Real-World Effectiveness and Optimal Dosage of Favipiravir for Treatment of COVID-19: Results from a Multicenter Observational Study in Thailand
Pinyo Rattanaumpawan, Supunnee Jirajariyavej, Kanokorn Lerdlamyong, Nattawan Palavutitotai, Jatuporn Saiyarin
Antibiotics, doi:10.3390/antibiotics11060805
Favipiravir is a broad-spectrum oral antiviral agent that shows in vitro activity against SARS-CoV-2. Presently, data on the real-world effectiveness and optimal dosage of favipiravir for treating COVID-19 are limited. We conducted a retrospective observational study of hospitalized adult patients with COVID-19 at five tertiary care hospitals in Thailand. We reviewed patient charts to obtain all necessary data. Among 247 COVID-19 patients, 63 (23.0%) received ≥1 dose of favipiravir. Of these 63 patients, 61.9% were male with a median age of 48 years (range 22-85 years), 27.0% required an O 2 nasal cannula, 9.5% required non-invasive ventilation and/or high-flow O 2 therapy, and 6.4% required invasive mechanical ventilation and/or ECMO. The median baseline NEWS2 score was 5 (0-16). The Day-7 clinical improvement rate [95%CI] was 66.7% [53.7-78.0%] in all patients, 92.5% [75.7-99.1%] in patients who did not require O 2 supplementation, and 47.2% [0.4-64.5%] in patients who required O 2 supplementation. No life-threatening adverse events were identified. The 28-day mortality rate was 4.8%. A multivariate analysis revealed three poor prognostic factors for Day-7 clinical improvement (odds ratio (95%CI); p-value): older age (0.94 (0.89-0.99); p = 0.04), a higher baseline NEWS2 score (0.64 (0.47-0.88); p = 0.006), and a lower favipiravir loading dose (≤45 mg/kg/day) (0.04 (0.005-0.4); p = 0.006). In conclusion, our study reports the promising effectiveness of favipiravir for treating COVID-19 patients. In addition to older age and a high baseline NEWS2 score, a low loading dose of favipiravir (≤45 mg/kg/day) was also identified as a poor prognostic factor for early clinical improvement. Further studies to explore the optimal dose and the optimal timing of drug initiation for favipiravir should be performed.
Author Contributions: Conceptualization, P.R.; methodology, P.R., investigation, S.J., K.L., N.P. and J.S.; writing-original draft preparation, P.R., S.J., K.L., N.P. and J.S.; writing-review and editing, P.R., funding acquisition, P.R. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Siriraj Research Fund, Grant number (IO) R016333038, Faculty of Medicine Siriraj Hospital, Mahidol University. The APC was funded by Faculty of Medicine Siriraj Hospital, Mahidol University.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of all involved hospitals. The Siriraj IRB approved the protocol on 1 May 2020 (certification of approval number: Si 357/2020). Informed Consent Statement: Written inform consent was waived due to a retrospective study design.
Conflicts of Interest: The authors declare no conflict of interest.
References
Bai, Mu, Kargbo, Song, Niu et al., Clinical and Virological Characteristics of Ebola Virus Disease Patients Treated With Favipiravir (T-705)-Sierra Leone, Clin. Infect. Dis,
doi:10.1093/cid/ciw571Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of Covid-19-Preliminary Report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Bosaeed, Alharbi, Mahmoud, Alrehily, Bahlaq et al., Efficacy of favipiravir in adults with mild COVID-19: A randomized, double-blind, multicentre, placebocontrolled clinical trial, Clin. Microbiol. Infect,
doi:10.1016/j.cmi.2021.12.026Cai, Yang, Liu, Chen, Shu et al., Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study, Engineering,
doi:10.1016/j.eng.2020.03.007Chen, Zhang, Huang, Yin, Cheng et al., Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial, Front. Pharmacol,
doi:10.3389/fphar.2021.683296Chuah, Chow, Hor, Cheng, Ker et al., Efficacy of Early Treatment with Favipiravir on Disease Progression among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical Trial, Clin. Infect. Dis,
doi:10.1093/cid/ciab962Dabbous, El-Sayed, El Assal, Elghazaly, Ebeid et al., Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial, Sci. Rep,
doi:10.1038/s41598-021-98683-5Doi, Hibino, Hase, Yamamoto, Kasamatsu et al., Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01897-20Fischer, Eron, Jr, Holman, Cohen et al., A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus, Sci. Transl. Med,
doi:10.1126/scitranslmed.abl7430Furuta, Komeno, Nakamura, Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase, Proc. Jpn. Acad. Ser. B,
doi:10.2183/pjab.93.027Gottlieb, Vaca, Paredes, Mera, Webb et al., Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients, N. Engl. J. Med,
doi:10.1056/NEJMoa2116846Goyal, Choi, Pinheiro, Schenck, Chen et al., Clinical Characteristics of Covid-19 in New York City, N. Engl. J. Med,
doi:10.1056/NEJMc2010419Grasselli, Zangrillo, Zanella, Antonelli, Cabrini et al., Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy, JAMA,
doi:10.1001/jama.2020.5394Hung, Ghula, Aziz, Makram, Tawfik et al., The efficacy and adverse effects of favipiravir on patients with COVID-19: A systematic review and meta-analysis of published clinical trials and observational studies, Int. J. Infect. Dis
Mahase, Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports, BMJ,
doi:10.1136/bmj.n2713Manaf, Nitya, Dhuha, Abdulkarim, Fatema et al., Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease, Sci. Rep,
doi:10.1038/s41598-022-08794-wNguyen, Guedj, Anglaret, Laouenan, Madelain et al., Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted, PLOS Negl. Trop. Dis,
doi:10.1371/journal.pntd.0005389Pavan, Saiprasad, Akash, Akash, Aneesh et al., Evaluation of the Safety and Efficacy of Favipiravir in Adult Indian Patients with Mild-to-Moderate COVID-19 in a Real-World Setting, Int. J. Gen. Med,
doi:10.2147/IJGM.S349241Udwadia, Singh, Barkate, Patil, Rangwala 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,
doi:10.1016/j.ijid.2020.11.142Wang, Fan, Salam, Horby, Hayden et al., Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection, J. Infect. Dis,
doi:10.1093/infdis/jiz656Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial, Lancet,
doi:10.1016/S0140-6736(20)31022-9Zhao, Zhang, Zhu, Chen, Chen et al., Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial, Int. Immunopharmacol,
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