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

基本信息

批准号：
10622648
负责人：
Christine Marie Durand
金额：
$ 3.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10622648
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

项目摘要

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.

由于同时感染丙型肝炎病毒，终末期肝病在 HIV 感染者 (HIV+) 中很常见（HCV）、乙型肝炎病毒（HBV）以及酒精性和非酒精性脂肪肝病（NAFLD）。肝脏移植 (LT) 在 HIV+ 个体中提供了明显的生存益处，并且直接作用的结果将进一步改善 HCV 抗病毒药物。器官已经严重短缺，等待时间很长，等待名单也越来越多尤其是 HIV+ 个体的死亡率，并且 HIV+ 个体对 LT 的需求预计会增加。来自 HIV+ 已故捐献者 (HIV D+) 的器官是 HIV+ 移植候选者的独特资源。经过扩大捐赠者库，使用来自 HIV D+ 的器官可能会对公共卫生产生重大影响，并且减少候补名单上所有个人的等待时间。这激发了国会希望（HIV Organ 政策公平）法案现在允许根据研究方案对 HIV+ 接受者 (R+) 进行 HIV D+ 移植。 HIV D+/R+ 移植的潜在风险包括与供体到受者 HIV 相关的并发症重复感染（HIV-SI）、器官排斥率增加以及肝纤维化和/或脂肪变性加速因病毒性肝炎或代谢性肝病而进行移植。 HIV D+ LT 的经验极其有限我们的团队在 HOPE 试点研究中仅报告了 2 个国际病例和 5 个美国病例。为了确定 HIV D+ 肝移植是否安全有效，正在进行一项前瞻性多中心试验需要。拟议的 HOPE in Action Liver 试验将比较 HIV+ 接受者之间的结果与 HIV 供体肝脏相比，在 16 个移植中心的 3 年时间内每组招募了 40 名个体。目标1将比较两组之间发生主要移植相关和艾滋病毒相关并发症的时间差异。目标 2 将比较肝脏疾病的发生率，包括 HCV 和 HBV 相关的纤维化和肝脏脂肪变性。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中的 HIV-SI 血液、淋巴结和肝脏中长寿命艾滋病毒储存库的组成和大小的变化。一个将创建综合数字病理存储库和组织生物存储库。我们与 NIAID 赞助的项目团队 (R34AI23023) 一起规划和设计了试验，并且我们已经组建了移植手术、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。该试验将受益于现有的研究和已建立的基础设施由我们小组进行，包括与器官采购局合作进行的一项全国范围内的 HIV D+ 研究移植网络 (R01AI120938) 和多中心 HOPE 肾脏试验 (U01AI134591)。总之，希望在行动：艾滋病毒到艾滋病毒死者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，但也将为艾滋病毒相关肝病的机制提供新的见解， HIV 重复感染，并将直接影响 HIV 治愈研究工作。