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: 10214504
• 负责人: Christine Marie Durand
• 金额: $ 165.11万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214504
• 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; experience; 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; 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混合感染，终末期肝病在艾滋病毒感染者(HIV+)中很常见 丙型肝炎(丙型肝炎)、乙肝病毒(乙肝)、酒精性和非酒精性脂肪性肝病(NAFLD)。肝移植 (LT)在HIV+个体中提供明显的生存益处，结果将通过直接作用进一步改善 丙型肝炎病毒的抗病毒药物。器官短缺已经很严重了，等待时间很长，等待名单也更高 特别是艾滋病毒感染者的死亡率，预计艾滋病毒感染者对LT的需求将会增加。 来自HIV+已故捐赠者(HIV D+)的器官是HIV+移植候选者的独特资源。通过 扩大捐赠者群体，使用来自艾滋病毒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个人的等待时间。这激发了国会的希望(艾滋病毒器官 政策公平)法案，现在允许根据研究协议对HIV+接受者(R+)进行HIV D+移植。 艾滋病毒D+/R+移植的潜在风险包括与供受者艾滋病毒相关的并发症 重叠感染(HIV-SI)，增加器官排斥率，并加速肝纤维化和/或脂肪变性 因病毒性肝炎或代谢性肝病而进行移植。对HIV D+LT的经验极其有限 在一项HOPE先导研究中，我们小组只报告了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，一项前瞻性的多中心试验是 需要的。拟议的HOPE in Action肝脏试验将比较HIV+感染者和HIV+感染者之间的结果 对比艾滋病毒捐赠者的肝脏，在16个移植中心的3年时间里，每组招募40人。目标1将 比较两组患者在主要移植相关并发症和艾滋病毒相关并发症方面的时间差异。 目的2将比较肝脏疾病的发生率，包括丙型肝炎病毒和乙肝病毒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，而目标4中将表征 血液、淋巴结和肝脏中长寿的艾滋病毒纵向储存库的组成和大小变化。一个 将创建全面的数字病理存储库和组织生物库。 我们与NIAID赞助的项目团队(R34AI23023)一起计划和设计了试验，我们已经 组建了一支由移植外科、艾滋病毒/传染病、肝病、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 由我们小组，包括与器官采购和器官采购中心合作在全国范围内进行的艾滋病毒D+研究 移植网络(R01AI120938)和多中心希望在行动肾脏试验(U01AI134591)。 综上所述，希望在行动：HIV对HIV死亡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，审判不仅会影响到 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， 艾滋病毒重叠感染，并将直接告知艾滋病毒治愈研究的努力。