HIV/AIDS Clinical Trial
Official title:
Evaluating Indicators of Cardiac Function in Children Living With HIV in Western Kenya
Background: In children and adults living with HIV, cardiomyopathy is a major source of
comorbidity. Traditional echocardiographic measures are insensitive and consequently
cardiomyopathy often goes undiagnosed until late stages of disease. Myocardial deformation
imaging represents a promising means to identify early dysfunction, but to date there have
been no large studies using strain or strain rate to assess cardiac function in children with
HIV and to establish predictors of worse cardiac function such as viral burden and ART
regimen. These studies are critically important as earlier diagnosis and intervention
represent the best means to alter the course of HIV-associated cardiomyopathy.
Objectives: To determine the association of biomarker levels, myocardial deformation, and
viral load level history in HIV infected children attending Moi Teaching and Referral
Hospital (MTRH) clinic.
Design: A cross-sectional study on clients attending HIV clinic, MTRH. Setting: Module 4 HIV
clinic at MTRH in western Kenya, Africa. Population: HIV-infected children attending clinic
in 2017 - 2018 Main Measures: Echocardiographic function assessment, Age, Immune status,
other illnesses, ART status.
Conclusions: The study will explore the NIH/HIV High Priority Target area of HIV-associated
cardiac co-morbidities and will enhance understanding of the relationship between cardiac
function and viremia. The investigators expect to be able to reliably define a subset of
children with worse cardiac function by risk factors: specific ART regimens, less time
virally suppressed, and increased BNP biomarker.
Research Summary:
1. Protocol Title: Evaluating Indicators of Cardiac Function in Children Living with Human
Immunodeficiency Virus in Western Kenya
2. Purpose of Study: To determine the association of biomarker levels and relevant HIV
history with cardiac function in HIV infected children attending Moi Teaching and
Referral Hospital (MTRH) clinic.
3. Background & Significance:
HIV-associated cardiomyopathy is a disease that exposes children with the infection to
tremendous morbidity and mortality. Detection of cardiomyopathy is limited by
traditional echocardiographic measures (i.e. left ventricular ejection fraction, LVEF),
which do not detect cardiomyopathy until late stages of disease. Therefore, a critical
need exists to determine HIV-associated cardiomyopathy risk through early detection.
Prior to changes in traditional echocardiographic measures, newer cardiac imaging
techniques such as myocardial deformation imaging (ie strain measurements) can detect
decreased myocardial performance when LVEF is still normal. The lack of methods to
detect early myocardial dysfunction and biomarkers that determine risk are major barrier
for outcomes and treatment research.
Myocardial deformation imaging represents a promising means to identify early
dysfunction, but to date there have been no large studies using strain to assess cardiac
function in children with HIV. Further, none have established predictors of worse
cardiac function such as viral burden, immune status, zidovudine-containing ART
regimens, and inflammatory state. This large-scale investigation utilizing the latest
imaging techniques in evaluating cardiac function will provide first-in-kind data
enabling estimation of prevalence of early HIV-associated cardiomyopathy as well as risk
stratification. The study will explore the NIH/HIV High Priority Target area of
HIV-associated cardiac co-morbidities and will enhance understanding of the relationship
between cardiac function and viremia. Although these data will substantively enhance our
understanding of early disease progression in children with subclinical HIV-associated
cardiomyopathy, my long-term objective is to use these data in support of future work
focused on early initiation of potentially, life altering therapies (such as
angiotensin-converting enzyme inhibitor and digoxin medications) to children at highest
risk for HIV-associated cardiac dysfunction in Africa and other resource poor regions of
the world.
The proposal objective is to determine the association of biomarker levels, myocardial
deformation, and viral load level history in children with perinatally acquired HIV. Our
central hypothesis is that risk of abnormal myocardial strain can be defined in terms of
HIV clinical parameters - including viral load, antiretroviral therapy (ART), CD4 count,
and serum biomarkers (such as b-natriuretic peptide, BNP). The investigators will
accomplish our objectives with the following Specific Aims:
AIM 1: Describe the prevalence of cardiomyopathy using myocardial deformation imaging
compared with traditional echocardiographic measures in a large cohort of children
living with HIV.
Hypothesis 1: Strain and rate measurements will demonstrate presence of early
cardiomyopathy not detected by traditional echocardiographic measures.
AIM 2: Evaluate the association between HIV viral load and global longitudinal strain
and strain rate.
Hypothesis 2: Children with detectable replicating virus will have worse global
longitudinal strain and strain rate measurements than those who are virally suppressed,
and increasing viral load will be associated with worsening longitudinal strain and
strain rate.
AIM 3: Evaluate the association between b-natriuretic peptide level and myocardial
strain.
Hypothesis 3: There will be an inverse relationship between b-natriuretic peptide level
and myocardial strain. The correlation between b-natriuretic peptide level and
myocardial strain will potentially lead to screening thresholds in children living with
HIV.
4. Design & Procedures:
The study will be a cross sectional design and conducted on consecutive HIV infected children
seen in the AMPATH Pediatric HIV clinic whose mothers or caregivers give consent.
Each subject will undergo a 2-dimensional transthoracic echocardiogram after enrollment
during her/his regularly scheduled clinic follow up as defined in the inclusion criteria. The
echocardiogram will be completed with a portable cardiovascular ultrasound machine (GE Vivid
q or similar) equipped with 4-8 MHz tissue-harmonic imaging probes. Images will be acquired
with raw data and DICOM data at frame rates 60-100 frames/min. Additionally,
electrocardiographic leads will be attached during image acquisition. The echocardiogram is
anticipated to take less than 20 minutes of procedure time for the patient.
Traditional echocardiographic measurements will include LVEF, fractional shortening, and
estimations of diastolic function such as mitral inflow E/A ratio. Additionally, assessment
of the right ventricle will include indicators of pulmonary hypertension such as tricuspid
regurgitant jet velocity, tricuspid valve annular plane systolic excursion (TAPSE), and
pulmonary insufficiency end-diastolic gradient. Measurements will be performed according to
American Society of Echocardiography standards. The definition of cardiomyopathy will be
restricted to reduced left ventricular systolic function. Reduced left ventricular systolic
function will be defined as ejection fraction less than 50% by traditional measures.
Fractional shortening and myocardial deformation imaging (longitudinal strain) will be
defined as reduced left ventricular systolic function if the value is less than 2 standard
deviations below the published means for age.
Left ventricular global longitudinal strain and strain rate measurements will be made using
the "length of line" technique from the apical 4-chamber, 2-chamber, and 3-chamber views.
Right ventricular longitudinal strain and strain rate measurements will be made from the
apical 4-chamber view using the same technique. All strain and strain rate measurements will
be performed utilizing GE console analysis package (Netherlands) and TomTec ImageComTM
software (Germany).
Data will be extracted from the electronic and paper medical record for key demographic and
historical data including but not limited to markers of HIV infection (e.g., white blood cell
counts, nadir and most recent CD4 counts, and HIV viral loads), duration since initiation of
ART, type of regimen, regimen changes, lifetime ART exposure, anthropomorphic data (age,
weight, height, sex, and gender), blood pressure measurements, and comorbidities.
Blood samples will be obtained as additional vials with the same clinically indicated
venipuncture for all subjects. The primary study population will be children undergoing a
routine clinically-indicated laboratory blood draw. However, children attending clinic for a
routine follow up visit but not due for a laboratory blood draw will still be offered the
opportunity to participate in the study as well. No more than 5 ml of blood will be drawn for
the study. Children less than 3.5 kg will be excluded. The blood samples transported daily to
the AMPATH Reference Laboratory at MTRH, which is accredited by the NIAID Division of AIDS.
Samples will be labeled with study identification number only. The reference laboratory will
be governed under the Duke - Moi Teaching and Referral Hospital data agreement. The
investigators will analyze b-natriuretic peptide (BNP) levels for all subjects. Additionally,
the remaining serum will be stored at the AMPATH Reference Laboratory for testing of
inflammatory markers at Duke University. In order to understand mechanisms of cardiomyopathy
in the HIV-infected, the investigators plan to secure additional funding to test markers of
inflammation thought to be causative in cardiac dysfunction including: tumor necrosis factor
alpha (TNF- α), interleukin (IL)-1b, IL-6, and IL-8. TNF- α, IL-1b, IL-6, and IL-8, and ST2.
The investigators will store the blood specimens for up to 2 years after the last patient has
been enrolled. Specimens will be destroyed or further IREC approval will be requested to
maintain the stores beyond May 2020.
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