Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.
Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.
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DOI：
10.1073/pnas.2014441117
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发表时间：
2020-10-27
影响因子：
11.1
通讯作者：
Delang L
中科院分区：
文献类型：
--
作者：
Kaptein SJF;Jacobs S;Langendries L;Seldeslachts L;Ter Horst S;Liesenborghs L;Hens B;Vergote V;Heylen E;Barthelemy K;Maas E;De Keyzer C;Bervoets L;Rymenants J;Van Buyten T;Zhang X;Abdelnabi R;Pang J;Williams R;Thibaut HJ;Dallmeier K;Boudewijns R;Wouters J;Augustijns P;Verougstraete N;Cawthorne C;Breuer J;Solas C;Weynand B;Annaert P;Spriet I;Vande Velde G;Neyts J;Rocha-Pereira J;Delang L
此前对羟氯喹用于COVID-19患者缺乏共识，这突出表明需要彻底评估抗SARS-CoV-2药物的体内疗效。小动物感染模型，如仓鼠模型，在本文中具有关键地位。我们在此展示了法匹拉韦的体内临床前结果，这表明只有在非常高的剂量下才能达到抗SARS-CoV-2的抗病毒功效。另一方面，羟氯喹完全缺乏抗病毒活性，因此无法为其进一步用于COVID-19患者提供科学依据。通过对两种关键抗病毒候选药物的研究，我们建立了SARS-CoV-2抗病毒治疗的基线，这将使我们能够在不久的将来确定上级抗病毒候选药物。2019年12月，严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）在武汉出现后，迅速在地球仪传播。由于没有特定的治疗和预防选择，该病毒已感染了数百万人，其中超过50万人死于病毒性疾病COVID-19。对有效治疗的迫切需要以及缺乏小动物感染模型导致了使用重新利用的药物的临床试验，而没有其体内疗效的临床前证据。我们在叙利亚仓鼠中建立了感染模型，以评估小分子对感染和传播的功效。用低剂量法匹拉韦或羟氯喹与阿奇霉素联合（不联合）治疗SARS-CoV-2感染的仓鼠，分别导致病毒水平轻度降低或无降低。然而，高剂量的法匹拉韦显著降低了肺部感染性病毒滴度，并显著改善了肺组织病理学。此外，高剂量的法匹拉韦降低了直接接触的病毒传播，而羟氯喹预防失败。羟氯喹的药代动力学模型表明，总肺暴露于药物不会导致失败。因此，我们关于羟氯喹的数据（以及之前在猕猴和雪貂中的报告）没有为在COVID-19患者中使用这种药物提供科学依据。相比之下，法匹拉韦的结果表明，无毒剂量的抗病毒药物在小动物模型中对SARS-CoV-2表现出明显的保护作用。需要进行临床研究，以评估是否可以在人类中实现类似的抗病毒效果而没有毒性作用。
The previous lack of consensus around the use of hydroxychloroquine for COVID-19 patients underlines the need to thoroughly assess the in vivo efficacy of drugs against SARS-CoV-2. Small animal infection models, such as the hamster model, have a pivotal place herein. We here show in vivo preclinical results with favipiravir which indicate that antiviral efficacy against SARS-CoV-2 might only be achieved with a very high dose. Hydroxychloroquine, on the other hand, completely lacks antiviral activity, thus providing no scientific basis for its further use in COVID-19 patients. With this study on two key antiviral candidates, we establish the baseline for SARS-CoV-2 antiviral treatment, which will allow us to identify superior antiviral candidates in the near future. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2−infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.
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