Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients

Clin Immunol. 2024 Feb:259:109901. doi: 10.1016/j.clim.2024.109901. Epub 2024 Jan 12.


Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Keywords: Favipiravir; Human norovirus infection; Immunodeficiency; Mutagenic antivirals; Virus whole-genome-sequencing; Zebrafish larvae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides*
  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Humans
  • Immunocompromised Host
  • Mutagenesis
  • Norovirus* / genetics
  • Pyrazines*
  • RNA-Dependent RNA Polymerase / genetics
  • Viruses*
  • Zebrafish


  • favipiravir
  • Antiviral Agents
  • RNA-Dependent RNA Polymerase
  • Amides
  • Pyrazines