Detection of Specific Metabolic Signatures by Nuclear Magnetic Resonance or Metabolomic NMR in Correlation With Markers of Inflammation or Immune Activation and the Risk of Developing Neurocognitive Disorders - Longitudinal Retrospective Study Nested in the ANRS12225 PEDIACAM III Cohort

Context

Worldwide, more than three million children are living with HIV, 90% of them in sub-Saharan Africa. With the generalisation of antiretroviral treatment (ART), most children living with HIV from birth or children exposed to HIV in utero are now adults (4). Cognitive disorders and dementia associated with HIV are well known in adults. Neurological damage has also been well described in children whose mothers transmitted HIV to them (MTCT), in particular the specific and severe HIV encephalopathy affecting 10-15% of infants living with HIV before the era of multi-drug antiretroviral therapy (5, 6). The very early administration of triple therapy-type ART to infants living with HIV considerably reduced infection-related mortality and co-morbidities, but exposed them very early and over the long term to a treatment whose neurological toxicity in association with mitochondrial dysfunction has been reported, particularly in exposed children not living with HIV (7). Recent publications on prospective studies of neurocognitive, neuromotor or visual monitoring of HIV+ children on treatment or HIV-exposed children from different paediatric cohorts in developing countries have shown that, overall, children exposed to HIV in utero and not living with HIV have the same cognitive development as unexposed children not living with HIV (1, 8). In contrast, children living with HIV with or without ART have a higher prevalence of cognitive problems than untreated children. These disorders may appear from the age of 2-3 years, be found around the age of 6-7 years and especially in adolescence (9, 10). A study of a cohort of HIV-positive adolescents on ART showed that their overall cognitive development appeared to be similar to that of their HIV-positive peers. However, the study showed that the trajectory of executive functioning appeared to be different in HIV+ adolescents on treatment, which could be explained by previous brain damage (8). Another study of HIV-positive children on ART shows that these children have altered cortical and subcortical structures and regional brain connectivity.

These brain defects may contribute to deficits in their neurocognitive functions. This study has not been continued longitudinally to confirm the persistence or otherwise of such deficits (9).

On the other hand, the causes of the appearance of neurodevelopmental disorders are thought to be linked to the virus, since even if the viral load has decreased under triple therapy, the virus can continue to activate the immune system and cause inflammation that could have an impact on children's developing brains throughout their growth. A very recent study shows that ART taken as prophylaxis for one year has no effect on the growth and neurodevelopment of precocious children (11). On the other hand, the causes of the onset of neurodevelopmental disorders are thought to be linked to the virus, because even if the viral load has decreased under triple therapy, the virus can continue to activate the immune system and cause inflammation that could have an impact on children's developing brains throughout their growth. A very recent study shows that ART taken as prophylaxis for one year has no effect on the growth and development of the brain.

A. HIV, Inflammation, Immune Activation and Neurodevelopment The brain is particularly vulnerable in utero and during infancy and early childhood, and damage during these critical periods has the potential to cause long-term damage (2, 12, 13). Several neurodevelopmental disorders have been linked to immune activation and inflammation in early life, including autism spectrum disorders (ASD), schizophrenia, cerebral palsy, epilepsy, cognitive impairment and depression (2, 14). Maternal immune activation increases pro-inflammatory cytokines such as IL-6 in the foetal brain and leads to long-lasting changes in brain cytokines during postnatal development. Most cytokines remain present in the serum and brain throughout development and can alter the development and behaviour of the CNS (15-18). In addition, the passage of inflammatory cytokines such as IL-17 across the placenta can cause neuroinflammation in the foetus, leading to neurodevelopmental disorders very early in the infant's life (19). Viral infections, and HIV in particular, cause various types of brain damage during the prenatal and postnatal periods in HIV+ children born to HIV-positive mothers (7, 9). The virus itself can settle in the brain, causing direct damage. However, even though ART started very early after the birth of these infants succeeded in considerably reducing mortality and the circulating viral load, immune activation and inflammation remain present in children living with HIV (20). In addition, soluble plasma markers such as CD163 have recently been correlated with neurocognitive impairment in children living with HIV treated early (21). Finally, long-term ART could be considered toxic to the developing brain, but recent studies have shown that starting treatment early in infancy through to adulthood does not affect the brain (8).