马拉韦罗用于巨细胞病毒激活的预防性治疗。
Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation.
机构信息
From the Hematology Department, University Hospitals Leuven, KU Leuven, Leuven (J.M.), and the Section of Hematology, Cliniques Universitaires Saint-Luc, Brussels (X.P.) - both in Belgium; the Hematology Department, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP) and University Paris-Est-Créteil, Créteil (C.C.), and AP-HP Hôpital Paul Brousse, Villejuif (F.S.) - all in France; the Medical University of Vienna, General Hospital, Vienna (P.J.); Shire, Wayne, PA (M.U., S.V.); Shire, Lexington, MA (J.W., A.W.); and the Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany (O.W.).
出版信息
N Engl J Med. 2019 Sep 19;381(12):1136-1147. doi: 10.1056/NEJMoa1714656.
BACKGROUND
Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.
METHODS
In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.
RESULTS
Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.
CONCLUSIONS
Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).
背景
马拉韦罗是一种具有抗巨细胞病毒（CMV）活性的苯并咪唑核苷。马拉韦罗用于预防造血细胞或实体器官移植受者 CMV 感染的安全性和疗效尚不清楚。
方法
在一项 2 期、开放性、马拉韦罗剂量盲法试验中，接受造血细胞或实体器官移植（≥18 岁，CMV 再激活[每毫升 1000 至 100000 个 DNA 拷贝]）的患者被随机分配接受 400、800 或 1200 mg 每日 2 次或标准剂量缬更昔洛韦治疗，最长不超过 12 周。主要疗效终点是治疗后 3 周和 6 周内达到治疗应答的患者百分比，定义为血浆中确证的 CMV DNA 不可检测。主要安全性终点是治疗期间发生或恶化的不良事件的发生率。
结果
在 161 名接受随机分组的患者中，159 名接受了治疗，156 名有基线后数据可用-117 名在马拉韦罗组，39 名在缬更昔洛韦组。在基线后数据可用的患者中，在 3 周内达到治疗应答的患者比例在接受马拉韦罗治疗的患者中为 62%，在接受缬更昔洛韦治疗的患者中为 56%。在 6 周内，分别有 79%和 67%的患者达到应答（风险比，1.20；95%置信区间，0.95 至 1.51）。在马拉韦罗剂量组中，达到治疗应答的患者比例相似。在接受 800mg 每日 2 次马拉韦罗治疗的 2 名达到治疗应答的患者中，CMV UL97 蛋白激酶中出现 T409M 耐药突变；在这 2 名患者中均发生了 CMV 感染。在马拉韦罗组中，发生或恶化的严重不良事件的发生率高于缬更昔洛韦组（119 名患者中有 52 例[44%] vs. 40 名患者中有 13 例[32%]）。在马拉韦罗组中，因不良事件而停止试验药物治疗的患者比例高于缬更昔洛韦组（119 名患者中有 27 例[23%] vs. 40 名患者中有 5 例[12%]）。马拉韦罗组报告了更高比例的胃肠道不良事件，缬更昔洛韦组报告了更高比例的中性粒细胞减少症。
结论
每日至少 400mg 剂量的马拉韦罗在清除造血细胞或实体器官移植受者的 CMV 病毒血症方面与缬更昔洛韦疗效相当。马拉韦罗组报告了更高比例的胃肠道不良事件-特别是味觉障碍，而缬更昔洛韦组报告了更高比例的中性粒细胞减少症。（由 ViroPharma/Shire Development 资助；EudraCT 编号，2010-024247-32。）
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