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: 10459319
• 负责人: Christine Marie Durand
• 金额: $ 167.36万
• 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/10459319
• 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.

由于与丙型肝炎病毒共同感染，末期肝病在HIV感染（HIV+）个体中很常见 （HCV），乙型肝炎病毒（HBV）以及酒精和非酒精性脂肪肝病（NAFLD）。肝移植 （LT）在艾滋病毒+个人中提供明显的生存益处，结果将进一步改善直接行动 HCV的抗病毒药。已经有严重的器官短缺，等待时间很长，等待列表较高 尤其是艾滋病毒+个体的死亡率，以及对艾滋病毒+个体中LT的需求增长。 来自HIV+已故供体的器官（HIV D+）是HIV+移植候选者的独特资源。经过 扩大供体池，使用HIV D+的器官可能会产生重大的公共卫生影响，并且 减少等待名单上所有个人的等待时间。这促使国会希望（HIV器官 策略权益）现在允许在研究方案下允许HIV+受体（R+）的HIV D+移植物。 HIV D+/R+移植的潜在风险包括与供体到艾滋病有关的并发症 超级感染（HIV-SI），器官排斥率提高以及加速肝纤维化和/或脂肪变性后 由于病毒肝炎或代谢性肝病而引起的移植。 HIV D+ LT的经验非常有限 在希望试点研究中，我们小组中只有2例国际案件和5例在美国进行的案件。 为了确定HIV D+肝移植是否安全有效，前瞻性多中心试验是 需要。拟议的希望肝试验将比较艾滋病毒+艾滋病毒+受体之间的结果 与艾滋病毒供体肝脏相比，在16个移植中心的3年中，每组中有40个人。目标1意志 将时间差异与两个臂之间的主要移植相关和与HIV相关的并发症进行比较。 AIM 2将比较肝病的发生率，包括HCV和HBV相关的纤维化和肝脏脂肪变性。 AIM 3中的机械研究将表征血液中的HIV-SI，而AIM 4则将表征 长寿命HIV储量的组成和血液，淋巴结和肝脏纵向的组成。一个 将创建全面的数字病理仓库和组织生物库。 我们已经计划并设计了NIAID赞助的项目团队（R34AI23023）的试验，我们已经 组建了一支由移植手术，艾滋病毒/传染病，肝病学，流行病学的专家团队 生物统计学，病理学和病毒学。该试验将从现有的研究和基础设施中受益 由我们的小组，包括与器官采购合作的全国性HIV D+研究 移植网络（R01AI120938）和一个多中心希望肾脏试验（U01AI134591）。 总而言之，希望：HIV至HIV死者供体肝移植的临床试验将 确定将HIV D+用于LT是否安全有效。此外，审判不仅会影响 器官移植场，但还将为与HIV相关肝病的机制提供新的见解， 艾滋病毒超级感染，并将直接告知艾滋病毒治疗研究工作。