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

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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.