Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Brian Kirmse, Tzy-Jyun Yao, Sean Hofherr, Deborah Kacanek, Paige L Williams, Charlotte V Hobbs, Rohan Hazra, William Borkowsky, Russell B Van Dyke, Marshall Summar, Brian Kirmse, Tzy-Jyun Yao, Sean Hofherr, Deborah Kacanek, Paige L Williams, Charlotte V Hobbs, Rohan Hazra, William Borkowsky, Russell B Van Dyke, Marshall Summar

Abstract

We sought to determine the prevalence of abnormal acylcarnitine profiles (ACP) in HIV-exposed uninfected (HEU) newborns and to explore the association of abnormal ACP with clinical laboratory outcomes and antiretroviral drug exposures. Clinically, ACP are used to assess for fatty acid oxidation (FAO) dysfunction and normal FAO is necessary for optimal fetal/neonatal growth and development. We analyzed serum ACP in 522 HEU neonates enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and evaluated the associations of abnormal ACP with in utero exposure to combination antiretroviral therapy (cART) in logistic regression models, adjusting for maternal demographic, disease, and behavioral characteristics. We evaluated the associations of abnormal ACP with laboratory parameters and measures of neurodevelopment and growth. Of 522 neonates, 89 (17%) had abnormal ACP. In adjusted analyses, in utero exposure to a protease inhibitor (PI) was associated with higher odds of having an abnormal ACP [adjusted odds ratio (aOR) = 2.35, 95% CI: 0.96, 5.76, p = 0.06] with marginal significance while exposure to a nonnucleoside reverse transcriptase inhibitor (NNRTI) was associated with lower odds (aOR = 0.23, 95% CI: 0.07, 0.80, p = 0.02). Mean ALT levels were slightly higher in those with abnormal ACP, but no differences in lactate, glucose, or CPK were observed. ACP status was not associated with neurodevelopment at 1 year or growth at 2 and 3 years of age. Abnormal ACP in HEU neonates are associated with exposure to PI-containing as opposed to NNRTI-containing antiretroviral (ARV) regimens but are not associated with serious postnatal clinical problems. Further studies are needed to determine the long-term health implications of abnormal acylcarnitine metabolism at birth in HEU children.

Figures

FIG. 1.
FIG. 1.
Proportions and patterns of abnormal ACP in HEU newborns. The pattern of acylcarnitine elevations can point to the level of biochemical dysfunction in FAO. Long-chain acylcarnitine elevations (C12–C18, where the number corresponds to the number of carbons chain length of fatty acid) indicate dysfunction in the carnitine shuttle (CPT1, CACT, CPT2), which transports long-chain fatty acids into the mitochondria, or the first steps (TFP, VLCAD) of beta-oxidation, which convert long-chain fatty acids into medium-chain fatty acids. Elevations of medium-chain acylcarnitines (C6–C10) indicate dysfunction in MCAD. Short-chain acylcarnitine elevations can indicate dysfunction in SCAD (C4) or in pathways of organic acid catabolism (C3, C5, C5-OH). Generalized acylcarnitine elevations can be seen in ETF-ETF:QO dysfunction or in primary dysfunction of oxidative phosphorylation. ACP, acylcarnitine profiles; ATP, adenosine triphosphate; HEU, HIV-exposed uninfected; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; CPT, carnitine palmitoyltransferase; CACT, carnitine-acylcarnitine translocase; TFP, trifunctional protein; VLCAD, very-long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase deficiency; SCAD, short-chain acyl-CoA dehydrogenase deficiency; ETF, electron transport flavoprotein; ETF:QO, electron transport flavoprotein oxidoreductase. Color images available online at www.liebertpub.com/aid

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