Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial
Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial
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DOI：
10.1016/s2213-2600(19)30268-1
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发表时间：
2020-02-01
影响因子：
76.2
通讯作者：
Humar, Atul
中科院分区：
文献类型：
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作者：
Cypel, Marcelo;Feld, Jordan J.;Humar, Atul
背景 很大一部分器官捐献者丙型肝炎病毒（HCV）感染检测呈阳性。迄今为止，只有少数研究评估了使用这些供体肺进行移植的安全性，并且尚未对供体器官进行直接干预以防止通过器官移植传播丙型肝炎病毒。我们的目的是评估应用离体肺灌注 (EVLP) 加紫外线 C (UVC) 灌注液照射后，从 HCV 阳性供体向 HCV 阴性受体进行肺移植的安全性和有效性。方法我们进行了一项单中心、前瞻性、开放标签、非随机试验，其中将来自 HCV 病毒血症供体（HCV 阳性）的供体肺移植到大学健康网络多伦多总医院（多伦多，多伦多）的 HCV 阴性受体中。加拿大安大略省）。捐献者年龄小于65岁，经核酸检测丙肝病毒呈阳性。乙型肝炎病毒、艾滋病毒、人类 T 淋巴细胞病毒 1 或 2 检测呈阳性的捐赠者被排除在外。肺移植等待名单上的受者没有明显的肝病（排除 2 期或更高级别的纤维化）或活动性 HCV 感染。植入前，所有 HCV 阳性供体肺均经过 EVLP 处理，有或没有 UVC 灌注液照射，以降低 HCV RNA 浓度和感染性。移植后第一周，每天测量一次患者的 HCV RNA 血液浓度，然后每周测量一次，持续 12 周。所有患者均在移植后至少 2 周开始接受为期 12 周的口服索磷布韦 400 mg 加维帕他韦 100 mg 治疗。主要终点是所有接受 HCV 阳性肺移植的患者在移植后 6 个月时的生存率和无 HCV 状态的综合终点。在研究期间，对接受 HCV 阳性肺移植的患者和所有接受 HCV 阴性肺移植的患者的生存率、住院时间和急性排斥反应发生率等患者结局进行了比较。该研究已在 ClinicalTrials.gov 注册，NCT03112044。调查结果从 2017 年 10 月 1 日到 2018 年 11 月 1 日，209 名患者接受了移植；在最初考虑的 27 名 HCV 阳性捐献者中，有 22 名适合移植。其余 187 名捐赠者的 HCV 呈阴性。植入前，11 个 HCV 阳性供体肺仅接受 EVLP 治疗，另外 11 个接受 EVLP 加 UVC 治疗。接受 HCV 阳性和 HCV 阴性肺部治疗的患者的肺部疾病、紧急状态和阳性供体-受者 HLA 交叉配型相似。 HCV 阳性组中有 20 名 (91%) 患者在移植后第一周内出现 HCV 病毒血症，并在移植后中位 21 天开始接受索非布韦加维帕他韦治疗 (IQR 16.76-24.75)。与单独使用 EVLP 相比，使用 EVLP 加 UVC 进行供体器官治疗可显着降低移植后第一周内受者血液中的病毒载量（中位数为 167 IU/mL [IQR 20-12 000] vs 第 7 天的 4390 IU/mL [1170-112 000]；p=0.048），并在 11 名患者中的 2 名（18%）中预防了病毒传播。所有 20 名感染患者在治疗开始后 6 周内 HCV PCR 均呈阴性。 HCV 阳性组的 22 名患者中有 19 名 (86%) 达到了移植后 6 个月的生存和无 HCV 状态的主要终点。接受 HCV 病毒血症供体肺的受者的 6 个月生存率为 95%，而接受 HCV 阴性供体肺的受者的 6 个月生存率为 94%。 HCV 阳性组中最常见的 3-4 级不良事件是呼吸道并发症（5 例 [23%]）和感染（4 例 [18%]）。十名 (45%) 患者发生了需要入院的严重不良事件。一名 (5%) 未感染 HCV 的患者在第 31 天死于与假单胞菌败血症相关的多器官衰竭。两名患者在索磷布韦加维帕他韦完成后 3 个月内出现 HCV 复发，需要重新治疗。 解释 接受病毒血症 HCV 供肺和 HCV 阴性供肺的患者之间的早期和中期临床结果没有显着差异。 EVLP 期间使用 UVC 灌注液照射的供体器官治疗在移植后的前 7 天内显着降低了 HCV 病毒载量，并证明了移植前最大限度地减少离体病毒载量的新方法的概念验证，旨在防止供体-受体传播。版权所有 (C) 2019 爱思唯尔有限公司。保留所有权利。
Background A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation.Methods We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044.Findings From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV- positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16.76-24.75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20-12 000] vs 4390 IU/mL [1170-112 000] at day 7; p=0.048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV- positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV- negative donors. The most common grade 3- 4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment.Interpretation Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor-recipient transmission. Copyright (C) 2019 Elsevier Ltd. All rights reserved.