Long-Term Effects of In Utero Antiretroviral Exposure: Systolic and Diastolic Function in HIV-Exposed Uninfected Youth

Abstract

The aim of this study was to evaluate the association of in utero exposure to highly active antiretroviral therapy (HAART) with left ventricular (LV) function and structure in HIV-exposed uninfected (HEU) children. A prospective, multisite cohort study in HEU children was conducted by the Pediatric HIV/AIDS Cohort Study (PHACS). Echocardiographic measures of LV systolic and diastolic function and cardiac structure were obtained from HEU subjects aged ‡6 years enrolled in the PHACS Surveillance Monitoring of ART Toxicities study. Echocardiographic Z-scores were calculated using normative data from an established reference cohort. We used adjusted linear regression models to compare Z-scores for echocardiographic measures from HEU children exposed in utero to HAART with those exposed to non-HAART, adjusting for demographic and maternal health characteristics. One hundred seventy-four HEU subjects with echocardiograms and maternal ARV information were included (mean age 10.9 years; 48% male, 56% black non-Hispanic). Among 156 HEU youth with any ARV exposure, we observed no differences in Z-scores for LV systolic function measures between youth exposed in utero to HAART (39%) and HAART-unexposed youth in either unadjusted or adjusted models. In adjusted models, those exposed to HAART had significantly lower mitral late diastolic inflow velocities (adjusted mean Z-score = 0.00 vs. 0.52, p = .04) and significantly higher adjusted mean LV mass-to-volume ratio Z-scores (adjusted mean Z-score = 0.47 vs. 0.11, p = .03) than HAART-unexposed youth. Uninfected children with perinatal exposure to HAART had no difference in LV systolic function. However, small but significant differences in LV diastolic function and cardiac structure were observed, suggesting that continued monitoring for cardiac outcomes is warranted in this population.

Cardiac and inflammatory biomarkers in perinatally HIV-infected and HIV-exposed uninfected children

“…Chronic inflammation is associated with LV diastolic dysfunction and heart failure in HIV-infected children and adults. 46–48 In HIV-infected patients with myocarditis, a complex interaction between HIV and other cardiotropic viruses, IL-1, IL-6, TNF-α, and suppression of the anti-inflammatory cytokine IL-10 may explain the cardiotoxic effects leading to dilated cardiomyopathy. 49–50…”

Cardiac and mitochondrial function in HIV-uninfected fetuses exposed to antiretroviral treatment

“…HEU children are mainly considered a healthy population, although recent studies have raised concerns regarding their cardiovascular health. Several studies have demonstrated significant changes in the cardiovascular structure and function of HEU offspring from fetal life to adolescence [7–12]. A recent study by our group suggested that fetal cardiac remodeling observed in HIV-infected pregnancies was associated with maternal use of zidovudine [11].…”

Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns

“…However, should they become inefficient, mtDNA deletions observed herein are likely to contribute, at least partially, to the health impairments observed in HEU children, especially those with increased deletion contents. It is striking that cardiac conduction dysfunctions, muscle weakness, or elevated lactate concentrations reported in HEU children [ 45 , 46 , 47 ] are also hallmarks of most mitochondrial disorders.…”