Experimental Treatment with Favipiravir for Ebola Virus Disease

Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the...

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Published in:	PLoS medicine Vol. 13; no. 3
Main Authors:	Sissoko, Daouda, Laouenan, Cedric, Folkesson, Elin, M'Lebing, Abdoul-Bing, Baize, Sylvain, Camara, Alseny-Modet, Shepherd, Susan, Danel, Christine, Gala, Jean-Luc, Colin, Géraldine, Savini, Hélène, Bore, Joseph Akoi, Le Marcis, Frederic, Koundouno, Fara Raymond, Petitjean, Frédéric, Diederich, Sandra, Poelart, Geertrui, Berbain, Emmanuel, Dindart, Jean-Michel, Lefevre, Annabelle, Leno, Tamba, Bangoura, N'Famara, Palich, Romain, Hinzmann, Julia, Berette, Sakoba, Camara, Mohamed Seto, Chanfreau Munoz, Valérie, Souley Harouna, Kighoma, Patient Mumbere, Koundouno, Fara Roger, Réné Lolamou, Loua, Cécé Moriba, Moumouni, Kinda, Provost, Célia, Samake, Nenefing, Sekou, Conde, Soumah, Abdoulaye, Arnould, Isabelle, Komano, Michel Saa, Gustin, Lina, Berutto, Carlotta, Camara, Diarra, Camara, Fodé Saydou, Colpaert, Joliene, Jansson, Lena, Kourouma, Etienne, Loua, Maurice, Malme, Kristian, Milinouno, Adele, Ombelet, Sien, Sidiboun, Aboubacar Youla, Verreckt, Isabelle, Yombouno, Pauline, Carbonnelle, Caroline, Mely, Stéphane, Nguyen, Vinh-Kim, Taburet, Anne-Marie, Treluyer, Jean-Marc, Kolie, Jacques, Moh, Raoul, Gonzalez, Minerva Cervantes, Kuisma, Eeva, Ngabo, Didier, Rudolf, Martin, Thom, Ruth, Kerber, Romy, Gabriel, Martin, Di Caro, Antonino, Wölfel, Roman, Badir, Jamal, Bentahir, Mostafa, Dumont, Catherine, Durant, Jean-François, El Bakkouri, Karim, Gasasira Uwamahoro, Marie, Smits, Benjamin, Van Cauwenberghe, Stéphane, Ezzedine, Khaled, Pizarro, Louis, Guedj, Jérémie, Barte de Sainte Fare, Eric, Murgue, Bernadette, Rapp, Christophe, Piguet, Pascal, Poncin, Marc, Draguez, Bertrand, Allaford Duverger, Thierry, Barbe, Solenne, Baret, Guillaume, Defourny, Isabelle, Raoul, Hervé, Eholie, Serge P, Levy-Marchal, Claire, Antierrens, Annick, Van Herp, Michel, Günther, Stephan, de Lamballerie, Xavier, Keïta, Sakoba, Mentre, France, Anglaret, Xavier
Format:	Journal Article
Language:	English
Published:	Public Library of Science 01-03-2016
Subjects:	Antiviral agents Drug therapy Ebola hemorrhagic fever Patient outcomes Guinea
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Summary:	Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age [greater than or equal to] 1 y, weight [greater than or equal to] 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.
ISSN:	1549-1277 1549-1676
DOI:	10.1371/journal.pmed.1001967