Université de Paris, IAME, INSERM, F-75018, Paris, France.
Laboratoire P4 Inserm-Jean Mérieux, US003 Inserm, 69365, Lyon, France.
Antiviral Res. 2020 May;177:104758. doi: 10.1016/j.antiviral.2020.104758. Epub 2020 Mar 2.
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.
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).
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.
尽管埃博拉病毒病反复爆发且情况严重，但目前尚无获批的治疗药物。法匹拉韦是一种 RNA 聚合酶抑制剂，对多种 RNA 病毒均具有活性，最近在埃博拉病毒病的非人灵长类动物模型中显示出显著但并非完全的保护作用。在这项研究中，我们评估了法匹拉韦联合另一种广谱抗病毒药物利巴韦林在同一模型中的疗效。
15 只雌性食蟹猴经肌肉注射感染 1000 个 FFU 的埃博拉病毒加蓬 2001 株，随后观察 21 天。所有动物均接受法匹拉韦 180mg/kg，每日两次（bid）治疗，分为单药治疗组（n=5）或联合利巴韦林治疗组（n=10）。利巴韦林的剂量分别为 10mg/kg bid（n=5）或 5mg/kg bid（n=5）。法匹拉韦和利巴韦林分别在病毒攻击前 2 天和 1 天开始给药，治疗持续 14 天。使用数学模型评估治疗对病毒和血液学标志物的影响。与法匹拉韦单药治疗组的 40%相比，接受法匹拉韦联合利巴韦林 10mg/kg bid 和 5mg/kg bid 的猴子的存活率分别为 0%和 20%（当比较单药治疗和联合治疗时，log-rank 检验 P=0.061）。病毒动力学模型分析未发现利巴韦林的血浆浓度与病毒载量水平之间存在关联。利用红细胞生成模型，发现利巴韦林的血浆浓度与血红蛋白下降密切相关（p=0.0015）。
在该动物模型中，与法匹拉韦单药治疗相比，利巴韦林联合法匹拉韦并未延长生存率，也未降低病毒复制率。在其他适应证（如拉沙热）中接受该联合治疗的患者应密切监测，以预防与贫血相关的潜在毒性。
