Metabolic Effects of In Utero Antiretrovirals on HIV Exposed Uninfected Infants

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DESCRIPTION (provided by applicant): The primary objective of this application is to support Dr. Jao's career development from a mentored researcher to an independent investigator in the field of metabolic complications in HIV-infected pregnant women and their children. Candidate - Career Goals and Objectives - Dr. Jao envisions herself as an independently funded researcher who will lead multi-disciplinary teams in designing, implementing, and analyzing prospective studies of HIV-infected pregnant women and children to evaluate a variety of long term health outcomes following in utero HIV/ARV exposures. In order to provide a strong foundation for future work of this kind, during the K Award, she plans to gain the full experience of conducting and analyzing a prospective study of pregnant women/infant dyads which is grounded in the scientific rationale behind metabolic complications of ARVs and disorders of insulin resistance. Dual-certified in internal medicine and pediatrics, she is well-suited to study this cohort. Her experience as the Director of HIV Services at a large health center and with the Mother-To-Child-Transmission (MTCT-Plus) Initiative of Columbia University has shaped her interest in HIV maternal-child issues domestically and internationally. She recently completed a fellowship in Infectious Diseases and a Master of Public Health degree at Mount Sinai School of Medicine (MSSM). She has also obtained competitive grants to fund her research in HIV-infected pregnant women both in Africa and the U.S. A year and half ago she launched a pilot study evaluating metabolic complications of in utero HIV and ARV exposure in HIV-exposed uninfected infants which is the basis of her current K Award research proposal. She anticipates that knowledge gained from this study and that of the K Award proposal will begin to establish the infrastructure needed to follow this key cohort longitudinally. She anticipates that her work may also direct investigators interested in transposing research in this field internationally and inform policy as questions regarding the long-term safety of ARVs administered in pregnancy are addressed globally. Career Training/Development Plan - The proposed training plan consists of 4 distinct modules: 1) HIV Maternal/ Child Cohort Study Design and Implementation, 2) Statistical Analysis of Longitudinal Cohort Data, 3) Metabolic Disorders of Insulin Resistance, and 4) Management of HIV-infected Pregnant Women and their Children. To develop expertise in each module, Dr. Jao will engage in 4 types of training activities: 1) Mentoring, 2) Coursework, 3) Conferences/ Research Seminars, and 4) Clinical Training. Her unique mentoring structure capitalizes on a multi-disciplinary panel of experts (Drs. Elaine Abrams, Derek LeRoith, and Rhoda Sperling) and the high levels of collaboration among neighboring institutions in Manhattan. Environment - MSSM has developed strong programs in research, education, and clinical services and is now ranked in the top 20 medical schools for NIH funding. As such, it will provide the practical backing needed to complete her proposed study. The Department of Medicine has already provided free use of a Biosafety Level 2 and freezer facility for storage of cord blood specimens in the pilot study. In addition, it has guaranteed Dr. Jao 75% protected research time. The Departments of Obstetrics and Pediatrics have provided their support through clinic staff and faculty who have collaborated successfully on the pilot project of this K23 Award. The Mount Sinai Clinical Research Centers (CRC) where the protocol-intensive 3rd visit of the pilot study is being carried out will continue to provide nursig and bioinformatics support during the K Award. Lastly, Dr. Moran's laboratory will continue to provide support for adipokine and cytokine testing in the study. Research - This study investigates the impact of in utero HIV and ARV exposure on infant metabolic disorders associated with insulin resistance. It combines expert mentors and collaborators in the fields of HIV, obstetrics, pediatrics, endocrinology, and immunology in order to address gaps in knowledge concerning the metabolic effects of in utero HIV and ARV exposure. The specific aims are: 1) to assess whether in utero HIV and ARV exposure is associated with insulin resistance in the first year of life, and 2) to assess whether indirect pathways involving known risk factors for insulin resistance and direct pathways involving inflammation play a role in insulin resistance associated with in utero HIV and ARV exposure. Building on a pilot study begun in 2009, a prospective cohort study of pregnant HIV-infected and -uninfected mother/child dyads will be conducted at Mount Sinai Hospital. The primary endpoint will be the Homeostatic Model Assessment (HOMA- IR) measurement of insulin resistance at 12 months of age. Key prenatal data will include medical and ARV history and measures of HIV infection. Data collected at delivery will include birth weight and outcomes as well as cord blood for specific adipokines and cytokines. Key postnatal data collected will consist of growth patterns in the first year of life and HOMA-IR. This study will expand our understanding of the early metabolic effects of in utero HIV and ARV exposure. If adverse metabolic effects are found to be present early in life, this may potentially impact current pediatric diabetes prevention and treatment strategies. Moreover, future studies would be crucial in distinguishing which ARVs may or may not represent a safer regimen for both the HIV- infected woman and her offspring.