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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. Author summary: Influenza viruses are associated with considerable disease burden and circulate annually causing seasonal epidemics. Antiviral drugs can be used to treat influenza infections and help reduce the disease burden. Occasionally, treatment can lead to the emergence of viruses with reduced antiviral susceptibility. Normally such viruses have reduced 'fitness', meaning they do not tend to spread or transmit widely, however on rare occasions, oseltamivir-resistant variants have become widespread in the community, thereby reducing the utility of the drug for treatment. Baloxavir is an antiviral recently licensed in many parts of the world for the treatment of influenza. Viruses with reduced susceptibility to baloxavir have been observed in clinical trials, but the frequency of such variants in the community has remained low (<0.1% globally since 2017–2018). We evaluated the fitness of viruses in ferrets and found that although 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. Surveillance to monitor for the frequency of viruses with reduced baloxavir susceptibility remains important. [ABSTRACT FROM AUTHOR]

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community. Author summary: During seasonal influenza outbreaks and global pandemics, influenza can cause significant morbidity and mortality and spread rapidly. Influenza viruses constantly change, and the effectiveness of vaccination can be low if the match between the vaccine and circulating viruses is poor. However, antiviral drugs target conserved parts of the virus and therefore typically remain effective against new seasonal or pandemic strains of influenza. The new antiviral baloxavir is more effective than existing drugs, such as oseltamivir, in reducing the amount of virus particles produced by infected people, suggesting it might reduce the onward spread of influenza viruses to others. To test this, we developed an effective way to deliver baloxavir to ferrets, the best available animal model of influenza virus transmission. We then treated influenza-infected ferrets with baloxavir to determine if they were less likely to pass their virus onto healthy ferrets housed in the same cage, or in the adjacent cage. In both cases, we found that compared to oseltamivir or placebo treatment, infected ferrets treated with baloxavir produced fewer virus particles and were less likely to transmit virus to healthy ferrets. Our results suggest baloxavir can contribute to the early control of influenza outbreaks by limiting community-based viral spread. [ABSTRACT FROM AUTHOR]