Abstract
Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-“boosted” lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero.
Highlights
The reduction of worldwide human immunodeficiency virus type 1 (HIV-1) mother-to-child transmission (MTCT) in the last few years represents one of the most successful preventive interventions in fighting a substantial health problem
The development of the central nervous system of the children protected against MTCT may be influenced in more subtle ways, since the developing CNS is a structure with great plasticity and after the peripheral nervous system, it is the most affected by mitochondrial disorders, which may cause induce epilepsy, stroke-like episodes, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, and hypophysial abnormalities
Millions of lives have been saved from AIDS-related deaths and generations of children have been protected against HIV-1 MTCT
Summary
The reduction of worldwide human immunodeficiency virus type 1 (HIV-1) mother-to-child transmission (MTCT) in the last few years represents one of the most successful preventive interventions in fighting a substantial health problem. The development of the central nervous system of the children protected against MTCT may be influenced in more subtle ways, since the developing CNS is a structure with great plasticity and after the peripheral nervous system, it is the most affected by mitochondrial disorders, which may cause induce epilepsy, stroke-like episodes, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, and hypophysial abnormalities For this reason, surveillance of adverse effects in children born to HIV-1-positive mothers receiving ART is strongly needed, and it is being applied in both developed countries (USA) [5] and resource-limited settings (Botswana, South Africa, Malawi, Mozambique, Burkina Faso and Kenya) [23]. As observed in one of the included studies, a prospective cross-sectional Canadian study involving 39 HIV-1-exposed but uninfected children (18 to 36 months of age) whose mothers had received ART for at least 1 week during pregnancy and AZT during delivery, maternal substance abuse had a stronger effect on BSID-II indexes (they were lower when compared to controls) than ART per se, possibly because it is strongly associated with preterm birth. Cellular models, firstly, and animal models, secondly, remain fundamental instruments to assess the neurotoxicity of these drugs
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