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（三）捐赠者增加。HCV+移植候选人的数量有限，因此500- 每年有1000个HCV+供体肾脏被丢弃。HCV阳性供者转HCV初治受者的一种新做法 (HCV D+/R-）肾移植（KT）与直接作用的抗病毒药物（DAA）已取得早期成功。然而，在这方面， 对于是否给予DAA作为预防或作为移植后治疗仍然存在平衡（“transfer- and-treat”）。使用传输和治疗，HCV在8-12周的DAA内治愈，但并发症，如 纤维化胆汁淤积性肝炎、排斥、CMV和BK病毒。预防似乎可以防止这些 并发症，但数据有限。尚未对预防和传播-治疗进行直接比较。 确定最佳策略将允许扩展HCV D+/R-KT并最小化临床并发症。 我们提出预防HCV，一项多中心随机对照试验，比较DAA预防与 在HCV D+/R-KT中的传播和治疗。我们将在6个移植中心在2年内进行120例HCV D+/R-KT。 目的1将比较传输和治疗（SOF/VEL，从治疗后第14天开始，持续12周）的安全性和有效性。 KT）与预防（在KT前几小时开始SOF/VEL，持续2周）。我们还将测量临床 HCV D+/R-KT的并发症，如肝损伤、排斥反应和感染。 在本试验中，传播的病毒接种物的确切时间、大小和遗传组成将是已知的， 为研究原发性HCV感染的最早期事件提供了前所未有的机会。利用这一点， 目标2将描述肝脏和血液中早期HCV的最早病毒动力学和遗传学特征， 以及传播的病毒组，识别新出现的病毒，包括SARSCoV 2，其中一些已经被 与拒绝有关。目的3将描述对原发性HCV的先天免疫应答，测量 细胞因子和先天免疫细胞的转录组。这些研究可以提供关于 HCV与疫苗的努力和对病毒组的更深入理解有关，可推广到移植之外。 我们的多学科团队包括移植手术、传染病、肾脏病学、 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 招募和开展多中心移植试验（U 01 AI 134591，U 01 AI 138897），并将利用 现有的基础设施，用于运营、数据管理、分析和安全监控。 总之，PREVENT HCV将量化HCV D+/R-KT的临床风险，并确定最佳DAA approach.这将有助于增加数千名KT，为白色的任务之一做出贡献。 众议院关于美国肾脏健康的行政命令。最后，这项试验包括独特的机制研究， 可以产生与疫苗工作相关的原发性HCV生物学的基本见解， 关于传播病毒组及其在免疫受损宿主中的意义。