Abstract
Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).
Highlights
The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has spread throughout the globe since late 2019 and caused an unprecedented pandemic
Other reported adverse events included serum triglyceride elevation (9/82 [11.0%]) and serum alanine aminotransferase elevation (7/82 [8.5%]). In this randomized clinical trial of asymptomatic to mild COVID-19 patients, there was no significant difference in the rate of SARS-CoV-2 clearance by day 6 between aac.asm.org 5
This is in line with the observations that the difference in the viral load decrease was largest between day 1 and day 2 and that the 50% logarithmic reduction in viral load by day 6 was numerically greater in the early treatment group, suggesting the presence of modest antiviral activity in this setting
Summary
The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has spread throughout the globe since late 2019 and caused an unprecedented pandemic. Its mechanism of action is selective inhibition of viral RNA polymerase in vivo by its triphosphorylated derivative (T-705RTP), which translates to broad-spectrum inhibition of RNA viruses [3]. It is currently approved in Japan for the treatment of emerging and reemerging influenza virus infection for which other anti-influenza drugs are ineffective or not sufficiently effective [4]. Favipiravir has in vitro activity against SARS-CoV-2, and a nonrandomized study conducted in China has shown significantly shorter time to viral clearance among patients with mild to moderate COVID-19 who were treated with favipiravir and interferon alpha than in those treated with lopinavir-ritonavir and interferon alpha [5]. The objective of this study was to evaluate the efficacy of favipiravir in achieving viral clearance for patients with asymptomatic to mildly symptomatic COVID-19 infection and clinical improvement among those showing symptoms
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