Abstract
The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza A and B virus infections in February 2018 in Japan. Because of the need to monitor influenza viruses for reduced susceptibility to this drug, we used two cell-based screening systems – a conventional plaque reduction assay and a focus reduction assay – to evaluate the susceptibility of influenza viruses to baloxavir. First, we generated a reference virus possessing an I38T substitution in the polymerase acidic subunit (PA), which is known to be associated with reduced susceptibility to baloxavir, and demonstrated the validity of our systems using this reference virus. We then determined the susceptibility of a panel of neuraminidase (NA) inhibitor-resistant viruses and their sensitive counterparts to baloxavir. No significant differences in baloxavir susceptibilities were found between the NA inhibitor-resistant and -sensitive viruses. We also examined seasonal influenza viruses isolated during the 2017–2018 influenza season in Japan and found that no currently circulating A(H1N1)pdm09, A(H3N2), or B viruses had significantly reduced susceptibility to baloxavir and none of the viruses possessed an amino acid substitution at PA residue 38. Use of a combination of methods to analyze antiviral susceptibility and detect amino acid substitutions is valuable for monitoring the emergence of baloxavir-resistant viruses.
Highlights
In Japan, four neuraminidase (NA) inhibitors – oseltamivir, zanamivir, peramivir, and laninamivir – are approved for therapeutic or prophylactic treatment of influenza virus infection
polymerase acidic subunit (PA) I38T and I38F substitutions emerged as a result of exposure to baloxavir marboxil in four (3.6%) of 112 A(H1N1)pdm09 viruses for which PA sequences were available in a Phase II clinical trial (Shishido et al, 2017; Omoto et al, 2018)
These results demonstrate that both cell-based screening systems are appropriate to evaluate the susceptibility of influenza viruses to baloxavir
Summary
In Japan, four neuraminidase (NA) inhibitors – oseltamivir, zanamivir, peramivir, and laninamivir – are approved for therapeutic or prophylactic treatment of influenza virus infection. The novel cap-dependent endonuclease inhibitor baloxavir marboxil (S-033188) was approved on 23 February 2018 for the therapeutic treatment of influenza A and B virus infections and became. In vitro studies have revealed that an I38T substitution in the polymerase acidic subunit (PA) is associated with reduced susceptibility of influenza A(H1N1), A(H3N2), and B viruses to baloxavir (Noshi et al, 2018; Omoto et al, 2018). PA I38T and I38F substitutions emerged as a result of exposure to baloxavir marboxil in four (3.6%) of 112 A(H1N1)pdm viruses for which PA sequences were available in a Phase II clinical trial (Shishido et al, 2017; Omoto et al, 2018). There is a need to develop convenient assays to monitor the baloxavir susceptibility of influenza viruses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
