Growth and Neurodevelopment of HIV-Exposed Uninfected Children: a Conceptual Framework

Abstract

Purpose of Review The population of HIV-exposed uninfected (HEU) children is expanding rapidly, and over one million HEU infants are born each year globally. Several recent studies have reported that HEU children, particularly in low-and middleincome countries, are at risk of poor outcomes, including impaired growth and neurodevelopment. However, the reasons for poor clinical outcomes amongst HEU children remain unclear. Recent Findings We summarise the findings from recent large studies that have characterised growth and neurodevelopment in HEU children, identified risk factors and explored underlying mechanistic pathways. We propose a conceptual framework to explain how exposure to HIV and antiretroviral therapy (ART) may lead to adverse growth and neurodevelopment in uninfected children, and review the available evidence and research gaps. Summary We propose that HEU children are affected both indirectly, through the augmentation of universal risk factors underlying poor growth and neurodevelopment, and directly through HIV/ART-specific pathways, which ultimately may converge through a series of common pathogenic mechanisms. In the era of universal ART, a better understanding of these pathways is crucial to inform future prevention and intervention strategies. Keywords HIV-exposed uninfected. Child. Growth. Stunting. Early child development 1000 days) represent a highly sensitive period of development, during which substantial physical growth, including brain maturation, occurs [7]. Early fetal exposures are recognised to have long-term consequences for the child Catherine J. Wedderburn and Ceri Evans contributed equally to this work.

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

“…Several mechanisms have been proposed to explain the adverse outcomes in HEU children including; maternal and child immune dysregulation, ART toxicity, higher exposure to infectious diseases and socio-environmental factors ( Wedderburn et al, 2019a ). The impact of HIV infection on the adaptive immune system has been well described in adults ( Mohan et al, 2014 ).…”

The Intergenerational Impact of a Slow Pandemic: HIV and Children

“…Many children still die, 100,000 in 2018. For all the children that die there are more that survive, but with stunted growth and poor cognitive development caused directly by the virus or indirectly by the side effects of drugs (Wedderburn et al, 2019).…”

“…As evidence accrues, it appears that some of the adverse development effects seen in CHEU were found when mothers were untreated. There is still though evidence of poorer early growth a neurodevelopment in CHEU, which has been explained through the direct effect of exposure to antivirals or through an exacerbation of other risk factors associated with poor growth (Wedderburn et al, 2019). The evidence continues to be mixed (Rotheram-Borus et al, 2019).…”

Mitochondrial DNA Parameters in Blood of Infants Receiving Lopinavir/Ritonavir or Lamivudine Prophylaxis to Prevent Breastfeeding Transmission of HIV-1

“…In 2019, 15.2 million children were CHEU worldwide, thus exposed to HIV and ARV [ 6 ]. Many unfavourable health outcomes have been reported in CHEU such as metabolic disorders [ 7 , 8 ], increased infectious disease morbidity and higher mortality [ 9 , 10 , 11 , 12 ], impaired growth [ 13 , 14 , 15 , 16 , 17 , 18 ], neurodevelopmental delays [ 17 , 19 , 20 , 21 ], altered immunity [ 10 , 22 , 23 , 24 , 25 , 26 ], and mitochondrial toxicity in comparison to never HIV-exposed children [ 27 , 28 , 29 , 30 ]. Taken together, this prompted Powis and Siberry to advocate for the long-term follow up of CHEU irrespective of their HIV/ARV exposures [ 31 ].…”