Published online March 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. 729-740 (doi:10.1542/peds.2004-2699)
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Health, Neurologic, and Cognitive Status of HIV-Infected, Long-Surviving, and Antiretroviral-Naive Ugandan Children

Danstan Bagenda, MSca,b, Annette Nassali, MBChB, MSca, Israel Kalyesubula, MBChB, MMeda, Becky Sherman, PhDc, Dennis Drotar, PhDc, Michael J. Boivin, PhDc,d and Karen Olness, MDc

a Makerere University Medical School, Kampala, Uganda
c Behavioral and Developmental Pediatrics, Case Western Reserve University, Cleveland, Ohio
b International Health/Infectious Diseases, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
d Department of Psychology, Indiana Wesleyan University, Marion, Indianapolis


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The purpose of this study was to assess the health status and school-age neurodevelopmental progress of antiretroviral treatment (ARVT)–naive, HIV-infected Ugandan children who had been followed as part of cohorts of children born to HIV-infected and -noninfected mothers between 1989 and 1993.

METHODS. Twenty-eight children, aged 6 to 12 years, vertically infected with HIV-1 and never treated with ARVT were evaluated in terms of health status, neurologic, and psychometric testing. A randomly selected group of 42 seroreverters and 37 HIV-1 negative children who were age- and gender-matched and who had been followed in the same cohorts were evaluated also. The families studied were homogenous in their socioeconomic status. None of the mothers or children had received ARVT or been exposed to illicit drugs.

RESULTS. The HIV-infected children showed significantly more evidence of acute malnutrition. They also had more illness, especially parotitis, otitis media, upper respiratory infections, and lymphadenopathy. However, they did not differ significantly in neurologic and cognitive assessments when compared with age- and gender-matched seroreverter and HIV-negative children. They were in the normal range with respect to neurologic and psychometric development measures.

CONCLUSIONS.These children seem to represent a significant subgroup of HIV-infected child survivors for whom the progress of the disease is less aggressive throughout early life. Given the fact that many infants, especially in developing countries, continue to be born without the benefit of perinatal ARVT, there will likely continue to be many older HIV-infected children in the same situation as those described in this follow-up study. They will not have been recognized as being HIV-infected. It is important that such children be identified and offered access to ARVT and other appropriate support services.

Key Words: HIV • pediatrics • AIDS • cognitive ability • intelligence • motor development • social development • neuropsychology • children • Africa • Kaufman Assessment Battery for Children • K-ABC

Abbreviations: CDC—Centers for Disease Control and Prevention • ARVT—antiretroviral treatment • SES—socioeconomic status • K-ABC—Kaufman Assessment Battery for Children • WRAT-3—Wide Range Achievement–Third Edition • ANOVA—analysis of variance • WAZ—weight-for-age z score(s) • HAZ—height-for-age z score(s) • FTT—failure to thrive • PE—progressive encephalopathy

The developmental deficits described in HIV-1–infected children have included language and motor skills,1–3 verbal and memory deficits,4 visual-spatial integrative ability,5,6 executive function,7 hypotonia, and/or hyperactivity.8 Our study on neurodevelopmental outcomes of Ugandan infants with HIV-1 infection found mental developmental abnormalities according to Bayley testing but normal information-processing abilities.1 In studies of very young HIV-infected children without Centers for Disease Control and Prevention (CDC) clinically defined AIDS, or with only lymphoid-interstitial pneumonitis, Nozyce et al9 found no significant differences compared with seroreverters or controls on the Bayley Mental Development Index or Psychomotor Development Index. They concluded that HIV-infected children with few symptoms of AIDS have relatively normal neurodevelopment. Radiologic studies of HIV-1–infected children have documented computed tomography scan abnormalities10 and MRI abnormalities11–13 in areas of the brain associated with motor development. These abnormalities include cortical atrophy and cerebral calcification in children with symptomatic but untreated acquired HIV-1 infections

There have been few prospective long-term follow-up studies of HIV-1–infected children from birth. Most of these studies have involved follow-up to a maximum of 5 years, with children who received antiretroviral treatment (ARVT), and none have focused on neurodevelopmental aspects of HIV infection.14–17 We began following a cohort of Ugandan infants born to HIV-1–infected mothers in 1989 for the primary purpose of assessing the natural history of HIV-1 infection in infants. Information was collected on 589 infants (429 born to HIV-1–seropositive and 160 to HIV-1–seronegative women). We enrolled a second cohort to follow neurodevelopmental status of HIV-1–infected infants (320 children born at term to HIV-1–infected mothers and 116 born at term to HIV-1–seronegative mothers). Numerous articles have been published about the natural history, growth, neurodevelopmental progress, infectious diseases, and laboratory status of these children during the early years of life.1,18–23 This study reports on the status of 28 long-term surviving HIV-1–infected children (18 females, 10 males) compared with an age-matched randomly selected group of 42 seroreverters (23 females, 19 males) and 37 children born to HIV-1–negative mothers (19 females, 18 males) after enrollment into the original study.

This is the only follow-up study providing data on school-aged, antiretroviral-naive, HIV vertically infected children (by narcotic drug-free mothers) who have additionally been carefully assessed regarding cognitive, neurologic, and psychometric development. Most studies have been done in developed-country settings, normally among drug-exposed children. This study is especially important because it provides such information for children of a low socioeconomic status (SES) who live in resource-constrained settings similar to those of the majority of HIV-infected children in the world. The findings from this study, therefore, are applicable to a large number of children in Africa who face such similar circumstances. In addition, this study determines the between-group differences of 3 peer groups of surviving children, all of whom were born to women who chose to attend the clinic, were homogenous in their SES, none of whom (mothers and children) had received ARVT or been exposed to illicit drug use, and for whom there was no differential adherence to the protocol; as such, this study is minimally affected by potential confounders other than those that are attributable to HIV disease.

Our hypotheses before the follow-up evaluations were as follows:

  1. HIV-infected children would have more neurologic impairment than age-matched seroreverters or children born to HIV-negative mothers.
  2. HIV-infected children would perform less well on the Kaufmann Assessment Battery (K-ABC) and the Wide Range Achievement–Third Edition (WRAT-3) test than would age-matched seroreverters or children born to HIV-negative mothers.
  3. HIV-infected children would have poorer growth than age-matched seroreverters or children born to HIV-negative mothers.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Between 1989 and 1993, 2 pediatric cohorts were established by enrolling pregnant women who attended prenatal clinics at Mulago Hospital (Kampala, Uganda) and lived within 15 km of the hospital. Mulago Hospital is a 1200-bed teaching hospital and a national referral hospital associated with Makerere University. Only women who attended the antenatal clinic, declared their intention to deliver at Mulago Hospital, and agreed to have their blood tested for HIV-1 infection were eligible to enter the study. After obtaining verbal informed consent, these women were tested for HIV-1 antibody by using an enzyme-linked immunosorbent assay (Recombigen; Cambridge Bioscience, Cambridge, United Kingdom). The manufacturer’s instructions were followed. Western blots (Novapath Immunoblot Assay; Bio-Rad, Hercules, CA) were performed to confirm HIV-1 infection. All seropositive women who met these criteria were enrolled. The women were followed through pregnancy, labor, and delivery and their infants were followed closely in a special study clinic until the age of 4 years. Laboratory criteria for diagnosis of HIV infection in infants were enzyme immunoassay–and Western blot–positive at ≥15 months of age or positive HIV DNA polymerase chain reaction (excluding cord blood) or positive neutralizable immune complex dissociation p24 antigen (excluding cord blood). Children who were born to mothers with HIV infection were defined as seroreverters if they became HIV-antibody–negative after 9 months of age, had no other laboratory evidence of HIV infection, and did not meet the acquired immunodeficiency syndrome surveillance CDC case-definition criteria.1 Laboratory measures of immune status such as CD4 were not available in this field setting at the time of the initial cohorts.

In the combined cohorts, ~61.6% of HIV-1–infected children died by their fourth year of age compared with 4.1% of the seroreverters and 2.9% of the HIV-1–negative children. Thus, after death and loss to follow-up (only 4.5% loss to follow-up in the first 4 years), 57, 486, and 261 of the original 151, 508, and 277 HIV-1–infected seroreverter, and HIV-1–negative first-cohort children, respectively, were alive after 4 years.

Prior data analysis has shown that familial, socioeconomic, and environmental factors have been well-controlled in these cohorts with respect to HIV-1–infected, seroreverter, and HIV-1–negative groups, and the children being followed were born to a relatively homogenous group of women who acquired HIV-1 infection almost entirely through heterosexual transmission.1,18 Confounding variables contributed by maternal drug use or child neglect do not exist in these cohorts, and to this point, family and home environments have been remarkably stable. The infants and mothers followed in these cohorts did not receive zidovudine, nevirapine, or any other antiretroviral agent because they were unavailable in this clinic and the country as a whole as a result of the lack of resources necessary to obtain these medications and the lack of infrastructure and capacity to safely administer them at the time. During the years after completion of the preschool neurodevelopmental assessments, the children and their families continued to come to the study clinic for diagnosis and treatment of acute illness and to access other available support services.

Growth and developmental parameters have been tracked carefully from the time of birth to the present. Through the study clinic, charitable organizations and individuals provided many of them with supplemental food, school fees for them and their school-going siblings, and small loans to parents/guardians for microenterprises. The continuous checkup by our health visitors of families of patients who attend the clinic made it relatively easy to trace those children who otherwise had no reason to keep visiting the clinic.

Participants for the long-term follow-up were drawn from the previously mentioned combined cohort. At the time of this follow-up (a minimum of 6 years), 28 of 57 HIV-infected children alive at 4 years were still living. None of these children had received ARVTs in the interim for the same reasons as stated. The mothers or guardians of the children agreed to join the study and provided signed consent. The seroreverters and those born to HIV-1–negative mothers were randomly selected and matched by age (maximum of 2 months’ difference) and gender to the surviving HIV-1–positive children.

A home visitor arranged for each child to come to the outpatient clinic on a designated day for their clinical, physical, neurologic, and psychometric examinations. If children had acute illnesses, the testing was deferred until they were well. Children from this cohort continued to receive clinical evaluation, treatment, and immunizations similar to that during their follow-up period. On clinical examination, diagnoses of present illnesses were made and recorded. However, because of previous nonspecificity/sensitivity of either one of the CDC and World Health Organization clinical pediatric HIV-staging algorithm in this setting, specific assessments relating to pediatric HIV staging were not attempted. Also, because of the lack of funds, laboratory-based immunologic and virologic assessments such as CD4 and viral load were not attempted. Each child also received a complete physical examination, which included a neurologic assessment. The neurologic assessment included evaluation of mental status, cranial nerves, muscle tone, sensation, upper and lower extremity reflexes, balance, and rapid and alternating movements. Power was tested by asking each child to push and pull the examiner’s upper limbs and opposing their movements.

All sensation tests were performed with the child’s eyes closed. The neurologic examination of cranial nerve function was performed by the tester using familiar nonirritating substances to determine the children’s ability to smell. We used tea leaves, coffee, and a box of matches. Children were asked to close their eyes, and the tester made certain that they were not seeing what we were challenging them to smell. Those who did not smell the substances were asked whether they were familiar with these substances in their homes. The tester also gave them an opportunity to smell the substances with open eyes. If the child continued to say that he or she could not smell, a diagnosis of cranial nerves category I (CNI) dysfunction was made. The tester was careful not to perform the olfactory assessment on children who had other potential explicable nonneurologic causes of CN I sensory loss such as rhinorrhea until a time after they were fully recovered. Other similarly administered sensory examinations included tests for pain, heat, coldness, and vibrations. Pain was elicited by lightly touching the child with a pin. For heat and coldness, the tester used objects with a relatively higher or cooler temperature, respectively, than the child’s body temperature. For the vibrations, we used a tuning fork previously started by lightly hitting on the examiner’s knee.

For the psychometric evaluations, the children were brought to the project clinic at the hospital by the mother or other family member who remained present throughout the assessment. The K-ABC24,25 was administered to each child by a child psychometrist who was blinded to their HIV status.

The K-ABC in this study setting was conducted in a clinic setting in the predominant local language (Luganda) after pilot testing. The examiners could readily communicate with the parents in the local dialect of Luganda. The mental-processing portions of the K-ABC (sequential and simultaneous processing) were administered (easels 1 and 2).

The K-ABC is a measure of intelligence and achievement for children aged 2 years 6 months through 12 years 5 months. The full K-ABC includes 4 scales: the sequential-processing scale, the simultaneous-processing scale, an achievement scale, and a nonverbal scale (Table 1). The achievement and nonverbal portions of the K-ABC were not administered in this study as a result of their cultural specificity. The achievement portion, however, was replaced by the more culturally transferable WRAT-3 test (Table 2).


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  		TABLE 1 Methods Used for Administering the Subscales of Kaufman Assessment Battery for Children (K-ABC)

 

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  		TABLE 2 Methods Used for Administering the Subscales of the WRAT-3 for Children

 
The WRAT-3 is a measure used to assess the basic skills needed for reading, spelling, and arithmetic.

The sequential-processing portion included tests that required the child to arrange stimuli in sequential/serial order in attempts to measure such ability as immediate memory recall, whereas the simultaneous processing included tests that required solving many stimuli at once to assess the child’s ability to solve spatial, analogical, and organizational problems (Table 1). The sequential- and simultaneous-processing scale portions of the K-ABC test were designed to reduce the effects of verbal, gender, and ethnic bias.

Although the K-ABC was developed initially for use in the Western world, it has been shown to be adaptable and culturally robust in various settings, including those similar to Uganda (such as in the Congo).

A principal component factor analysis completed on K-ABC data from Congolese (Zairian) children in previous studies26,27 revealed that, although the instrument had been administered in the African dialect of Kituba, the internal factor structure of the subtests remained the same, which supports the validity of the instrument when administered in this cultural setting.

Ethical Issues
Institutional review board approval for both the initial cohort and the current long-term follow-up was obtained from both University Hospitals of Cleveland and Makerere University in Kampala as well as from the national oversight body. Written consent to be a part of this study was obtained on behalf of the children in this study from their mother (and father if available) or other main caregiver of the child.

All the children (and their mothers) in the initial and follow-up cohorts were being provided with the best treatment available at the clinic. This treatment was generally much better than the standard of care in the country and indeed in the main referral hospital in the country, as has been indicated by the lower age-specific mortality rates for this cohort compared with the prevailing countrywide rates and despite this clinic serving a very low-income nonpay population with relatively limited resources at its disposal.28

However, neither the children nor their mothers were provided with ARVT at any point in the described initial or long-term follow-up. ARVT was not available in the clinic (or in the country at the time) because of the lack of resources (the 2001 expenditure on health in Uganda is approximately $13.80 per person per year29) to acquire ARVT and to train and put in place the infrastructure necessary for the safe administration and monitoring of ARVT. It should be noted that at enrollment time (1989) of these cohorts, ARVT was not widely available even in resource-rich settings.

Indeed, in Africa, this study clinic has since been at the forefront in advocating for, testing, developing, and implementing infrastructure for delivery of various feasible interventions (including affordable ARVT). The clinic is the site of the landmark trial of use of nevirapine to prevent mother-to-child HIV transmission30,31 and the site of the multicenter Perinatal Transmission Study (PETRA), which investigated short-course zidovudine interventions in pregnancy,32 and Prevention of Mother-to-Child Services and Comprehensive Care and Treatment to HIV-Positive Pregnant Women/Mothers and Their Children (PMTCT-PLUS) antiretroviral interventions administered to the mother and infant postpartum, just to mention a few. These interventions have become standard use around most of Africa based on our efforts, vigilance, and concern for the plight of our population. During this time, the clinic has been developing the capacity to deliver and monitor ARVT. As a result, it should be noted that this study site is one of very few centers with the current (as of 2002) capability of (effectively and routinely) delivering ARVT in Africa despite recent availability of cheaper antiretroviral generics and initiatives such as those by the Joint United Nations Programme on HIV/AIDS Global Fund "3-by-5" initiative and the President’s Emergency Plan for AIDS Relief (both started in 2005), which highlights the challenge faced in providing and delivering ARVT in these settings. The study site is now also the major trainer of antiretroviral providers in the country for the Ministry of Health.

With these developments, a collaborative pediatric HIV/AIDS clinic that specifically provides ARVT to HIV-infected children and adolescents has been set up at the study site for referral of all HIV-infected children, including any survivors from our initial cohorts.

Statistical Analyses
Data entry and management was performed by using Epi Info 6.0 (CDC, Atlanta, GA). Analysis was performed by using SPSS 11.0 for Windows (SPSS Inc, Chicago, IL) and Stata 8.0 (Stata Corp, College Station, TX). Statistical analyses consisted of comparisons of proportions using Fisher’s exact test as well as computation of appropriate 95% confidence intervals and comparisons of group averages based on analysis of variance (ANOVA) and the Bonferroni test for pairwise comparisons. The relatively small number of long-surviving HIV-1–infected children (n = 28) determined the overall sample size of the study and resulted in this study being low-powered to detect very small group differences. Thus, the sample size achieved for the long-term follow-up evaluation in this study determined that, for proportions only, differences of a magnitude of at least 25% to 35% between study groups could be identified as statistically significant at the .05 significance level with a power of at least 80%. For comparison of averages, this sample size ensured detection of differences of at least a magnitude of 2.5 in the subscale scores and differences of at least a magnitude of between 5.5 and 10.0 in the global-performance scores with 80% power at the {alpha} = .05 level. As such, this study is weakly powered to determine group differences for the very rarely occurring cognitive and neurologic abnormalities.

Although there is a potential selection bias as to who comes for health care in the women (which should affect all the 3 groups equally), there is no evidence of bias resulting from differential adherence to the protocol for the 3 groups of women. Loss to follow-up of children was low in all 3 groups (4.5%), and although differentially more HIV-positive women died in the course of the follow-up, the spouse or other guardians (normally the child’s grandmother) were reliable in continuing to bring the child to the clinic. This and the vigilant use of health visitors to perform home visits resulted in low loss to follow-up and a low lack of adherence to the protocol. The result is that the selection bias as a result of a differential lack of adherence is minimal if present.

All the children in this and the original cohorts received the same optimal care. Some died and others survived through a self-selecting process (resulting in a survival bias). We acknowledge that, and although we have offered some possible factors that may be associated with survival in this and other publications of the cohort,23 we emphasize that our article is simply a description of those children (especially the HIV-infected) who, for whatever reason, survive and how they fare compared with their noninfected peers (who are, somewhat likewise, "survivors" in a setting of high general background child mortality). We think that describing the status of these children is important regardless of whether they are a unique group of survivors.

Thus, although we advise caution in interpreting any generalization beyond this population of children who attend the clinic (a free clinic), because this study emphasizes the between-group differences of 3 peer groups of surviving children, all of whom were born to women who chose to attend the clinic, were homogenous in their SES, none of whom (mothers and children) had received ARVT or been exposed to illicit drug use, and for whom there was no differential adherence to the protocol, the comparisons between groups presented here should be affected minimally by the previously stated potential selection biases other than those that are attributable to HIV disease.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Demographic Characteristics
The children ranged from 6 to 12 years of age, and 56% were female (60 girls and 48 boys).

The HIV-infected (M+C+), HIV-negative seroreverter (M+C–), and HIV-negative control (M–C–) groups were well age- and gender-matched (Table 3).


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  		TABLE 3 Comparison of HIV-Positive (M+C+), HIV-Negative (Seroreverters [M+C–]), and Control Children’s (M–C–) Health and Anthropometric Indicators

 
Health Status
Consistent with our hypothesis, HIV-infected (M+C+) children showed more evidence of acute malnutrition as indicated by significantly (P < .02) lower weight-for-age z scores (WAZ) compared with negative seroreverter (M+C–) and negative control (M–C–) children (as shown in Table 3). There was also significant evidence of failure to thrive (FTT) as indicated by clinical examination (P = .01) and WAZ below or equal to –2 (P = .02) (see Table 3).

In addition, as we had hypothesized, there was significantly greater stunting (P < .0001) in the M+C+ group compared with the M+C– and M–C– children (see Table 3).

Approximately three fourths of the HIV-infected children and almost half of the HIV-negative children were ill at the index visit. HIV-infected children were significantly more likely to have parotitis, splenomegaly, and hepatomegaly than were the uninfected children (see Table 3).

Although there were no specific attempts to clinically classify these children into the CDC or World Health Organization AIDS-staging categories, presence of lymphadenopathy is usually associated with stage A of the CDC pediatric HIV/AIDS staging. Based on this observation, ~61% of the HIV-infected children had at least been in this symptomatic AIDS stage (Table 3). In addition, children that are ≤3 SDs on their WAZ or height-for-age z scores (HAZ) can be considered to have severe FTT. Severe FTT is associated with CDC pediatric HIV/AIDS stage C. At least 29% of the HIV-1–infected children had severe FTT (as defined by WAZ or HAZ ≤ –3 SD; Table 3), which is indicative of CDC pediatric HIV/AIDS symptomatic stage C.

Neurologic Status
Contrary to our hypothesis, the 3 groups were comparable in terms of neurologic status, with only a slight nonsignificant trend toward an abnormal cranial nerve 1 for HIV-infected children (see Table 4).


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  		TABLE 4 Comparison of HIV-Positive (M+C+), HIV-Negative (Seroreverters [M+C–]), and Control Children (M–C–) on Cognitive Examination and Neurologic Examination of Cranial Nerve Function

 
Psychometric Status: K-ABC
Simultaneous Processing (Visual-Spatial Organization)
There were no significant group differences in any of the K-ABC simultaneous-processing (visual and spatial organization) subscale standardized scores, a finding that is inconsistent with our hypothesis (Table 5).


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  		TABLE 5 Comparison of HIV-Positive (M+C+), HIV-Negative (Seroreverters, [M+C–]), and Control Children (M–C–) on the Standardized Scores From the K-ABC

 
Sequential Processing (Immediate Recall Memory)
There were no significant differences in most sequential-processing subscale scores by HIV category. There are, however, significantly higher hand-movement scores for the negative seroreverter children compared with the HIV-infected children (P = .019, Bonferroni correction). However, there were no differences in the hand-movement scores between HIV-infected and control children (P = .91, Bonferroni correction) (as shown in Table 5).

Global Sequential Measures
There were no significant differences in the global sequential measures (as shown in Table 5).

Academic-Achievement Subscales
Seroverter (M+C–) children had significantly higher reading scores compared with HIV-infected (M+C+) and control (M–C–) children, respectively (P = .03, Bonferroni correction). However, inconsistent with our hypothesis, there was no difference in reading scores between HIV-infected children and control children (P = 1.00, Bonferroni correction). There were also no significant differences between any of the study groups in the spelling (P = .23) and arithmetic (P = .12) components of the WRAT-3 (Table 6).


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  		TABLE 6 Comparison of HIV-Positive (M+C+), HIV-Negative (Seroreverters [M+C–]), and Control Children (M–C–) on the Standardized-Score Measures From the WRAT-3

 
Thus, these infected children did not show significant differences on most of the subscale and global measures of the K-ABC and WRAT-3, a finding that is inconsistent with our hypothesis.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our study provides the only data on school-aged, antiretroviral-naive, HIV-1 vertically infected children, longitudinally followed from birth, who have additionally been carefully assessed on their cognitive, neurologic, and psychometric development.

Our hypothesis that HIV-infected children would perform less well on the K-ABC was not upheld. The present sample of HIV-positive schoolchildren was well within the normal range of cognitive ability and academic-achievement measures as measured by the K-ABC. Our hypothesis that HIV-infected children would have more neurologic impairment was also disproved. Neurologic status was comparable among the 3 groups. The hypothesis that the HIV-infected children would have poorer growth was upheld. The HIV-positive schoolchildren had more evidence of acute illness and malnutrition than did the seroreverter and control groups.

In comparing the HIV-positive with HIV-negative children in this study, significant deficits were not noted for the HIV-infected children with respect to the sequential- and simultaneous-processing abilities assessed with the K-ABC. The HIV-infected children had a trend toward some slightly poorer academic-achievement measures but remained within the normal ranges and were not significantly different from control children. Based on the use of the K-ABC with HIV-positive Congolese (Zairian) children5 and reports by Diamond et al33 and Belman et al,11 who used the K-ABC with HIV-infected children, we would have expected significant deficits. We also found no significant differences in neurologic tests, including motor function, although the original cohort from which this subset was drawn did manifest lower Bayley motor development scores when they were tested during infancy and through the second year of life. Significant differences on motor development were apparent for HIV-positive children in both toddlers (≤2 years) and older children (aged 8–12 years) in separate studies by Boivin et al5 despite the fact that the sample used in those studies was selective in that they were African children who were asymptomatic with respect to the immunodeficiency associated with the initial stages of AIDS and who, like the children in our cohort, were socially responsive enough to complete the assessment. That study suggests that the language and global cognitive deficits observed in the HIV-infected children were possibly the result of the direct effects of the virus on neuropsychologic development and the impact of maternal infection on the favorability of the home environment for the child. According to Belman et al,11 such a sample may represent only those children with a static subacute course of pediatric HIV infection as opposed to an acute progressive encephalopathic course for the disease.

Frank et al34 studied 27 HIV-positive children ranging in age from 6 to 17 years and investigated the relationship between cognitive functioning and stage of disease, drug therapy, mode of transmission, and quality of caretaker. Visuomotor skills was the most affected cognitive area in relation to stage of disease, mode of transmission, and the children’s living environment.

In addition, Nozyce et al9 found that HIV-infected children without CDC-defined AIDS and children with only lymphoid-interstitial pneumonitis AIDS were not significantly different from seroreverters or control on the Bayley Mental Development Index or Psychomotor Development Index. They concluded that HIV-infected children who are not highly symptomatic have relatively normal neurodevelopment.

Other studies have reported that children with HIV infection display greater difficulties in cognitive functioning, language development, motor skills, and emotional and behavioral functioning, especially if they are symptomatic,35 than was the case with the Ugandan children described in this study.

Henry et al36 examined immune system dysfunction, HIV-1 serostatus, and psychosocial and environmental factor effects on cognitive functioning in children and concluded that the degree of immune system dysfunction is related to the level of cognitive functioning in either seroreverters or HIV-positive children

However, more recent research has also shown that perinatally infected children can vary dramatically in terms of the course of the disease and their subsequent neurodevelopmental profiles. This is especially evident when one considers school-aged vertically infected "survivors." Rausch and Stover37 estimated that ~13% to 23% of HIV-1–infected children have a progressive encephalopathy (PE) course of the disease marked by impaired brain growth, progressive motor dysfunction, and significant delay in achieving neurodevelopmental milestones.

Without highly active antiretroviral therapy, as was the case with this study cohort, the prognosis for children in terms of survival beyond a few years of birth is very poor. Possibly those HIV-infected children in our original study cohort with a more aggressive expression of PE did not survive, leaving those children with a static/stable expression of the disease who performed within or near the normal range of cognitive and academic assessments.

It has been reported by others that even children with vertically transmitted HIV infection who are symptomatic and who survive until school age may be within the normal range in terms of intelligence, receptive language, expressive language, visual and verbal memory, and academic achievement.38,39 In such children, according to Blancette et al,39 comprehensive neuropsychologic examination may only reveal consistent deficits with respect to fine motor and motor strength.

In another study, Fishkin et al40 matched preschool black and Haitian HIV-infected children with an equal number of noninfected controls based on ethnicity, age, gender, and prenatal drug exposure. The Wechsler Preschool and Primary Scale of Intelligence–Revised was used to analyze cognitive ability. Both the HIV-infected children and the controls scored below normal, although the HIV-positive children scored significantly lower on one portion of the test. They concluded that cognitive defects in HIV-positive children are not evident in preschool children.

We note that the children described in these studies were receiving ARVT, which was not the case for the children we describe in this report.

Brouwers et al13 conclude in their review that although more severe courses of encephalopathy can often be observed in groups of infants and young children, the neurodevelopmental course of the disease in most older children is best described as static encephalopathy or central nervous system compromise. According to their review, it is not at all clear why one subgroup of HIV-infected infants develops a more severe PE, whereas another subgroup does not. They conclude that it may be related to the timing of the central nervous system infection in the developing brain in utero, the accompanying viral load, and the biogenetic vulnerability of children. Mitchell’s12 review of the neurologic and developmental effects of HIV and AIDS in children showed similar conclusions.

Smith et al41 concluded that the timing of the perinatal HIV-1 infection was a significant consideration in the degree of early neurodevelopmental impairment as well as poor early immunologic and clinic outcome, and Pollack et al42 postulated that viral load in the first 6 months of life may be a deciding factor in the degree of neurodevelopmental impairment. Mitchell12 also concluded that with very early infection and high viral loads, the risk of clinical HIV encephalopathy dramatically increases with corresponding neurodevelopmental impairments.

Other factors that explain the relative lack of neurodevelopment impairment in this group of children may relate to the social, emotional, medical, and educational support that they and their families were receiving over the years through the study clinic because of their study participation.

Aside from the emotional impact of stigma, isolation, and grief from the loss of family members to the disease, infected and noninfected children with infected parents or family members are also at greater risk for economically poorer developmental outcomes because of the skewing of familial resources toward the care and treatment of infected family members, with the economic impact being especially acute with poorer families in resource-poor settings in the developing world.43

Several studies have revealed how this may be mediated. Sixty-seven HIV-infected children 3 to 16 years of age were administered standardized measures of cognitive, adaptive, and behavioral functioning. Mean group performance fell below the normative samples on cognitive and adaptive skills and above normative samples for behavior. Hierarchical regression equations found a relationship between SES and cognitive functioning that was mediated by the ratio of children to adults in the home. Furthermore, the child-to-adult ratio in the home was predictive of adaptive behavior.44

For 43 HIV-infected children between the ages of 2.5 and 12 years, quality of the home environment mediated the relationship between SES and overall cognitive ability performance. SES and quality of the home environment were much more significantly related to IQ than degree of illness and health status for the children. Quality of the home environment was defined by the organization of the environment, play materials, parental involvement, variety of stimulation, and parental attitudes toward the provision of a cognitively stimulating environment. Furthermore, the mediational role of quality of the home environment was stronger for children in a more advanced stage of illness from the disease as determined by health status and CD4 counts.45

Even in the absence of HIV infection (eg, seroreverters), characteristics of the home environment for the infected parent(s) can significantly compromise the cognitive and behavioral development of the child over the long-term.46 These characteristics involve the direct effects on the child of having key family members, especially the mother, chronically ill from the disease. These effects can be especially severe among more impoverished socioeconomic classes in developing countries. For example, 74% of the world’s HIV infections and 84% of the world’s AIDS deaths that occurred in 1999 were in sub-Saharan Africa. Ninety-one percent of child HIV infections and 94% of child AIDS deaths occurred in Africa.47 In these areas, family resources are strained by the environment and the disease. In rural areas of sub-Saharan Africa, the family must rely on labor-intensive subsistence agriculture to provide for the nutritional needs of the family. Maternal HIV disease can severely disrupt the nutritional resources of the family and undermine this vital aspect of the early development of the children.5

Furthermore, chronic illness in any family member in the absence of a national or universal healthcare insurance system or social welfare safety net can quickly drain the meager financial resources of the family as they meet the expenses of treatment. This is an important consideration in light of the significant relationship between overall economic well-being for the family and the long-term development of cognitive ability and performance that has been documented in such African environments.26,27 Children also differ as to the effects of maternal illness on the quality of attachment, caregiving, and the emotional toll of the burden of the disease on the family. The percentage of children without their natural mother is highest in both HIV-infected children and HIV-uninfected children born to infected mothers, and both suffer from the effects of the disease on caregiving and quality of the home environment.48 When AIDS or any serious long-term illness ravages a family in a developing country, it has the potential of profoundly influencing the neuropsychologic development and well-being of both infected and noninfected children within the family.5

There may be additional factors related to micronutrients or immunologic reactivity, to a different strain of HIV, or to quality of education, which have contributed to the findings in our cohort of long-term survivors. However, without precise understanding of the pathogenesis of central nervous system injury in HIV-infected infants and children, we are unable to explain the relatively normal neurodevelopmental profile for school-aged HIV children observed in this long-term follow-up study. We are also not able to explain the long survival of children who received no antiretroviral medications.

It is possible that the lack of neurologic, motor, and psychometric impairment relates to the social, emotional, medical, and educational support that HIV-infected children and their families received from their study participation. These relatively inexpensive interventions may benefit children in other Ugandan health clinics.

Because these otherwise capable infected children do not have the financial support from their sick or deceased parents, there should be arrangements that ensure their access to education. The government of Uganda has put in place a free universal primary education program for up to 4 children in each household. All HIV-infected children in a household should have access to free universal primary education.

This study shows that it is possible to perform cognitive, neurologic, and psychometric testing in resource-poor settings, and it therefore may be important to invest in the capacity for outreach centers or health visitors to perform such testing for all children regardless of HIV status. Referral centers should also have the capacity to administer necessary interventions for those children who fall well below the acceptable values of these measures. These measures, however, will necessitate an increase in the budget allocated to the health and education sectors by the government.

None of the children in the initial or long-term cohort, including these survivors, had received ARVT. Their long-term survival may reflect children who had low HIV viral loads throughout infancy and their early years or possibly a different strain of the virus. Their survival and ability to perform satisfactorily in school and other activities is hopeful and should stimulate ministries of health and education to anticipate and plan for the large numbers of similar children now attending school throughout the world. The observation of significantly more ill health and failure of growth development of these children, however, reflects their compromised immunity. This ill health and poor growth may influence these children’s capacity to attend school regularly and to participate in physical and social activities that their noninfected peers enjoy. Thus, interventions that improve HIV-infected children’s chances of survival as well as their health status are a priority. To achieve this, the health system should put in place the capacity for these children (and their HIV-infected parents) to be identified as early as possible (possibly within the framework of ongoing PMTCT-PLUS programs) and for them to have easy access to ARVT and other nutritional and biomedical interventions that help prevent and/or treat the common opportunistic infections that they encounter. At the present time, ~12% of pregnant Ugandan women who attend the antenatal clinics at Mulago Hospital test positive for HIV-1. In those mothers and infants who receive nevirapine, the rate of HIV-1 transmission is substantially reduced from the ~25% that we observed during this study to ~12% to 14%.1,30,31 Nonetheless, nevirapine is not yet available to all pregnant women in Uganda. Currently, through various initiatives of the study clinic with other collaborating partners, 700 children have been on ARVT since 2002. The President’s Emergency Plan for AIDS Relief and the Joint United Nations Programme on HIV/AIDS Global Fund, which only began in 2005, aim to assist the clinic in getting to 1000 antiretrovirals by the end of 2005.

In Uganda, as is the case in many other developing areas of the world, many women are HIV-1–infected without awareness of their status or the status of their infants. It is likely that the majority of schoolchildren with HIV-1 infection acquired in the perinatal period are not identified. To benefit from these potential interventions, there is an urgent need for the development of feasible mechanisms for their identification. Routine HIV testing of schoolchildren in countries in which HIV is prevalent is expensive may encounter resistance in communities and would also require the availability of counselors and health professionals. Plans to expand ARVT in developing countries must include these considerations.

It is important to continue research to determine the factors that determine the long-term survival of these HIV-infected children in the hope that potential interventions that ensure that a larger number of infected children stay alive and experience the full potential of their noninfected peers and also determine the role of advancing HIV disease on the neurodevelopmental measures. Some of this research is currently been undertaken by our pediatric HIV/AIDS clinic.

Limitations of this study include the lack of recent information about caretaking and types of schooling available to children who were followed. Although we confirmed the continuing presence of HIV infection in these children, we did not have resources to test the children for CD4 or HIV viral loads or to relate this information to the psychometric testing. Also, the failure of this study to attempt HIV clinical staging resulting from the lack of a sufficiently reliable pediatric HIV-staging clinical algorithm appropriate for a population with a multitude of background infections poses a limitation in terms of relating this information to the psychometric testing and to comparison with other populations. Another limitation is the relatively low power to detect what may be clinically important small differences in group scores attributable to the small sample size (from a statistical perspective) of HIV-1–infected children available for long-term follow-up as well as the very rare occurrence of cognitive and neurologic abnormalities in this group.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This long-term prospective study of HIV-infected Ugandan children who were followed from birth found that they did not show evidence of significant differences in neurologic, motor, and psychometric development when compared with seroreverter children or with HIV-negative children who were born to HIV-negative mothers.

We recommend the following: (1) create awareness among teachers, child health professionals, and ministries of health and education that children such as those reported here do survive and with normal cognitive capacities; (2) put into place support interventions in other centers similar to those in our study clinic; (3) create additional provision for a free education and/or financial support program; (4) consider mechanisms at the health center level for neurodevelopmental testing for all HIV-infected (if not all) children; (5) provide for early HIV testing (eg, through Prevention of Mother-to-Child Transmission [PMTCT]), access to antiretrovirals, and care of opportunistic infections and nutritional support for children and family members); (6) provide a mechanism for the identification of perinatally infected children who were not identified earlier and that exist in the population who would benefit from recommendations 1 through 5; and (7) perform additional research with respect to (a) factors that determine the long-term survival of these HIV-infected children, (b) the role of advancing HIV disease on the neurodevelopmental measures, and (c) how these children progress to adulthood.


   FOOTNOTES
 
Accepted Jul 13, 2005.

Address correspondence to Karen Olness, MD, Rainbow Babies & Children’s Hospital, 11100 Euclid Ave, MS #6038, Cleveland, OH 44106. E-mail: kno{at}cwru.edu

Financial Disclosure: this work was supported by a research grant through Health Frontiers, Kenyon, Minnesota.

Portions of these findings were presented by Drs Nassali, Sherman, Kalyesubula, and Olness at the annual meeting of the Pediatric Academic Society; April 28 to May 1, 2001; Baltimore, MD.


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 RESULTS
 DISCUSSION
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