Eloy Philippine, Laouénan Cédric, Beavogui Abdoul Habib, Keita Sakoba, Manchon Pauline, Etard Jean-François, Sissoko Daouda, Mentré France, Malvy Denis
AP-HP, Nord - Université de Paris, Département d'Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, F-75018 Paris, France.
INSERM, Centre d'Investigations Cliniques-Epidémiologie Clinique 1425, Hôpital Bichat, F-75018 Paris, France.
IDCases. 2022 Jan 21;27:e01412. doi: 10.1016/j.idcr.2022.e01412. eCollection 2022.
Persistence of Ebola virus (EBOV) in semen remains of deep concern, as sexual transmission of EBOV seems plausible up to 6 months after acute phase of Ebola virus disease (EVD). Favipiravir, a broad spectrum antiviral product, has been evaluated in reducing EVD mortality in Guinea in 2014-2015 in the JIKI trial, the pharmacokinetic results of which suggest that an increase of dose might be necessary to achieve a therapeutically relevant exposure. In FORCE trial, we aimed at evaluating the tolerance and activity of high doses of favipiravir in male EVD survivors with EBOV RNA detection in semen in Guinea.
In 2016, we launched a phase IIa open-labeled multicenter dose escalation study. Male survivors of EVD with EBOV RT-PCR positive on semen received a loading dose of 2400 mg BID of favipiravir on day 1 then a maintenance dose of 1800 mg BID from day 2-14. The primary outcome was the tolerance, assessed daily during period treatment and up to day 90. Unfortunately only two participants were included and the trial was stopped for lack of recruitment. No clinical adverse event of grade 3/4 was reported for both patients. One patient experienced a grade 3 hypocalcemia at day 10 and 14.
High doses of favipiravir were well tolerated in these two participants. Better characterized tolerance and pharmacokinetics of high doses of favipiravir are of utmost importance considering that favipiravir is a candidate treatment for a variety of emerging severe viral diseases with poor prognosis.
埃博拉病毒（EBOV）在精液中持续存在仍然令人深感担忧，因为在埃博拉病毒病（EVD）急性期后长达6个月，EBOV通过性传播似乎是可能的。法匹拉韦是一种广谱抗病毒产品，在2014 - 2015年于几内亚进行的JIKI试验中评估了其降低EVD死亡率的效果，该试验的药代动力学结果表明可能需要增加剂量以实现具有治疗意义的暴露水平。在FORCE试验中，我们旨在评估高剂量法匹拉韦对几内亚精液中检测到EBOV RNA的男性EVD幸存者的耐受性和活性。
2016年，我们开展了一项IIa期开放标签多中心剂量递增研究。精液EBOV RT - PCR呈阳性的EVD男性幸存者在第1天接受2400 mg bid的法匹拉韦负荷剂量，然后从第2天至第14天接受1800 mg bid的维持剂量。主要结局是耐受性，在治疗期间每日评估直至第90天。不幸的是，仅纳入了两名参与者，该试验因缺乏招募而停止。两名患者均未报告3/4级临床不良事件。一名患者在第10天和第14天出现3级低钙血症。
这两名参与者对高剂量法匹拉韦耐受性良好。鉴于法匹拉韦是治疗多种预后不良的新发严重病毒性疾病的候选药物，更好地表征高剂量法匹拉韦的耐受性和药代动力学至关重要。
