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 (PA) 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 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/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.
Highlights
Antivirals are important for the treatment of influenza infections, in high-risk individuals such as the immunocompromised and the elderly
We evaluated the fitness of viruses in ferrets and found that A/H1N1 and A/H3N2 viruses with reduced baloxavir susceptibility were able to replicate and transmit among ferrets, they had a moderate reduction in fitness compared to normal ‘wild-type’ viruses, suggesting a reduced likelihood of spread
Pre- and post-treatment clinical isolate influenza A viruses were tested by plaque reduction assay to assess the baloxavir susceptibility of treatment-emergent variant viruses harboring the polymerase acidic (PA)/I38T substitution
Summary
Antivirals are important for the treatment of influenza infections, in high-risk individuals such as the immunocompromised and the elderly. Neuraminidase inhibitors (NAIs) such as oseltamivir are the current standard of care for treating influenza-related hospitalizations during seasonal epidemics [1], and are stockpiled in some countries as pandemic contingency [2]. The high frequency of mutations during influenza virus replication combined with the selective pressure of antiviral treatment can lead to the emergence of viral variants with reduced antiviral susceptibility or resistance. M2 ion channel blockers are no longer prescribed to treat influenza A viruses, as nearly 100% of circulating influenza viruses contain an S31N amino acid substitution that confers resistance to these antiviral drugs [3]. H275Y substitutions in viral neuraminidase (NA) can lead to reduced susceptibility of influenza viruses to oseltamivir and another NAI, peramivir [4]. There is an ongoing need for the development of antivirals that utilize novel mechanisms of action, such that multiple effective treatment options are available in the case that resistance towards an existing class of antiviral drugs becomes widespread
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