Neurological development of children who are HIV‐exposed and uninfected

Abstract

Widespread use of antiretroviral drugs for pregnant/breastfeeding females with human immunodeficiency virus (HIV) has led to declining vertical transmission. Despite being HIV‐uninfected, the increasing number of children who are HIV‐exposed and uninfected (CHEU) often present with developmental alterations. We review seminal and recent evidence on the neurological development of CHEU and associations with early life HIV/antiretroviral exposure. Our conceptual model highlights the numerous exposures and universal risk factors for CHEU developmental disorders. Early studies suggest a significant association between HIV exposure and neurological abnormalities, varying according to the burden of HIV‐specific exposures and other risk factors. More recent observations from the modern era are inconsistent, although some studies suggest specific antiretrovirals may adversely affect neurological development of CHEU. As the CHEU population continues to grow, alongside simultaneous increases in types and combinations of antiretrovirals used in pregnancy, long‐term monitoring of CHEU is necessary for understanding the effects of HIV/antiretroviral exposure on CHEU developmental outcomes. Evidence on the neurological development of children who are human immunodeficiency virus (HIV)‐exposed and uninfected (CHEU) is synthesized. Comparisons are made to children who are HIV‐unexposed, across treatment eras and settings, and by antiretroviral drug regimens and drug classes. CHEU exposures are complex and include HIV‐specific and universal risk factors which may affect development during the early years of life.

Early neurodevelopment of HIV-exposed uninfected children in the era of antiretroviral therapy: a systematic review and meta-analysis

“…We did not specifically evaluate mechanisms in our review, but others have discussed this in detail. 71 …”

Altered methionine-sulfone levels are associated with impaired growth in HEU-children

“…Ceramide intracellular levels are fine-tuned and alteration of the sphingomyelin-ceramide signalling profile are associated with the development of age-related, neurological and neuroinflammatory diseases [37–39]. Although under debate, studies suggest that HEU-children may be at risk of altered neurological development [7]. Our findings, although important to note not reaching biochemical-specific significance after correction for multiple testing, may suggest that sphingolipid metabolism could be altered in HEU-children and indicate that further studies are needed.…”

“…Compared to HIV-unexposed-uninfected (HUU) children, HEU-children, despite being uninfected, experience reduced in utero and postnatal growth, altered cardiac functioning, impaired immunity and enhanced susceptibility to infections [4][5][6]. In addition, concerns have been raised regarding neurodevelopment in HEUchildren [7]. HIV-associated maternal immune activation as well as adverse effects of cART have been suggested to underlie these clinical observations [8,9].…”

Trends in antiretroviral use in pregnancy in the UK and Ireland, 2008–2018

“…This is important in light of concerns around potential toxic effects and teratogenic effects of such exposures on the developing embryo/foetus, particularly as most women are on ART from before conception [ 5 , 46 ]. The literature on children who are HIV‐exposed and uninfected (CHEU) reports differences in their health compared with unexposed children, including metabolic, mitochondrial, immunological, developmental and haematological differences [ 47 , 48 , 49 ]. Furthermore, CHEU are being increasingly exposed to newly approved antiretroviral agents for which information about both short‐ and long‐term safety is limited.…”