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.

Public Health Relevance

Public Health Relevance Individuals infected with HIV are at risk for certain types of lymphoma and leukemia that are treated with bone marrow transplantation. Continuing HIV medications during bone marrow transplant therapy is difficult because of drug interactions and side effects from chemotherapy. There is interest in whether bone marrow transplant can cure HIV infection but this may depend on continuing HIV medications during the transplant. This grant includes a clinical trial that uses special approaches to continue HIV medications during bone marrow transplant and will assess whether this approach contributes to HIV elimination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA177321-03
Application #
9113154
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Radaev, Sergei
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Nguyen, Anh Q; Anjum, Saad K; Halpern, Samantha E et al. (2018) Willingness to Donate Organs Among People Living With HIV. J Acquir Immune Defic Syndr 79:e30-e36
Durand, Christine M; Bowring, Mary G; Brown, Diane M et al. (2018) Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial. Ann Intern Med 168:533-540
Durand, Christine M; Halpern, Samantha E; Bowring, Mary G et al. (2018) Organs from deceased donors with false-positive HIV screening tests: An unexpected benefit of the HOPE act. Am J Transplant 18:2579-2586
Van Pilsum Rasmussen, Sarah E; Bowring, Mary Grace; Shaffer, Ashton A et al. (2018) Knowledge, attitudes, and planned practice of HIV-positive to HIV-positive transplantation in US transplant centers. Clin Transplant 32:e13365
Shaffer, Ashton A; Durand, Christine M (2018) Solid Organ Transplantation for HIV-Infected Individuals. Curr Treat Options Infect Dis 10:107-120
Cash, Ayla; Luo, Xun; Chow, Eric K H et al. (2018) HIV+ deceased donor referrals: A national survey of organ procurement organizations. Clin Transplant 32:
Durand, Christine M; Bowring, Mary G; Thomas, Alvin G et al. (2018) The Drug Overdose Epidemic and Deceased-Donor Transplantation in the United States: A National Registry Study. Ann Intern Med 168:702-711
Riddler, Sharon A; Zheng, Lu; Durand, Christine M et al. (2018) Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART. Open Forum Infect Dis 5:ofy242
Doby, Brianna L; Tobian, Aaron A R; Segev, Dorry L et al. (2018) Moving from the HIV Organ Policy Equity Act to HIV Organ Policy Equity in action: changing practice and challenging stigma. Curr Opin Organ Transplant 23:271-278
Bowring, Mary G; Kucirka, Lauren M; Massie, Allan B et al. (2018) Changes in Utilization and Discard of HCV Antibody-Positive Deceased Donor Kidneys in the Era of Direct-Acting Antiviral Therapy. Transplantation 102:2088-2095

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