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1.  Cardiac Status of HIV-Infected Children Treated With Long-Term Combination Antiretroviral Therapy: Results from the Adolescent Master Protocol of the NIH Multicenter Pediatric HIV/AIDS Cohort Study 
JAMA pediatrics  2013;167(6):520-527.
To determine the cardiac effects of prolonged exposure to highly active antiretroviral therapy (HAART) on HIV-infected (HIV+) children.
In the National Institutes of Health (NIH)-funded Pediatric HIV/AIDS Cohort Study’s Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiogram measures.
14 U.S. pediatric HIV clinics.
Perinatally-infected HIV+ children receiving HAART with HIV-exposed but uninfected (HEU) children and HIV+ (mostly HAART-unexposed) historical pediatric controls from the NIH-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-HIV) Study.
Main Exposure
Long-term HAART.
Outcome Measures
Echocardiographic measures of left ventricular (LV) function and structure.
The 325 AMP HIV+ children had lower viral loads, higher CD4 counts, and longer duration of antiretroviral therapy than 70 P2C2 HIV+ children (all P’s < 0·001). Z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among P2C2 HIV+ children than among the AMP HIV+ group or the 189 AMP HEU controls (P < 0.05). For HIV+ children, lower nadir CD4 percentage and higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening Z scores; P’s = 0.001) and increased LV end-systolic dimension Z score (P’s < 0.03). In an interaction analysis by HIV+ cohort, P2C2 HIV+ children with longer ART exposure or lower nadir CD4 percentage had lower mean LV fractional shortening Z scores, while mean Z scores were relatively constant among AMP HIV+ children (P<0·05 for all interactions).
HAART appears to be cardioprotective in HIV+ children and adolescents.
PMCID: PMC4180681  PMID: 23608879
2.  Cardiac Biomarkers in HIV-Exposed Uninfected Children: The Pediatric HIV/AIDS Cohort Study (PHACS) 
AIDS (London, England)  2013;27(7):1099-1108.
To evaluate associations of cardiac biomarkers with in utero antiretroviral (ARV) drug exposures and cardiac function/structure measured by echocardiograms in HIV-exposed but uninfected (HEU) children.
Design and methods
We analyzed the association of three cardiac biomarkers (cardiac troponin T, cTnT; high sensitivity C-reactive protein, hsCRP; and N-terminal pro-brain natriuretic peptide, NT-proBNP) with prenatal ARV exposures, maternal-child characteristics, and echocardiographic parameters.
Among 338 HEU children (mean age=4.3 years), 51% had at least 1 elevated cardiac biomarker. Maternal tobacco use was associated with elevated NT-proBNP (adjusted odds ratio [aOR]=2.28, P=0.02). Maternal alcohol and abacavir use were associated with elevated cTnT levels (aOR=3.56, P=0.01 and aOR=2.33, P=0.04, respectively). Among 94 children with paired echocardiogram-biomarker measurements, cTnT measurements were correlated with increased left ventricular (LV) thickness-to-dimension ratio (r=0.21, P=0.04); and elevated cTnT was associated with higher mean LV end-diastolic (ED) posterior wall thickness (P=0.04). hsCRP measurements were negatively correlated with septal thickness (r=-0.22, P=0.03) and elevated hsCRP was associated with lower mean LV contractility Z-scores (P=0.04). NT-proBNP measurements were correlated with increased LVED dimension (r=0.20, P=0.05) and elevated NT-proBNP was associated with lower mean end-systolic septal thickness (P=0.03).
Our findings suggest that cardiac biomarkers may help identify HEU children who require further cardiac evaluation including echocardiography. Potential cardiac effects of prenatal abacavir exposure in this population need further investigation.
PMCID: PMC4142694  PMID: 23211773
cardiac biomarkers; echocardiography; HIV; antiretroviral drugs; pediatric
3.  Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants 
AIDS (London, England)  2012;26(9):1151-1159.
To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants.
US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure.
We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5kg); weight-for-age z-scores (WAZ), length-forage z-scores (LAZ) and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age one year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ and HCAZ by TDF exposure.
Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with versus without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age one year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, p=0.04; HCAZ: 0.17 vs. 0.42, p=0.02).
TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age one year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.
PMCID: PMC3476702  PMID: 22382151
Tenofovir disoproxil fumarate; perinatal HIV exposure; infant growth; antiretroviral drugs; pregnancy
4.  Association between HLA Inheritance and Asthma MEDICATION USE in HIV+ Children 
AIDS (London, England)  2010;24(13):2133-2135.
This study's purpose was to determine whether asthma medication use in HIV+ children is associated with HLA alleles. We reviewed HLA and medication data collected during the Women and Infants Transmission Study for 124 HIV+ children and their mothers. Analysis revealed that HLA-A68 (P=0.006) was independent and predictive for time to first asthma medication use. There was a preventive association of Cw6 (P=0.008) with AT. HAART was also associated with time to first asthma medication use (P=0.05). HLA alleles may modulate risk of developing a need for asthma medications and seem to function independently of the actions of HAART therapy.
PMCID: PMC3665405  PMID: 20613458
6.  Cardiac Effects of Antiretroviral Therapy in HIV-Negative Infants Born to HIV-Positive Mothers: The NHLBI CHAART-1 Cohort Study 
To investigate the possible effects of antiretroviral therapy (ART) in utero on cardiac development and function in HIV-negative children.
ART reduces vertical HIV transmission. Long-term cardiotoxicity after in utero exposure to ART is unknown in children but has occurred in young animals.
Using a prospective multi-site cohort study design, we compared echocardiograms taken between birth and 24 months in two groups of HIV-negative infants of HIV-positive mothers: 136 infants exposed to ART (ART+) and 216 unexposed infants (ART−).
Mean LV mass Z-scores were consistently lower in ART+ girls than in ART− girls: differences in mean Z-scores were −0.46 at birth (P=0.005), −1.02 at 6 months (P<0.001), −0.74 at 12 months (P<0.001), and −0.79 at 24 months (P<0.001). Corresponding differences in Z-scores for boys were smaller: 0.13 at 1 month (P=0.42), −0.44 at 6 months (P=0.01), −0.15 at 12 months (P=0.37), and −0.21 at 24 months (P=0.21). Septal wall thickness and LV dimension were smaller than expected in ART+ infants, but LV contractility was consistently about 1 SD higher at all ages (P<0.001). In ART+ infants, LV fractional shortening was higher than in ART− infants; girls showed a greater difference.
Fetal exposure to ART is associated with reduced LV mass, LV dimension, and septal wall thickness Z-scores and increased LV fractional shortening and contractility up to age 2 years. These effects are more pronounced in girls than in boys. Fetal ART exposure may impair myocardial growth while improving depressed LV function.
PMCID: PMC3243620  PMID: 21185505
Pediatric; HIV; Antiretroviral Therapy; Cardiomyopathy
Immunoreconstitution of HIV-infected (HIV+) patients after treatment with highly antiretroviral therapy (HAART) appears to provoke inflammatory diseases.
Determine whether HIV+ children on HAART (HIV+ HAART+) have a higher incidence of asthma than HIV+ children not on HAART (HIV+ HAART−).
To investigate this possibility, 2,664 children (193 HIV+, 2,471 HIV−) born to HIV+ women were evaluated for the incidence and prevalence of asthma (i.e., asthma medication use), and change of CD4+ T cell percentage with time.
The HIV+ HAART+ children had higher CD4+ T cell percentages, lower CD8+ T cell percentages, and lower viral burdens than the HIV+ HAART− children (P≤0.05 to P≤0.01). The cumulative incidence of asthma medication use in HIV+ HAART+ children at 13.5 year rose to 33.5% vs. 11.5% in HIV+ HAART− children (hazard ratio=3.34, P=0.01) and was equal to that in the HIV− children. In children born prior to the HAART era, the prevalence of asthma medication use for HIV+ HAART+ children at 11 years of age was 10.4% vs. 3.8% for HIV+ HAART− children (odds ratio=3.38, P=0.02) and was equal to that of the HIV− children. The rate of change of CD4+ T cells (percent/year) around the time of first asthma medication for HIV+ HAART+ vs. HIV+ HAART− children was 0.81 vs. −1.43 (P=0.01).
The increased incidence of asthma in HIV+ HAART+ children may be driven by immunoreconstitution of CD4+ T cells.
This HIV model of pediatric asthma may yield clues to help explain the epidemic of asthma in the general pediatric population.
PMCID: PMC3246282  PMID: 18547627
pediatric HIV infection; CD4+ T cell mediated induction of asthma; HAART-produced immunoreconstitution
8.  Antiretroviral Exposure and Lymphocyte mtDNA Content Among Uninfected Infants of HIV-1-Infected Women 
Pediatrics  2009;124(6):e1189-e1197.
Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase γ, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction.
We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay.
Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure.
Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children.
PMCID: PMC2904486  PMID: 19933732
HIV; mitochondria; antiretroviral agents
9.  Immunoreconstitution by Peripheral Blood Leukocytes in Adenosine Deaminase-deficient Severe Combined Immunodeficiency 
Journal of Clinical Investigation  1980;66(2):389-395.
Transplantation of histocompatible allogeneic peripheral blood leukocytes resulted in successful reconstitution of an adenosine deaminase (ADA)-deficient, severe combined immune-deficient patient. Erythrocyte transfusions before the transplant were associated with a rise of serum immunoglobulin concentration to normal without improvement in T cell function. The patient received 5 × 107 peripheral blood mononuclear leukocytes/kg obtained from the histocompatible father by leukopheresis. 3 wk after the transplant the lymphocyte count, proportion of E rosetting lymphocytes, and the ADA content of the patient's mononuclear leukocytes became normal while the phytohemagglutinin-stimulated blastogenic responses improved and became normal 52 d after the transplant. Antibody response to diphtheria immunization and response to naturally acquired herpes simplex infection were normal while isohemagglutinins progressively increased. Immunization with a neoantigen, bacteriophage φX 174, resulted in a small but definite antibody response but no amplification of the response after secondary immunization. A positive reaction to a skin test for Candida albicans developed. Erythrocyte deoxy ATP (dATP) concentration decreased during the course of erythrocyte transfusions. 9 mo after the transplant, the erythrocyte dATP was elevated to twice pretransfusion levels while mononuclear leukocyte dATP varied from normal to elevated during the first 4 mo of the posttransplant period, but remained normal during the last 8 mo. The improvement in immune function persisted during the 12-mo posttransplant observation period while the mononuclear leukocyte ADA concentration stabilized at ∼0.25 of normal, which is similar to the enzyme activity of the donor cells. This in vivo study supports the hypothesis that lymphoid precursor cells are present in peripheral blood which may partially reconstitute an immune-deficient recipient.
PMCID: PMC371722  PMID: 7400322

Results 1-9 (9)