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

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.

Fig 1. Patient flow diagram.

Twenty-six patients were enrolled but 3 were excluded from the favipiravir efficacy analyses because of negative RT-PCR for SFTSV genome amplification (left column). Pharmacokinetic (PK) analyses were done using seven patients (right column).

Fig 2. Survival rate in the 23 SFTS patients who received favipiravir.

Overall survival rate in the 23 SFTS patients who received favipiravir is shown based on the survival time plotted using the Kaplan-Meier method (A). Survival probabilities of patients with higher SFTSV viremia level (≥ 1 × 10⁵ copies/mL, dotted line, n = 10) and that of patients with lower SFTSV viremia level (< 1 × 10⁵ copies/mL, solid line, n = 13) are shown (B).

Fig 3. Transition in the amount of SFTSV in overall patients, the Non-fatal group, and Fatal group.

Transition in the amount of SFTSV in overall patients, the Non-fatal group, and Fatal group as determined by real-time RT-PCR is shown (A). The genome levels in each patient who died of SFTS are also plotted as well as those of the Non-fatal group (B). The SFTSV survival rate in terms of the isolation test for SFTSV is shown (C). “n” indicates the number of serum samples tested for virus isolation. When a serum sample became negative for SFTSV genome with qRT-PCR in one patient, the serum samples collected from the patients after the day on which it became SFTSV genome negative were not always subjected for virus isolation. Therefore, the numbers of serum samples subjected for virus isolation collected on Day 1, Day 4, Day 7, and Day 10 became 23, 23, 8, and 3, respectively. The rates of positive virus isolation were 78% (18/23), 35% (8/23), 12% (1/8), and 0% (0/3) on Day 1 and pre-dose (pre.), Day 4, Day 7, and Day10, respectively.

Fig 4. The favipiravir concentration of the patients with SFTS who were administered favipiravir orally.

The data were analyzed from the favipiravir concentrations of seven patients. Black and grey dotted lines indicate the mean concentration of favipiravir and predicted concentration of individual patients, respectively. Round circles indicate the concentration of each individual at the designated time points.