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

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中，Christine Durand博士将研究HIV-1感染的血液恶性肿瘤患者的同种异体造血干细胞移植（alloHSCT），以努力改善这类患者群体的临床护理，并为根除HIV-1提供新的策略。拟议的研究，连同结构化的指导和临床研究方法的正式指导，将把杜兰德博士培养成一名独立的研究者，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大学接受了十多年的培训，在医学院（SOM）获得了医学博士学位，完成了内科住院医师和传染病（ID）的奖学金。她在Robert Siliciano博士的实验室完成了第三年的博士后研究，Robert Siliciano博士是HIV-1潜伏期领域的领导者。在此期间，她研究了HIV-1在骨髓中的持久性，并在ID部门和肿瘤科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，包括同种异体造血干细胞移植。她将于2013年7月加入学院，担任ID部门的助理教授。Durand博士在转化实验室研究方面拥有坚实的基础；然而，她的职业目标是领导临床试验。在K23的支持下，她将有保障的时间接受正规的临床研究培训，并获得临床试验设计、实施和分析的实践经验。环境。Rich Ambinder博士将是主要导师；他是约翰霍普金斯综合癌症中心血液恶性肿瘤部门的主任和骨髓移植项目的联合主任。他是美国唯一一个在hiv -1感染患者中进行造血干细胞移植的合作小组试验的主席。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，艾滋病临床试验部门的首席研究员，以及公共卫生学院临床调查研究生培训计划（GTPCI）的主任。对于拟议的研究，杜兰德博士得到了肿瘤科临床试验设施的支持，并得到了霍普金斯艾滋病研究中心的支持。对HIV-1储存库的研究将在她的合作者和顾问Robert Siliciano博士的实验室进行。为了她的职业发展培训，杜兰德博士将在约翰霍普金斯大学的全额学费支持下，通过SPH和SOM的GTPCI完成临床研究的综合课程。研究。越来越多的证据表明，同种异体造血干细胞移植可以成功地扩展为治疗复发性侵袭性淋巴瘤和高危白血病的hiv感染者。此外，由于同种异体效应，所有宿主造血细胞都被供体造血细胞取代，异体造血移植可以根除HIV-1储存库的想法引起了人们的极大兴趣。如果抗逆转录病毒治疗（ART）能够在同种异体造血干细胞移植期间继续进行，就可以保护供体细胞免受感染，并最终治愈HIV-1。为了探索这一假设，在Aim 1中，Durand博士将进行一项临床试验，以确定优化ART策略在同种异体造血干细胞移植中是否可行；优化的抗逆转录病毒治疗包括使用避免药物-药物相互作用的抗逆转录病毒药物，以及在口服药物不能耐受期间使用恩福韦肽（ENF）这一皮下抗逆转录病毒药物。这项试验的主要结果将是维持抗逆转录病毒治疗的患者的百分比。次要结果包括同种异体造血干细胞移植环境中ENF的耐受性和感染并发症。在第二阶段，杜兰德博士将会

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.