HOPE in Action: A Clinical Trial of HIV-to-HIV Liver Transplantation

希望在行动：HIV 至 HIV 肝移植的临床试验

• 批准号: 10681594
• 负责人: Christine Marie Durand
• 金额: $ 12.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681594
• 关键词: Acquired Immunodeficiency Syndrome; Alcoholic Fatty Liver; Allografting; Antibodies; Antiviral Agents; Area; Biological; Biological Assay; Biometry; Biopsy; Blood; CD4 Positive T Lymphocytes; Case Report Form; Case Study; Cessation of life; Clinical Trials; Collaborations; Communicable Diseases; Communities; Consent; Databases; Development; Donor person; Enrollment; Ensure; Epidemiology; Event; Failure; Fatty Liver; Fibrosis; Funding; Graft Rejection; HIV; HIV drug resistance; Health Benefit; Hepatitis B Virus; Hepatitis C; Hepatitis C Antiviral; Hepatitis C virus; Hepatology; Immune system; Incidence; Individual; Infection; Infrastructure; International; Kidney; Kidney Failure; Kidney Transplantation; Legal; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Lymph Node Tissue; Malignant Neoplasms; Measures; Mediating; Metabolic; Multi-Institutional Clinical Trial; Multicenter Studies; Multicenter Trials; National Institute of Allergy and Infectious Disease; Organ; Organ Donor; Organ Transplantation; Outcome; Parents; Pathogenesis; Pathologic; Pathology; Pilot Projects; Policies; Population; Protocols documentation; Public Health; Publishing; Research; Resistance development; Resources; Rest; Risk; Safety; Safety Management; Savings; Severities; Source; Switzerland; Time; Tissues; Transplant Recipients; Transplantation; Transplantation Surgery; United Network for Organ Sharing; United States National Institutes of Health; Viral; Viral hepatitis; Virus Activation; Wait Time; Waiting Lists; arm; attenuation; biobank; co-infection; data management; design; digital; digital imaging; early experience; elastography; end stage liver disease; experience; fatty liver disease; feasibility trial; improved; insight; laser capture microdissection; latent HIV reservoir; liver function; liver transplantation; lymph nodes; mortality; next generation sequencing; non-alcoholic fatty liver disease; novel; operation; organ procurement transplantation network; organ transplant rejection; pilot trial; post-transplant; primary endpoint; prospective; public health relevance; repository; superinfection; transplant centers; trial design; viral rebound; virology; whole slide imaging

End-stage liver disease is common in HIV-infected (HIV+) individuals due to co-infection with hepatitis C virus (HCV), hepatitis B virus (HBV), and alcoholic and non-alcoholic fatty liver disease (NAFLD). Liver transplant (LT) in HIV+ individuals provides a clear survival benefit and outcomes will improve further with direct-acting antivirals for HCV. There is already a severe organ shortage, with long waiting times, and a higher waitlist mortality for HIV+ individuals in particular, and the need for LT in HIV+ individuals is expected to grow. Organs from HIV+ deceased donors (HIV D+) are a unique resource for HIV+ transplant candidates. By expanding the donor pool, use of organs from HIV D+ could have a significant public health impact and decrease wait times for all individuals on the waitlist. This motivated the Congressional HOPE (HIV Organ Policy Equity) Act which now allows HIV D+ transplants for HIV+ recipients (R+) under research protocols. Potential risks of HIV D+/R+ transplants include complications related to donor-to-recipient HIV superinfection (HIV-SI), increased organ rejection rates, and accelerated liver fibrosis and/or steatosis after transplant due to viral hepatitis or metabolic liver disease. Experience with HIV D+ LT is extremely limited with only 2 international cases reported and 5 cases in the US performed by our group within a HOPE pilot study. In order to determine if HIV D+ liver transplantation is safe and effective, a prospective multicenter trial is needed. The proposed HOPE in Action Liver Trial will compare outcomes between HIV+ recipients of HIV+ versus HIV- donor livers, enrolling 40 individuals in each group over 3 years at 16 transplant centers. Aim 1 will compare difference in time to major transplant-related and HIV-related complications between the two arms. Aim 2 will compare the incidence of liver disease including HCV- and HBV-related fibrosis and liver steatosis. Mechanistic studies in Aim 3 will characterize HIV-SI in blood and in Aim 4 will characterize both the composition and changes in size of long-lived HIV reservoirs in blood, lymph nodes, and liver longitudinally. A comprehensive digital pathologic repository and a tissue biorepository will be created. We have planned and designed the trial with NIAID-sponsored project team (R34AI23023) and we have assembled a team of experts in Transplant Surgery, HIV/Infectious Diseases, Hepatology, Epidemiology, Biostatistics, Pathology, and Virology. The trial will benefit from existing studies and infrastructure established by our group, including a study of HIV D+ nationally in collaboration with the Organ Procurement and Transplantation Network (R01AI120938) and a Multicenter HOPE in Action Kidney Trial (U01AI134591). In summary, HOPE in Action: A clinical trial of HIV-to-HIV deceased donor liver transplantation will determine whether the use of HIV D+ for LT is safe and effective. In addition, the trial will impact not only the field of organ transplantation, but will also provide new insight into mechanisms of HIV-related liver disease, HIV superinfection, and will directly inform HIV cure research efforts.

终末期肝病在HIV感染者（HIV+）中很常见，因为合并感染了丙型肝炎病毒 (HCV)、肝炎B病毒（HBV）以及酒精性和非酒精性脂肪性肝病（NAFLD）。肝移植 (LT)在HIV+个体中提供了明确的生存益处，并且结果将进一步改善直接作用 抗HCV药物目前已经出现了严重的器官短缺，等待时间很长，等待名单也越来越长 特别是HIV+个体的死亡率，预计HIV+个体对LT的需求将增加。 来自HIV+已故捐献者（HIV D+）的器官是HIV+移植候选人的独特资源。通过 扩大捐献者库，使用艾滋病毒D+的器官可能会对公共卫生产生重大影响， 减少等待名单上所有人的等待时间。这促使国会希望（艾滋病毒器官） 该法案现在允许根据研究协议为艾滋病毒+接受者（R+）进行艾滋病毒D+移植。 HIV D+/R+移植的潜在风险包括与供体-受体HIV相关的并发症 重叠感染（HIV-SI），增加器官排斥率，加速肝纤维化和/或脂肪变性， 由于病毒性肝炎或代谢性肝病而进行肝移植。HIV D+ LT的经验极其有限， 在HOPE初步研究中，我们组仅报告了2例国际病例和5例美国病例。 为了确定HIV D+肝移植是否安全有效， needed.拟议的HOPE in Action肝脏试验将比较HIV+接受者与HIV+接受者之间的结果。 与HIV供体肝脏相比，在16个移植中心，每组招募40名个体，为期3年。目标1将 比较两组之间发生主要移植相关并发症和HIV相关并发症的时间差异。 目的2将比较肝病的发病率，包括HCV和HBV相关的纤维化和肝脂肪变性。 目标3中的机制研究将表征血液中的HIV-SI，目标4中的机制研究将表征 血液、淋巴结和肝脏中的长寿HIV储库的组成和大小的纵向变化。一 将建立一个全面的数字病理学储存库和一个组织生物储存库。 我们与NIAID申办的项目团队（R34 AI 23023）一起计划和设计了试验， 组建了一个移植手术、艾滋病毒/传染病、肝病学、流行病学、 生物统计学、病理学和病毒学。试验将受益于现有的研究和建立的基础设施 我们的小组，包括与器官采购合作在全国范围内进行的艾滋病毒D+研究， 移植网络（R 01 AI 120938）和一项多中心HOPE在行动肾脏试验（U 01 AI 134591）。 总之，希望在行动：一项艾滋病毒对艾滋病毒死亡供体肝移植的临床试验将 确定使用HIV D+进行LT是否安全有效。此外，审判不仅会影响 器官移植领域，而且还将为艾滋病毒相关肝病的机制提供新的见解， 艾滋病病毒重叠感染，并将直接告知艾滋病病毒治愈的研究工作。