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.

中文翻译：

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利巴韦林在非人类灵长类动物中不能增强依维拉韦抗埃博拉病毒的抗病毒活性。

背景技术尽管复发和剧烈爆发，但尚无批准用于抗埃博拉病毒病的疗法。Favipiravir是一种对几种RNA病毒具有活性的RNA聚合酶抑制剂，最近在埃博拉病毒病的非人类灵长类动物模型中显示出显着但不完全的保护作用。在这项研究中，我们评估了在同一模型中联合使用favipiravir和利巴韦林（另一种广谱抗病毒药物）的益处。方法用1,000 FFU埃博拉病毒加蓬2001菌株肌肉注射15只雌性食蟹猕猴，然后进行21天。所有动物每天接受两次180 mg / kg法维拉韦（BID）单独治疗（n = 5）或与利巴韦林联合使用（n = 10）。利巴韦林的剂量为BID 10 mg / kg（n = 5）或BID为5 mg / kg（n = 5）。分别在病毒攻击前两天和第一天开始使用Favipiravir和利巴韦林，并继续治疗14天。使用数学模型评估对病毒和血液学指标的治疗效果。接受favipiravir加上10和5 mg / kg BID的猕猴的存活率分别为0％和20％，而favipiravir单药治疗组的存活率为40％（比较单药治疗和双药治疗时P = 0.061，对数秩）。病毒动力学建模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。使用红细胞生成模型，利巴韦林的血浆浓度与血红蛋白下降密切相关（p = 0.0015）。结论在该动物模型中，利巴韦林加法维吡韦与法维吡韦单药治疗相比，并未延长生存率，也未降低病毒复制率。接受其他适应症（例如拉沙热）治疗的患者应密切监测，以防止与贫血相关的潜在毒性。