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

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%Cl,0.174-1.247).Cox regression showed a significant reduction in case fatality rate(CFR)with an adjusted hazard ratio of 0.366(95%Cl,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.