Ped HIV - Echo Study: Kenya
Condition: HIV/AIDS; Cardiomyopathies
MeSH terms: Cardiomyopathies
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Echocardiogram
Intervention type(s): Diagnostic Test
Intervention description(s): Screening echocardiogram
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Children living with HIV attending regular scheduled follow up visit.
      
Biospecimen description: 
      Plasma for viral load and inflammatory marker testing
    
Keywords: Pediatric