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

由于阿片类药物过量和丙型肝炎病毒(丙型肝炎病毒)的流行，丙型肝炎病毒携带者肾脏的可用性 丙型肝炎病毒(丙型肝炎病毒)捐赠者正在增加。丙型肝炎病毒移植候选者的数量有限，因此- 每年有1000个丙型肝炎病毒供体肾脏被丢弃。丙型肝炎病毒供者为丙型肝炎病毒单纯接受者的新做法 使用直接作用抗病毒药物(DAA)的(丙型肝炎病毒D/R-)肾移植(KT)已取得早期成功。然而， 对于是给予DAA作为预防措施还是作为移植后的治疗方法，仍然存在平衡。 和--款待“)。通过传输和治疗，丙型肝炎病毒可以在8-12周的DAA内治愈，但并发症如 纤维性淤胆性肝炎、排斥反应、巨细胞病毒和BK病毒被报道。预防措施似乎可以防止这些 情况复杂，但数据有限。还没有对预防和传播治疗进行直接比较。 确定最佳策略将允许扩大丙型肝炎病毒D/R-KT，并将临床并发症降至最低。 我们提出了预防丙型肝炎的多中心随机对照试验，比较了DAA预防和 丙型肝炎病毒D/R-KT中的传递和治疗。我们将在6个移植中心进行为期2年的120例丙型肝炎D/R-KTS。 目标1将比较传输和治疗(SOF/VEL)12周的安全性和有效性，从术后第14天开始 KT)与预防性治疗(SOF/VEL在KT前几个小时开始，为期2周)。我们还将测量临床 丙型肝炎病毒D/R-KT的并发症，如肝损伤、排斥反应和感染等。 在这项试验中，将知道传播的病毒疫苗的确切时间、大小和遗传组成， 为研究原发丙型肝炎病毒感染的最早事件提供了前所未有的机会。利用这一点， 目标2将描述早期丙型肝炎病毒在肝脏和血液中的最早病毒动力学和系统发生学，如 以及传播的病毒，识别新出现的病毒，包括SARsCoV2，其中一些已经 牵涉到拒绝。目标3将描述针对原发丙型肝炎病毒的先天免疫反应，测量 细胞因子与先天免疫细胞的转录组。这些研究可以为我们提供关于 丙型肝炎病毒与疫苗努力和对病毒体的更深入了解有关，可推广到移植以外。 我们的多学科团队包括移植外科、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 招募和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，预防丙型肝炎将量化丙型肝炎病毒D/R-KT的临床风险，并确定最佳的DAA 接近。这可能会为数千名额外的KT提供便利，为白宫的一项任务做出贡献 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械研究， 可以产生对与疫苗努力相关的初级丙型肝炎病毒生物学的基本见解，以及知识 关于传播的病毒及其在免疫受损宿主中的意义。

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.