Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174–1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142–0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.

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

“…Compared with the previous RCT study [14] , we have displayed for the first time that the effect of FPV was remarkably determined by occasion and duration of drug use. This were in line with previous animal studies showing that SFTSV infected mice had a higher survival rate when the FPV treatment was initiated on or earlier than three days post infection [13] .…”

“…In clinical practice, FPV has been reported for treatment of human infections with life-threatening hemorrhagic fever virus, such as Ebola virus [18] , Lassa virus [19] , Arenavirus [20] and SFTSV [15] , but only limited to case report or case series report with very small case number. Despite of FPV treatment benefit shown in the most recent RCT of SFTS [14] , the result was obtained under near-ideal test conditions in highly selected patient populations, for whom the behavior of patients and investigators are highly compliant and adherent, and non-representative of routine clinical practice. Here by integrating three lines of data to enable the largest study on FPV therapy evaluation to date, we have displayed that FPV had a significant effect on decreasing SFTS related CFR (9.0% vs. 20.0%), which corresponded to a 55.0% (95% CI 23.2%-66.8%) reduced OR of fatal within non-FPV group.…”

“…This study presents an integrated analysis using data collected from three studies: a RCT study [14] (clinical trial registry number: ChiCTR1900023350), a single-arm study (clinical trial registry number: ChiCTR2100043342) on the therapy effect of FPV in treating SFTS, and a hospital-based sentinel surveillance study on SFTS patients. All studies had been conducted in the 990th Hospital, a designated hospital for SFTS therapy in Xinyang city, Henan province, China.…”

“…FPV treated mice with SFTSV infection had seen no deaths, demonstrating robust protective effect of FPV against SFTSV when compared with ribavirin treated group which suffered many deaths [13] . Inspired by the potential therapy effect of FPV, we have performed the first randomized controlled trial (RCT) in the context of good quality supportive care, confirmed the therapeutic benefit of FPV in SFTS [14] . A multicenter non-randomized, uncontrolled single arm trial that was performed in Japan also supported the effectiveness of favipiravir for patients with SFTS [15] .…”

“…Here by using an integrated analysis on multiple data sources from a single-arm study, a surveillance study and a previous RCT study [14] , we evaluated the clinical efficacy and safety of FPV treatment for SFTS patients, with the purpose of examining the generalizability of RCT findings to the overall disease population.…”