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J Infect Dis. 2019 Jul 16. pii: jiz244. doi: 10.1093/infdis/jiz244. [Epub ahead of print]

Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.

Author information

1
Shionogi & Co., Ltd, Osaka, Japan.
2
University of Virginia School of Medicine, Charlottesville.
3
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia.
4
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, the Netherlands.
5
Hirotsu Clinic, Kawasaki, Japan.
6
Department of Pediatrics, Keiyu Hospital, Yokohama, Japan.
7
Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada.
8
Shionogi Inc., Florham Park, New Jersey.
9
Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.

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.

KEYWORDS:

antiviral susceptibility; baloxavir marboxil; cap-dependent endonuclease; influenza; polymerase acidic protein

PMID:
31309975
DOI:
10.1093/infdis/jiz244

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