How HIV harms young brains

This article originally appeared in HIV Treatment Update, a newsletter published by NAM between 1992 and 2013.
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HIV paediatrician Anton Tan and clinical psychologist Diane Melvin write about the challenges to development and maturity that HIV imposes on children.

Glossary

neurological

Relating to the brain or nervous system.

encephalopathy

A disease or infection affecting the brain. HIV-encephalopathy (also called AIDS dementia complex) is the result of damage to the brain by advanced HIV disease.

cerebral

Involving the brain.

The last ten years have seen marked reductions in death and sickness in children infected with HIV from their mothers, particularly for those who live in well-resourced countries like the UK.1,2 Since more children are now surviving into adolescence and adulthood, we are faced with an increasing need to understand and manage the long-term consequences of growing up with HIV on teenagers’ coping abilities, their independence and achievements, and their quality of life and social and emotional wellbeing.3,4

Knowledge of their longer-term prospects helps us plan for their future treatment needs and also helps us understand the complex relationship between their past and present health, their treatment and adherence history, and the stresses of life.

In the UK there are, as yet, relatively few published data on longer-term developmental and psychological outcomes in children infected as babies. Although a lot can be learned from other countries, there are big differences in the characteristics and life experiences of different HIV populations, making some comparisons invalid. In the US, for instance, parents of children with HIV infection are more likely to be injecting drug users, while in poorer countries nutrition and access to antenatal and health care will differ from the UK.

The UK cohort is also diverse, with a wide range of health, cultural and social experiences amongst the children. The majority of UK children with HIV have African parents and live with their biological families. But, of these, some were born here, others arrived when young, and an increasing number have arrived more recently as adolescents, often with undiagnosed or untreated HIV and many having experienced extreme disadvantage or traumas.

Social disadvantage, lack of opportunities, family death and ill health, lack of stability, lack of English and missed schooling can all affect young people’s development, making it hard to tease out the causes of developmental difficulties.

We do know, however, that children infected from birth are more likely to have neurological and developmental problems than people who acquire HIV in later life. These problems manifest both as an acute condition in young children and subtle developmental difficulties later on, with a wide range of severity.

Neurological problems and how they happen

The most common neurological problem is stiffness in one or both lower limbs, similar to cerebral palsy, which can affect mobility to varying degrees. This is associated with damage around the time of birth to the motor areas of the developing brain. Other co-factors such as premature birth, failing to thrive and early AIDS-related infections, like cytomegalovirus (CMV), increase the likelihood of this problem. These motor symptoms often, but not always, occur with other developmental difficulties. Good management of HIV can minimise the impact of damage on the nervous system but will not reverse it.

HIV does directly infect some types of nerve cells, but more importantly it infects immune cells within the brain that in turn cause inflammation that damages nerve cells. We don’t know exactly how it crosses the blood-brain barrier; some researchers think it is able to traverse it directly, while others think it smuggles itself in within ‘Trojan horse’ immune cells that can pass this barrier.

We also don’t know if HIV infection in the brain proceeds alongside infection in the rest of the body, with immune cells trafficking between the bloodstream and the brain, or if the virus develops independently within the brain because the immune environment and the concentration of various antiretroviral drugs are different. There’s some evidence the first picture is true of early infection and the second of more chronic infection.

What is HIV encephalopathy and how common is it?

HIV infection of the brain in a child may lead to HIV encephalopathy. In the 1994 Centers for Disease Control and Prevention (CDC) classification, this is an AIDS-defining illness and is defined as:

  • failure to attain or loss of developmental milestones or loss of intellectual ability
  • impaired brain growth or acquired microcephaly (= abnormally small head)
  • acquired symmetrical motor deficit, in the absence of a concurrent infection other than HIV, persisting for at least two months.

Risk factors for HIV-positive children developing HIV encephalopathy include a low CD4 count, high viral load in both blood and in the brain, and advanced maternal disease.

Because definitions of encephalopathy have varied across studies, reporting on how common brain impairment is in children with HIV is difficult. Early studies looking at untreated children often reported up to 50% of their young cohort with encephalopathy.5,6

In these children, delays in early milestones - walking, talking - were common. However, in pre-treatment years, there was already some suggestion of more chronic effects of HIV on the later progress of longer-term survivors, including poorer expressive skills and sometimes difficulties with attention.7 Cognitive abilities (the ability to think clearly) were in the low average range, a number of children needed support at school for learning, and compared to uninfected children, the HIV-positive children had consistently lower scores.8

The outlook today

The most immune-compromised children may have died in the early years and so the long-term survivors who now predominate in the UK are less likely to have severe difficulties. More recent studies suggest that neuro-developmental problems are now more likely to be in the range of 10 to 15% and that often their severity is less.

The introduction of antiretroviral (ARV) therapy in the mid-1990s changed the outcome for HIV-infected children in developed countries as much as for adults. Their overall survival rate is increasing and their admission rate to hospitals is decreasing. There is also evidence that ARVs can reduce the incidence of HIV encephalopathy.

The important question here is whether therefore we should offer ARVs to all children without delay after diagnosis, irrespective of their age and CD4 count.

Treatments and improved care for children with HIV have resulted in a reduction of severe neurological and motor consequences and progressive encephalopathy is now rare where HIV has been effectively managed.

The Children with HIV Early Antiretroviral Therapy (CHER) study showed that early treatment (within the first three months of life), as compared to deferred treatment, reduced the mortality rate by 76%,9 and a substudy showed that early treatment significantly improved children’s neurocognitive development when assessed at the age of ten to 15 months. It is therefore recommended that all HIV-positive children up to the age of a year should commence ARVs as soon as possible after diagnosis.

Early neurological damage will have lifelong effects, but there are older children in HIV cohorts whose neurological damage occurred early in life but who now have minimal symptoms due to better treatment and increased general wellbeing.10 In more recent years, we are tending only to see neurological deficits in children diagnosed late, and where HIV was diagnosed after a catastrophic illness.

With access to careful monitoring and appropriate treatments when needed there has been a reduction in the numbers being reported with severe delays and progressive deterioration and early motor delays are now rare. In studies, the performance of children who took early treatment is similar to HIV-negative children, and further reports are now showing that as they get older children maintain scores within normal limits.11,12 Recent research by our team with a group of HIV-positive schoolchildren aged nine to twelve confirmed that most of them had IQ and basic attainment scores in the average range.13

Clinical issues for teenagers

However, the more subtle weaknesses noted in earlier studies are still being recorded and - for some - are becoming more marked as children are getting older. While not all children will have evidence of these weaknesses, there is a common profile of difficulties, affecting what are called ‘executive functions’. These include dealing with complex verbal material, being able to maintain attention and concentration, memory and the ability to sustain effort.14,15

Impairment of executive functions can affect learning and application to tasks, especially at older ages as the demands of life increase, and may also have some associated behavioural consequences such as being over-impulsive or not planning ahead or thinking through consequences – exacerbations, you might say, of normal teenage struggles.

Where MRI or CT scans have been used, it has been found that those children with HIV with evidence of nervous system damage on their scan are also particularly poor on tasks of executive functioning.

In the UK, there are clinical reports that suggest a notable number of children have difficulties with attention and overactivity in the early years and others with remembering, sustaining effort and applying themselves to school learning, even if they have intact thinking skills. Further, the numbers of HIV-positive children receiving extra learning support in school is higher compared to other children of the same age and ability. This increase in numbers needing support was found for those born in the UK - not just for those more recently arrived - and appears not to be due to adjusting to UK language and culture.

As more children with HIV are living longer, healthier lives there is evidence emerging that some of the more chronic effects of living with HIV are becoming apparent and having some influence on later learning and performance. This pattern of neurocognitive weaknesses can have an influence on behaviour as well as potential to achieve. Adolescence, because of the increased learning, social and emotional demands, may be a particularly stressful time when any underlying difficulties may become more evident. Adolescence is also a time when adherence to medicines may be most difficult and underlying clinical and neurological difficulties may themselves have an influence on remembering to take medicines or sustaining the effort to. This has to be taken on board when planning adherence support.

There is a need to collect more data on developmental outcomes for children with HIV, but in-depth assessments are often not practical due to limited resources, and it may not be appropriate to refer to other services because of concerns both about confidentiality and because they are already over stressed. Subtle difficulties may not meet the criteria for access to such services.

The UK population of children with HIV is growing older and entering adulthood. There is an urgent need to collect more data on the longer-term health outcomes, which will not only guide treatment decisions but may also provide a better understanding of how lifestyle and psychosocial factors will impact on our young HIV-positive patients as they grow up. Enabling more children and youngsters to attain their potential and achieve a fulfilling and independent life is a core aim of good HIV care.

References

1. Gibb DM et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ 327:1019, 2003.

2. CHIPS Collaborative HIV paediatric Study. 2009. See www.chipscohort.ac.uk

3. Judd A et al. Morbidity, Mortality and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care. Clinical Infectious Diseases 45:918-924, 2007.

4. Patel K et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clinical Infectious Diseases, 46:507-515, 2008.

5. Brouwers P et al. Central nervous system involvement: Manifestations, evaluation, and pathogenesis. in Pizzo PA & Wilfert CM (Eds.) Pediatric AIDS: The challenge of HIV infection in infants, children and adolescents. (2nd ed., pp. 433–455), Baltimore: Williams & Wilkins, 1994.

6. Willen Elizabeth J Neurocognitive Outcomes in Pediatric HIV. Mental Retardation and Developmental Disabilities. Research Reviews 12: 223–228, 2006.

7. Nozyce M et al. A behavioral and cognitive profile of clinically stable HIV- infected children. Pediatrics 117, 763-770, 2006.

8. Wachsler-Felder JL, Golden CJ Neuropsychological consequences of HIV in children: a review of current literature. Clinical Psychology Review 22:443-464, 2002.

9. Violari A et al. Early Antiretroviral Therapy and Mortality among HIV-Infected Infants. NEJM 359:2233-2244, 2008.

10. Melvin D and Biggs R A multidisciplinary approach to monitoring neurological & functional outcomes in paediatric HIVinfection. See www.chiva.org.uk/guidelines/2009/pdf/monitoring-neurological09.pdf. 2007.

11. Malee K et al. The role of cognitive functioning in medication adherence of children and adolescents with HIV infection. Journal of Pediatric Psychology, 164-175, 2009.

12. Martin, SC et al. Cognitive functioning in school-aged children with vertically acquired HIV infection being treated with Highly Active Antiretroviral Therapy (HAART). Developmental Neuropsychology: 30(2):633-657, 2006.

13. Krechevsky D & Melvin D A case note review of cognitive , learning and quality of life outcomes from a UK cohort of HIV infected school age children. Poster 16, CHIVA conference, Brighton, 2010.

14. Brackis-Cott E et al. The impact of perinatal HIV infection on older school-aged children’s and adolescents’ receptive language and word recognition skills. AIDS Patient Care, Vol 23, Number 6, 415–421, 2009.

15. Koekkoek S et al. Neurocognitive function profile in HIV-infected school-age children. European Journal of Paediatric Neurology 2008, 12:290-297, 2008.