Adults with HIV are at increased risk of cardiovascular and metabolic complications compared to HIV-uninfected control populations. Compared to what is known in adults, little is known about these risks in the pediatric population and even less in the setting of sub-Saharan Africa. Although inflammation has been linked to cardiovascular disease in adults with HIV, the role of inflammation on markers of cardiovascular disease risk has been scarcely investigated in HIV-infected children and adolescents. Furthermore, the impact of non-AIDS co morbidities may be greater in sub-Saharan Africa, though no studies of CVD have been conducted in children on ART in this setting. The overall objective of this proposed K23 research plan is to use surrogate markers of cardiovascular disease to identify HIV-infected children and youth at risk of early heart disease and to understand the mechanisms of these changes, so that risk- reduction therapies can be appropriately targeted and novel preventive strategies may be developed in the future. In a longitudinal study of 100 HIV-infected youth and 100 healthy controls, this project aims to use carotid intima media thickness (cIMT), pulse wave velocity (PWV) and insulin resistance to identify early cardiometabolic risks in HIV- infected youth compared to age and gender match HIV uninfected controls in Kampala, Uganda. Additionally, we will investigate whether these makers of cardiometabolic disease correlate with biomarkers of inflammation and gut integrity. This study will provide a comprehensive view of how inflammation, immune activation and bacterial translocation relate to cardiometabolic disease among HIV-infected children and adolescents. The PI, Dr Dirajlal-Fargo, is an exceptional candidate who is seeking to become an internationally recognized clinician-investigator in the field of cardiometabolic complications in pediatric HIV. She also has experience conducting clinical research in Uganda. Dr Dirajlal-Fargo has strong institutional support from Case Western Reserve University and the Department of Pediatrics at Rainbow Babies and Children's Hospital. She will have guaranteed 75% protected research time and access to a wealth of resources that will ensure a successful transition to independently funded investigator. Her robust training plan includes: 1)high quality mentorship from her primary mentor, Dr Grace McComsey, as well as co-mentors in the field of immunology, infectious disease and cardiovascular complications of HIV and pediatric HIV in Uganda, a biostatistician and a group of collaborators; 2) coursework in fundamental immunology with a focus on chronic HIV infection; 3) training in cardiovascular imaging and physiology; 4) training in clinical research design and statistics; 5) experience in international interdisciplinary team science; and 6) field experience in integrating clinical care and research programs.

Public Health Relevance

People living with HIV are suffering from several non-infectious complications of HIV including heart disease. Cardiovascular disease and its link to inflammation have been studied in adults with HIV but no studies have been performed to assess the clinical significance of inflammation and immune activation markers in HIV-infected youth. The available limited research evaluating the impact of inflammation in HIV-infected children and youth has been focused in resource rich settings and it remains unclear how this related to pediatric patients in Sub-Saharan Africa where the majority of HIV-infected children and adolescents live. This proposal will advance our knowledge of the risk of cardiovascular complications in HIV-infected Ugandan youth and their relationship to inflammation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23HD088295-01A1
Application #
9270212
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Lee, Sonia S
Project Start
2016-09-25
Project End
2021-08-31
Budget Start
2016-09-25
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$130,164
Indirect Cost
$9,642
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Dirajlal-Fargo, Sahera; Alam, Khurshid; Sattar, Abdus et al. (2017) Comprehensive assessment of the arginine pathway and its relationship to inflammation in HIV. AIDS 31:533-537
Dirajlal-Fargo, Sahera; Sattar, Abdus; Kulkarni, Manjusha et al. (2017) HIV-positive youth who are perinatally infected have impaired endothelial function. AIDS 31:1917-1924
Dirajlal-Fargo, Sahera; Musiime, Victor; Cook, Adrian et al. (2017) Insulin Resistance and Markers of Inflammation in HIV-infected Ugandan Children in the CHAPAS-3 Trial. Pediatr Infect Dis J 36:761-767
Dirajlal-Fargo, Sahera; Moser, Carlee; Brown, Todd T et al. (2016) Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s. Open Forum Infect Dis 3:ofw174