OBJECTIVE. The purpose of this research was to characterize behavioral and cognitive profiles of clinically and immunologically stable antiretroviral-experienced HIV-infected children.
METHODS. Two hundred seventy-four previously treated HIV-infected children aged 2 to 17 years were assessed for behavioral, developmental, and cognitive functioning. Correlations between neuropsychological measures, age, and CD4 lymphocyte count were investigated.
RESULTS. The most common behavioral problems, as measured by the Conners' Parent Rating Scale, were psychosomatic (28%), learning (25%), hyperactivity (20%), impulsive-hyperactive (19%), conduct (16%), and anxiety (8%) problems. Mean Wechsler Intelligence Scale for Children-III scores were less than established population norms; the mean verbal IQ was 85, the mean performance IQ was 90, and the mean full-scale score was 86. Hyperactivity was more frequent in children with a Wechsler Intelligence Scale for Children-III performance IQ of <90. Anxiety problems were more likely in children ≥9 years of age. Children with CD4 counts of <660 cells per mm3 were more likely to be identified as having a conduct disorder. No association was noted between behavioral problems and neuroimaging.
CONCLUSIONS. Clinically and immunologically stable HIV-infected children had more frequent behavioral problems and lower developmental and cognitive scores than established childhood norms.
- behavioral symptoms
- attention-deficit disorder with hyperactivity
- neuropsychological tests
- antiretroviral agents
Children with human immunodeficiency virus (HIV) infection are at high risk for developing neurologic and neurodevelopmental impairments.1–5 A variety of problems, including specific expressive and receptive language impairments and psychomotor delays, have been documented over time and are associated with the direct or indirect effect of HIV on the central nervous system.6–9 However, despite numerous studies documenting these neurodevelopmental deficits in children with HIV infection, the effect of HIV on specific behavioral issues is not well understood.
HIV-infected children frequently exhibit behaviors such as impulsivity, hyperactivity, and difficulties attending and focusing on stimuli. These behaviors are often associated with attention-deficit/hyperactivity disorder (ADHD). A variety of etiologies have been proposed as causes for these difficulties in HIV-infected children. Brain damage secondary to HIV infection is considered one of the principal determinants.10–13 Through neuroimaging techniques, there is now ample evidence of HIV involvement in the neurologic functioning of the frontal cortex, basal ganglia, and connecting structures in the central nervous system.14–22 These structures have been associated with regulation of attention and concentration and other regulatory behaviors that are problematic in children diagnosed with ADHD. Nevertheless, studying the factors associated with developmental and behavioral problems in HIV-infected children is complicated because of the influence of environmental factors such as prenatal drug exposure, difficult family situations, and poverty.23–26
To study behavioral problems in HIV-infected children, Pediatric AIDS Clinical Trials Group (PACTG) protocol 338, a multicenter treatment study of clinically and immunologically stable, previously treated HIV-infected children, included the Conners' Parent Rating Scale (CPRS) as part of a neurodevelopmental battery of tests. The CPRS, a widely used parental questionnaire, assesses various aspects of behavior including those associated with ADHD. Assessments performed at study entry regarding frequency of these behaviors and their relationship with cognition, immunologic, and neurologic functioning are reported here.
Study Design and Patients
PACTG protocol 338 was a multicenter, randomized clinical trial that compared change from current antiretroviral therapy to either zidovudine and lamivudine or 1 of 2 ritonavir-containing regimens (a 3-drug regimen of ritonavir, zidovudine, and lamivudine or a 2-drug regimen of ritonavir and stavudine) in HIV-infected, clinically and immunologically stable children. All of the subjects were aged 24 months to 17 years; had stable CD4 cell number or percentage maintained in Centers for Disease Control and Prevention immune category 1 or 2 during the 4 months before study entry; had experienced no new Centers for Disease Control and Prevention clinical category C diagnosis in the 12 months before study entry; received continuous antiretroviral therapy in the 16 weeks before study entry; and were either zidovudine- and lamivudine-naive or had received ≤6 weeks of zidovudine and lamivudine in the year before study entry and none in the 4 months before study entry.27 Exclusion criteria included current grade 3 or 4 clinical or laboratory toxicities; active opportunistic or serious bacterial infection; documented hypersensitivity to any of the therapies under study; prior protease inhibitor therapy; or current diagnosis of malignancy or pregnancy. Two hundred ninety-eight HIV-infected children from 48 clinical sites entered this study between February 6 and April 30, 1997 (see Nachman et al28 for additional information). Informed consent was obtained from all of the patients, their parents, or their legal guardians.
Age-appropriate, standardized behavioral and cognitive assessments were performed within 14 days before the start of therapy. Cognitive scores were obtained by using age-appropriate tests of developmental and intellectual functioning. All of the developmental and cognitive testing was administered by a psychologist at the clinical site. All of the testing was conducted in English.
Behavioral assessment used the CPRS for children aged 3 to 17 years.29 This behavioral assessment was completed by the primary caretaker. The CPRS characterizes patterns of a child's behavior and compares them with appropriate normative groups. It is a 48-item questionnaire that focuses on particular aspects of behavior and yields 6 factors: conduct problems, learning problems, psychosomatic problems, impulsive-hyperactive problems, anxiety problems, and hyperactivity. The primary caretaker responds to each question on a 4-point scale (not at all, just a little, pretty much, and very much). A score of ≥65 indicates a significant behavioral problem. Although the CPRS identifies specific behavioral problems, this single test should not be considered to provide a definitive behavioral diagnosis.
Developmental and Cognitive Assessments
The Bayley Scales of Infant Development II is a standardized developmental assessment that provides a mental development index and a psychomotor development index.30 The Wechsler Preschool and Primary Scales of Intelligence-Revised (WPPSI-R)31 and the Wechsler Intelligence Scale for Children-3rd edition (WISC-III)32 are standardized assessments of intelligence that provide 3 scores: verbal IQ, performance IQ, and full-scale score. Children from birth to 42 months were assessed by using the Bayley Scales of Infant Development II. Children >42 months to 5 years 11 months received the WPPSI-R, and children 6 to 16 years 11 months were assessed by using the WISC-III.
Children were evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) of the brain within 8 weeks before to 4 weeks after study entry by the participating site's neuroradiologist. Results were assessed locally by the neuroradiologist at each site.
Only patients with an available baseline CPRS evaluation were included in the analysis. Neuropsychological evaluation scores were compared with 100, the mean of the normative populations on which the tests were standardized, using a 1-sample t test. Groups were compared by Fisher's exact test for categorical variables and Wilcoxon test or a t test for continuous variables.33–35 Values of quantitative variables were divided into 4 subgroups of similar size for the purpose of investigating associations between variables. All of the P values were 2-sided and not adjusted for multiple comparisons.
Baseline Patient Characteristics
Of the 298 children enrolled in protocol 338, 1 child did not begin treatment, and 23 children did not have the baseline CPRS questionnaires completed, primarily because of the child being <3 years of age or language difficulties for the primary caregivers. Of the 274 children (92%) with a completed baseline CPRS questionnaire, the median age was 7.2 years, median CD4 cell count was 665 cells per mm3, and median plasma HIV-1 RNA was 22012 copies per mL (Table 1). The majority of the patients were either black (49%) or Hispanic (34%); 47% were male. Children in PACTG protocol 338 had received prior treatment with didanosine monotherapy (31%), other monotherapy (13%), the combination of zidovudine and didanosine (44%), or other combination therapy (13%).
Two children did not have a cognitive evaluation at baseline and were excluded from the cognitive data analysis. The mean indices and scores of the cognitive evaluations for the children with a valid baseline evaluation were all significantly less than the mean score of 100 in the general population (P < .001), although the SDs were close to the reference SD values (Table 1). Because of the small number of children <42 months of age (n = 11) with both a CPRS and a Bayley developmental score, these analyses were not included.
The average CPRS score (the sum of the scale scores to the 48 questions) was 28.4 at study entry. The CPRS was self-administered by a parent or guardian in 63% of the cases and was completed during a face-to-face interview or telephone interview in the remainder of the cases; 38% were completed by a biological parent. Of the 274 children, 16% were classified as having a conduct problem (scored ≥65), 25% were classified as having a learning problem, 28% were defined to be psychosomatic, 19% were defined to be impulsive-hyperactive, 8% were classified as having an anxiety problem, and 20% were classified as hyperactive (Table 2). Children may experience >1 behavioral problem; 52% were identified to have at least 1 behavioral problem.
Children >9 years of age were more likely to have an anxiety problem than younger children (16% vs 5%; P = .006; see Table 2). Conduct problems, learning problems, and hyperactivity were less likely for children who were living with their biological parent (P = .02, .02, and .04, respectively). Children with a CD4 count of <660 cells per mm3 were more likely to be identified as having a conduct problem than those with higher CD4 cell counts (22% vs 11%; P = .02). There were no statistically significant associations between behavioral problems and race/ethnicity, gender, weight/height adjusted for age and gender, and median HIV-1 RNA at baseline.
Association Between Behavioral and Cognitive Factors
The correlation between baseline neuropsychological evaluations and behavioral problems is shown in Table 3. Children with a higher WISC-III IQ score were significantly less likely to also have a learning problem or behaviors associated with ADHD as described by the CPRS. Hyperactivity was more frequent in children with a WISC-III performance IQ of <90 (31% vs 13%; P = .006).
Association Between Behavioral Problems and Neuroimaging
CT scans were performed on 236 children (91%), and MRI was performed on 22 different children (9%) at baseline. Fourteen children (7%) had basal ganglia/subcortical calcification, 6 (3%) had mild cortical atrophy (none had worse atrophy), 3 (1%) had white matter abnormalities, and 2 (1%) had focal mass lesions. There were no significant associations between these CT or MRI findings and any of the 6 behavior problems at baseline (data not shown).
The purpose of this evaluation was to characterize the baseline behavioral, developmental, and cognitive functioning of clinically and immunologically stable HIV-infected children who were treated previously with antiretroviral therapy and to attempt to correlate these findings with clinical data. Children on PACTG protocol 338 manifested significant behavioral and cognitive difficulties as assessed by the CPRS, WPPSI-R, and WISC-III. Behavioral manifestations included hyperactivity, impulsive and hyperactive behaviors, anxiety, and conduct problems. Cognitively, overall IQ scores were lower than the norm for the general population, and a significant number of the children were reported to have learning problems. The lower the cognitive scores, the greater the likelihood of a child being classified as having apparent learning problems or behaviors associated with ADHD. Children >9 years of age were more likely to have anxiety.
HIV-infected, clinically stable children seem to have significant behavioral problems when compared with the general, non–HIV-infected population. Particularly evident were behaviors most frequently associated with ADHD, such as hyperactivity and impulsivity. The prevalence rate for ADHD in the general population, according to the American Psychiatric Association, is 3% to 5%,36 whereas 20% of the children in the present cohort were identified as having behaviors associated with ADHD as described by the caregivers. This percentage is high even when compared with children with other types of chronic illnesses that have been found to increase the likelihood of behavioral problems. In a study by Gortmaker et al,37 children with chronic illnesses such as arthritis, asthma, cystic fibrosis, or diabetes were approximately one and a half times more likely to have behavioral problems than the general population. Our study found at least a fourfold increase, which may be attributable in part to the fact that children living in HIV-infected families have additional problems not often experienced by children with other chronic illnesses, such as poverty, social instability, a high incidence of illicit drug use, deaths of family members, and issues related to disclosure of HIV diagnosis. It is also of interest that Mellins et al38 found no higher incidence of behavioral problems in HIV-infected children than in HIV-exposed but uninfected children.
A high proportion of the families of HIV-infected children are in lower socioeconomic groups. Some studies have reported higher rates of ADHD-related behaviors in children living in lower socioeconomic settings when compared with those living in communities with higher socioeconomic conditions.39 However, other investigators have found only slight differences in the prevalence of hyperactivity across social class.40 It seems that social class, in and of itself,41 is not predictive of ADHD and, therefore, cannot fully explain the high rate of ADHD-type symptoms in the present population.
Prevalence rates of various behavioral disorders, including ADHD, have been found to differ by gender.40,42,43 Males are affected up to 5 times more frequently than females with a range of 2.5:1 to 5.1:1. In our study, no gender imbalance was observed for any of the behavioral parameters evaluated. Gender differences in behavioral and cognitive performance are frequently attributed to male/female differences in brain functioning. The effects of HIV infection on the brain seem not to be gender-specific.
Studies of non–HIV-infected children have established that behavioral impairments are found in one quarter to one half of children with significant learning problems.44,45 These behavioral problems include aggressive and oppositional behaviors, as well as ADHD. ADHD and learning problems are by far the most common comorbid diagnoses. According to our study, as well as previous studies, HIV-infected children have significantly more cognitive and neurodevelopmental impairments than children in the general population.46 In addition, our study found a clear association of lower cognitive scores with learning difficulties and behaviors that may be related to ADHD, particularly hyperactivity. The lowered cognitive functioning with corresponding learning problems in this cohort may contribute to the high preponderance of children with behavioral manifestations. Although an association between low cognitive scores and learning difficulties was not unexpected, it was surprising that the rates of learning problems were not higher than reported for children with low cognitive scores. This may be because of the fact that children with low cognitive scores are frequently provided with special classes or therapeutic services and are being taught at their academic level. When a child is taught at an appropriate level, he or she can learn and may no longer be seen by the caretaker as having learning problems. Although there is low correlation between results of the Bayley developmental score and the 2 Wechsler scales (WPPSI-R and WISC-III), there is high correlation between the 2 Wechsler scales (coefficients of correlation of 0.85, 0.73, and 0.85 for the verbal IQ, performance IQ, and full-scale score, respectively).32 We minimized the impact of the low correlation by reporting the Bayley results separately and only combined results from the Wechsler scales.
Anxiety was found to be associated with age in our study. High rates of anxiety observed for children >9 years of age could be related to the frustrations faced by children with learning difficulties. Their inability to cope with academic demands could certainly be a cause for anxiety. Furthermore, older HIV-infected children are more likely to know the relevance of their HIV status and have a mother or father who has succumbed to their HIV infection. Issues of disclosure and death may increase levels of anxiety and interfere with school performance.
Our study found that children living with their biological parent were less likely to be described as manifesting conduct or learning problems or hyperactivity. According to Rutter,47 the aggregate of adversity factors, rather than the presence of any single factor, leads to impaired development. Thus, it may be that children not living with their biological parent have been exposed to greater levels of adversity because of parental death, frequent morbidity, or exposure to a more dysfunctional lifestyle (or that the biological parents may be biased and report fewer problems for their children). This family-environment risk factor may be contributing to the higher reported levels of behavior problems in our study.
We did not find an association between behavior or cognitive functioning and degree of cortical atrophy, white matter abnormalities, focal mass lesions, or basal ganglia calcification to the extent that these abnormalities are measurable by CT and MRI evaluations. Children enrolled in PACTG protocol 338 were clinically stable and had no or only moderate immune suppression. Nevertheless, they displayed apparent cognitive, learning, and behavior difficulties that are generally thought to be more common in children with sicker health status. The fact that this analysis found no significant association between CD4 counts and apparent hyperactivity, psychosomatic, impulsive-hyperactive, and anxiety problems may imply that these types of behavioral impairments are not related to the severity of the illness but are present, to some degree, across all stages of HIV disease. Furthermore, because there were no apparent neurologic signs of deterioration, it may be that behavioral manifestations are common and present in the absence of neurologic symptoms. A potential explanation for the association between CD4 cell count and conduct problems is the likelihood that a child with a low CD4 cell count is less likely to be living with their biological parents. Advanced disease in the biological parents is likely to be associated with increased morbidity, hospitalization, or death, thus necessitating movement of the child to foster care or care by a member of their extended family. This is a difficult experience for a child and may trigger negative behaviors.
The etiology of behavioral abnormalities in HIV-infected children is likely to be multifactorial, including factors such as prenatal drug exposure, difficult family environment, level of maternal education, changes in caregivers, exposure to lead, nutrition, and poverty. Information on these factors was not available and could not be explored in this analysis. Nevertheless, comparison of our results versus the national norms gives a firm point of reference and provides a basis for additional exploration of this issue. Limitations of our study include the absence of a non–HIV-infected control group and the fact that we did not collect data concerning frequency of hospitalizations and time since disclosure of the HIV diagnosis.
Our study showed that clinically and immunologically stable previously treated HIV-infected children experienced more frequent behavioral problems and lower developmental and cognitive scores when compared with established childhood norms. Current clinical research primarily focuses on virologic and immunologic considerations to identify effective treatments in this patient population. As therapies improve and children live longer, studies such as ours will help raise awareness and promote the development of therapeutic interventions designed to improve learning and behavior in this population of children.
This work was supported in part by the PACTG of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development, National Institutes of Health, the Statistical and Data Management Center of the PACTG (National Institute of Allergy and Infectious Diseases cooperative agreement AI-41110), Abbott Laboratories, Agouron Pharmaceuticals Inc, Boehringer-Ingelheim Pharmaceuticals, Inc, the Bristol-Myers Squibb Company, and Glaxo-Wellcome, Inc.
PACTG protocol 338 team members included: Anita Ballow (Frontier Science and Technology Research Foundation, Amherst, NY); Stephen Spector, MD (University of California, San Diego, CA); Steve Douglas, MD (Children's Hospital of Philadelphia, Philadelphia, PA); William Borkowsky (New York University Medical Center, New York, NY); Lynette Purdue, PharmD (Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD); Bethany Griffin (Social Scientific Systems, Rockville, MD); Susan Fiscus, PhD (University of North Carolina School of Medicine, Chapel Hill, NC); Courtney V. Fletcher, PharmD (University of Colorado Health Sciences Center, Denver, CO); John Sleasman, MD (University of Florida College of Medicine, Gainesville, FL); Ross McKinney, MD (Duke University Medical Center, Durham, NC); Jeanne Berg and Becky Hoffman, MD (Abbott Laboratories, Abbott Park, IL); Maria Gigliotti and Patrick Robinson, MD (Boehringer-Ingelheim Pharmaceuticals, Ridgefield, CT); Laurie Reynolds and Vicki Rutkiewicz (Bristol-Myers Squibb Company, Wallingford, CT); Barbara Lane, RN (Glaxo-Wellcome, Research Triangle Park, NC); Bach-Yen Nguyen, MD, and Linda A. Hawe (Merck Research Laboratories, Blue Bell, PA); Kathleen Mohan, ARNP (Children's Hospital and Medical Center, Seattle, WA); Moraima Rivera (San Juan City Hospital, San Juan, Puerto Rico); and Virginia Parks (San Francisco, CA).
Individuals and institutions participating in the study included: Paul Palumbo, MD, Mary Jo Hoyt, RN, Arry Dieudonne, MD, and Jennis Hannah, PhD (University of Medicine and Dentistry of New Jersey Medical School, Newark, NJ); Joseph A. Church, MD (Childrens Hospital Los Angeles, Los Angeles, CA); Margaret A. Keller, MD, Nasser Redjal, MD, Ken Zangwill, MD, and ChrisAnna Mink, MD (Harbor General and UCLA Medical Center, Torrance, CA); Kathleen Malee, PhD, Amy Talsky, CPNP, and Lynn Heald, CPNP (Children's Memorial Hospital, Chicago, IL); James B. McAuley, MD (Rush University Medical Center, Chicago, IL); Jean Hurwitz, BSPharm, Megan Valentine, PA-C, Lori Ferguson, RN, and John Swetnam, MEd (Duke University Medical Center, Durham, NC); Elaine J. Abrams, MD, Maxine Frere, RN, Susan Champion, and Delia Calo, CCRC (Harlem Hospital Center, New York, NY); Edward Handelsman, MD, Jean Kaye, RN, Hamid Moallem, MD, and Denise Swindell (State University of New York Health Sciences Center, Brooklyn, NY); Kenneth C. Rich, MD, Karen Hayani, MD, Renee Smith, PhD, and Carolyn Everett, RN (University of Illinois, Chicago, IL); Coleen K. Cunningham, MD, Kathie A. Contello, PNP, Emily Barr, CPNP, and Maureen Famiglietti, BSN (State University of New York Health Science Center, Syracuse, NY); Lorraine Rubino, Silvia Muniz, and Michele Kelly (State University of New York Health Science Center, Stony Brook, NY); Mark Bagarazzi, MD, Harold Lischner, MD, Audrey Kamrin, MSN, and Kelly Hassey, MSN (St Christopher's Hospital for Children, Philadelphia, PA); Mahrukh Bamji, MD, Savita Manwani, MD, Indu Pathak, MD, and Santa Paul, MD (Metropolitan Hospital Center, New York, NY); Patricia Sirois, PhD, Margarita Silio, MD, Dawn Sokol, MD, and Cheryl Borne, RN (Tulane University Health Sciences Center, New Orleans, LA); Katherine Luzuriaga, MD, and Dorothy Smith, NP, University of Massachusetts Medical School, Worcester, MA); and MariPat Toye, RN, Barbara W. Stechenberg, MD, Donna J. Fisher, MD, and Alicia M. Johnston, MD (Baystate Medical Center, Springfield, MA).
We thank the children, their parents and guardians, and the site staff for participating in this investigation. We also thank Kay Malee, PhD, for critical review of the manuscript and thoughtful comments.
- Accepted July 19, 2005.
- Address correspondence to Molly L. Nozyce, PhD, Neurodevelopmental Service Jacob Medical Center, 1400 Pelham Pkwy South, Bronx, NY 10461. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
Ms Lee's current address is Biogen, Boston, MA 02142.
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