Lassa viral dynamics in non-human primates treated with favipiravir or ribavirin

Abstract

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 μg.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.

Fig 1. Observed survival according to treatment received.

Black curve: animals receiving vehicle treatment; green: animals treated with RBV; blue: animals treated with FPV 150 mg/kg/day; red: animals treated with FPV 300 mg/kg/day.

Fig 2. Ratio of titers to viral load at the time of peak viral load in cynomolgus macaques infected with Lassa (top) or Ebola (bottom) virus.

The ratio of titers is given by ${\text{log}}_{10}\left(\frac{TCI{D}_{50}.m{L}^{-1}}{RNAcopies.m{L}^{-1}}\right)$. Animals infected with Lassa virus were either untreated (black), treated with FPV 150 mg/kg/day (blue) or 300 mg/kg/day (red), and treated with RBV (green). Similar ratio was calculated in animals infected with Ebola virus that were either untreated, treated with FPV 200 mg/kg/day (blue), FPV 300 mg/kg/day (red), or FPV 360 mg/kg/day. Empty circles correspond to undetectable viral titers imputed to the limit of detection (2 log₁₀TCID₅₀.mL^-1). * = p<0.05 (Wilcoxon test).

Fig 3. Individual fits of viral load (plain lines) and viral titers (dashed line) for best model considered (κ = 5).

Plain circles represent observed viral loads and empty circles represent observed viral titers. Data below the limit of detection were represented by crosses (viral load) or crossed empty circles (viral titers).

Fig 4. Mutagenesis model simulations.

Constant favipiravir plasmatic concentration (a-c) or constant ribavirin plasmatic concentration (d). Treatment started at D4 (navy blue), D6 (blue), or D8 (red).