Antiviral susceptibility of influenza viruses isolated from patients pre- and post-administration of favipiravir.
Favipiravir, a viral RNA-dependent RNA polymerase inhibitor, has recently been approved in Japan for influenza pandemic preparedness. Here, we conducted a cell-based screening system to evaluate the susceptibility of influenza viruses to favipiravir. In this assay, the antiviral activity of favipiravir is determined by inhibition of virus-induced cytopathic effect, which can be measured by using a colorimetric cell proliferation assay. To demonstrate the robustness of the assay, we compared the favipiravir susceptibilities of neuraminidase (NA) inhibitor-resistant influenza A(H1N1)pdm09, A(H3N2), A(H7N9) and B viruses and their sensitive counterparts. No significant differences in the favipiravir susceptibilities were found between NA inhibitor-resistant and sensitive viruses. We, then, examined the antiviral susceptibility of 57 pairs of influenza viruses isolated from patients pre- and post-administration of favipiravir in phase 3 clinical trials. We found that there were no viruses with statistically significant reduced susceptibility to favipiravir or NA inhibitors, although two of 20 paired A(H1N1)pdm09, one of 17 paired A(H3N2) and one of 20 paired B viruses possessed amino acid substitutions in the RNA-dependent RNA polymerase subunits, PB1, PB2 and PA, after favipiravir administration. This is the first report on the antiviral susceptibility of influenza viruses isolated from patients after favipiravir treatment.
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan.
Emi
E
Takashita
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan.
Miho
M
Ejima
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan.
Rie
R
Ogawa
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan.
Seiichiro
S
Fujisaki
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
Gabriele
G
Neumann
Toyama Chemical Co., Ltd., 4-1, Shimookui 2-chome, Toyama, 930-8508, Japan.
Yousuke
Y
Furuta
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
Yoshihiro
Y
Kawaoka
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan.
Masato
M
Tashiro
Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan. Electronic address: todagiri@nih.go.jp.
Takato
T
Odagiri
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000302:isolation & purification; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D014764:Viral Proteins / Q000037:antagonists & inhibitors
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D014764:Viral Proteins; C487630:NA protein, influenza A virus; D009439:Neuraminidase; C462182:favipiravir
Antiviral resistance; Favipiravir; Influenza; Polymerase inhibitor; T-705