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.
Highlights
Severe fever with thrombocytopenia syndrome (SFTS), an emerging and severe hemorrhagic fever disease caused by a bunyavirus (SFTS virus, SFTSV), was first discovered in China in 2009 and subsequently reported in South Korea and Japan in 2012, with a high case fatality rate (CFR) ranging from 12 to 50%.1–4 Increasing number of SFTS cases was soon recorded in these countries, with cumulative numbers of cases by 2018 attaining 11995 in China, 866 in South Korea, and 395 in Japan
Mechanism of T-705 against SFTSV in vitro Previous studies have demonstrated that T-705 could inhibit the replication of several viruses of the Bunyavirales in cell culture;[21,26,31] the antiviral mechanism has been investigated in only Rift Valley fever virus (RVFV), a mosquitoborne bunyavirus.[32]
We examined the association between virus extinction and SFTSV mutagenesis that was induced by T-705 in cell culture under different drug concentrations, various virus passages, and different inoculation doses
Summary
Severe fever with thrombocytopenia syndrome (SFTS), an emerging and severe hemorrhagic fever disease caused by a bunyavirus (SFTS virus, SFTSV), was first discovered in China in 2009 and subsequently reported in South Korea and Japan in 2012, with a high case fatality rate (CFR) ranging from 12 to 50%.1–4. Two new patients were recently reported in Vietnam,[5] indicating a further geographical expansion in Asia. Oceania, and North America.[8] Human-to-human transmission has been seen in a few family and nosocomial clusters of cases, and the most common risk of the transmission is direct blood exposure.[9,10] The potential droplet transmission has been posed due to SFTSV RNA was continuously detected in the sputum.[11,12] The possible sexual transmission has recently been postulated as that SFTSV RNA was detected in semen after the virus had already disappeared from serum.[13] All these findings raised the possibility of pandemic transmission of SFTSV outside of
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