More rapid influenza virus elimination on baloxavir versus oseltamivir can be explained by drug mechanism
Abstract
Abstract Influenza causes significant annual morbidity and mortality and remains a pandemic threat. Unlike other human viral pathogens, influenza viral load reduction has yet to be established as a surrogate endpoint for clinical outcomes. Licensed treatments, baloxavir and oseltamivir, provide equivalent clinical benefit, though baloxavir reduces viral load more rapidly. To explain this discrepancy, we developed a data-validated mathematical model that recapitulates serial nasal viral loads in untreated human challenge study participants. Model predictions suggest that the speed of immune effector cell activation distinguishes individuals with low peak viral load and rapidly controlled infection from those with higher peak viral load and more prolonged shedding. We next incorporated oseltamivir, a neuraminidase inhibitor which blocks viral release, and baloxavir, a cap-dependent endonuclease which inhibits viral replication, into the model. Our simulations predict that to match clinical trial data, both drugs must have nearly maximal efficacy in vivo. Yet, by acting earlier during the viral replication cycle, baloxavir leads to considerably more rapid viral clearance than oseltamivir. Our results suggest that baloxavir may achieve the most rapid viral load clearance possible with an influenza targeting drug. In addition, viral load surrogate endpoints may need to be independently established for each influenza drug class.
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