#Baloxavir marboxil #treatment of nude mice infected with #influenza A virus (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Baloxavir marboxil treatment of nude mice infected with influenza A virus

Maki Kiso, Seiya Yamayoshi, Jurika Murakami, Yoshihiro Kawaoka

The Journal of Infectious Diseases, jiz665, https://doi.org/10.1093/infdis/jiz665

Published: 14 December 2019

 

Abstract

Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses. Here, we examined the efficacy of baloxavir marboxil in nude mice, which are immunologically deficient. Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment. Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected.

influenza, baloxavir marboxil, drug resistance, immunocompromised

Issue Section: Brief Report

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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antivirals; Drugs Resistance; Influenza A; Oseltamivir; Baloxavir; Animal models.

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#Influenza A #variants with reduced susceptibility to #baloxavir isolated from #Japanese patients are fit and transmit through respiratory #droplets (Nat Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Nat Microbiol. 2019 Nov 25. doi: 10.1038/s41564-019-0609-0. [Epub ahead of print]

Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets.

Imai M1, Yamashita M2, Sakai-Tagawa Y2, Iwatsuki-Horimoto K2, Kiso M2, Murakami J2, Yasuhara A2, Takada K2, Ito M2, Nakajima N3, Takahashi K3, Lopes TJS2,4, Dutta J5, Khan Z5, Kriti D5, van Bakel H5, Tokita A6,7, Hagiwara H7,8, Izumida N7,9, Kuroki H10, Nishino T7,11, Wada N7,12, Koga M13, Adachi E14, Jubishi D2,15, Hasegawa H3,16, Kawaoka Y17,18,19.

Author information: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. mimai@ims.u-tokyo.ac.jp. 2 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 3 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. 4 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA. 5 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6 Clinic Bambini, Tokyo, Japan. 7 Members of the Tokyo Pediatric Association Public Health Committee, Tokyo, Japan. 8 Hagiwara Clinic, Tokyo, Japan. 9 Akebonocho Clinic, Tokyo, Japan. 10 Sotobo Children’s Clinic, Chiba, Japan. 11 Alpaca Kids Ent Clinic, Tokyo, Japan. 12 Wada Pediatric Clinic, Tokyo, Japan. 13 Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 14 Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan. 15 Nezu Clinic, Tokyo, Japan. 16 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan. 17 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu. 18 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA. yoshihiro.kawaoka@wisc.edu. 19 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. yoshihiro.kawaoka@wisc.edu.

 

Abstract

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

PMID: 31768027 DOI: 10.1038/s41564-019-0609-0

Keywords: Antivirals; Drugs Resistance; H1N1pdm09; H3N2; Seasonal Influenza; Japan.

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Treatment of Highly Pathogenic #H7N9 Virus-Infected Mice with #Baloxavir Marboxil (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Nov 15;11(11). pii: E1066. doi: 10.3390/v11111066.

Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil.

Kiso M1, Yamayoshi S1, Furusawa Y1, Imai M1, Kawaoka Y1,2,3.

Author information: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA. 3 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

 

Abstract

Viral neuraminidase inhibitors show limited efficacy in mice infected with H7N9 influenza A viruses isolated from humans. Although baloxavir marboxil protected mice from lethal challenge infection with a low pathogenic avian influenza H7N9 virus isolated from a human, its efficacy in mice infected with a recent highly pathogenic version of H7N9 human isolates is unknown. Here, we examined the efficacy of baloxavir marboxil in mice infected with a highly pathogenic human H7N9 virus, A/Guangdong/17SF003/2016. Treatment of infected mice with a single 1.5 mg/kg dose of baloxavir marboxil protected mice from the highly pathogenic human H7N9 virus infection as effectively as oseltamivir treatment at 50 mg/kg twice a day for five days. Daily treatment for five days at 15 or 50 mg/kg of baloxavir marboxil showed superior therapeutic efficacy, largely preventing virus replication in respiratory organs. These results indicate that baloxavir marboxil is a valuable candidate treatment for human patients suffering from highly pathogenic H7N9 virus infection.

KEYWORDS: H7N9; baloxavir marboxil; highly pathogenic; influenza

PMID: 31731678 DOI: 10.3390/v11111066

Keywords: Antivirals; Avian Influenza; H7N9; Baloxavir Marboxil; Animal models.

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#Adult #influenza A (#H3N2) with reduced susceptibility to #baloxavir or #peramivir cured after switching anti-influenza agents (IDCases, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

IDCases. 2019 Oct 1;18:e00650. doi: 10.1016/j.idcr.2019.e00650. eCollection 2019.

Adult influenza A (H3N2) with reduced susceptibility to baloxavir or peramivir cured after switching anti-influenza agents.

Seki M1, Sakai-Tagawa Y2, Yasuhara A2, Watanabe Y3.

Author information: 1 Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan. 2 Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 3 Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan.

 

Abstract

We describe two adults with A/H3N2 influenza with (patient 1), and without (patient 2) polymerase acidic (PA) subunit I38 T substitution during the same season. Patient 1 had a reduced clinical response to baloxavir, a cap-dependent endonuclease inhibitor (CEI), but was cured by peramivir, a neuraminidase inhibitor. Baloxavir was clinically effective for patient 2, for whom peramivir had been ineffective. Susceptibility to baloxavir can be decreased by a PA unit mutation, but response to treatment can be increased by switching and/or combination with a neuraminidase inhibitor, even though CEI are clinically effective against influenza in adults.

© 2019 The Authors.

KEYWORDS: Baloxavir; Peramivir; Polymerase; Polymerase acidic subunit; Viral infection

PMID: 31692637 PMCID: PMC6804930 DOI: 10.1016/j.idcr.2019.e00650

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; H3N2; Japan; Baloxavir; Peramivir.

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Replicative #fitness of seasonal #influenza A viruses with decreased susceptibility to #baloxavir (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir

Anton Chesnokov, Mira C Patel, Vasiliy P Mishin, Juan A De La Cruz, Lori Lollis, Ha T Nguyen, Vivien Dugan, David E Wentworth, Larisa V Gubareva

The Journal of Infectious Diseases, jiz472, https://doi.org/10.1093/infdis/jiz472

Published: 21 September 2019

 

Abstract

Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness. While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment.

Cap-dependent endonuclease inhibitor, replicative fitness, polymerase acidic protein, influenza, drug resistance, ferret, baloxavir acid, antiviral

Issue Section: Brief Report

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Author notes

These authors contributed equally to this article and share first authorship

Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir.

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#Human-to-Human #Transmission of #Influenza A(H3N2#) Virus with Reduced Susceptibility to #Baloxavir, #Japan, February 2019 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 11—November 2019 / Dispatch

Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019

Emi Takashita  , Masataka Ichikawa, Hiroko Morita, Rie Ogawa, Seiichiro Fujisaki, Masayuki Shirakura, Hideka Miura, Kazuya Nakamura, Noriko Kishida, Tomoko Kuwahara, Hiromi Sugawara, Aya Sato, Miki Akimoto, Keiko Mitamura, Takashi Abe, Masahiko Yamazaki, Shinji Watanabe, Hideki Hasegawa, and Takato Odagiri

Author affiliations: National Institute of Infectious Diseases, Tokyo, Japan (E. Takashita, H. Morita, R. Ogawa, S. Fujisaki, M. Shirakura, H. Miura, K. Nakamura, N. Kishida, T. Kuwahara, H. Sugawara, A. Sato, M. Akimoto, S. Watanabe, H. Hasegawa, T. Odagiri); Ichikawa Children’s Clinic, Kanagawa, Japan (M. Ichikawa); Eiju General Hospital, Tokyo (K. Mitamura); Abe Children’s Clinic, Kanagawa (T. Abe); Zama Children’s Clinic, Kanagawa (M. Yamazaki)

 

Abstract

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses’ whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

Keywords: Influenza A; H3N2; Seasonal Influenza; Antivirals; Drugs resistance; Baloxavir; Japan.

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Impact of the #baloxavir #resistant #polymerase acid (PA) I38T substitution on the #fitness of contemporary #influenza A #H1N1pdm09 and A(#H3N2) strains (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Impact of the baloxavir-resistant polymerase acid (PA) I38T substitution on the fitness of contemporary influenza A(H1N1)pdm09 and A(H3N2) strains

Liva Checkmahomed, Zeineb M’hamdi, Julie Carbonneau, Marie-Christine Venable, Mariana Baz, Yacine Abed, Guy Boivin

The Journal of Infectious Diseases, jiz418, https://doi.org/10.1093/infdis/jiz418

Published: 16 August 2019

 

Abstract

Background

Baloxavir is a cap-dependent inhibitor of the polymerase acid (PA) protein of influenza viruses. While appearing virologically superior to oseltamivir, baloxavir exhibits a low barrier of resistance. We sought to assess the impact of the common baloxavir-resistant I38T PA substitution on in vitro properties and virulence.

Methods

Influenza A/Quebec/144147/2009 (H1N1)pdm09 and A/Switzerland/9715293/2013 (H3N2) recombinant viruses and their I38T PA mutants were compared in single and competitive infection experiments in ST6GalI-MDCK cells and C57/BL6 mice. Virus titers in cell culture supernatants and lung homogenates were determined by virus yield assays. Ratios of wild-type (WT) and I38T mutant were assessed by digital RT-PCR.

Results

I38T substitution did not alter the replication kinetics of A(H1N1)pdm09 and A(H3N2) viruses. In competition experiments, a 50:50% mixture evolved to 70:30% (WT/mutant) for A(H1N1) and 88:12% for A(H3N2) viruses after a single cell passage. The I38T substitution remained stable after 4 passages in vitro. In mice, the WT and its I38T mutant induced similar weight loss with comparable lung titers in both viral subtypes. The mutant virus tended to predominate over the WT in mouse competition experiments.

Conclusion

The fitness of baloxavir-resistant I38T PA mutants appears relatively unaltered in seasonal subtypes warranting surveillance for its dissemination.

Influenza, baloxavir, resistance, I38T, PA, A(H1N1)pdm09, A(H3N2)

Topic: lung – influenzavirus a – mice – viruses – influenza a virus, h1n1 subtype – influenza a virus, h3n2 subtype – swine influenza – swine-origin influenza virus

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antivirals; Influenza A; Seasonal Influenza; Drugs resistance; Baloxavir; H3N2; H1N1pdm09.

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