Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada; Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada.
Lancet Respir Med. 2020 Feb;8(2):192-201. doi: 10.1016/S2213-2600(19)30268-1. Epub 2019 Oct 9.
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.
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.
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.
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.
Canadian Institutes of Health Research.
相当一部分器官捐献者的丙型肝炎病毒 (HCV) 检测呈阳性。迄今为止，只有少数研究评估了使用这些供体的肺进行移植的安全性，并且尚未对供体器官进行任何直接干预，以防止通过器官移植传播 HCV。我们旨在评估 HCV 阳性供体肺在 HCV 阴性受者中进行体外肺灌注 (EVLP) 加紫外线 C (UVC) 灌洗液照射后的安全性和有效性。
我们在多伦多总医院、大学健康网络（加拿大安大略省多伦多）进行了一项单中心、前瞻性、开放性、非随机试验，在该试验中，来自 HCV 病毒血症供体 (HCV 阳性) 的供体肺被移植到 HCV 阴性受者体内。供体年龄小于 65 岁，经核酸检测检测到 HCV 阳性。排除了乙型肝炎病毒、艾滋病毒、人类 T 淋巴细胞病毒 1 或 2 检测阳性的供体。受者在等待肺移植名单上，无明显肝脏疾病（排除 2 期纤维化或更高）或活动性 HCV 感染。在植入前，所有 HCV 阳性供体肺均接受 EVLP 治疗，加或不加 UVC 灌洗液照射，以降低 HCV RNA 和感染性浓度。移植后第一周，每天测量一次患者的 HCV RNA 血浓度，然后在接下来的 12 周内每周测量一次。所有患者均在移植后至少 2 周开始接受 12 周的口服索磷布韦 400mg 加维帕他韦 100mg 治疗。主要终点是所有接受 HCV 阳性肺的患者在移植后 6 个月时的生存和 HCV 无状态的复合终点。比较了接受 HCV 阳性肺和研究期间所有接受 HCV 阴性肺移植的患者的生存时间、住院时间和急性排斥反应发生率等患者结局。该研究在 ClinicalTrials.gov 注册，NCT03112044。
从 2017 年 10 月 1 日至 2018 年 11 月 1 日，有 209 名患者接受了移植；在最初考虑的 27 名 HCV 阳性且适合移植的供体中，有 22 名适合移植。其余 187 名供体为 HCV 阴性。在植入前，11 名 HCV 阳性供体肺仅接受 EVLP 治疗，其余 11 名接受 EVLP 加 UVC 治疗。接受 HCV 阳性和 HCV 阴性肺的患者的肺疾病、紧急状态和阳性供受者 HLA 交叉匹配相似。HCV 阳性组中有 20 名（91%）患者在移植后第一周内发生 HCV 病毒血症，并开始接受索磷布韦加维帕他韦治疗，中位时间为移植后 21 天（IQR 16-24.75）。与单独接受 EVLP 相比，供体器官接受 EVLP 加 UVC 处理后，移植后第一周内患者血液中的病毒载量明显较低（第 7 天中位数为 167IU/ml[IQR 20-12000]比 4390IU/ml[1170-112000]；p=0.048），并可预防 11 名患者中的 2 名患者的传播。所有 20 名感染患者在治疗开始后 6 周内均实现了 HCV PCR 阴性。HCV 阳性组中 22 名患者中有 19 名（86%）达到了移植后 6 个月时的生存和 HCV 无状态的主要终点。接受 HCV 病毒血症供体肺的受者 6 个月生存率为 95%，而接受 HCV 阴性供体肺的受者为 94%。HCV 阳性组中最常见的 3-4 级不良事件是呼吸并发症（5 例[23%]）和感染（4 例[18%]）。10 名（45%）患者发生需要住院治疗的严重不良事件。1 名（5%）未发生 HCV 感染的患者在第 31 天因与铜绿假单胞菌败血症相关的多器官衰竭而死亡。2 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，需要再次治疗。
接受 HCV 阳性供体肺和 HCV 阴性供体肺的患者在早期和中期临床结局方面没有显著差异。供体器官在 EVLP 期间接受 UVC 灌洗液照射可显著降低移植后第 7 天内的 HCV 病毒载量，并为在移植前体外最小化病毒载量的新方法提供了概念验证，目的是防止供受者传播。
加拿大卫生研究院。
