Barbara Laughton

Early antiretroviral therapy improves neurodevelopmental outcomes in infants

Objectives:To evaluate the effect of early versus deferred antiretroviral therapy (ART) on the neurodevelopment of infants from Cape Town participating in the Children with HIV Early Antiretroviral Therapy (CHER) trial. Design:HIV-infected infants were randomized to early (<3 months) or deferred ART. HIV-uninfected infants (HIV-exposed and HIV-unexposed) provide background data. Methods:Neurological examination and Griffiths Mental Development Scales (GMDS) were administered between 10–16 months of age by testers blind to HIV status and randomized allocation. Mean quotients were compared using paired Students t-tests. Results:Sixty-four infants on early ART and 26 on deferred ART (of potential 77 and 38 respectively on CHER trial) were assessed at median age 11 months (range 10–16). On the GMDS, all scores were lower in the deferred arm and the General Griffiths and Locomotor Scores were significantly lower: mean (SD) = 100.1 (13.8) vs. 106.3 (10.6) P = 0.02; and 88.9 (16.3) vs. 97.7 (12.5), P < 0.01, respectively. Children with HIV who received early ART performed as well as children without HIV except on the Locomotor subscale. Both infected and uninfected mean GMDS scores were within the average range. Conclusion:Infants initiated on early ART have significantly better Locomotor and general scores on the GMDS at median age 11 months compared to infants on deferred ART, despite careful monitoring and ready access to ART in the latter.

Neurodevelopment in perinatally HIV-infected children: a concern for adolescence

Globally, an estimated 3.4 million children are living with HIV, yet little is known about the effects of HIV and antiretroviral treatment (ART) on the developing brain, and the neurodevelopmental and behavioural outcomes of perinatally HIV‐infected (PHIV+) adolescents.

White matter signal abnormalities in children with suspected HIV-related neurologic disease on early combination antiretroviral therapy.

Background: The natural history and manifestation of HIV-related neurologic disease have been ameliorated by combination antiretroviral therapy (ART). We describe the characteristics of white matter signal abnormalities (WMSA) on magnetic resonance imaging in children with HIV-related neurologic disease. Methods: We reviewed magnetic resonance imaging scans of children with suspected HIV-related neurologic disease despite early ART and correlated with clinical, neurodevelopmental data, virologic markers and time on ART. These children were also on the Children with HIV Early Antiretroviral (CHER) trial. Results: Magnetic resonance imaging scans were performed at a mean age 31.9 months (range 8–54) on 44 children: 10 on deferred and 34 on early treatment arms, commencing ART at mean age of 18.5 and 8 weeks, respectively. Multiple high signal intensity lesions on T2/fluid attenuated inversion recovery were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) white matter. No differences in neurodevelopmental scores comparing children with and without WMSA were found. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurologic examination. Normal head growth was more common in the WMSA group (P = 0.01). There was a trend for association of WMSA and longer time on ART (P = 0.13) and nadir CD4% (P = 0.08). Conclusions: Half of children referred with HIV-related brain disease had WMSA on T2/fluid attenuated inversion recovery. Our findings of the association with normal head growth and duration of ART require further study. We suspect that WMSA can occur early and that initiating ART by 8 weeks of life may be too late to prevent HIV from entering the central nervous system.

Early Antiretroviral Therapy in South African Children Reduces HIV-1–Infected Cells and Cell-Associated HIV-1 RNA in Blood Mononuclear Cells

We measured cell-associated human immunodeficiency virus (HIV)-1 DNA (CAD) and RNA (CAR) and plasma HIV-1 RNA in blood samples from 20 children in the Children with HIV Early Antiretroviral (CHER) cohort after 7-8 years of suppressive combination antiretroviral therapy (cART). Children who initiated cART early (<2 months; n = 12) had lower HIV-1 CAD (median, 48 vs 216; P < .01) and CAR (median, 5 vs 436; P < .01) per million peripheral blood mononuclear cells than children who started later (≥ 2 months; n = 8). Plasma HIV-1 RNA levels were not significantly lower in early-treated children (0.5 vs 1.2 copies/mL; P = .16). Early treatment at <2 months of age reduces the number of HIV-infected cells and HIV CAR.

Characteristics of children with pervasive developmental disorders attending a developmental clinic in the Western Cape Province, South Africa

Background. Little has been published on autism in Africa, and it is not known whether South African children present with the same characteristics and challenges as described internationally. Objectives. To describe the demographics, history, clinical features, co-morbidity and yield of aetiological investigations in children diagnosed with a pervasive developmental disorder (PDD). Methods. This was a retrospective review of medical records of children fulfilling Diagnostic and Statistical Manual of Mental Disorders , 4th edition, text revision (DSM-IV-TR) criteria for a PDD who attended a tertiary developmental clinic at Tygerberg Hospital, Western Cape, South Africa, over a 2-year period (2008 - 2010). Results. Fifty-eight children were included. The median age at diagnosis was 42 months (range 15 - 106 months), and 45 (77.6%) were boys. Forty per cent had complex autism (dysmorphism with or without microcephaly), and 12.1% were macrocephalic. Most children (72.4%) were non-verbal (using fewer than 10 non-echoed words), and 89.0% had behavioural problems as reported by caregivers. The diagnostic yield of investigations was low. Conclusion. The profile of children with PDD attending a tertiary hospital developmental clinic in the Western Cape revealed that a high proportion had severe language impairment, behavioural problems and complex autism.

Maternal post-traumatic stress disorder, depression and alcohol dependence and child behaviour outcomes in mother–child dyads infected with HIV: a longitudinal study

Objectives HIV and psychiatric disorders are prevalent and often concurrent. Childbearing women are at an increased risk for both HIV and psychiatric disorders, specifically depression and post-traumatic stress disorder (PTSD). Poor mental health in the peripartum period has adverse effects on infant development and behaviour. Few studies have investigated the relationship between maternal PTSD and child behaviour outcomes in an HIV vertically infected sample. The aim of this study was to investigate whether maternal postpartum trauma exposure and PTSD were risk factors for child behaviour problems. In addition, maternal depression, alcohol abuse and functional disability were explored as cofactors. Setting The study was conducted in Cape Town, South Africa. Participants 70 mother–child dyads infected with HIV were selected from a group of participants recruited from community health centres. Design The study followed a longitudinal design. Five measures were used to assess maternal trauma exposure, PTSD, depression, alcohol abuse and functional disability at 12 months postpartum: Life Events Checklist (LEC), Harvard Trauma Scale (HTS), Alcohol Use Disorders Identification Test (AUDIT), Center for Epidemiological Studies Depression (CESD) Scale and the Sheehan Disability Scale (SDS). Child behaviour was assessed at 42 months with the Child Behaviour Checklist (CBCL). Results The rate of maternal disorder was high with 50% scoring above the cut-off for depression, 22.9% for PTSD and 7% for alcohol abuse. Half of the children scored within the clinical range for problematic behaviour. Children of mothers with depression were significantly more likely to display total behaviour problems than children of mothers without depression. Maternal PTSD had the greatest explanatory power for child behaviour problems, although it did not significantly predict child outcomes. Conclusions This study highlights the importance of identifying and managing maternal PTSD and depression in mothers of children infected with HIV. The relationship between maternal PTSD and child behaviour warrants further investigation.

Longitudinal developmental profile of children from low socio-economic circumstances in Cape Town, using the 1996 Griffiths Mental Development Scales

BACKGROUND: The Griffiths Mental Development Scales (GMDS) have not been standardised in South African children Neurodevelopmental scores of infants from deprived environments decline with age, but there is no evidence on how young South African children from such backgrounds perform on serial assessments. AIM: To describe the longitudinal developmental profile of infants from low socio-economic backgrounds at Tygerberg Childrens Hospital by comparing the GMDS scores performed at 10 - 12 months and 20 - 22 months. METHODS: Infants born to HIV-uninfected women attending the public service programme were recruited from a vaccine study in Cape Town, South Africa. The GMDS 0 - 2 years and a neurological examination were performed between 10 and 12 months and between 20 and 22 months. RESULTS: Thirty-one infants (14 girls, 17 boys) were assessed. Their mean (standard deviation (SD)) age was 11.6 (0.8) months and 21.0 (0.5) months at the first and second assessments, respectively. The mean (SD) general quotient decreased significantly from 107.3 (11.7) to 95.0 (11.0) (p<0.001). All sub-quotients decreased significantly except for locomotor. The hearing and language sub-quotient was most affected, with a decrease in mean quotients from 113.0 to 93.2 (p<0.001). There was no evidence of intercurrent events to explain the decline. INTERPRETATION: Scores on the GMDS of this group of children from low socio-economic backgrounds were normal at 11 months and, other than locomotor, decreased significantly at 21 months, with language the most affected. Further research is needed to determine the specific reasons for the decline.

Aetiology of cerebral palsy in children presenting at Tygerberg Hospital.

Two hundred and forty-two records of children with cerebral palsy were reviewed with regard to the aetiology of their condition. The origin of the insult was prenatal in 70 (28.9%), perinatal/neonatal in 92 (38%), acquired in 51 (21%) and unclassifiable in 29 (11.98%). Cerebral malformations (15.7%) and stroke (5.7%) were the most frequent antenatal causes, while birth asphyxia (17.3%), encephalopathy of prematurity (17.7%) and to a lesser degree kernicterus (2%) constituted the most frequent perinatal causes. Acquired cerebral palsy, particularly secondary to nervous system infections (82%), constituted a significant proportion of cases. Spastic quadriplegia (40%) was the most common type of cerebral palsy. The predominance of cases of perinatal and acquired aetiology is in contrast to the antenatal preponderance reported in developed countries.

No evidence of HIV replication in children on antiretroviral therapy

It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1-infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 × 10-4 substitutions/site/month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection.

Motion artifact reduction in pediatric diffusion tensor imaging using fast prospective correction

To evaluate the patterns of head motion in scans of young children and to examine the influence of corrective techniques, both qualitatively and quantitatively. We investigate changes that both retrospective (with and without diffusion table reorientation) and prospective (implemented with a short navigator sequence) motion correction induce in the resulting diffusion tensor measures.