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

J Infect Dis. 2020 Jan 14;221(3):346-355. doi: 10.1093/infdis/jiz244.


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.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Substitution
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Child
  • Dibenzothiepins
  • Double-Blind Method
  • Drug Resistance, Viral / drug effects*
  • Female
  • Humans
  • Influenza A Virus, H3N2 Subtype / drug effects*
  • Influenza A Virus, H3N2 Subtype / genetics*
  • Influenza, Human / drug therapy*
  • Influenza, Human / virology
  • Male
  • Middle Aged
  • Morpholines
  • Oseltamivir / therapeutic use
  • Oxazines / pharmacology
  • Oxazines / therapeutic use*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Pyridones
  • Risk Factors
  • Thiepins / pharmacology
  • Thiepins / therapeutic use*
  • Treatment Outcome
  • Triazines / pharmacology
  • Triazines / therapeutic use*
  • Viral Load / drug effects
  • Young Adult


  • Antiviral Agents
  • Dibenzothiepins
  • Morpholines
  • Oxazines
  • Pyridines
  • Pyridones
  • Thiepins
  • Triazines
  • Oseltamivir
  • baloxavir

Associated data