A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome.

Koichiro Suemori,Hiroki Ohge,Masaki Yasukawa,Akitsugu Furumoto,Takashi Haku,Norimitsu Kadowaki,Yasuyuki Kakihana,Tomoki Yoshikawa,Masayuki Shimojima,Chinatsu Kamikokuryo,Daisuke Himeji,Toru Takahashi,Shigetoshi Sakabe,Kenichi Ikeda,Toshiyuki Ishimaru,Takeshi Kurosu,Taichi Azuma,Atsushi Yamanaka,Masayuki Saijo,Tomohiro Taniguchi,Masafumi Kawamura,Katsuto Takenaka,Masaaki Hidaka ,M Ishida ,Masayuki Kaneko

doi:10.1371/journal.pntd.0009103

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7–14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.

Highlights

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne virus infection caused by Dabie bandavirus, which belongs to the Bandavirus genus of the Phenuiviridae family
The case fatality rate of patients with SFTS is high ranging from 16.2% to 47%
It was suggested that favipiravir treatment lowered the case fatality rate of patients with SFTS by approximately 10% in comparison with those reported so far through epidemiological survey in Japan

Summary

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne virus infection caused by Dabie bandavirus (formerly SFTS virus, SFTSV), which belongs to the Bandavirus genus (formerly Phlebovirus genus) of the Phenuiviridae family (formerly Bunyaviridae family). SFTS has been identified in China, South Korea, and Japan since the early 2010s [1,2,3,4]. The virus name SFTSV is used in this article. SFTSV is maintained in nature between several species of tick and both wild and domestic animals [5]. Humans are usually infected with SFTSV through tick bites. Some patients with SFTS were infected with the virus through close contact with sick domestic animals such as cats infected with SFTSV [6]. SFTS patients were reported in Vietnam and Taiwan [7,8,9]

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