arise during treatment with either type of agent. The resistance landscape of the NAIs is well defined because these agents have been used for more than 20 years [ 2 , 3 ]. In contrast, BXM entered the market only recently (2018), and identification of molecular markers associated with reduced susceptibility to its active metabolite, baloxavir acid (BXA), is ongoing [ 2 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Zagribelnyy

Pascua

et al. 2022

PLoS Pathog

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Baloxavir marboxil (BXM) is approved for treating uncomplicated influenza. The active metabolite baloxavir acid (BXA) inhibits cap-dependent endonuclease activity of the influenza virus polymerase acidic protein (PA), which is necessary for viral transcription. Treatment-emergent E23G or E23K (E23G/K) PA substitutions have been implicated in reduced BXA susceptibility, but their effect on virus fitness and transmissibility, their synergism with other BXA resistance markers, and the mechanisms of resistance have been insufficiently studied. Accordingly, we generated point mutants of circulating seasonal influenza A(H1N1)pdm09 and A(H3N2) viruses carrying E23G/K substitutions. Both substitutions caused 2- to 13-fold increases in the BXA EC50. EC50s were higher with E23K than with E23G and increased dramatically (138- to 446-fold) when these substitutions were combined with PA I38T, the dominant BXA resistance marker. E23G/K-substituted viruses exhibited slightly impaired replication in MDCK Calu-3 cells, which was more pronounced with E23K. In ferret transmission experiments, all viruses transmitted to direct-contact and airborne-transmission animals, with only E23K+I38T viruses failing to infect 100% of animals by airborne transmission. E23G/K genotypes were predominantly stable during transmission events and through five passages in vitro. Thermostable PA–BXA interactions were weakened by E23G/K substitutions and further weakened when combined with I38T. In silico modeling indicated this was caused by E23G/K altering the placement of functionally important Tyr24 in the endonuclease domain, potentially decreasing BXA binding but at some cost to the virus. These data implicate E23G/K, alone or combined with I38T, as important markers of reduced BXM susceptibility, and such mutants could emerge and/or transmit among humans.

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“…In addition to a possible effect of blocking the host neuraminidase by NAI, emergence of NAI resistant influenza strains can occur that warrant the need for alternative antivirals. Currently, resistance to NAI in community isolates remains at low levels (<1%), however higher incidences of oseltamivir-resistant variants exist [17,18]. In 2009, the influenza A (H1N1)pdm09 virus with the NA-H275Y amino acid substitution occurred as a widespread oseltamivir-resistant influenza strain [17,[19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, resistance to NAI in community isolates remains at low levels (<1%), however higher incidences of oseltamivir-resistant variants exist [17,18]. In 2009, the influenza A (H1N1)pdm09 virus with the NA-H275Y amino acid substitution occurred as a widespread oseltamivir-resistant influenza strain [17,[19][20][21]. In a French multicenter observational cohort study, a highly reduced sensitivity to oseltamivir was found in 23% of the patients with a severe influenza A(H1N1)pdm09 [NA-H275Y] pneumonia [19].…”

Section: Introductionmentioning

confidence: 99%

Overcome Double Trouble: Baloxavir Marboxil Suppresses Influenza Thereby Mitigating Secondary Invasive Pulmonary Aspergillosis

Seldeslachts

Jacobs

Tielemans

et al. 2021

JoF

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Influenza-associated pulmonary aspergillosis (IAPA) is a global recognized superinfection in critically ill influenza patients. Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is a newly approved anti-influenza therapeutic. Although the benefits as a treatment for influenza are clear, its efficacy against an influenza-A. fumigatus co-infection has yet to be determined. We investigated the therapeutic effect of baloxavir marboxil in a murine model for IAPA. Immunocompetent mice received intranasal instillation of influenza A followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Administration of baloxavir marboxil or sham was started at day 0, day 2 or day 4. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). In vivo imaging was supplemented with virological, mycological and biochemical endpoint investigations. We observed an improved body weight, survival and viral clearance in baloxavir marboxil treated mice. µCT showed less pulmonary lesions and bronchial dilation after influenza and after Aspergillus co-infection in a treatment-dependent pattern. Furthermore, baloxavir marboxil was associated with effective inhibition of fungal invasion. Hence, our results provide evidence that baloxavir marboxil mitigates severe influenza thereby decreasing the susceptibility to a lethal invasive Aspergillus superinfection.

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Influenza polymerase inhibitor resistance: Assessment of the current state of the art - A report of the isirv Antiviral group

Cited by 30 publications

References 137 publications

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission

Overcome Double Trouble: Baloxavir Marboxil Suppresses Influenza Thereby Mitigating Secondary Invasive Pulmonary Aspergillosis

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