Optimal Antiretroviral Therapy During Bone Marrow Transplant in HIV-1 Infection

HIV-1 感染者骨髓移植期间的最佳抗逆转录病毒治疗

• 批准号: 8635550
• 负责人: Christine Marie Durand
• 金额: $ 16.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635550
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Allogenic; Anti-Retroviral Agents; Area; Award; Berlin; Blood; Bone Marrow; Bone Marrow Transplantation; Cells; Chimerism; Clinical Investigator; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Clinical Trials Unit; Collaborations; Communicable Diseases; Comprehensive Cancer Center; Cytotoxic Chemotherapy; Doctor of Medicine; Drug Interactions; Environment; Faculty; Fellowship; Foundations; Gastrointestinal tract structure; Genetic; Goals; Grant; HIV; HIV Infections; HIV-1; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Incidence; Individual; Infection; Instruction; Internal Medicine; International AIDS; Interruption; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Lymphocyte; Lymphoma; Malignant Neoplasms; Marrow; Measures; Mentors; Mentorship; Methodology; Mucositis; Nausea and Vomiting; Oral; Patients; Pharmaceutical Preparations; Postdoctoral Fellow; Principal Investigator; Protocols documentation; Public Health Schools; Relapse; Reporting; Research; Research Personnel; Residencies; Resistance; Risk; Schools; Sequence Analysis; Societies; Structure; T-20; Time; Tissues; Toxic effect; Training; Training Programs; Transplantation; Viral; Virus; antiretroviral therapy; base; cancer therapy; career; career development; chemotherapy; clinical care; design; experience; high risk; improved; in utero; insight; interest; killings; leukemia; leukemia/lymphoma; medical schools; meetings; memory CD4 T lymphocyte; novel; oncology; patient oriented; patient population; peripheral blood; prevent; primary outcome; professor; programs; public health relevance; secondary outcome; skills; stem cell therapy; subcutaneous; translational study; virology

DESCRIPTION (provided by applicant): In this Patient-Oriented Mentored Career Development Award, Dr. Christine Durand will study allogeneic hematopoietic stem cell transplantation (alloHSCT) in HIV-1-infected individuals with hematologic malignancy both in an effort to improve the clinical care of this patient population and to provide new insight into strategies for HIV-1 eradication. The proposed studies, together with structured mentorship, and formal instruction in methodologies of clinical investigation will train Dr. Durand as an independent investigator who will design and lead trials focused on patients with HIV-1-infection who require cancer and transplant-based treatments. Candidate. Dr. Durand has trained at Johns Hopkins for more than a decade, earning her M.D. at the School of Medicine (SOM), completing her residency in Internal Medicine and fellowship in Infectious Diseases (ID). She is completing her third year of post-doctoral research in the laboratory of Dr. Robert Siliciano, a leader in the field of HIV-1 latency. During this time, she has investigated HIV-1 persistence in bone marrow and established collaborations between the Division of ID and the Department of Oncology, to facilitate novel investigation into HIV-1 persistence during cancer treatment, including alloHSCT. She will join faculty in July of 2013 as an Assistant Professor within the ID Division. Dr. Durand has a strong foundation in translational laboratory research; however her career goal is to lead clinical trials. With the support of a K23, she will have the protected timeto obtain formal training in clinical investigation and obtain practical experience in the design, implementation, and analysis of clinical trials. Environment. Dr. Rich Ambinder will be the primary mentor; he is director of the Hematologic Malignancies Division and co-director of the Bone Marrow Transplant Program at the Johns Hopkins Comprehensive Cancer Center. He is chair of the only US cooperative group trials of HSCT in HIV-1-infected patients. Dr. Charles Flexner is co-mentor. He is a Professor in Infectious Diseases/Clinical Pharmacology, Principal Investigator of the AIDS Clinical Trials Unit, and the Director of the Graduate Training Program in Clinical Investigation (GTPCI) at the School of Public Health (SPH). For the proposed studies, Dr. Durand has support of the Division of Oncology's clinical trial facilities, and support from th Hopkins Center for AIDS Research. Studies on HIV-1 reservoirs will be performed in the laboratory of her collaborator and advisor, Dr. Robert Siliciano. For her career development training, Dr. Durand will complete comprehensive coursework in Clinical Investigation through the GTPCI at the SPH and SOM with full tuition support from Johns Hopkins. Research. Growing evidence suggests that alloHSCT can be successfully extended as curative therapy to HIV-infected individuals with relapsed aggressive lymphoma and high-risk leukemia. Moreover, there is great interest in the idea that alloHSCT could eradicate HIV-1 reservoirs due to the allogeneic effect, whereby all host hematopoietic cells are replaced by donor hematopoietic cells. If antiretroviral therapy (ART) can be continued during alloHSCT this could protect donor cells from becoming infected and ultimately lead to HIV-1 cure. To explore this hypothesis, in Aim 1 Dr. Durand will perform a clinical trial in order to determine whether a strategy of optimized ART is feasible in alloHSCT; optimized ART includes the use of antiretrovirals that avoid drug-drug interactions as well as the use of enfuvirtide (ENF), a subcutaneous antiretroviral, during periods when oral medications are not tolerated. The primary outcome of this trial will be the percent of patients who maintain ART. Secondary outcomes will include the tolerability of ENF in the alloHSCT setting and infectious complications. In Aim 2, Dr. Durand will explore the impact of alloHSCT on long term HIV-1 reservoirs in peripheral blood and in tissues within the optimized ART trial (Aim 1) as well as within a national trial of alloHSCT with standard ART in HIV-1 infected individuals with hematologic malignancy.

描述（由申请人提供）：在这个以患者为导向的指导职业发展奖，克莉丝汀杜兰德博士将研究异基因造血干细胞移植（alloHSCT）在HIV-1感染的血液系统恶性肿瘤的个人都在努力改善这一患者群体的临床护理，并提供新的见解到HIV-1根除策略。拟议的研究，加上结构化的指导，以及临床研究方法的正式指导，将培养杜兰德博士成为一名独立的研究者，他将设计和领导针对需要癌症和移植治疗的HIV-1感染患者的试验。候选人杜兰德博士在约翰霍普金斯接受了十多年的培训，获得了医学博士学位。在医学院（SOM），完成她的住院医师在内科和奖学金在传染病（ID）。她在HIV-1潜伏期领域的领导者Robert Siliciano博士的实验室完成了第三年的博士后研究。在此期间，她研究了HIV-1在骨髓中的持久性，并在ID部门和肿瘤学部门之间建立了合作关系，以促进对癌症治疗期间HIV-1持久性的新研究，包括alloHSCT。她将于2013年7月加入教师，担任ID部门的助理教授。Durand博士在转化实验室研究方面有着坚实的基础;但她的职业目标是领导临床试验。在K23的支持下，她将有受保护的时间获得临床研究的正式培训，并获得临床试验设计，实施和分析的实践经验。环境里奇·安宾德博士将是主要的导师;他是约翰霍普金斯综合癌症中心血液肿瘤科主任和骨髓移植项目的联合主任。他是美国唯一一个合作小组在HIV-1感染患者中进行HSCT试验的主席。查尔斯·弗莱克斯纳博士是共同导师。他是传染病/临床药理学教授，艾滋病临床试验单位的首席研究员，以及公共卫生学院（SPH）临床研究研究生培训计划（GTPCI）的主任。Durand博士的研究计划得到了肿瘤科临床试验机构和霍普金斯艾滋病研究中心的支持。关于HIV-1储库的研究将在她的合作者和顾问Robert Siliciano博士的实验室进行。对于她的职业发展培训，杜兰德博士将通过SPH和SOM的GTPCI完成临床研究的综合课程，并获得约翰霍普金斯的全额学费支持。Research.越来越多的证据表明，异基因造血干细胞移植可以成功地扩展到艾滋病毒感染的复发性侵袭性淋巴瘤和高危白血病的治疗。此外，人们对alloHSCT由于同种异体效应而可以根除HIV-1储库的想法非常感兴趣，由此所有宿主造血细胞都被供体造血细胞取代。如果在alloHSCT期间可以继续抗逆转录病毒治疗（ART），这可以保护供体细胞免受感染，并最终导致HIV-1治愈。为了探索这一假设，在目标1中，Durand博士将进行一项临床试验，以确定优化的ART策略在alloHSCT中是否可行;优化的ART包括使用避免药物相互作用的抗逆转录病毒药物，以及在口服药物不耐受期间使用恩夫韦肽（ENF），一种皮下抗逆转录病毒药物。这项试验的主要结果是维持ART的患者百分比。次要结果包括在alloHSCT环境中ENF的耐受性和感染并发症。在目标2中，杜兰德博士将 探索alloHSCT对优化ART试验（Aim 1）中外周血和组织中长期HIV-1储库的影响，以及在国家alloHSCT试验中使用标准 HIV-1感染的恶性血液病患者的ART。