Lassa Viral Dynamics In Non-Human Primates Treated With Favipiravir Or Ribavirin

Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC50 in vivo to 2.89 mu g.mL(-1), which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.Author summaryLassa virus is the etiological agent of Lassa fever, an haemorrhagic fever endemic that cause nearly 5000 deaths every year in West Africa. Here, we provide the first within-host mathematical model of the infection by Lassa virus in a macaque model and we analyze the antiviral effect of two candidate drugs, favipiravir or ribavirin. We show that both drugs act primarily by increasing mutagenesis in vivo. Both drugs had a strong antiviral efficacy in reducing the proportion of non infectious virus produced by infected cells, up to 91 and 40% for favipiravir and ribavirin, respectively. We bridge these predictions with our knowledge of the drugs pharmacokinetics to identify target concentrations having the capability to rapidly clear infectious virus from infected individuals.