Guillaume Lingas (1), Kyle Rosenke (2), David Safronetz (3,4), Jérémie Guedj (1)
(1) Université de Paris, IAME, INSERM, F-75018 Paris, France (2) Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA (3) Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba Canada (4) Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Objectives: Lassa fever is a potentially lethal/disabling hemorrhagic fever, endemic in West Africa, caused by Lassa virus (LASV), that afflicts between 100000 and 300000 people each year according to the CDC, resulting in an estimated 5,000 deaths due to hemorrhage and multi-organ failure [1]. With no vaccine currently available, only one treatment, ribavirin (RBV), is currently recommended by the WHO [2]. However, its efficacy is not proven in humans. Furthermore, this treatment is associated with potential hematologic side effects [3]. In a non-human primate (NHP) model of Lassa Fever, high doses of the polymerase inhibitor favipiravir (FPV) showed a survival rate 100% (as compared to 0% in untreated animals) [4], suggesting that the drug could be a new therapeutic option against LASV.
Taking advantage of our experience gained in the context of Ebola virus on favipiravir pharmacokinetics/pharmacodynamics in both NHPs and humans [5][6][7], our goal was to build a within-host model of Lassa viral infection in order to unravel the host-pathogen-drug interactions. We aimed to determine RBV and FPV main modes of action (MOA) against LASV as well as drug EC50. Finally, using this model, we predicted the antiviral efficacy of FPV and RBV on LASV when used at human dosing regimens.
Methods: We develop the first mathematical model recapitulating Lassa viral dynamics in NHP, using virological data from 24 cynolmogus macaques, treated by either FPV, RBV or left untreated. Animals treated with FPV received a loading dose of 300 mg/kg intravenously the first day of treatment, followed by subcutaneous injection of 50 mg/kg TID (N = 4) or 300 mg/kg QD (N = 4). Animals treated with RBV received a loading dose of 30 mg/kg the first day of treatment, followed by subcutaneous injections of 10 mg/kg TID (N = 4) or 30 mg/kg QD (N = 4). Animals were frequently sampled for RNA viral load and TCID50, the latter being considered as the subgroup effectively infectious among all viruses produced. We built a viral dynamic model describing the links between different types of virions, cells, immune system and treatments effects.
Favipiravir and ribavirin are generally considered to block viral production by disrupting the RNA polymerase. However recent findings in Marburg and Ebola viruses show that FPV could cause lethal mutagenesis [8]. Therefore, we considered both drugs to either act as viral production blockers or as mutagenesis agents i.e. decreasing infectivity, under the form of an Emax model, adding a Hill coefficient for FPV. We compared both MOA in their ability to reproduce our data in order to discriminate the one most likely to occur, and considered uncertainty on FPV Hill coefficient for both MOA using a model averaging (MA) approach. Finally, we simulated viral kinetic profiles using human concentrations of FPV found in the JIKI trial that assessed its efficacy in Ebola and human concentrations of RBV found in LASV infected patients.
Results: With this biological model of LASV infection, we were able to properly reproduce our data and enlighten a specific MOA of both drugs against LASV, causing mutagenesis and decreasing infectivity. Indeed, models considering this MOA consistently provided a better fit than a model assuming that the drugs blocked viral production, irrespective of the Hill coefficient.
We estimated average efficacies throughout treatment course in reducing infectivity of RBV at 40% at 30 mg/kg/day and FPV at 60% and 91% at doses 150 mg/kg/day and 300 mg/kg/day respectively. High dose favipiravir efficacy was about twice the one found in Ebola with the same daily dose [6]. Conducting MA on Hill coefficient showed a consistency in EC50s estimations, and simulations taking into account model uncertainty on this parameter showed a high level of antiviral efficacy for high dose FPV regardless of MOA.
Finally, at human plasmatic concentrations, simulations showed that FPV would be able to suppress infectivity within 2 days of treatment, even when started late in the course of the disease.
Conclusions: This model describes for the first time LASV pathogenesis and clarifies RBV and FPV modes of action. However, estimating whether those two MOA could act together could not be brought to light. FPV was shown to be much more efficient than RBV and simulations using human concentrations showed a very high antiviral efficacy of FPV (>99%). Taken together, these results provide a milestone towards an eventual use in humans.
References:
[1] CDC. Estimated number of Lassa fever cases in West Africa each year Death rate from Ebola Death rate from Lassa fever. 2015
[2] World Health Organization, Lassa Fever; https://www.who.int/news-room/fact-sheets/detail/lassa-fever.
[3] Lee DU, Je SH, Yoo SJ, Kwon T, Shin JY, Byun JJ, et al. Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration. Journal of Veterinary Pharmacology and Therapeutics. 2017;40(5):561{568. doi:10.1111/jvp.12394.
[4] Rosenke K, Feldmann H, Westover JB, Hanley PW, Martellaro C, Feldmann F, et al. Use of favipiravir to treat lassa virus infection in Macaques. Emerging Infectious Diseases. 2018;24(9):1696{1699. doi:10.3201/eid2409.180233
[5] Madelain V, Guedj J, Mentré F, Nguyen THT, Jacquot F, Oestereich L, et al. Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses. Antimicrobial Agents and Chemotherapy. 2017;61(1). doi:10.1128/AAC.01305-16.
[6] Madelain V, Baize S, Jacquot F, Reynard S, Fizet A, Barron S, et al. Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies. Nature Communications. 2018;9(1):1{11. doi:10.1038/s41467-018-06215-z.
[7] Nguyen THT, Guedj J, Anglaret X, Laou_enan C, Madelain V, Taburet AM, et al. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Neglected Tropical Diseases. 2017;11(2):1{18. doi:10.1371/journal.pntd.0005389.
[8] Espy N, Nagle E, Pfeffer B, Garcia K, Chitty AJ, Wiley M, et al. T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques. Antiviral Research. 2019;170(May):104529. doi:10.1016/j.antiviral.2019.06.001.
Reference: PAGE () Abstr 9294 [www.page-meeting.org/?abstract=9294]
Poster: Oral: Drug/Disease Modelling