Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019

Takashita, Emi; Kawakami, Chiharu; Ogawa, Rie; Morita, Hiroko; Fujisaki, Seiichiro; Saijo, Masayuki; Miura, Hideka; Nakamura, Kenzo; Kishida, Noriko; Kuwahara, Tomoko; Ota, Akira; Togashi, Hayato; Saito, Ayako; Mitamura, Keiko; Abe, Takashi; Ichikawa, Masataka; Yamazaki, Masahiko; Watanabe, Shinji; Odagiri, Takato

doi:10.2807/1560-7917.es.2019.24.12.1900170

Cited by 98 publications

(64 citation statements)

References 7 publications

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“…The problem of drug resistance faced by current and near-market antivirals is a serious concern, as exemplified by the alarming emergence of resistance to the recently approved antiviral baloxavir marboxil (Xofluza) [ 2 , 36 , 37 ]. Targeting the virus proteins directly applies a strong selection pressure for the emergence of drug-resistance escape mutants [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

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Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication

Goulding

Yang

Jiang

et al. 2020

Viruses

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Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.

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Section: Discussionmentioning

confidence: 99%

“…There is no entirely satisfactory antiviral treatment for influenza A infections. By directly targeting the highly mutable virus, current and near-market antivirals are inherently susceptible to virus resistance [ 1 , 2 ]. Thus, there is an unmet need for antivirals to be clinically effective and less vulnerable to viral mutation.…”

Section: Introductionmentioning

confidence: 99%

Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication

Goulding

Yang

Jiang

et al. 2020

Viruses

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“…An isoleucine-to-threonine substitution at amino acid position 38 of the PA gene (PA/I38T) has been shown to confer reduced susceptibility to BXA [22,23]. Based on pyrosequencing or Donor ferrets were intranasally inoculated with 10 3 TCID 50 of influenza A/Perth/265/2009.…”

Section: No Viruses With Pa/i38x Amino Acid Substitutions Were Detectedmentioning

confidence: 99%

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

et al. 2020

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Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels.

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“…80,87,88 Moreover, a resistant H3N2 virus was detected in a pediatric patient without prior exposure to baloxavir marboxil, supporting that this mutant strain spread between humans. 89 Even though baloxavir marboxil has not yet been used extensively in the clinic and long-term field data are scarce, the available evidence indicates that the genetic barrier against resistance to the drug is low and that escape comes with little penalty to viral fitness, pathogenesis, or transmission success. Accordingly, there is considerable risk that pre-exiting resistance to baloxavir marboxil could become widespread with increasing duration of clinical use.…”

Section: Clinically Used Drugs and Selected Daa Candidates In Advancementioning

confidence: 99%

Next-generation direct-acting influenza therapeutics

Toots

Plemper

2020

Translational Research

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Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.

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Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019

Cited by 98 publications

References 7 publications

Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication

Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

Next-generation direct-acting influenza therapeutics

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