Virological and genomic analysis of SARS-CoV-2 from a favipiravir clinical trial cohort

Suzuki, Masahiro; Imai, Takumi; Sakurai, Aki; Komoto, Satoshi; Ide, Tomihiko; Lim, Chang Kweng; Shintani, Ayumi; Doi, Yohei; Murata, Takayuki

Introduction Several clinical studies have reported the efficacy of favipiravir in reducing viral load and shortening the duration of symptoms. However, the viability of SARS-CoV-2 in the context of favipiravir therapy and potential for resistance development is unclear. Methods We sequenced SARS-CoV-2 in nasopharyngeal specimens collected from patients who participated in a randomized clinical trial of favipiravir at hospitals across Japan between March and May 2020. Paired genomes were sequenced from those who remained RT-PCR-positive 5-8 days into favipiravir therapy. Daily nasopharyngeal specimens from 69 patients who were RT-PCR-positive at randomization were examined for a cytopathic effect (CPE). Results Some strains early in the trial belonged to clade 19B, whereas the majority belonged to clade 20B. The median time from the disease onset to negative CPE was 9 days. CPE strongly correlated with the time from disease onset, viral load, age and male sex. Among 23 patients for whom paired genomes were available, all except one had identical genomes. Two mutations were observed in one patient who received favipiravir, neither in the RdRp gene. Conclusions The SARS-CoV-2 genome distribution in this clinical trial conducted in Japan reflected the early influx of strains from China followed by replacement by strains from Europe. CPE was significantly associated with age, male sex and viral loads, but not with favipiravir therapy. There was no evidence of resistance development during favipiravir therapy.