Background

An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.

Methods

HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6–12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.

Findings

30 patients (23 men and seven women; median age 61 years (IQR 48–66) received transplants (13 lung, ten kidney, six heart, and one kidney–pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log₁₀IU/mL (IQR 4·55–5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25–47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.

Interpretation

Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.

Funding

Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.

中文翻译：

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短期、直接作用抗病毒药物和依折麦布预防 HCV 感染供体器官受者感染 HCV：一项 3 期、单中心、开放标签研究。

背景

越来越多的潜在器官捐献者感染丙型肝炎病毒（HCV）。从受感染的供体进行移植后，未感染的受者体内几乎普遍会出现 HCV 感染，因此需要进行移植后抗病毒治疗。本研究的目的是确定移植前和移植后 7 天联合使用抗病毒药物和 HCV 进入阻滞剂是否安全，并可降低 HCV 感染供体器官受者感染 HCV 的可能性。

方法

年龄小于 70 岁的 HCV 感染供体，在移植前和移植后，对未感染 HCV 且无肝病的器官受者进行依折麦布（10 mg；一种 HCV 进入抑制剂）和 glecaprevir-pibrentasvir（300 mg/120 mg）治疗。合并感染 HIV、乙型肝炎病毒或人类 T 细胞白血病病毒 1 或 2。受者在移植前 6-12 小时接受单剂，术后 7 天每天一次（共 8 剂）。HCV RNA 每天评估一次，持续 14 天，然后每周评估一次，直至移植后 12 周。主要终点是预防慢性 HCV 感染，移植后 12 周时血清 HCV RNA 检测不到，并在意向治疗人群中进行评估。安全监测是根据移植后的常规做法进行的。报告前 30 名患者的 12 周数据。该试验已在 ClinicalTrials.gov 上注册，NCT04017338。该试验已结束招募，但后续工作正在进行中。

发现

30 名患者（23 名男性和 7 名女性；中位年龄 61 岁（IQR 48-66））接受了来自 18 名 HCV 感染捐献者的移植物（13 个肺、10 个肾、6 个心脏和 1 个肾-胰腺）。捐献者病毒载量中位数为5·11 log ₁₀ IU/mL (IQR 4·55–5·63) 和至少三种 HCV 基因型（九名 [50%] 捐献者基因型 1，两名 [11%] 捐献者基因型 2，五名 [28%] 捐献者] 基因型 3，两名 [11%] 基因型未知）。所有 30 名移植受者 (100%) 在移植后 12 周均达到了 HCV RNA 检测不到的主要终点，并且在最后一次随访时为 HCV RNA 阴性（移植后中位 36 周 [IQR 25-47]）。在移植后早期，30 名受者中有 21 名 (67%) 短暂检测到低水平病毒血症，但在第 14 天后则没有。治疗耐受性良好，没有出现任何症状。剂量减少或停止治疗；20 名 (67%) 接受者发生 32 例严重不良事件，其中 1 例丙氨酸氨基转移酶 (ALT) 升高可能与治疗有关。研究给药期间 ALT 和肌酸激酶非严重短暂升高治疗完成后解决。严重不良事件包括两名受者因与研究药物治疗无关的原因死亡（移植后 49 天败血症和移植后 109 天蛛网膜下腔出血），且两名患者均未出现 HCV 病毒血症。

解释

依泽替米贝联合 glecaprevir-pibrentasvir 在移植前和移植后 7 天给予一剂，可防止来自 HCV 感染供体的不同器官的受者建立慢性 HCV 感染。这项研究表明，超短疗程的直接作用抗病毒药物和依折麦布可以预防受者体内形成慢性 HCV 感染，从而减轻对 HCV 感染供体移植器官的许多担忧。

资金

加拿大健康研究所；器官移植计划，大学健康网络。