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）的流行病，HCV病毒症的肾脏可用性 （HCV+）捐助者正在增加。 HCV+移植候选者数量有限，结果500- 每年丢弃1000 HCV+供体肾脏。 HCV+捐赠者的新练习对HCV的接受者 （HCV D+/r-）具有直接作用抗病毒药（DAAS）的肾脏移植（KT）已经取得了早期成功。然而， 关于是将DAA作为预防或移植后治疗时仍有平衡（“传播 - and-treat”）。通过传输和治疗，HCV用8-12周的DAA治愈，但并发症如并发症（例如 据报道纤维状肝炎，排斥，CMV和BK病毒。预防似乎阻止了这些 并发症但数据有限。尚未进行预防和发射和治疗的直接比较。 确定最佳策略将允许扩展HCV D+/R-KT并最大程度地减少临床并发症。 我们提出了防止HCV，这是一项比较DAA预防的多中心随机对照试验 HCV D+/R- KT中的传输和治疗。在6个移植中心，我们将在2年内执行120个HCV D+/R-KT。 AIM 1将比较发射和治疗的安全性和易度性（在第14天开始12周， KT）vs预防（SOF/VEL 2周开始了数小时的KT）。我们还将测量临床 HCV D+/R-KT的并发症，例如肝损伤，排斥和感染这两种策略。 在这项试验中，将知道传播病毒接种物的确切时机，大小和遗传组成， 提供了前所未有的机会来研究原发性HCV感染中最早的事件。利用这个， AIM 2将表征肝脏和血液中早期HCV的最早病毒动力学和系统发育学，如 以及传播的病毒瘤，识别包括Sarscov2在内的新兴病毒，其中一些已经是 在拒绝中实施。 AIM 3将表征对主要HCV的先天免疫反应，测量 细胞因子和先天免疫细胞的转录组。这些研究可以贡献有关的新知识 HCV与疫苗的努力以及对病毒蛋白的更深入了解，可推广的超越移植。 我们的多学科团队包括移植手术，传染病，肾脏病， 流行病学，生物统计学，病理学，病毒学和免疫学。我们的团队有成功的经验 注册和进行多中心移植试验（U01AI134591，U01AI138897），并将利用 现有用于操作，数据管理，分析和安全监控的基础架构。 总之，预防HCV将量化HCV D+/R- KT的临床风险，并确定最佳DAA 方法。这可能会促进成千上万的额外KTS，从而有助于白人的任务之一 美国肾脏健康的众议院行政命令。最后，该试验包括独特的机械研究 可以对与疫苗努力相关的主要HCV生物学生物产生基本见解和知识 关于传播的病毒蛋白及其在免疫功能低下的宿主中的重要性。