REACTION!

REACTION!

The REACTION! Project comprises a direct-aid response to the EBOLA crisis in 2015. The project was initiated by an international project team to provide rapid aid and health-care to the Ebola-infected population in Guinea, and by directly collecting rapid evidence of the efficacy of Favipiravir in reducing the mortality and Ebola viral load in the infected population.

Summary of the context & Overall objectives

The Ebola outbreak in West Africa was the largest and deadliest the world has ever seen. In September 2014, the number of Ebola Virus Disease (EVD) cases exceeded the total of all cases from previous known outbreaks. On Sept 4-5 2014, the WHO gathered expertise on experimental therapies and vaccines and their role in containing the EVD outbreak in West Africa. During this consuRltation, experts identified several therapeutic and vaccine interventions that should be the focus of priority evaluation. Among these candidates is the existing antiviral drug Favipiravir (FAV), that has proven activity against many RNA viruses in vivo and in vitro including Ebola virus (EBOV). The current crisis requires both an immediate response to treat patients and prevent the further spread of the epidemic, as well as long term commitment in the complex sociocultural context. REACTION! will address both needs.

The overall objectives of REACTION!:

  • Deliver evidence for the effective and safe use of FAV for the treatment and prevention of EVD in patients through a human Phase 2b trial with Ebola infected patients;
  • Deliver additional scientific data on the tolerance, optimal dose and administration timings of FAV in non-human primates infected with EBV to optimize use of FAV in the current and for further outbreaks;
  • To assure successful application of FAV in a large group of Ebola patients directly after this project if the drug shows efficacy;
  • A platform of translational research on Ebola in West Africa, including European and African researchers and technicians from various fields, and anticipate future studies that will have to be done after our trial is finished;
  • Train and educate local aid professionals and the community to ensure social mobilization and community engagement.

The secondary objectives are: to assess the efficacy of FAV in decreasing plasma RNA and infectious loads; to assess the tolerance of the drug; and to describe the evolution of viral subpopulations of EBOV (including the analysis of mutations potentially associated with antiviral resistance) using deep sequencing approaches.

The REACTION! Project was divided into 5 scientific work packages, supported by one further work package around dissemination, management and coordination.

Overall, the conclusions of the action were that there was a good tolerance of FAV and the relationship with the local communities as well as the NGOs has been excellent. Further research is necessary to better understand of FAV pharmacokinetics as well as testing of higher doses relevant for the EBOV. The REACTION! Consortium has also published extensively – with no less than 25 project related publications. Work continues beyond the lifetime of the project focusing on research and engagement has now moved into further prevention of the EBOV.

Work performed in this project

The main objective of the REACTION! project was to provide rapid evidence of FAV anti-Ebola efficacy in reducing mortality and Ebola viral load in humans with EVD. We initiated the JIKI trial, a trial in a response to the emergency in Guinea, aimed to assess the efficacy of FAV in reducing mortality in humans with EVD in Guinea. The first experiments of WP3 and WP4 provided robust PK/efficacy information to design the therapeutic protocols for this JIKI trial. Over the study-period from December 2014 to April 2015 we recruited more than 100 patients in 4 EVD treatment centers. During the -trial WP1, in addition to providing medical aid where required, collected data on viral load, mortality, tolerability and procedures related to standard-of-care. Partners of WP2 in turn put effort into increasing overall community acceptability of clinical research in this emergency and described how to turn experiences into practical tools for next outbreaks. Results of the JIKI trial revealed (1) that FAV has encouraging tolerability. (2) that low Ct values have a high prognostic value and (3) that FAV efficacy cannot yet be concluded upon. It is recommended that baseline Ct values should be used to systematically stratify analyses of drug trial in EVD. Further it is recommended to further investigate FAV monotherapy in patients with medium to high viremia. The experience of JIKI taught us that clinical research can be integrated into standard care towards evaluation of EVD-specific therapies and it even improves healthcare. Still, we recognize that there is a need for recognition of the community, though in general the local community shows good acceptability of vaccine trials. Still, it was observed that survivors and caregivers in EVD affected regions were ostracized; a huge problem after the Ebola epidemic. To this end we highly recommend to include a community mobilization strategy in clinical research in emergency situations. After the JIKI trial ended (April 2015), WP3 and WP4, performed their work by treating EVD-infected and uninfected Non Human Primates (NHP) with inoculum doses FAV to determine effective dose and collected samples for virology, genomics, biochemistry, haematology and PK studies. The work packages worked closely together and achieved the following results (1) a NHP model to analyse virus diversity by NGS in infected untreated NHPs (2) doses in the range of 150-180mg/kg were shown to significantly improve survival time and survival rate, and reduce viral replication in NHP infected by EBOV (3) a PK model relevant for analysing PK of FAV in EVD and other viruses (MARV, ZIKV, LAV, YFV). We recommend to evaluate the tolerance of higher doses FAV in patients.

Our results are published in no less than 25 book chapters/scientific publications. In the years during and following the JIKI-trial, we have disseminated our work at international conferences. Our expertise in clinical trials in emergency situation is called upon in many follow-up emergency trials.

Progress beyond state of the art

The JIKI trial was the first to evaluate a specific anti-EVD treatment, and is, to our knowledge, the largest that has been performed in EVD to date. This trial presented many challenges from inception to the final analysis which have been met pragmatically. The results of the study, as well as the challenges that were encountered, provide useful information for future clinical research in EVD.

Whilst the results of the FAV clinical trial were shown not to be conclusive, it has been very important to show the effect of FAV on the viral replication in patients with a Ct≥20 or a viral load below 108 genome copies/ml. The JIKI trial, performed in an international emergency situation, was unrandomized and provided immediate care to patients with EVD; it realized improved care for Ebola patients through the clinical trial, and improved broader scientific literacy.

In future studies, further trials should be powered, to show that monotherapy with FAV decreases mortality by at least 30%. It may also be of interest to evaluate higher doses than used in the JIKI trial as well as investigating possible combination therapies.

Other initiatives have been started to continue research on treatment of EVD in patients. Additionally, the trial team has contributed actively to the epidemiologic investigations of the last clusters of EVD beyond the epidemic in Guinea – including the FORCE, PREVAC and PREVAIL II trials.

Publications resulting from this project:

  1. Carémel, Jean François, Faye Sylvain, Ouédraogo Ramatou. 2016. “The Humanitarian Response in Guinea during Ebola outbreak” in Hofman M and Au S, editors, The Politics of Fear: Médecins sans Frontières and the West African Ebola Epidemic, Oxford: Oxford University Press, pp 63-83.
  2. Carémel, Jean François, Faye Sylvain, Ouédraogo Ramatou. 2016. « La réponse humanitaire à l’épidémie en Guinée : entre routines et exceptions » dans Hofman M et Au S, directeurs, Waterloo : Éditions La Renaissance du Livre/MSF, pp 105-128.
  3. Faye Sylvain, 2015. « L’ exceptionnalité » d’Ebola et les « réticences » populaires en Guinée Conakry. Réflexions à partir d’une approche d’anthropologie symétrique. Anthropologie et santé 11 : https://anthropologiesante.revues.org/1796.
  4. Faye Sylvain. 2017. “Pratiques de « mobilisation des communautés » dans l’urgence sanitaire par les humanitaires en Afrique de l’Ouest”, in Fouquet T et Troit V., Transition humanitaire en Côte d’Ivoire 2016, Karthala, pp. 123-145
  5. Faye Sylvain. 2017 « Confrontations des « grammaires » de la «participation» communautaire en contexte d’urgence sanitaire d’Ebola en Guinée Conakry ».  CODESRIA, HESP 2017.
  6. Gomez-Temesio Veronica et Le Marcis, Frédéric. 2017. La mise en camp de la Guinée: Ebola et l’expérience postcoloniale. L’Homme – Revue française d’anthropologie 221 : 57-90.
  7. Le Marcis Frédéric, 2015. « Traiter les corps comme des fagots » Production sociale de l’indifférence en contexte Ebola (Guinée) »  Anthropologie et Santé 11 : https://anthropologiesante.revues.org/1907.
  8. Le Marcis, F. 2015 (with Benkimoun Paul, Potier Gilbert, Janssens Michel, & Petibon Antoine). 2015. « Ebola : chronique d’une catastrophe annoncée », Humanitaire, 2015, nᵒ 40, p. 12-31.
  9. Le Marcis, F., Nguyen, V-K. 2015. An Ebola photo essay. – Limn 5:47-52 (http://limn.it/an-ebola-photo-essay/).
  10. Peiffer-Smadja et al. 2017. Vaccination and blood sampling acceptability during Ramadan fasting month: A cross-sectional study in Conakry, Guinea. Vaccine 5(19):2569-2574.
  11. Frédéric Le Marcis, Daouda Sissoko, Xavier Anglaret and Denis Malvy (2018)  “Doing Science in an Emergency. Challenging clinical trial standards and producing care.”in J. Graham et al. (ed) Localizing Standards, Vancouver UBC Press
  12. Dose regimen of favipiravir for Ebola virus disease. Mentré F, Taburet AM, Guedj J, Anglaret X, Keïta S, de Lamballerie X, Malvy D. Lancet Infect Dis. 2015 Feb;15(2):150-1.
  13. Favipiravir for children with Ebola. Bouazza N, Treluyer JM, Foissac F, Mentré F, Taburet AM, Guedj J, & all. The Lancet. 2015 Feb 14, Vol. 385, No. 9968, p603–604. 15
  14. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. Sissoko D & all. PLoS Med. 2016 Mar 1;13(3)
  15. Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. Sissoko D & all. PLoS Med. 2016 Apr 5;13(4)
  16. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, Mentré F. Clin Pharmacokinet. 2016 Aug;55(8):907-23
  17. Frédéric Le Marcis « Traiter les corps comme des fagots » Production sociale de l’indifférence en contexte Ebola (Guinée) Anthropologie & Santé
  18. Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With    Virus Persistence in Seminal Fluid for More Than 500 Days. Diallo B, Sissoko D, Loman NJ, Bah HA, Bah H, Worrell MC, Conde LS, Sacko R, Mesfin S, Loua A, Kalonda JK, Erondu NA, Dahl BA, Handrick S, Goodfellow I, Meredith LW, Cotten M, Jah U, Guetiya Wadoum RE, Rollin P, Magassouba N, Malvy D, Anglaret X, Carroll MW, Aylward RB, Djingarey MH, Diarra A, Formenty P, Keïta S, Günther S, Rambaut A, Duraffour S. Clin Infect Dis. 2016; 63(10):1353-1356
  19. Ebola virus dynamics in mice treated with favipiravir. Madelain V, Oestereich L, Graw F, Nguyen TH, de Lamballerie X, Mentré F, Günther S, Guedj J. Antiviral Res. 2015 Nov;123:70-7.
  20. Ebola virus persistence in breast milk after no reported illness: a likely        source of virus transmission from mother to child. Sissoko D, Keïta M, Diallo B, Aliabadi N, David L. Fitter DL, Dahl BA, Bore JA, Koundouno FR, Singethan K, Meisel S, Enkirch T, Mazzarelli A, Amburgey V,  Faye O, Sall AA, Magassouba N, Carroll MW, Anglaret X, Malvy D, Formenty P,  Aylward RB, Keïta S, Djingarey MH, Nicholas J. Loman NJ, Günther S, Duraffour S. Clin Infect Dis. 2017 Feb 15;64(4):513-516
  21. Favipiravir pharmacokinetics in non-human primates: insights for future efficacy studies of haemorrhagic fever viruses. Madelain V, Guedj J, Mentré F, N’Guyen THT, Jacquot F, Oestereich L, Kadota T, Yamada K, Taburet AM, de Lamballerie X, Raoul H. Antimicrob Agents Chemother. 2016 Dec 27;61(1).
  22. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Sissoko D, Duraffour S, Kerber R, Kolie JS, Beavogui AH, Camara AM, Colin G, Rieger T, Oestereich L, Pályi B, Wurr S, Guedj J, Nguyen THT, Eggo RM, Watson CH, Edmunds WJ, Bore JA, Koundouno FR, Cabeza-Cabrerizo M, Carter LL, Kafetzopoulou LE, Kuisma E, Michel J, Patrono LV, Rickett NY, Singethan K, Rudolf M, Lander A, Pallasch E, Bockholt S, Rodríguez E, Di Caro A, Wölfel R, Gabriel M, Gurry C, Formenty P, Keïta S, Malvy D, Carroll MW, Anglaret X, Günther S. Lancet Glob Health. 2017 Jan;5(1)
  23. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. Nguyen TH, Guedj J, Anglaret X, Laouénan C, Madelain V, Taburet AM, Baize S, Sissoko D, Pastorino B, Rodallec A, Piorkowski G, Carazo S, Conde MN, Gala JL, Bore JA, Carbonnelle C, Jacquot F, Raoul H, Malvy D, de Lamballerie X, Mentré F; JIKI study group. PLoS Negl Trop Dis. 2017 Feb 23;11(2)
  24. How to treat Ebola virus infections? A lesson from the field. Duraffour S, Malvy D, Sissoko D. Curr Opin Virol. 2017 Jun;24:9-15
  25. Antiviral efficacy of favipiravir against Ebola virus in cynomolgus macaques. Guedj J, Piorkowski G, Jacquot F, Madelain V, Nguyen T-H-T, Rodallec A, Gunther S, Carbonelle C, Mentré F, Raoul H, de Lamballerie X. Submitted to PLOS Medicine

 

Video about the project (French with English subtitles)

JIKI: l’histoire d’un espoir (French with English subtitles) – https://www.youtube.com/watch?v=9JWAhBB_jHQ&t=3s

 

Project Team

  1. INSERM – Institut National de la Santé et de la Recherche Medicale – France
  2. Bernhard-Nocht Institut Fur Tropenmedizin – Germany
  3. Ecolé Normale Superieure de Lyon – France
  4. Université Cheikh Anta Diop de Dakar – Senegal
  5. Fondation Pour l’Institut de Hautes Etudes Internationales et du Developpement – Switzerland
  6. Institut Pasteur – France
  7. Ruprecht-Karls-Universitaet Heidelberg – Germany
  8. Université D’Aix Marseille
  9. Association pour le Developpement de l’Enseignement et des Recherches Aupres des Universites – France
  10. Universiteit Utrecht – the Netherlands
  11. Public Health England – Department of Health – Great Britain
  12. Drug Discovery Factory BV (Catalyze) – the Netherlands

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