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，丙型肝炎病毒血症肾脏的可用性