Rapid communication Open Access
Like 0


The anti-influenza therapeutic baloxavir targets cap-dependent endonuclease activity of polymerase acidic (PA) protein. We monitored baloxavir susceptibility in the United States with next generation sequencing analysis supplemented by phenotypic one-cycle infection assay. Analysis of PA sequences of 6,891 influenza A and B viruses collected during 2016/17 and 2017/18 seasons showed amino acid substitutions: I38L (two A(H1N1)pdm09 viruses), E23G (two A(H1N1)pdm09 viruses) and I38M (one A(H3N2) virus); conferring 4–10-fold reduced susceptibility to baloxavir.


Article metrics loading...

Loading full text...

Full text loading...



  1. U.S. Food and Drug Administration (FDA). FDA approves new drug to treat influenza. Silver Spring: FDA; 2018. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm.
  2. Heo YA. Baloxavir: First Global Approval. Drugs. 2018;78(6):693-7.  https://doi.org/10.1007/s40265-018-0899-1  PMID: 29623652 
  3. XOFLUZATM. Drug label. San Francisco: Genentech USA, Inc.; 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210854s000lbl.pdf.
  4. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018;379(10):913-23.  https://doi.org/10.1056/NEJMoa1716197  PMID: 30184455 
  5. Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. 2018;8(1):9633.  https://doi.org/10.1038/s41598-018-27890-4  PMID: 29941893 
  6. Sugaya N, editor. Cap-dependent endonuclease inhibitor baloxavir marboxil for the treatment of influenza: results from a phase 3, open label study in otherwise healthy pediatric patients with seasonal influenza. 2nd International Meeting on Respiratory Pathogens; 2018 March 7-9; Singapore.
  7. Shishido T, Kurihara N, Rokushima M, Omoto S, Noshi T, Naito A, et al. Genotypic and phenotypic monitoring of treatment-emergent resistance to S-033188, an influenza cap-dependent endonuclease inhibitor, in a phase 2, randomized, double-blind, placebo-controlled study in otherwise healthy adults with seasonal influenza. 5th ISIRV-AVG Conference: Prevention and Treatment of RVIs: Antivirals, Traditional Therapies and Host-Directed Interventions; 2017 June 4-16; Shanghai, China.
  8. Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, et al. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018;160:109-17.  https://doi.org/10.1016/j.antiviral.2018.10.008  PMID: 30316915 
  9. Jester B, Schwerzmann J, Mustaquim D, Aden T, Brammer L, Humes R, et al. Mapping of the US domestic influenza virologic surveillance landscape. Emerg Infect Dis. 2018;24(7):1300-6.  https://doi.org/10.3201/eid2407.180028  PMID: 29715078 
  10. Takashita E, Morita H, Ogawa R, Nakamura K, Fujisaki S, Shirakura M, et al. Susceptibility of influenza viruses to the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Front Microbiol. 2018;9(3026):3026.  https://doi.org/10.3389/fmicb.2018.03026  PMID: 30574137 
  11. Stevaert A, Dallocchio R, Dessì A, Pala N, Rogolino D, Sechi M, et al. Mutational analysis of the binding pockets of the diketo acid inhibitor L-742,001 in the influenza virus PA endonuclease. J Virol. 2013;87(19):10524-38.  https://doi.org/10.1128/JVI.00832-13  PMID: 23824822 
  12. Jorquera PA, Mishin VP, Chesnokov A, Nguyen H, Mann B, Garten R, et al. Insights into the antigenic advancement of influenza A(H3N2) viruses, 2011-2018. Sci Rep. 2019. Forthcoming.
  13. Gubareva LV, Trujillo AA, Okomo-Adhiambo M, Mishin VP, Deyde VM, Sleeman K, et al. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir Ther. 2010;15(8):1151-9.  https://doi.org/10.3851/IMP1678  PMID: 21149922 
  14. Omoto S, Kurihara N, Noshi T, Nishimori S, Iwasaki M, Okamoto H, et al. editors. Phenotypic, genotypic and phylogenetic analyses reveal potent activity of baloxavir acid on a wide diversity of circulating influenza viruses. 6th ISIRV-AVG: Advances in respiratory virus therapeutics; 2018 November 13-15; Washington DC, USA.
  15. Deyde VM, Okomo-Adhiambo M, Sheu TG, Wallis TR, Fry A, Dharan N, et al. Pyrosequencing as a tool to detect molecular markers of resistance to neuraminidase inhibitors in seasonal influenza A viruses. Antiviral Res. 2009;81(1):16-24.  https://doi.org/10.1016/j.antiviral.2008.08.008  PMID: 18835410 
  16. International Reagent Resource (IRR). Manassas: IRR. Available from: https://www.internationalreagentresource.org/

Data & Media loading...

Supplementary data

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error