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

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.

Newly developed artificial intelligence algorithm for COVID-19 pneumonia: utility of quantitative CT texture analysis for prediction of favipiravir treatment effect.

PURPOSE: Using CT findings from a prospective, randomized, open-label multicenter trial of favipiravir treatment of COVID-19 patients, the purpose of this study was to compare the utility of machine learning (ML)-based algorithm with that of CT-determined disease severity score and time from disease onset to CT (i.e., time until CT) in this setting. MATERIALS AND METHODS: From March to May 2020, 32 COVID-19 patients underwent initial chest CT before enrollment were evaluated in this study. Eighteen patients were randomized to start favipiravir on day 1 (early treatment group), and 14 patients on day 6 of study participation (late treatment group). In this study, percentages of ground-glass opacity (GGO), reticulation, consolidation, emphysema, honeycomb, and nodular lesion volumes were calculated as quantitative indexes by means of the software, while CT-determined disease severity was also visually scored. Next, univariate and stepwise regression analyses were performed to determine relationships between quantitative indexes and time until CT. Moreover, patient outcomes determined as viral clearance in the first 6 days and duration of fever were compared for those who started therapy within 4, 5, or 6 days as time until CT and those who started later by means of the Kaplan-Meier method followed by Wilcoxon's signed-rank test. RESULTS: % GGO and % consolidation showed significant correlations with time until CT (p < 0.05), and stepwise regression analyses identified both indexes as significant descriptors for time until CT (p < 0.05). When divided all patients between time until CT of 4 days and that of more than 4 days, accuracy of the combined quantitative method (87.5%) was significantly higher than that of the CT disease severity score (62.5%, p = 0.008). CONCLUSION: ML-based CT texture analysis is equally or more useful for predicting time until CT for favipiravir treatment on COVID-19 patients than CT disease severity score.

Effectiveness of remdesivir in hospitalized nonsevere patients with COVID-19 in Japan: A large observational study using the COVID-19 Registry Japan.

OBJECTIVES: To evaluate the effectiveness of remdesivir in the early stage of nonsevere COVID-19. Although several randomized controlled trials have compared the effectiveness of remdesivir with that of a placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. METHODS: We evaluated the effectiveness of remdesivir in the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalized patients with COVID-19 in Japan. Two regimens ("start remdesivir" therapy within 4 days from admission versus no remdesivir during hospitalization) among patients without the need for supplementary oxygen therapy were compared by a 3-step processing (cloning, censoring, and weighting) method. The primary outcome was a supplementary oxygen requirement during hospitalization. Secondary outcomes were 30-day in-hospital mortality and the risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). The data of 12,487 cases met our inclusion criteria. The "start remdesivir" regimen showed a lower risk of supplementary oxygen requirement (hazard ratio [HR]: 0.850, 95% confidence interval [CI]: 0.798-0.906, p value < 0.001). Both 30-day in-hospital mortality and risk of IMV/ECMO introduction were not significantly different between the 2 regimens (HRs: 1.04 and 0.983, 95% CI: 0.980-1.09 and 0.906-1.07, p values: 0.210 and 0.678, respectively). CONCLUSIONS: Remdesivir might reduce the risk of oxygen requirement during hospitalization in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction in IMV/ECMO requirement.

Effectiveness of Favipiravir on Nonsevere, Early-Stage COVID-19 in Japan: A Large Observational Study Using the COVID-19 Registry Japan.

INTRODUCTION: Several randomized controlled trials have compared the effectiveness of favipiravir with that of placebo. However, evidence regarding its effect on nonsevere, early-stage coronavirus disease 2019 (COVID-19) remains insufficient. METHODS: We used the COVID-19 Registry Japan, a nationwide registry of inpatients with COVID-19, for evaluating the effectiveness of favipiravir on patients with nonsevere, early-stage COVID-19. Eligible patients, who did not need supplementary oxygen therapy at admission, were classified according to two regimens (starting favipiravir therapy within 4 days from admission vs. no favipiravir during hospitalization) and were then compared using a three-step method (cloning, censoring, and weighting). The primary outcome was supplementary oxygen requirement during hospitalization, and the secondary outcomes were the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO) and overall mortality at 30 days. RESULTS: A total of 7654 cases were analyzed. The "start favipiravir" regimen did not show substantial differences in the primary outcome [hazard ratio 0.825, 95% confidence interval (CI) 0.657-1.04, p = 0.098] and both of the secondary outcomes [need for IMV/ECMO and overall 30-day mortality, hazard ratio 1.02 (95% CI 0.649-1.60) and 0.869 (95% CI 0.519-1.46), p = 0.929 and 0.594, respectively]. CONCLUSIONS: In this large cohort from a COVID-19 registry, favipiravir was not associated with a positive effect on the clinical outcome on patients with nonsevere, early-stage COVID-19, suggesting that it is not an essential drug for COVID-19 treatment.

Clinical characteristics of the first three waves of hospitalised patients with COVID-19 in Japan prior to the widespread use of vaccination: a nationwide observational study.

Background: Before widespread coronavirus disease (COVID-19) vaccinations, Japan experienced three COVID-19 epidemic waves. This study aimed to evaluate the characteristics of hospitalised COVID-19 patients and reveal temporal changes. Methods: This study included 33,554 hospitalised patients with COVID-19 from 553 healthcare facilities. Data were analysed by age group and epidemic wave (first wave, 01/01/2020-05/31/2020; second wave, 06/01/2020-10/31/2020; and third wave, 11/01/2020-03/31/2021). Findings: By age group, 3% (under 18), 22% (young), 34% (middle-aged), and 41% (older patients) were aged 0-17, 18-39, 40-64, and >65 years; while 16%, 35%, and 49% were in the first, second, and third wave, respectively. The patients' overall median age (58 years; interquartile range, 39-74) was lowest and highest during the second and third waves, respectively. The frequency of any comorbidity was lowest and highest during the second (44·5%) and third (63·6%) waves, respectively. The symptoms at admission and exposure history differed considerably with age. The overall case fatality rate (5%) was highest among older patients (11·4%). Case fatality rate was highest and lowest during the first (7·3%) and second (2·8%) waves, respectively. Medication use changed over time. Interpretation: Although the overall case fatality rate remained relatively low, it was more than twice as high among older patients. After adjusting for age and comorbidities, the risk of death was highest in the first wave. Funding: This work was supported by the Ministry of Health, Labour and Welfare "Research on Emerging and Re-emerging Infectious Diseases and Immunization" 19HA1003].

Evaluation of the efficacy of anticoagulation therapy in reducing mortality in a nationwide cohort of hospitalized patients with coronavirus disease in Japan.

OBJECTIVES: To determine whether anticoagulation therapy improves outcomes in patients with coronavirus disease 2019 (COVID-19) in Japan given their lower risk of thrombosis compared with Western cohorts. METHODS: The efficacy of anticoagulation therapy in hospitalized patients with COVID-19 was evaluated using a nationwide registry: the COVID-19 Registry Japan. The inverse probability of weight treatment method was used to adjust for baseline confounders in the anticoagulation and non-anticoagulation groups. RESULTS: Of the 1748 patients included, anticoagulants were used in 367 patients (treatment group). The patients in the anticoagulant group were older, predominantly male, and often presented with obesity, hyperlipidaemia, hypertension, diabetes and elevated D-dimer levels. Twenty-nine-day mortality was 7.6% in the whole cohort (treatment group, 11.2%; no treatment group, 6.6%), 6% in patients who were not treated with steroids (treatment group, 12.3%; no treatment group, 5.2%), and 11.2% in patients treated with steroids (treatment group, 10.5%; no treatment group, 11.8%). Mortality in the whole cohort was similar between the treatment and no treatment groups (P=0.99), and an insignificant decreasing trend in mortality was observed in patients treated with steroids (P=0.075). CONCLUSIONS: Anticoagulants may be beneficial in Asians, in whom comorbidities and risk of thrombosis may differ from other ethnic groups.

Antibody Responses to BNT162b2 Vaccination in Japan: Monitoring Vaccine Efficacy by Measuring IgG Antibodies against the Receptor-Binding Domain of SARS-CoV-2.

To fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), mass vaccination has begun in many countries. To investigate the usefulness of a serological assay to predict vaccine efficacy, we analyzed the levels of IgG, IgM, and IgA against the receptor-binding domain (RBD) of SARS-CoV-2 in the sera from BNT162b2 vaccinated individuals in Japan. This study included 219 individuals who received two doses of BNT162b2. The levels of IgG, IgM, and IgA against RBD were measured by enzyme-linked immunosorbent assay before and after the first and second vaccination, respectively. The relationship between antibody levels and several factors, including age, gender, and hypertension were analyzed. Virus-neutralizing activity in sera was measured to determine the correlation with the levels of antibodies. A chemiluminescent enzyme immunoassay (CLEIA) method to measure IgG against RBD was developed and validated for the clinical setting. The levels of all antibody isotypes were increased after vaccination. Among them, RBD-IgG was dramatically increased after the second vaccination. The IgG levels in females were significantly higher than in males. There was a negative correlation between age and IgG levels in males. The IgG levels significantly correlated with the neutralizing activity. The CLEIA assay measuring IgG against RBD showed a reliable performance and a high correlation with neutralizing activity. Monitoring of IgG against RBD is a powerful tool to predict the efficacy of SARS-CoV-2 vaccination and provides useful information in considering a personalized vaccination strategy for COVID-19. IMPORTANCE Mass vaccination campaigns using mRNA vaccines against SARS-CoV-2 have begun in many countries. Serological assays to detect antibody production may be a useful tool to monitor the efficacy of SARS-CoV-2 vaccination in individuals. Here, we reported the induction of antibody isotype responses after the first and second dose of the BNT162b2 vaccine in a well-defined cohort of employees in Japan. We also reported that age, gender, and hypertension are associated with differences in antibody response after vaccination. This study not only provides valuable information with respect to antibody responses after BNT162b2 vaccination in the Japanese population but also the usefulness of serological assays for monitoring vaccine efficacy in clinical laboratories to determine a personalized vaccination strategy for COVID-19.

Clinical Epidemiology of Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan: Report of the COVID-19 Registry Japan.

BACKGROUND: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. METHODS: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. RESULTS: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. CONCLUSIONS: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

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.).