Abstract
Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.
Competing Interest Statement
Keiko Baba, Takashi Hashimoto, Shinya Omoto, Takao Shishido and Takeki Uehara are employees of Shionogi & Co. Klaus Kuhlbusch, Steffen Wildum and Aeron C Hurt are employees of F. Hoffmann-La Roche. Neil Collinson and Barry Clinch are employees of Roche Products Ltd. Leo YY Lee, Paulina Koszalka, Jie Zhou, Rubaiyea Farrukee, Rebecca Frise, Edin Mifsud, Monica Galiano and Shahjahan Miah have nothing to disclose. Wendy Barclay has received honoraria from Roche, Sanofi Pasteur and Seqirus.