A Randomized Controlled Trial of Prophylaxis with Direct-acting Antivirals for Kidney Transplantation from Hepatitis C virus-infected donor to Uninfected Recipients (PREVENT-HCV)

直接作用抗病毒药物预防丙型肝炎病毒感染供者肾移植至未感染受者的随机对照试验 (PREVENT-HCV)

• 批准号: 10597168
• 负责人: Christine Marie Durand
• 金额: $ 138.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597168
• 关键词: 2019-nCoV; Acute; Acute Hepatitis C; Adoption; Aftercare; Age; Agreement; Alanine Transaminase; American; Antiviral Agents; BK Virus; Biology; Biometry; Blood; Cells; Cessation of life; Cholestasis; Clinical; Clinical Research; Collaborations; Communicable Diseases; Cytomegalovirus; Data; Data Collection; Dose; Enrollment; Ensure; Epidemiology; Equipoise; Event; Failure; Fibrosis; Genetic; Genetic Polymorphism; Graft Survival; Health; Hepatitis; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Hepatocyte; Hour; IL18 gene; Immune; Immune response; Immunocompromised Host; Immunologics; Immunology; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Infrastructure; Innate Immune Response; Interleukin-1; Kidney; Kidney Transplantation; Knowledge; Life; Link; Liver; Measures; Mediating; Monitor; Nephrology; Nested Case-Control Study; Oncology; Opioid; Organ; Organ Donor; Organ Transplantation; Outcome; Pathology; Perfusion; Pharmaceutical Preparations; Phylogenetic Analysis; Plasma; Primary Infection; Prophylactic treatment; Race; Randomized; Randomized, Controlled Trials; Reporting; Resistance; Safety; Shapes; Standardization; Subgroup; Testing; Transplant Recipients; Transplantation; Transplantation Surgery; Treatment Failure; Uncertainty; Vaccines; Viral; Viremia; Virus; Virus Diseases; Virus Replication; acute liver injury; arm; clinical practice; clinical risk; co-infection; cytokine; data management; donor-specific antibody; epidemic virus; epidemiology study; experience; immune activation; improved; innovation; insight; intrahepatic; laser capture microdissection; liver biopsy; liver injury; multidisciplinary; novel virus; operation; opioid epidemic; opioid overdose; post-transplant; prevent; primary outcome; sample collection; secondary endpoint; sex; success; transcriptome; transmission process; transplant centers; trial comparing; vaccine development; viral RNA; viral transmission; virology; virome

Due to epidemics of opioid overdose and hepatitis C virus (HCV), the availability of kidneys from HCV-viremic (HCV+) donors is increasing. There are limited numbers of HCV+ transplant candidates, and as a result 500- 1000 HCV+ donor kidneys are discarded each year. A new practice of HCV+ donor to HCV-naïve recipient (HCV D+/R-) kidney transplantation (KT) with direct-acting antivirals (DAAs) has had early success. However, there remains equipoise about whether to give DAAs as prophylaxis or as treatment post-transplant (“transmit- and-treat”). With transmit-and-treat, HCV is cured with 8-12 weeks of DAAs, but complications such as fibrosing cholestatic hepatitis, rejection, CMV, and BK virus are reported. Prophylaxis seems to prevent these complications but data is limited. A direct comparison of prophylaxis and transmit-and-treat has not been done. Determining the best strategy would allow for expansion of HCV D+/R- KT and minimize clinical complications. We propose PREVENT HCV, a multicenter randomized controlled trial comparing DAA prophylaxis with transmit-and-treat in HCV D+/R- KT. We will perform 120 HCV D+/R- KTs over 2 years at 6 transplant centers. Aim 1 will compare the safety and efficacy of transmit-and-treat (SOF/VEL for 12 weeks starting day 14 post- KT) vs prophylaxis (SOF/VEL for 2 weeks started several hours pre-KT). We will also measure clinical complications of HCV D+/R- KT such as liver injury, rejection, and infection with these two strategies. In this trial, the exact timing, size, and genetic composition of the transmitted viral inoculum will be known, providing an unprecedented opportunity to study the earliest events in primary HCV infection. Leveraging this, Aim 2 will characterize the earliest viral dynamics and phylogenetics of early HCV in the liver and blood, as well as the transmitted virome, identifying emerging viruses, including SARsCoV2, some of which have been implicated in rejection. Aim 3 will characterize the innate immune response to primary HCV, measuring cytokines and the transcriptome of innate immune cells. These studies can contribute new knowledge about HCV related to vaccine efforts and deeper understanding of the virome, generalizable beyond transplantation. Our multidisciplinary team includes experts in Transplant Surgery, Infectious Diseases, Nephrology, Epidemiology, Biostatistics, Pathology, Virology, and Immunology. Our team has experience successfully enrolling and conducting multicenter transplantation trials (U01AI134591, U01AI138897) and will leverage existing infrastructure for operations, data management, analysis, and safety monitoring. In summary, PREVENT HCV will quantify clinical risks of HCV D+/R- KT and determine the optimal DAA approach. This could facilitate thousands of additional KTs, contributing to one of the mandates of the White House Executive Order on American Kidney Health. Finally, this trial includes unique mechanistic studies that can generate fundamental insights into the biology of primary HCV relevant to vaccine efforts, and knowledge about the transmitted virome and its significance in immunocompromised hosts.

由于阿片类药物过量和丙型肝炎病毒 (HCV) 的流行，HCV 病毒血症的肾脏可用性 (HCV+) 捐赠者的数量正在增加，HCV+ 移植候选者的数量有限，因此只有 500- 每年有 1000 个 HCV+ 供体肾脏被丢弃 将 HCV+ 供体捐献给未接触过 HCV 的受者的新做法。 (HCV D+/R-) 肾移植 (KT) 与直接作用抗病毒药物 (DAA) 已取得早期成功。 关于给予 DAA 作为预防还是作为移植后治疗（“传播- 通过传输和治疗，HCV 可通过 8-12 周的 DAA 治愈，但出现以下并发症： 据报道，纤维化胆汁淤积性肝炎、排斥反应、巨细胞病毒和 BK 病毒的预防似乎可以预防这些疾病。 并发症，但数据有限，尚未对预防和传播与治疗进行直接比较。 确定最佳策略将允许扩大 HCV D+/R- KT 并最大限度地减少临床并发症。 我们提出 PREVENT HCV，这是一项多中心随机对照试验，比较 DAA 预防与 HCV D+/R- KT 的传播和治疗 我们将在 6 个移植中心进行 120 次 HCV D+/R- KT。 目标 1 将比较传输和治疗（SOF/VEL）的安全性和有效性，从传输后第 14 天开始，持续 12 周。 KT）与预防（KT 前几个小时开始的 2 周 SOF/VEL）我们还将测量临床。 这两种策略的 HCV D+/R- KT 并发症包括肝损伤、排斥反应和感染。 在这项试验中，将了解传播病毒接种物的确切时间、大小和遗传组成， 为研究原发性 HCV 感染的最早事件提供了前所未有的机会， 目标 2 将表征肝脏和血液中早期 HCV 的最早病毒动态和系统发育，如下所示 以及传播的病毒组，识别新出现的病毒，包括 SARsCoV2，其中一些已被 目标 3 将描述对原发性 HCV 的先天免疫反应，并进行测量。 这些研究可以贡献关于细胞因子和先天免疫细胞的转录组的新知识。 HCV 与疫苗工作和对病毒组的更深入了解有关，可推广到移植之外。 我们的多学科团队包括移植外科、传染病、肾病学、 我们的团队在流行病学、生物统计学、病理学、病毒学和免疫学方面拥有成功的经验。 招募并进行多中心移植试验（U01AI134591、U01AI138897）并将利用 用于运营、数据管理、分析和安全监控的现有基础设施。 总之，PREVENT HCV 将量化 HCV D+/R- KT 的临床风险并确定最佳 DAA 这可以促进数千个额外的 KT，为白方的任务之一做出贡献。 最后，这项试验包括独特的机制研究： 可以对与疫苗工作相关的原发性 HCV 生物学产生基本见解和知识 关于传播的病毒组及其在免疫功能低下宿主中的意义。