Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children

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.

Pediatric Neurodevelopmental Functioning After In Utero Exposure to Triple-NRTI vs. Dual-NRTI + PI ART in a Randomized Trial, Botswana

“…Antenatal or perinatal ARV or HIV exposure may be associated with worse child neurodevelopmental functioning through multiple potential mechanisms. 7 Many antiretrovirals have been shown to cross the placental barrier, and may induce changes to the central nervous system structure in the fetus and the developing brain. In utero or perinatal exposure to nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens has been associated with depletion of mitochondrial DNA, a marker of mitochondrial toxicity in animal 8 and human 9 studies; NRTI exposure has been associated with neurologic anomalies in newborns, 10 and mitochondrial dysfunction in the form of a wide spectrum of clinical abnormalities including CNS disorders 11 which has heightened concern regarding possible links between exposure to these regimens and lower than expected neurodevelopmental functioning.…”

In utero and peripartum antiretroviral exposure as predictor of cognition in 6‐ to 10‐year‐old HIV‐exposed Ugandan children – a prospective cohort study

“…A total of 201 HIV-affected children were enrolled and followed for 12 later, even after adjusting for caregiving context and HIV-specific factors (Table 3).…”

“…Maternal ART is effective for prevention of MTCT (PMTCT) of HIV [2] but this exposure comes with several known neurodevelopmental risks: low birth weight [3], metabolic dysregulations [4], mitochondrial toxicity [5][6][7][8] and neurotoxicity [9,10]. For children born to HIV-infected women, this risk will necessarily continue making higher neurodevelopmental risk a price paid to avert the more adverse outcome of HIV transmission [11,12]. Given this reality, there is a corresponding imperative for long-term surveillance of neurodevelopmental outcomes among in utero/peripartum ART (IPA)-exposed children to determine the extent of impairments and to inform interventions research so as to mitigate them.…”

HIV-Infected Mothers Who Decide to Breastfeed Their Infants Under Close Supervision in Belgium: About Two Cases

“…However, in addition to the risk of HIV transmission during breastfeeding, infants are exposed to repeated blood tests and to potentially harmful prophylactic antiretroviral therapy. Studies have also shown that cART pass into breast milk (19) but their adverse effects, namely on psychomotor and cognitive development, have not been clearly established (20,21).…”