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- Title
Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.
- Authors
Uehara, Takeki; Hayden, Frederick G; Kawaguchi, Keiko; Omoto, Shinya; Hurt, Aeron C; Jong, Menno D De; Hirotsu, Nobuo; Sugaya, Norio; Lee, Nelson; Baba, Keiko; Shishido, Takao; Tsuchiya, Kenji; Portsmouth, Simon; Kida, Hiroshi; De Jong, Menno D
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.<bold>Clinical Trial Registration: </bold>NCT02954354.
- Subjects
INFLUENZA viruses; AMINO acids; INFLUENZA; SULFUR compounds; PYRIDINE; RESEARCH; HETEROCYCLIC compounds; VIRAL load; RESEARCH methodology; ANTIVIRAL agents; EVALUATION research; MEDICAL cooperation; TREATMENT effectiveness; COMPARATIVE studies; BLIND experiment; DRUG resistance in microorganisms; INFLUENZA A virus, H3N2 subtype; OSELTAMIVIR; PHARMACODYNAMICS
- Publication
Journal of Infectious Diseases, 2020, Vol 221, Issue 3, p346
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiz244