HIV Exposed Uninfected Children at School Age: Developing Country Context

C l i n M e d International Library Citation: Kandawasvika GQ, Gumbo FZ, Kuona P (2016) HIV Exposed Uninfected Children at School Age: Developing Country Context. Int J Virol AIDS 3:024 Received: December 01, 2015: Accepted: July 09, 2016: Published: July 14, 2016 Copyright: © 2016 Kandawasvika GQ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Kandawasvika et al. Int J Virol AIDS 2016, 3:024


Background
The millennium development goals have come and gone and yet the same threats to gains made on the child survival agenda of the 1980s remain undaunted.Globally an estimated 2.3 million children under the age of 14 years are living with HIV infection, 90% of whom acquired the infection antenatally, intrapartum or postnatally through breast feeding [1].With the success of chemoprophylaxis for the prevention of perinatal transmission of the human immunodeficiency virus (HIV), an increasing number of HIV-exposed but uninfected (HEU) children will have in utero and post-partum exposure to antiretroviral drugs and survive beyond infancy.The proportion of HEU children who survive to school age is largely unknown and the majority live in sub-Saharan Africa [2].The long term effect of antiretroviral drugs on children`s developing brains is not fully understood.A few studies from developing countries have reported on growth, morbidity and mortality outcomes of HEU children standards [17].They had normal brain growth as reflected by normal head circumference for age.In Zimbabwe [18], HUU and HEU were 7.5 cm and 5.4 cm taller than HIV infected children above 5 years respectively.HUU and HEU children were 3.5 kg and 2.7 kg heavier than HIV infected children.HUU and HEU had mid-upper arm circumference 11 mm longer than the HIV infected children.There was also no difference in head circumference in these children above 5 years.In Zambia, HEU exposed to nevirapine at birth had lower values of most anthropometric variables compared to the HUU and main reason was poor socio-economic factors [19].In the Dart trial carried out in Zimbabwe and Uganda, there was no evidence that in utero tenofovir affected growth after 2 years and no increase in congenital, renal, or growth abnormalities was observed [20].

Neurodevelopment
During the critical periods in childhood development, spanning from pregnancy to adolescence the developing nervous system is susceptible to psychological, environmental biological risk factors.Similar to adults, HIV type 1 in the paediatric population invades the CNS during primary infection and is often followed by compartmentation in sanctuary sites.This poses challenges to treatment modalities [21].
HIV infection and neurodevelopmental outcomes in infancy are determined by maternal and infant host factors both of which also influence HIV disease onset and severity.The timing of vertical HIV infection and exposure has been noted to influence growth of children including those above 5 years.HEU children have lower weight and length z scores at birth compared to HIV unexposed uninfected (HUU) children [10,11] and also seem to have suboptimal postnatal growth even in breastfeeding populations from low income settings.The risk of small for gestational age in HEU children is higher than in HUU but lower than in HIV infected children [11].This increased risk for small for gestational age in HEU could be a reflection of poor maternal health during pregnancy.The subsequent suboptimal postnatal growth [11,12] could also be reflecting the maternal ill health including subclinical mastitis, environmental and poor sociodemographics factors frequently found in low income settings.High income countries have demonstrated lower birth anthropometry in HEU but comparable postnatal growth with HUU [13].
HIV exposed uninfected children from the United States of America had better scores of bone mineral density [14] and higher total body fat compared to HIV infected children [15].In Europe HEU children were 7 kg heavier and 7.5 cm taller than HIV infected children [16].Advanced HIV infection impaired growth substantially.However, there were no major differences between HEU and the British growth standards from normal children.There is limited data of comparison of HUU, HEU and HIV infected children (HI) above 5 years from low income countries.In Uganda, both HEU and HIV infected pre-school children followed up to just above 5 years had sustained lower weight and height compared to WHO growth infection also influences the rate of disease progression.Children infected with HIV who survived to school age were found to have neurodevelopmental deficits in general cognitive impairment, visual spatial, motor, language expression, perceptive performance and executive function [22][23][24].
A few studies have reported on HEU and compared them to the reference population, in some studies unexposed uninfected peers of similar socioeconomic status.Studies have demonstrated conflicting results since controlling for confounding factors such as socioeconomic status, child stimulation in the home, care giver characteristic is problematic (Table 1).

Behavioral Problems
Conduct disorders in HEU children remains largely unknown in developing countries due unavailable data.Furthermore, there is lack of adapted and validated tools for assessing behavior in these settings [36,37].In a study among 6-8 year old Zimbabwean children, HIV exposure did not influence prevalence of behavioral problems [35].However a study among Ugandan adolescent orphans infected with HIV, a reported higher than normal rates of behavioral problems in that cohort [38].

Antiretroviral Exposure and Neurodevelopment
The relationship between cART and child neurodevelopment is extrapolated from evidence from developed world setting where PMTCT programs are wide spread and the infants are predominantly formula fed.The early initiation of cART has resulted in reduced the incidence of progressive encephalopathy by 50% in children infected perinatally with HIV, in a prospective study among 2389 American children [39].In a South African study comparing the neurodevelopment of 27 infants infected with HIV to 29 infants exposed uninfected, the use of cART, prevented further deterioration in neurodevelopment function in the HIV infected group, but did not reverse the neurological damage present [40].
Concerns remain regarding the safety of cART on the developing brain [40].Evidence on the long term neurodevelopmental effects of antiretroviral therapy exposure is largely unknown.Maternal antenatal exposure to protease containing regimens was associated with increased risk of prematurity in an American PMTCT clinical trial comparing HIV transmission rates in the protease inhibitors group versus the non-reverse transcriptase inhibitor group [41].A review of studies investigating the impact of HIV exposure and antiretroviral therapy or prophylaxis on neurodevelopmental outcomes reported subtle speech and language delay among children exposed uninfected with HIV [42].Due to different methodologies used in assessing the effect of maternal cART exposure on neurodevelopment, comparison of the results is limited.Further studies on the long term neurodevelopment outcomes following maternal cART exposure in children without HIV infection are needed.
In a study by Barret et al. circumstantial evidence for mitochondrial dysfunction was found in HEU children exposed to antiretroviral therapy.All the children presented with neurological symptoms, often associated with abnormal magnetic resonance image (10 of 12) and/or a significant episode of hyperlactatemia (seven of 12).All had either a profound deficit in one of the respiratory chain complexes (11 of 12) and/ or a typical histological pattern (two of 12).All were perinatally exposed to antiretrovirals drugs.None of them had perinatal morbidity that could explain this symptomatology [43].Hernandez et al. reported that mitochondrial parameters were reduced in HIV infected mothers and their newborn; especially newborn mitochondrial DNA levels, maternal and fetal mitochondrial protein synthesis and maternal glycerol-3phosphate + complex III function without adverse perinatal outcome [44].
HIV or ARV exposure is associated with dysfunctional intermediary metabolism in newborns.Abnormal acylcarnitine levels were more frequent in ARV-exposed infants, suggesting that ARV may disturb fatty acid oxidation in some infants.Studies designed to validate and determine the clinical significance of these findings are needed [45].

Sociocultural Factors and Cognitive Development
The structure and cultural background of a family is critical in child development.Culture influences all aspects of child development and is reflected in child rearing practices.Protective cultural practices such breastfeeding are widely practiced in the developing communities [46].It is the cultural norms that dictate the role of adults in child play, investment in child development and the degree to which society will embrace child protective practices such as child stimulation.Unfortunately, the AIDS epidemic has resulted in an increase in orphaned children as their parents succumb to HIV related illnesses.The family structure and dynamics have changed with more AIDS orphans growing up under the care of aged grandparents, older siblings or other relatives [47].However, there is a lack of data on how the change in household composition impacts on child neurodevelopment, especially when the care givers change is due to death of a parent.In a case study among 193 Uganda orphans aged 15-19 years, 29% continued schooling undisrupted, 25% spent time off school and 45% dropped out of school and the least chance of continuing with education was reported in those fostered by grandparents (7%) [48].

Poverty and Child Development
Although definitions of poverty vary according to social, cultural and geographical location, the epidemiological perspective definition of low socioeconomic status, unemployment and low levels of education cuts across all cultures [49].Universally, poverty increases the risk for emotional distress in families and children which may interfere with educational achievements.Poverty was correlated with increased maternal stress or depression and inadequate child stimulation in the home [50].Studies demonstrated that the electrical brain activity of newborns of depressed mothers show reduced ability to learn from environment [51].In the context of HIV infection, maternal mental health disorders compromise the parent-child interaction influencing cognitive stimulation.Poverty also negatively impact on the family's nutritional status.A study conducted in Kenya among children under 3 years living in poverty reported anthropometric measures such as height and weight as mediators of the relationship between socioeconomic status and psychomotor development [52].

Morbidity and Mortality
Prevention of Mother-to-Child HIV Transmission (PMTCT) programs in sub-Saharan Africa has been extremely successful in reducing the numbers of children infected with HIV.However, HEU children have substantially increased morbidity and mortality compared with children born to uninfected mothers HUU, predominantly from infectious causes.Moreover, a range of phenotypical and functional immunological differences between HEU and HUU children has been reported [53].These differences have been reported particularly for infants below 2 years of age [31,54].
Possible reasons why the HIV exposed uninfected infants are at increased risk include less exposure to breast milk as mothers are either less able to breastfeed or stop breastfeeding early to protect their infant from HIV infection.Other contributing factors are parental illness or death resulting in inadequate care of the children, increased exposure to other infections and possibly exposure to antiretroviral drugs [55].Maternal CD4 count predicts child mortality in HIVuninfected children born to HIV-infected women [56].Prematurity, teenage motherhood and symptomatic HIV-1 maternal disease were important predictors for post-neonatal mortality in a cohort of HIV-1 exposed uninfected infants according to a Kenyan study by Gichuhi [57].These factors should be considered in monitoring and follow up in prevention of mother-to-child HIV-1 transmission (PMTCT) programs.In addition a broad approach for psychosocial support of HIV-affected families is needed to improve health of HIV-EU children.High quality programmatic research is needed to determine how to deliver such care [55].
Although nutrition has been examined, the effects of CMV infection have not been evaluated in HEU children.The effects of CMV infection on the growth, development, and health of maternally HIV-exposed and unexposed infants in Zambia was studied.All CMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants.In HIV-exposed infants CMV positive infants compared with those who were negative, had reduced head size and lower psychomotor development.HIV-exposed, CMVviremic infants were more commonly referred for hospital treatment than CMV-negative infants.CMV seems to be a risk factor for poor child health in this region [58].
Infections may be more common and severe among HEU children than among unexposed children, which could contribute to both slower growth and higher mortality.A nearly study in Zaire (DRC) found that the incidence of persistent diarrhoea (> 14 days) among HIV-EU infants was twice that among HIV-unexposed infants [59].An HIV exposure, rather than infection, based analysis of treatment failure among children with pneumonia to showed that failure odds among HIV-exposed uninfected infants were intermediate between their unexposed and infected counter parts [60].The clinical and basic immunological findings of eight HIV-exposed uninfected infants hospitalized with serious infectious morbidity and referred for immunological evaluation showed that severe infections were likely.These included, Pneumocystis jiroveci pneumonia (three), cytomegalovirus colitis with perforation (one), Pseudomonas sepsis (two), hemorrhagic varicella (one) and Group A streptococcal meningitis and endocarditis (one).Five required intensive care, four for assisted ventilation and one for post-surgical care.The median age at presentation was 5.5 (1.5-15) months.Follow-up to 36 months suggested resolution of a transient immunodeficiency in two infants, one of whom had CD4 and the other B-cell depletion [61].The HEU infants experience high rates of all-cause and infectious hospitalization (particularly gastroenteritis) and in-hospital mortality [62].With cardiac function, non-HIV-infected infants born to HIVinfected mothers, fetal exposure to ART is associated with reduced Left Ventricular dimension, Left Ventricular mass, and septal wall thickness and with higher Left Ventricular fractional shortening and contractility during the first two years of life [63].The important immune findings in HEU children are expanded memory T cell subsets and increased immune activation with increased apoptosis, reduced thymic function and fewer naïve T cells, accompanied by functional differences consistent with Th1/Th17 polarization and impaired APC function, in a setting of reduced transfer of maternal antibodies [64].
It is evident that few longitudinal studies have followed up HEU children to school age.In resource limited settings, future operational research studies are needed to inform HIV programmes on how best to promote the health of HEU children and their families in that context.Interventions to improve household family food security and assess availability of energy and micronutrient dense foods for school age children are a priority.Staple diets in Africa and other low income countries are frequently bulky with low energy and micronutrient density [65].Cognitive stimulation therapy has been shown to improve cognitive function in HI children [66].In HEU, there is need for further basic research using larger sample sizes and validated neurodevelopmental tools to assess the feasibility of including child cognitive stimulation intervention in child health programmes.More research is required to assist healthcare workers in managing HEU and their families.It is unclear if HEU children respond adequately to vaccines, need extra vaccine boosters, they benefit from antibiotic prophylaxis and the duration of such interventions.Strengthening family-centered HIV prevention and treatment programs will improve health outcomes and socioeconomic participation of HIV infected parents and their HEU children.

Study Location Study Type Sample size Participants Age (range) Developmental scale Exposure to ARV Findings HEU
HI-Child with HIV infection; HEU-Child exposed but uninfected with HIV; HUU-Unexposed Uninfected; US-United States of America; RCT-Randomised Controlled Trial; KABC-Kaufman Assessment Battery for children; MSCA-McCarthy Scales of Children`s Abilities; SON-R-Snijders-Oomen nonverbal intelligence test for children and adolescents (abridged); WASI-Wechsler Abbreviated Scale of Intelligence; WPPSI-Wechsler Preschool and Primary Scale of Intelligence-Revised; WISC-R-Wechsler Intelligence Scale for Children-Revised; WISC-Thai Wechsler Intelligence Scale for Children Thai version; GMDS-ER-Griffiths Mental Development Scales-Extended Revised Version

Table 1 :
Summary of studies reporting the effect of HIV on neurodevelopment among HEU children.