Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome.
Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome.
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T-705治疗重症发热伴血小板减少综合征的临床疗效及抗病毒机制
DOI：
10.1038/s41392-021-00541-3
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发表时间：
2021-04-16
影响因子：
39.3
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Li H;Jiang XM;Cui N;Yuan C;Zhang SF;Lu QB;Yang ZD;Xin QL;Song YB;Zhang XA;Liu HZ;Du J;Fan XJ;Yuan L;Yuan YM;Wang Z;Wang J;Zhang L;Zhang DN;Wang ZB;Dai K;Bai JY;Hao ZN;Fan H;Fang LQ;Xiao G;Yang Y;Peng K;Wang HQ;Li JX;Zhang LK;Liu W
严重发热伴血小板减少综合征(SFTS)病毒(SFTSV)是一种新出现的、病死率高、流行范围不断扩大的硬虱传播病毒。目前，仍然没有有效的抗SFTSV干预措施。法维拉韦(T-705)最近被报道在体外和动物模型中显示出对SFTSV的抗病毒效果。在这里，我们进行了一项单盲、随机对照试验，以评估T-705治疗SFT的有效性和安全性(中国临床试验注册网站，编号ChiCTR1900023350)。从2018年5月至8月，实验室确认的SFTS患者从指定的医院招募，并随机分配到接受口服T-705联合支持性护理或支持性护理的患者。T-705治疗组和对照组的死亡结果分别为9.5%(7/74)和18.3%(13/71)(优势比，0.466，95%CI，0.174-1.247)。COX回归显示，调整后的危险比为0.366(95%CI，0.142-0.944)，病死率显著降低。在低病毒载量亚组(RT-PCR周期阈值≥26)中，T-705治疗显著降低CFR11.5至1.6%(P = 0.029)，而在高病毒载量亚组(RT-PCR周期阈值Lt；26)中，臂间差异无统计学意义(P>0.05)。与对照组相比，T-705治疗组的病毒清除时间更短，出血体征的发生率更低，实验室异常恢复更快。体外和动物实验表明，T-705的抗病毒作用与SFTSV的突变率成比例，特别是来自两种过渡突变类型。对T-705处理的血清样本的突变分析显示，在降低SFTSV病毒载量方面，与体外或动物实验中的突变模式部分一致，进一步支持了T-705的抗SFTSV作用，特别是对低病毒载量。
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.
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