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Favipiravir for symptomatic COVID-19: A nationwide observational cohort study

  • Yohei Doi
    Correspondence
    Corresponding author. Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
    Affiliations
    Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

    Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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  • Takuma Ishihara
    Affiliations
    Innovative and Clinical Research Promotion Center, Gifu University Hospital, Yanagido, Gifu, Japan
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  • Sumi Banno
    Affiliations
    Center for Clinical Trial and Research Support, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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  • Masahiko Ando
    Affiliations
    Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Aichi, Japan
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  • Masashi Kondo
    Affiliations
    Center for Clinical Trial and Research Support, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

    Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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  • on behalf ofthe Favipiravir Observational Study
Published:November 04, 2022DOI:https://doi.org/10.1016/j.jiac.2022.10.008

      Abstract

      Introduction

      Favipiravir, an antiviral agent with activity against SARS-CoV-2, was made available to hospitals in Japan for off-label use among COVID-19 patients between 2020 and 2021.

      Methods

      A nationwide observational cohort study was conducted on patients who received favipiravir as part of clinical care between February 2020 and December 2021. Information was collected on demographics, comorbidities, severity of illness, use of favipiravir and other medications targeting COVID-19, adverse events, clinical status at 7 and 14 days and clinical outcome one month after admission to the hospital.

      Results

      A total of 17,508 hospitalized patients who received favipiravir were registered from 884 hospitals. In terms of demographics, 55.9% were age ≥60 years, and 62.3% were male. At least one of the four surveyed comorbidities was present in 45.5% of the patients. The rates of clinical improvement at 7 and 14 days were 72.4% and 87.5%, 61.4% and 76.6%, and 45.4% and 59.5% for mild, moderate, and severe diseases, respectively. The case fatality rates within a month from hospitalization were 3.3%, 12.6%, and 29.1% for mild, moderate, and severe diseases, respectively. Significant correlations were observed between death and advanced age, male sex, moderate or severe disease, diabetes, cardiovascular diseases, and immunosuppression. Commonly reported adverse events included uric acid level increase or hyperuricemia (16.8%), liver function abnormalities (6.9%), and rash (1.0%).

      Conclusions

      Favipiravir was well tolerated among COVID-19 patients. The study provides insights into the use of this agent at hospitals across Japan in the early phase of the pandemic.

      Keywords

      1. Introduction

      Favipiravir is a nucleoside analog antiviral agent that inhibits RNA-dependent RNA polymerase and demonstrates a wide spectrum of activity against RNA viruses. In Japan, favipiravir has been approved for the treatment of patients with novel or re-emerging pandemic influenza against which other treatments are ineffective, but the inventory is managed by the government and the drug is not routinely available for prescription. Given its in vitro activity against SARS-CoV-2, favipiravir was made available to hospitals for off-label use among patients with COVID-19 between February 2020 and December 2021, the period during which approved oral antiviral treatment options for COVID-19 were not yet available. Hospitals were asked to register the cases to this observational cohort study after it was administered to patients. This was the first occasion in which a large number of patients received favipiravir for the treatment of a viral infection in Japan. Here, we report the final dataset from the cohort, with a focus on demographics, disease course, and safety of favipiravir.

      2. Methods

      2.1 Off-label use of favipiravir

      Favipiravir was made available to hospitals between February 2020 and December 2021 from FUJIFILM Toyama Chemical Co., Ltd., the manufacturer of favipiravir, after a request for off-label use of the agent was made by the hospitals to the Ministry of Health, Labour and Welfare and the requirements for close management of the medication were met, which practically restricted its use to hospitalized patients. The physicians prescribed favipiravir to patients with a confirmed diagnosis of COVID-19 upon consent in accordance with institutional regulations governing off-label use at each hospital.

      2.2 Study design

      This study was conducted as a retrospective study to collect clinical information after favipiravir was administered to patients as part of clinical care. Informed consent was on an opt-out basis given the non-interventional nature of the study. The hospitals were asked to provide anonymized information regarding the patient demographics, comorbidities, severity of illness, location of patient (inpatient or outpatient), dose and duration of favipiravir, use of other medications targeting COVID-19, adverse events likely related to favipiravir use, clinical status 7 and 14 days from the start of the use of favipiravir and clinical outcome approximately one month after admission to the hospital. This study was approved by the Institutional Review Board of Fujita Health University.

      2.3 Data collection and analysis

      The data were collected using the survey function of REDCap. Query and data cleaning was conducted to address apparent errors such as duplicate record entry, missing values and outliers. Site monitoring was not conducted.
      Continuous variables were described using median and interquartile range and categorical variables using frequencies. For the analysis of prognosis, the Kaplan-Meier estimate and Cox proportional hazards model were used. The date of the first dose of favipiravir was used as the baseline date, and a period up to the date of entry of clinical outcome was handled as the follow-up period. Only the clinical outcome recorded as died in hospital was defined as death. Age, sex, severity of illness, and underlying diseases (diabetes, cardiovascular diseases, chronic lung diseases, and immunosuppression) were considered to possibly affect death, and each of these factors was selected as explanatory variables of the Cox proportional hazards model. No correlations suspected of multicollinearity were noted between each variable. The proportional hazards assumption was confirmed using Schoenfeld's partial residuals of the independent variables included in the model. Age was handled as a continuous variable, and other variables were handled as categorical variables. We used R (version 4.1.3 patched) for all statistical analyses. A two-sided p < 0.05 was considered statistically significant.
      Interim reports of the study have previously been released on the Japanese Association of Infectious Diseases website (https://www.kansensho.or.jp/modules/en/) in May and September 2020, and April and November 2021.

      3. Results

      3.1 Overview

      A total of 17,508 hospitalized patients who received favipiravir were registered from 884 hospitals. Of these patients, the patient demographics, clinical status at Day 7, clinical status at Day 14, and clinical outcome at approximately one month after hospital admission were available for 17,366, 16,512, 13,425, and 17,461 patients, respectively. Fig. 1 shows the number of patients started on favipiravir by month. Over two thousand patients were treated with favipiravir in April 2020 at the height of the first surge. Its use then increased again in the summer and winter of 2020, corresponding to the second and third surges, respectively, then decreased in 2021 over the course of the fourth and fifth surges. Since the cohort only includes patients who received favipiravir, clinical effectiveness of this agent cannot be evaluated from this dataset. Rather, below describes the general features of patients who opted into this off-label use program.
      Fig. 1
      Fig. 1Number of patients started on favipiravir based on month.

      3.2 Patient demographics

      The age distribution, sex, presence or absence of underlying disease (diabetes, cardiovascular diseases, chronic lung diseases, and immunosuppression), and use of other antiviral agents are shown in Table 1. In terms of demographics, 55.9% were age ≥60 years, and 62.3% were male. At least one of the four surveyed comorbidities (diabetes, cardiovascular diseases, chronic lung diseases, and immunosuppression) was present in 45.5% of the patients.
      Table 1Demographics and concomitant COVID-19-related medications of patients with COVID-19 who received favipiravir.
      VariablesCategoriesn (%)
      Demographics
      Age group (n = 17,508)<101 (0.0%)
      10–1967 (0.4%)
      20–29694 (4.0%)
      30–391074 (6.1%)
      40–492383 (13.6%)
      50–593501 (20.0%)
      60–693134 (17.9%)
      70–793499 (20.0%)
      80–892491 (14.2%)
      ≥90664 (3.8%)
      Sex (n = 17,508)Female6597 (37.7%)
      Male10,911 (62.3%)
      Diabetes (n = 17,429)Present4070 (23.4%)
      Absent13,359 (76.6%)
      Cardiovascular diseases (n = 17,440)Present4034 (23.1%)
      Absent13,406 (76.9%)
      Chronic lung diseases (n = 17,415)Present1611 (9.3%)
      Absent15,804 (90.7%)
      Immunosuppression (n = 17,410)Present775 (4.5%)
      Absent16,635 (95.5%)
      Any of the above comorbidities (n = 17,457)Present7951 (45.5%)
      Absent9506 (54.5%)
      Concomitant COVID-19-related medications
      Ciclesonide (n = 17,508)Given4289 (24.5%)
      Not given13,219 (75.5%)
      Lopinavir–ritonavir (n = 17,508)Given72 (0.4%)
      Not given17,436 (99.6%)
      Hydroxychloroquine (n = 17,508)Given198 (1.1%)
      Not given17,310 (98.9%)
      Nafamostat (n = 17,508)Given1084 (6.2%)
      Not given16,424 (93.8%)
      Camostat (n = 17,508)Given702 (4.0%)
      Not given16,806 (96.0%)
      Remdesivir (n = 17,508)Given2312 (13.2%)
      Not given15,196 (86.8%)
      Dexamethasone (n = 17,508)Given7012 (40.1%)
      Not given10,496 (59.9%)
      Methylprednisolone (n = 17,508)Given2064 (11.8%)
      Not given15,444 (88.2%)
      Outcome (n = 17,461)Died in hospital1203 (6.9%)
      Transferred for escalation of care934 (5.3%)
      Still in hospital (alive)179 (1.0%)
      Transferred for de-escalation of care1303 (7.5%)
      Discharged alive13,842 (79.3%)

      3.3 Administration of favipiravir

      Administration of favipiravir is shown in Table 2. In 94.8% of the patients, favipiravir was dosed at two doses of 1800 mg followed by 800 mg twice a day. The median days from the first positive COVID-19 test and hospital admission to the initiation of favipiravir therapy were 2 and 0 days, respectively. The median duration of treatment was 8 days.
      Table 2Administration of favipiravir.
      (a) Dosing of favipiravir
      nDosingn (%)
      17,4782 doses of 1600 mg followed by 600 mg twice a day550 (3.1%)
      2 doses of 1800 mg followed by 800 mg twice a day16564 (94.8%)
      Others364 (2.1%)
      (b) Duration of favipiravir
      nMedianQ1 (25%)Q3 (75%)
      17,5088510
      (c) Days from first positive test to first dose of favipiravir
      nMedianQ1 (25%)Q3 (75%)
      17,508214
      (d) Days from hospital admission to first dose of favipiravir
      nMedianQ1 (25%)Q3 (75%)
      17,508001

      3.4 Severity of illness

      For this study, mild, moderate, and severe diseases at the start of favipiravir were defined as those not requiring supplemental oxygen, those breathing spontaneously but requiring supplemental oxygen, and those requiring mechanical ventilation or extracorporeal membrane oxygenation, respectively. By this definition, 11,680 patients (66.7%) had mild disease, 5303 patients (30.3%) had moderate disease, and 525 patients (3%) had severe disease.

      3.5 Clinical course and outcome by severity of disease

      The clinical course at 7 and 14 days after the start of favipiravir therapy was evaluated as improved, worsened, or unchanged by the treating physicians. The rates of clinical improvement at 7 and 14 days were 72.4% and 87.5%, 61.4% and 76.6%, and 45.4% and 59.5% for mild, moderate, and severe diseases, respectively (Table 3). The rates of clinical worsening at 7 and 14 days were 14.5% and 6.8%, 24.4% and 16%, and 28% and 25.5% for mild, moderate, and severe diseases, respectively.
      Table 3Clinical status and outcome stratified by severity of illness in patients who received favipiravir.
      (a) At 7 days after start of favipiravir
      ImprovedUnchangedWorsened
      Day 7 (n = 16,512)Mild8057 (72.4%)1449 (13%)1618 (14.5%)
      Moderate3010 (61.4%)697 (14.2%)1199 (24.4%)
      Severe219 (45.4%)128 (26.6%)135 (28%)
      (b) At 14 days after start of favipiravir
      ImprovedUnchangedWorsened
      Day 14 (n = 13,425)Mild7753 (87.5%)512 (5.8%)600 (6.8%)
      Moderate3161 (76.6%)305 (7.4%)659 (16%)
      Severe259 (59.5%)65 (14.9%)111 (25.5%)
      (c) Clinical outcome one month from hospital admission
      Died in hospitalTransferred for escalation of careStill in hospital (alive)Transferred for de-escalation of careDischarged alive
      Outcome (n = 17,461)Mild386 (3.3%)475 (4.1%)86 (0.7%)621 (5.3%)10,074 (86.5%)
      Moderate665 (12.6%)438 (8.3%)75 (1.4%)534 (10.1%)3585 (67.7%)
      Severe152 (29.1%)21 (4%)18 (3.4%)148 (28.4%)183 (35.1%)
      The clinical outcome was assessed at approximately one month from hospitalization as discharged alive, died in hospital, transferred for de-escalation of care, transferred for escalation of care, or still in hospital. The case fatality rates within a month from hospitalization were 3.3%, 12.6%, and 29.1% for mild, moderate, and severe diseases, respectively.

      3.6 Clinical course and outcome by age group

      The clinical course and outcome based on age groups are shown in Table 4. Both the clinical course and outcome were worse in older patients. The case fatality rate was 1.2% in the 50–59 age group, whereas the rates were 3.7%, 9.4%, 21%, and 27.6% in the 60–69, 70–79, 80–89, and ≥90 age groups, respectively.
      Table 4Clinical status and outcome stratified by age group in patients who received favipiravir.
      (a) At 7 days after start of favipiravir
      ImprovedUnchangedWorsened
      Day 7 (n = 16,512)<101 (100%)0 (0%)0 (0%)
      10–1958 (89.2%)6 (9.2%)1 (1.5%)
      20–29587 (89.1%)49 (7.4%)23 (3.5%)
      30–39863 (83.2%)101 (9.7%)73 (7%)
      40–491820 (80%)243 (10.7%)211 (9.3%)
      50–592485 (75.4%)339 (10.3%)473 (14.3%)
      60–692005 (68.2%)398 (13.5%)539 (18.3%)
      70–791950 (59.5%)550 (16.8%)775 (23.7%)
      80–891224 (52.3%)438 (18.7%)678 (29%)
      ≥90293 (47.1%)150 (24.1%)179 (28.8%)
      (b) At 14 days after start of favipiravir
      ImprovedUnchangedWorsened
      Day 14 (n = 13,425)<101 (100%)0 (0%)0 (0%)
      10–1937 (90.2%)3 (7.3%)1 (2.4%)
      20–29484 (94.5%)20 (3.9%)8 (1.6%)
      30–39758 (93.6%)32 (4%)20 (2.5%)
      40–491660 (93.4%)65 (3.7%)52 (2.9%)
      50–592430 (91.1%)119 (4.5%)118 (4.4%)
      60–692022 (85.7%)129 (5.5%)209 (8.9%)
      70–792111 (77.6%)226 (8.3%)382 (14%)
      80–891352 (67.6%)201 (10.1%)447 (22.4%)
      ≥90318 (59.1%)87 (16.2%)133 (24.7%)
      (c) Clinical outcome one month from hospital admission
      Died in hospitalTransferred for escalation of careStill in hospital (alive)Transferred for de-escalation of careDischarged alive
      Outcome (n = 17,461)<100 (0%)0 (0%)0 (0%)0 (0%)1 (100%)
      10–190 (0%)0 (0%)1 (1.5%)1 (1.5%)65 (97%)
      20–292 (0.3%)10 (1.4%)2 (0.3%)28 (4%)652 (93.9%)
      30–392 (0.2%)35 (3.3%)4 (0.4%)31 (2.9%)1001 (93.3%)
      40–4910 (0.4%)88 (3.7%)3 (0.1%)74 (3.1%)2200 (92.6%)
      50–5943 (1.2%)185 (5.3%)11 (0.3%)144 (4.1%)3106 (89%)
      60–69116 (3.7%)233 (7.5%)24 (0.8%)188 (6%)2566 (82.1%)
      70–79327 (9.4%)268 (7.7%)64 (1.8%)336 (9.6%)2495 (71.5%)
      80–89520 (21%)102 (4.1%)44 (1.8%)374 (15.1%)1442 (58.1%)
      ≥90183 (27.6%)13 (2%)26 (3.9%)127 (19.2%)314 (47.4%)

      3.7 Prognostic factors

      Univariable analysis showed significant correlations between death and advanced age, moderate or severe disease, diabetes, cardiovascular diseases, chronic lung diseases, and immunosuppression (Table 5). A multivariable analysis showed significant correlations between death and advanced age, male sex, moderate or severe disease, diabetes, cardiovascular diseases, and immunosuppression (Table 6). Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8 show survival curves stratified by each factor.
      Table 5Predictors of death in hospital (univariable analysis).
      VariablesHazard ratioLower limit of 95% CIUpper limit of 95% CIP-value
      Age1.071.061.07<0.001
      Male (vs. female)1.120.991.250.068
      Moderate (vs. mild)2.782.453.15<0.001
      Severe (vs. mild)3.663.024.43<0.001
      Diabetes1.391.231.56<0.001
      Cardiovascular diseases1.821.622.05<0.001
      Chronic lung diseases1.611.381.86<0.001
      Immunosuppression1.751.462.11<0.001
      Table 6Predictors of death in hospital (multivariable analysis).
      VariablesHazard ratioLower limit of 95% CIUpper limit of 95% CIP-value
      Age1.081.071.08<0.001
      Male (vs. female)1.621.431.83<0.001
      Moderate (vs. mild)2.322.052.64<0.001
      Severe (vs. mild)4.453.665.4<0.001
      Diabetes1.261.121.42<0.001
      Cardiovascular diseases1.151.021.290.022
      Chronic lung diseases1.150.991.340.067
      Immunosuppression1.911.582.3<0.001
      Fig. 5
      Fig. 5Survival by presence or absence of diabetes.
      Fig. 6
      Fig. 6Survival by presence or absence of cardiovascular disease.
      Fig. 7
      Fig. 7Survival by presence or absence of chronic lung disease.
      Fig. 8
      Fig. 8Survival by presence or absence of immunocompromising condition.

      3.8 Adverse events

      A total of 4312 (24.6%) patients had probable or possible adverse events in association with favipiravir use recorded based on the treating physicians’ assessment (Table 7). Commonly reported adverse events included uric acid level increase or hyperuricemia in 2934 patients, liver function abnormalities in 1205 patients, and rash in 170 patients. The adverse event rates by age groups are shown in Fig. 9. They were reported more commonly in younger age groups, and hyperuricemia or increase in serum uric acid level was reported most frequently in those between 30 and 39.
      Table 7Adverse events associated with favipiravir use.
      Adverse eventNumber of events
      Hyperuricemia, increase in serum uric acid level2934
      Liver function abnormalities1205
      Fever161
      Rash (toxicoderma, eczema, purpura, erythema)170
      Renal dysfunction, increase in serum creatinine level57
      Diarrhea, loose stool56
      Hypoxemia53
      Nausea52
      Bradycardia39
      Dyslipidemia19
      Leukopenia18
      Anorexia18
      Hyperkalemia13
      Gout13
      Coagulation abnormalities13
      Rhabdomyolysis, increase in serum creatine kinase level12
      Neutropenia11
      Dizziness10
      Increase in serum inflammatory marker level9
      Thrombocytopenia8
      Pruritus8
      Constipation7
      Laboratory abnormalities relating to biliary tract7
      Increase in serum amylase level6
      Eosinophilia6
      Heartburn6
      Hyperglycemia6
      Fatigue5
      Thrombocytosis5
      Pneumonia, worsening thereof5
      Headache4
      Increase in serum blood urea nitrogen level4
      Anemia4
      Increase in serum lactate dehydrogenase level3
      Worsening of COVID-19 symptoms3
      Hypernatremia3
      Abdominal pain3
      Lymphocytopenia3
      Gastrointestinal symptoms3
      Melena3
      Hypertension2
      Stomatitis2
      Worsening of laboratory values2
      Altered mental status2
      Stroke2
      Increase in serum ferritin level2
      Agitation2
      Seizure2
      Cough, worsening thereof2
      Arthritis, arthralgia2
      Acute pancreatitis2
      Cytopenia2
      Thromboembolism2
      Increase in serum aldolase level1
      Increase in estimated glomerular filtration rate1
      QT prolongation1
      Allergic reaction1
      Increase in SARS-CoV-2 viral load1
      Stevens-Johnson syndrome1
      Lymphadenopathy1
      Jaundice1
      Lower extremity numbness1
      Eye mucus1
      Hiccup1
      Angina pectoris1
      Hyperkalemia1
      Hematuria1
      Hematochezia1
      Visual field defect1
      Gum bleeding1
      Premature ventricular contraction1
      Psychiatric symptoms1
      Cramps in the groin1
      Secondary pneumothorax1
      Dehydration1
      Hyponatremia1
      Diaphoresis1
      Eye floater1
      Dysgeusia1
      Drowsiness1
      Lacrimation1
      Splenic infarction1

      3.9 Outpatients

      Separate from the data shown on hospitalized patients above, 219 patients from 19 hospitals were recorded as having been started on favipiravir in an outpatient setting. As information on location of care was not collected otherwise, they may have been hospitalized subsequently or followed up as outpatients. These patients were younger than inpatients with 71.7% less than 60 years of age. Males accounted for 53.9%, and at least one of the four surveyed comorbidities was present in 25.3%. The median day from the first positive COVID-19 test to the initiation of favipiravir was 1 day, and the median duration of treatment was 6 days. Among these patients, 216 patients (98.6%) had mild disease, 3 patients (1.4%) had moderate disease, and none had severe disease. The combined rates of clinical improvement at 7 and 14 days were 79.1% and 86.7%, respectively. At approximately one month, 89.0% of the patients had improved, 1.4% had not improved and the outcome was unknown for 2.7%. Adverse events reported were uric acid level increase or hyperuricemia (13 patients), liver function abnormalities (3 patients), and palpitation (1 patient).

      4. Discussion

      Favipiravir became available for off-label use in the treatment of COVID-19 in Japan beginning in February 2020 in response to the unprecedented pandemic which was quickly unfolding at the time. The off-label use program was coordinated through the Ministry of Health, Labour and Welfare, and the hospitals participating in this off-label use program were invited to register the cases to this observational cohort study in order to monitor its use, safety and patient outcomes. As the incidence of COVID-19 decreased and other oral antiviral treatment options became available, the off-label use program was concluded at the end of December 2021. Prior to this final report, four interim reports from this study have been published on the website of the Japanese Association of Infectious Diseases. In this final report, over seventeen thousand patients were registered, making it one of the largest cohorts of patients who received favipiravir.
      Favipiravir shows variable degrees of in vitro activity against SARS-CoV-2 depending on the cells and experimental conditions [
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      The common adverse events associated with favipiravir use were uric acid level increase and liver function test abnormalities. Elevation of uric acid levels, believed to be caused by its reduced excretion into the urine, have been observed among patients receiving favipiravir across clinical studies, and are known to normalize after discontinuation of the agent [
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      A prospective, randomized, open-label trial of early versus late favipiravir therapy in hospitalized patients with COVID-19.
      ]. The reason for the higher frequencies of uric acid elevation in younger age groups was unclear. Importantly, there were no unanticipated safety signals in this large cohort of patients who received favipiravir.
      The study has several key limitations to be acknowledged. As this was an observational cohort study, not all patients who received favipiravir on an off-label basis were captured. Also, the study used the survey function of RedCap to minimize data entry effort on the part of the hospitals. This meant that the assessment of clinical improvement or worsening was delegated to the treating physicians, and data cleaning was also kept to a minimum. Underreporting of adverse events is another possibility. Despite these caveats, the study provides unique insights into how favipiravir was utilized in the management of COVID-19 at Japanese hospitals in the early phase of the pandemic.

      Funding

      This study was supported by Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP19fk0108150 , JP20fk0108150 .

      Availability of data and materials

      The data will not be shared because of participant confidentiality.

      Authors’ contributions

      YD was the principal investigator and responsible for the data analysis. SB and MK contributed to the study design and ethical approval. TI conducted the statistical analysis. MA conducted quality control of the database. YD drafted the manuscript, and all authors contributed substantially to its revision.

      Declaration of competing interest

      YD has served on a scientific advisory board of FujiFilm, the manufacturer of favipiravir, for an unrelated study. All other authors declare no competing interests.

      Acknowledgements

      We thank all hospitals and healthcare providers across Japan that provided the clinical data for this study.

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