Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Takayama-Ito, Mutsuyo; Saijo, Masayuki

Ribavirin, a nucleotide analog, exerts a broad spectrum of antiviral activity against various viruses, such as respiratory syncytial virus, influenza, measles, herpesvirus, human immunodeficiency virus, Lassa virus, and [in combination with interferon (IFN)-α] hepatitis C virus. Ribavirin can be administered orally, intravenously, or via a nebulizer (Snell, 2001) . The proposed mechanisms of action of ribavirin against viruses are indirect (inosine monophosphate dehydrogenase inhibition and immunomodulatory effects) as well as direct (interference with RNA capping, polymerase inhibition, and lethal mutagenesis) (Graci and Cameron, 2006) . Shimojima et al. (2014) first reported the efficacy of ribavirin in vitro using three cell lines: monkey kidney-derived Vero, human hepatoma-derived Huh7, and human osteosarcomaderived U2OS cells. When treated with ribavirin before and during infection with SFTSV, the 99% inhibitory concentration (IC 99 ) of ribavirin was 263, 83, and 78 µM in Vero, Huh7, and U2OS cells, respectively (Table 1) . However, when Vero cells were treated with ribavirin 3 days after the inoculation, the inhibitory effect was dramatically decreased, suggesting that ribavirin could be used as post-exposure prophylaxis for the prevention of SFTS and also mentioned that ribavirin could be effective as part of a combination therapy to treat SFTS patients (Shimojima et al., 2014) . The efficacy of ribavirin against SFTSV replication was also observed in another study, where Vero cells infected with a Korean SFTSV strain were treated at 24 and 48 h post inoculation, and the 50% inhibitory concentration (IC 50 ) range was 3.69-8.72 µg/mL (Lee et al., 2017) (Table 1) . Despite several differences in viral strains and treatment procedure, ribavirin suppressed SFTS replication, suggesting that it was effective against various SFTSVs for at least 48 h after SFTSV inoculation. Shimojima et al. (2015) investigated the improvement in efficacy when ribavirin was used in combination with IFNs. All IFNs showed dose-dependent inhibitory effects when used alone. The IC 90 of IFNα, IFNβ, and IFNγ was 29 U/ml, 24 U/ml, and 12 ng/ml, respectively, and that of ribavirin was 43 µg/mL ( Table 1) . When IFNs were combined with ribavirin at IC 90 , significant inhibitory effects were observed, with reductions of >3 log 10 in viral titers. This study suggested that the combination of ribavirin with IFNs or other agents that function via different mechanisms might be useful in treating patients with SFTS. Ribavirin has shown a limited protective effect in lethal SFTSV challenges in animal experiments (Tani et al., 2016; ( Table 2 ). The Chinese Ministry of Health initially approved the use of ribavirin to treat SFTS based on the results of in vitro studies (Ministry of Health People's Republic of China, 2011). However, a clinical study in China showed that the case fatality rate was similar between patients who received ribavirin and those who did not (Liu et al., 2013) . This study included 311 patients, of whom 54 died; in those who received ribavirin therapy, the platelet counts did not increase and the viral loads did not decrease in comparison with those who did not receive the therapy. Furthermore, although the differences were not statistically significant, it was unexpectedly observed that the patients who received ribavirin therapy had lower platelet counts than those who did not. Another study reported that two patients, in whom plasma exchange