1. Ribavirin does not potentiate favipiravir antiviral activity against Ebola virus in non-human primates
- Author
-
Vincent Madelain, Aurélie Duthey, France Mentré, Frédéric Jacquot, Caroline Solas, Bruno Lacarelle, Audrey Vallvé, Stéphane Barron, Laura Barrot, Stéphanie Mundweiler, Damien Thomas, Caroline Carbonnelle, Hervé Raoul, Xavier de Lamballerie, and Jérémie Guedj
- Subjects
0301 basic medicine ,Anemia ,viruses ,030106 microbiology ,Favipiravir ,medicine.disease_cause ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,chemistry.chemical_compound ,Virology ,Ribavirin ,medicine ,Animals ,Lassa fever ,Survival rate ,Pharmacology ,Ebola virus ,business.industry ,virus diseases ,Hemorrhagic Fever, Ebola ,Viral Load ,medicine.disease ,Ebolavirus ,Amides ,Disease Models, Animal ,Macaca fascicularis ,030104 developmental biology ,chemistry ,Viral replication ,Pyrazines ,Female ,business ,Viral load - Abstract
Background In spite of recurrent and dramatic outbreaks, there are no therapeutics approved against Ebola virus disease. Favipiravir, a RNA polymerase inhibitor active against several RNA viruses, recently demonstrated significant but not complete protection in a non-human primate model of Ebola virus disease. In this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model. Methods 15 female cynomolgus macaques were challenged intramuscularly with 1,000 FFU of Ebola virus Gabon 2001 strain and followed for 21 days. All animals received favipiravir 180 mg/kg twice a day (BID), either as monotherapy (n = 5) or in combination with ribavirin (n = 10). Ribavirin was given either at the dose 10 mg/kg BID (n = 5) or 5 mg/kg BID (n = 5). Favipiravir and ribavirin were initiated two and one days before viral challenge respectively and treatment were continued for 14 days. Treatment effects on viral and hematological markers were assessed using a mathematical model. Survival rate of 0% and 20% were obtained in macaques receiving favipiravir plus ribavirin 10 and 5 mg/kg BID, respectively, compared to 40% in the favipiravir monotherapy group (P = 0.061 when comparing monotherapy and bitherapy, log rank). Viral dynamic modeling analysis did not identify an association between plasma concentrations of ribavirin and viral load levels. Using a model of erythropoiesis, plasma concentrations of ribavirin were strongly associated with a hemoglobin drop (p = 0.0015). Conclusion Ribavirin plus favipiravir did not extend survival rates and did not lower viral replication rate compared to favipiravir monotherapy in this animal model. Patients receiving this combination in other indications, such as Lassa fever, should be closely monitored to prevent potential toxicity associated with anemia.
- Published
- 2019