Clinical efficacy and safety of favipiravir in the treatment of COVID-19 patients
Authors: Ping-Jen Chen, Chien-Ming Chao, Chih-Cheng Lai
Journal: Journal of Infection (2020)

Dear Editor, Recently, Saito et al.1.Saito S. Asai Y. Matsunaga N. Hayakawa K. Terada M. Ohtsu H. et al.First and second COVID-19 waves in Japan: a comparison of disease severity and characteristics.J Infect. 2020; (Nov 2:S0163-4453(20)30693-9)Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar showed the first two COVID-19 waves in Japan and found the difference between first and second waves in terms of the burden of medical system, patients' clinical characteristics and outcomes. In addition, we also noted that 1806 (68.3%) patients had received favipiravir for at least once during their hospitalization in this series.1.Saito S. Asai Y. Matsunaga N. Hayakawa K. Terada M. Ohtsu H. et al.First and second COVID-19 waves in Japan: a comparison of disease severity and characteristics.J Infect. 2020; (Nov 2:S0163-4453(20)30693-9)Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar However, the efficacy of favipiravir for treating COVID-19 remained unclear and was not assessed in this study. In fact, several clinical studies2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar, 3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar, 4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar, 5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar investigating the usefulness of favipiravir for COVID-19 patients have been published and provides us the opportunity to re- assess the clinical efficacy and safety of favipiravir. Therefore, we did a meta-analysis of these clinical studies to provide an update data to clarify this issue –the clinical efficacy and safety of favipiravir in the treatment of COVID-19 patients. Only clinical studies that compared the clinical efficacy of favipiravir and other alternative agents or placebo in the treatment of COVID-19 patients were identified. The results of clinical improvement were extracted for the analysis of primary outcome. In addition, the rate of viral clearance and the risk of adverse events (AEs) were collected as secondary outcomes. All statistical analyses were performed using Review Manager (RevMan) version 5.3. Overall, five clinical studies2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar, 3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar, 4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar, 5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar fulfilled the inclusion criteria and were included in this meta-analysis. A total of 552 patients were enrolled in this study, including 252 and 300 patients received favipiravir and comparator, respectively. Except Cai et al's study was before-after controlled trial,3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar all the other were randomized controlled trials.2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar,4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar, 5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar Three studies3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar, 4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar, 5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar was conducted in a single center and two were multicenter studies.2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar,6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar Three studies were conducted in China3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar,4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar,6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar and one each in Russia2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar and Oman.5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar The comparator varied, including lopinavir/ritonavir,3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar umifenovir,6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar hydroxychloroquine,5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar baloxavir4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar and standard of care.2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar,4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar First, the pooled analysis of five studies2.Ivashchenko A.A. Dmitriev K.A. Vostokova N.V. Azarova V.N. Blinow A.A. Egorova A.N. et al.AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial.Clin Infect Dis. 2020; (Aug 9;ciaa1176)https://doi.org/10.1093/cid/ciaa1176Crossref PubMed Scopus (138) Google Scholar, 3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar, 4.Lou Y. Liu L. Yao H. Hu X. Su J. Xu K. et al.Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.Eur J Pharm Sci. 2020; (Oct 25)105631https://doi.org/10.1016/j.ejps.2020.105631Crossref PubMed Scopus (102) Google Scholar, 5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar showed that favipiravir was associated with a higher clinical improvement rate than control group, but the difference did not reach statistical significance (odds ratio [OR], 1.54; 95% CI, 0.78–3.04; I2 = 43%, Fig. 1). Second, no significant difference was observed between favipiravir and comparator in terms of viral clearance rate at day 4–5 (OR, 2.70; 95% CI, 0.65–11.28; I2 = 85%), at day 7–8 (OR, 1.08; 95% CI, 0.58–1.98; I2 = 0%), at day 10–12 (OR, 2.69 95% CI, 0.98–7.35; I2 = 57%) and at day 14–16 (OR, 2.32; 95% CI, 0.81–6.66; I2 = 36%). Finally, favipiravir group was associated with a similar risk of adverse event as control group (OR, 0.571.05; 95% CI, 0.15–7.13; I2 = 93%) in the pooled analysis of 3 studies.3.Cai Q. Yang M. Liu D. Chen J. Shu D. Xia J. et al.Experimental treatment with favipiravir for COVID-19: an open-label control study.Engineering (Beijing). 2020; (Mar 18)https://doi.org/10.1016/j.eng.2020.03.007Crossref Scopus (1002) Google Scholar,5.Udwadia Z.F. Singh P. Barkate H. Patil S. Rangwala S. Pendse A. et al.Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial.Int J Infect Dis. 2020; (Nov 16;S1201-9712(20)32453-X)https://doi.org/10.1016/j.ijid.2020.11.142Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar,6.Chen C. Zhang Y. Huang J. Yin P. Cheng Z. Wu J. et al.Favipiravir versus arbidol for COVID-19: a randomized clinical trial.medRxiv. 2020; (2020. 03.17)20037432Google Scholar In this study, we cannot find the better clinical improvement and higher viral clearance rate of COVID-19 patients receiving favipiravir than those receiving comparators or standard of care. In addition, we also did not find that favipiravir was associated with a higher risk of adverse events than comparators. However, our findings should be interpreted cautiously due to several limitation. First, the study design and the comparators in each clinical study varied. Second, the numbers of study and patients were limited. Third, most findings were based on the analysis of data with high heterogeneity. Therefore, further large scale randomized controlled trial is warranted to investigate the role of favipiravir in the treatment of COVID-19 patients. In conclusion, based on low-quality evidence, there is no conclusive evidence that favipiravir would provide any additional benefit to COVID-19 patients. Therefore, further recommendation of favipiravir for COVID-19 patients should be halted until high-quality evidence from further ongoing randomized controlled trials. No.