The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution

Abstract

Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated.

Inferring Demography and Selection in Organisms Characterized by Skewed Offspring Distributions

“…0:25g in the case where the correct value of N is specified. These illustrative parameter values were chosen to match general features of common viral experimental evolution studies (e.g., Foll et al 2014a;Bank et al 2016;Ormond et al 2017).…”

The mechanism of resistance to favipiravir in influenza

“…The influenza virus RdRP consists of the viral proteins PB1, PB2, and PA. All three subunits contribute to the formation of the polymerase active site, which is strongly conserved and therefore a good target for antiviral drugs as the functional constraints on the amino acids of the active site may preclude the emergence of resistance ( 24 ). So far, experimental studies have not found any mutations in influenza viruses that lead to significant resistance against favipiravir ( 11 , 16 , 25 – 29 ). In addition, no resistant mutants have yet been identified in animal models ( 19 ) or in patients treated with favipiravir ( 30 ).…”

Considering mutational meltdown as a potential SARS-CoV-2 treatment strategy

“…Also working in IAV, Ormond et al (2017) examined the combined effect of favipiravir with oseltamivir, a widely-used treatment with well-studied resistance mutations. A similar mutational meltdown outcome was observed, with the selective sweeps of oseltamivir-resistant mutations appearing to actually speed population decline, owing to the resulting hitchhiking of linked deleterious variants in the viral population (and see the related work of Pénnison et al 2017).…”