Significance 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.
【저자키워드】 SARS-CoV-2, antiviral therapy, Hydroxychloroquine, Favipiravir, preclinical model, 【초록키워드】 COVID-19, Treatment, Efficacy, High dose, coronavirus, clinical trial, Antiviral, Human, Infection, lung, Transmission, animal model, virus transmission, drug, Antiviral treatment, antiviral activity, Prophylactic, virus, antiviral drug, Antiviral effect, Prophylaxis, Repurposed drug, Spread, clinical, low dose, Wuhan, therapeutic, Mild, antiviral efficacy, viral disease, macaque, small molecule, hamster, in vivo, COVID-19 patients, protective effect, Evidence, dose, Contact, COVID-19 patient, toxic effects, Candidates, Consensus, acute respiratory syndrome, candidate, ferrets, virus levels, Lung histopathology, effective, identify, lack, evaluate, globe, significantly, required, reduced, suggested, reduction in, exhibit, baseline, infectious virus titer, nontoxic, Significance, use of hydroxychloroquine, 【제목키워드】 High dose, hamsters, antiviral activity, lack,