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Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.
J Infect Dis. 2020 01 14; 221(3):346-355.JI

Abstract

BACKGROUND

Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.

METHODS

We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.

RESULTS

Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.

CONCLUSIONS

The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

CLINICAL TRIAL REGISTRATION

NCT02954354.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Uehara T
Shionogi & Co., Ltd, Osaka, Japan.
Hayden FG
University of Virginia School of Medicine, Charlottesville.
Kawaguchi K
Shionogi & Co., Ltd, Osaka, Japan.
Omoto S
Shionogi & Co., Ltd, Osaka, Japan.
Hurt AC
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.
De Jong MD
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, the Netherlands.
Hirotsu N
Hirotsu Clinic, Kawasaki, Japan.
Sugaya N
Department of Pediatrics, Keiyu Hospital, Yokohama, Japan.
Lee N
Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada.
Baba K
Shionogi & Co., Ltd, Osaka, Japan.
Shishido T
Shionogi & Co., Ltd, Osaka, Japan.
Tsuchiya K
Shionogi & Co., Ltd, Osaka, Japan.
Portsmouth S
Shionogi Inc., Florham Park, New Jersey.
Kida H
Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.

MeSH

AdolescentAdultAmino Acid SubstitutionAntiviral AgentsChildDibenzothiepinsDouble-Blind MethodDrug Resistance, ViralFemaleHumansInfluenza A Virus, H3N2 SubtypeInfluenza, HumanMaleMiddle AgedMorpholinesOseltamivirOxazinesPyridinesPyridonesRisk FactorsThiepinsTreatment OutcomeTriazinesViral LoadYoung Adult

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31309975

Clinical Trial Links

Clinical trial which this article describes

Citation

Uehara, Takeki, et al. "Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact On Clinical and Virologic Outcomes in Uncomplicated Influenza." The Journal of Infectious Diseases, vol. 221, no. 3, 2020, pp. 346-355.
Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020;221(3):346-355.
Uehara, T., Hayden, F. G., Kawaguchi, K., Omoto, S., Hurt, A. C., De Jong, M. D., Hirotsu, N., Sugaya, N., Lee, N., Baba, K., Shishido, T., Tsuchiya, K., Portsmouth, S., & Kida, H. (2020). Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. The Journal of Infectious Diseases, 221(3), 346-355. https://doi.org/10.1093/infdis/jiz244
Uehara T, et al. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact On Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020 01 14;221(3):346-355. PubMed PMID: 31309975.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. AU - Uehara,Takeki, AU - Hayden,Frederick G, AU - Kawaguchi,Keiko, AU - Omoto,Shinya, AU - Hurt,Aeron C, AU - De Jong,Menno D, AU - Hirotsu,Nobuo, AU - Sugaya,Norio, AU - Lee,Nelson, AU - Baba,Keiko, AU - Shishido,Takao, AU - Tsuchiya,Kenji, AU - Portsmouth,Simon, AU - Kida,Hiroshi, PY - 2019/01/12/received PY - 2019/05/09/accepted PY - 2019/7/17/pubmed PY - 2020/9/22/medline PY - 2019/7/17/entrez KW - antiviral susceptibility KW - baloxavir marboxil KW - cap-dependent endonuclease KW - influenza KW - polymerase acidic protein SP - 346 EP - 355 JF - The Journal of infectious diseases JO - J Infect Dis VL - 221 IS - 3 N2 - BACKGROUND: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge. METHODS: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses. RESULTS: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers. CONCLUSIONS: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study. CLINICAL TRIAL REGISTRATION: NCT02954354. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/31309975/Treatment_Emergent_Influenza_Variant_Viruses_With_Reduced_Baloxavir_Susceptibility:_Impact_on_Clinical_and_Virologic_Outcomes_in_Uncomplicated_Influenza_ DB - PRIME DP - Unbound Medicine ER -