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. 2022 Mar 30;16(3):e0010289.
doi: 10.1371/journal.pntd.0010289. eCollection 2022 Mar.

Ribavirin for treating Lassa fever: A systematic review of pre-clinical studies and implications for human dosing

Alex P Salam  1   2 , Alexandre Duvignaud  3   4   5 , Marie Jaspard  4   5   6 , Denis Malvy  3   4   5 , Miles Carroll  7 , Joel Tarning  1   8 , Piero L Olliaro  1 , Peter W Horby  1
Affiliations

Ribavirin for treating Lassa fever: A systematic review of pre-clinical studies and implications for human dosing

Alex P Salam et al. PLoS Negl Trop Dis. .

Abstract

Ribavirin is currently the standard of care for treating Lassa fever. However, the human clinical trial data supporting its use suffer from several serious flaws that render the results and conclusions unreliable. We performed a systematic review of available pre-clinical data and human pharmacokinetic data on ribavirin in Lassa. In in-vitro studies, the EC50 of ribavirin ranged from 0.6 μg/ml to 21.72 μg/ml and the EC90 ranged from 1.5 μg/ml to 29 μg/ml. The mean EC50 was 7 μg/ml and the mean EC90 was 15 μg/ml. Human PK data in patients with Lassa fever was sparse and did not allow for estimation of concentration profiles or pharmacokinetic parameters. Pharmacokinetic modelling based on healthy human data suggests that the concentration profiles of current ribavirin regimes only exceed the mean EC50 for less than 20% of the time and the mean EC90 for less than 10% of the time, raising the possibility that the current ribavirin regimens in clinical use are unlikely to reliably achieve serum concentrations required to inhibit Lassa virus replication. The results of this review highlight serious issues with the evidence, which, by today standards, would be unlikely to support the transition of ribavirin from pre-clinical studies to human clinical trials. Additional pre-clinical studies are needed before embarking on expensive and challenging clinical trials of ribavirin in Lassa fever.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Pharmacokinetic simulations of the different ribavirin regimens.
A) McCormick regimen day 0–10 and B) 0–72 hours. C) Irrua non-pregnant regimen day 0–10 and D) 0–72 hours. E) Irrua pregnant regimen day 0–10 and F) 0–72 hours. Dash lines represent mean EC50 and mean EC90.
See this image and copyright information in PMC

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The UK Public Health Rapid Support Team is funded by UK Aid from the Department of Health and Social Care and is jointly run by UK Health Security Agency and the London School of Hygiene & Tropical Medicine. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and Social Care.