A metabolomics investigation of in utero antiretroviral exposure to neonates

Abstract

This thesis, with the title "A metabolomics investigation of in utero antiretroviral exposure to neonates", deals with the concern over adverse metabolic consequences reported for some neonates prenatally exposed to antiretroviral treatment (HIV-ART). The pandemic due to HIV infection, the cause of AIDS, has become globally the most devastating infectious disease. Mother-to-child transmission (MTCT) of HIV during the intrapartum period became a pressing issue of the HIV pandemic. The development of ART and its use in HIV positive pregnant women to prevent mother-to-child transmission (PMTCT), is described as one of the greatest successes in medical history of the 20th century and became a standard recommendation of the WHO to combat the AIDS pandemic. We present here the first metabolomics investigation of HIV-ART exposure to neonates, studied on cord blood taken at birth. Chapter 1 gives the background to the study, which formed part of a larger international inter-university project, whereas Chapters 2 and 3 provide (1) a literature review of the societal, biological and biochemical aspects of HIV-ART and (2) of the use of metabolomics in the study of a biological question, respectively. The aim of the study is defined as an investigation to address the concern following treatment to PMTCT by exploring metabolic profiles in exposed neonates. The research question that was investigated was to determine whether any HIV-ART-induced metabolic perturbations are discernible during birth when the fetus is exposed to the trauma of birth hypoglycaemia. Chapter 4 describes the use of an untargeted metabolomics [1H nuclear magnetic resonance (NMR) spectrometry] to analyse cord blood from HIV-ART exposed and unexposed neonates, as well as serum from healthy infants. Decreased levels of 3-hydroxybutyrate and alarming increase in hypoxanthine, indicators of metabolic stress, were observed in the cord blood of exposed neonates. Although the newborns that were subject to HIV-ART exposure seem to cope with the metabolic stress of birth, the biomarkers indicated some of them to be at risk, which warrants further monitoring. Chapter 5 focuses on the analytical aspects of liquid chromatography-mass spectrometry (LC-MS) required for a method of higher sensitivity to complement the NMR investigation. Triple quad mass spectrometry (LC-QQQ) proved to be a method of choice given its high repeatability for a targeted analysis of acylcarnitines and amino acids in cord blood. Chapter 6 provides results that support the benefits of ART for HIV-infected pregnant women as recommended by the WHO, but the amino acid profiles of cord blood, and to a lesser extent of the acylcarnitines, add to the observed metabolic risks with potential adverse consequences for some infants exposed in utero to HIV-ART, which might affect their future health. Results from a lipidomics study of an independent cohort of HIV-ART exposed newborns (a complementary part of the inter-university study) furthermore support the conclusions from the present study. Chapter 7 discusses the findings of the investigation presented in this thesis, indicates some of its limitations and concludes with a mini-review on the potential of cord blood for metabolomics studies in the field of neonatology.