Clinical efficacy and safety evaluation of favipiravir in treating patients with severe fever with thrombocytopenia syndrome

Abstract

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available.

Methods: The effect of favipiravir (FPV) in treating SFTS was evaluated by an integrated analysis on data collected from a single-arm study (n=428), a surveillance study (n=2350) and published data from a randomized controlled trial study (n=145). A 1:1 propensity score matching was performed to include 780 patients: 390 received FPV and 390 received supportive therapy only. Case fatality rates (CFRs), clinical progress, and adverse effects were compared.

Findings: FPV treatment had significantly reduced CFR from 20.0% to 9.0% (odds ratio 0.38, 95% confidence interval 0.23-0.65), however showing heterogeneity when patients were grouped by age, onset-to-admission interval, initial viral load and therapy duration. The effect of FPV was significant only among patients aged ≤70 years, with onset-to-admission interval ≤5 days, therapy duration ≥5 days or baseline viral load ≤1 × 10⁶ copies/mL. Age-stratified analysis revealed no benefit in the aging group >70 years, regardless of their sex, onset-to-admission interval, therapy duration or baseline viral load. However, for both ≤60 and 60-70 years groups, therapy duration and baseline viral load differentially affected FPV therapy efficiency. Hyperuricemia and thrombocytopenia, as the major adverse response of FPV usage, were observed in >70 years patients.

Interpretation: FPV was safe in treating SFTS patients but showed no benefit for those aged >70 years. Instant FPV therapy could highly benefit SFTS patients aged 60-70 years.

Funding: China Natural Science Foundation (No. 81825019, 82073617 and 81722041) and China Mega-project for Infectious Diseases (2018ZX10713002 and 2015ZX09102022).

Keywords: Efficacy; Favipiravir; Heterogeneity; Safety; Severe fever with thrombocytopenia syndrome.

Fig. 1

Flowchart of the study design.^aContraindications to FPV referred to either of the following: pregnant/lactating women, having a history of gout or hyperuricemia and having a history of hypersensitivity to an antiviral nucleoside-analog drug targeting a viral RNA polymerase. FPV, favipiravir.

Fig. 2

The effect of FPV treatment in reducing case fatality rate of SFTS patients. a: Kaplan-Meier curves for FPV administration on the probability of survival for all SFTS patients. The numbers of at-risk patients at each time point were shown under the x-axis. P values were calculated by log-rank test. b: Kaplan-Meier curves for FPV administration on the probability of survival in three age groups. The numbers of at-risk patients at each time point were shown above the x-axis. P values were calculated by log-rank test. c: Forest plot in all patients and subgroups. Datapoints show odds ratios and error bars show 95% confidence interval. The red color represents P<0.05 and the black color represents P≥0.05. In the subgroups of sex, therapy delay and duration, P values were calculated by multivariable conditional logistic regression model, after adjustment for comorbidities. In the subgroup of viral load, P values were calculated by multivariable logistic regression model, after adjustment for age, sex, delay from symptom onset to admission, and comorbidities. *P values were calculated by Pearson chi-square test. The odds ratio in the group of low viral load (≤1 × 10⁶ copies/mL) on admission was 0.033 (0.004-0.265). FPV, favipiravir.

Fig. 3

Age-based subgroup analysis of the effect of FPV treatment in reducing case fatality rate of SFTS patients. The effect of FPV usage in reducing case fatality rate compared for sex (a), therapy delay (b), viral load (c) and therapy duration (d) in three age groups of SFTS patients. Datapoints show odds ratios and error bars show 95% confidence interval. The red color represents P<0.05 and the black color represents P≥0.05. In the subgroups of sex, therapy delay and duration, P values were calculated by multivariable conditional logistic regression model, after adjustment for comorbidities. In the subgroup of viral load, P values were calculated by multivariable logistic regression model, after adjustment for age, sex, delay from symptom onset to admission, and comorbidities. *P values were calculated by Pearson chi-square test. CFR, case fatality rate; OR, odds ratio.

Fig. 4

Kinetics of viral loads in SFTS patients with or without FPV treatment. a: All patients; b: stratified by initial viral load on admission. Datapoints are median values and error bars show 95% confidence interval. LVL: low viral load (≤1 × 10⁶ copies/mL) on admission; HVL: high viral load (>1 × 10⁶ copies/mL) on admission. The numbers of patients who contributed to the at-risk population at each time point are shown under the x-axis.