Published online February 1, 2005
PEDIATRICS Vol. 115 No. 2 February 2005, pp. 380-387 (doi:10.1542/peds.2004-1108)
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Human Immunodeficiency Virus...

Neuropsychological Functioning and Viral Load in Stable Antiretroviral Therapy-Experienced HIV-Infected Children

Rita J. Jeremy, PhD*, Soyeon Kim, ScD{ddagger}, Molly Nozyce, PhD§, Sharon Nachman, MD||, Kenneth McIntosh, MD, Stephen I. Pelton, MD#, Ram Yogev, MD**, Andrew Wiznia, MD{ddagger}{ddagger}, George M. Johnson, MD§§, Paul Krogstad, MD||||, Kenneth Stanley, PhD{ddagger} for the Pediatric AIDS Clinical Trials Group (PACTG) 338 & 377 Study Teams

* Pediatric Clinical Research Center, Department of Pediatrics, School of Medicine, University of California, San Francisco, California
{ddagger} Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
§ Neurodevelopmental Service, Jacobi Medical Center, Bronx, New York
|| Department of Pediatrics, State University of New York Health Science Center, Stony Brook, New York
Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
# Boston Medical Center, Boston, Massachusetts
** Children's Memorial Hospital and Northwestern University School of Medicine, Chicago, Illinois
{ddagger}{ddagger} Department of Pediatrics, Jacobi Medical Center and Albert Einstein College of Medicine, Bronx, New York
§§ Pediatric Infectious Diseases, Medical University of South Carolina, Charleston, South Carolina
|||| Departments of Pediatrics and Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen.

Methods. Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load.

Results. Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA ≤400 copies/mL) still showed poorer neuropsychological functioning compared with established norms.

Conclusion. Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Key Words: HIV • child • neuropsychological tests • cognitive science • neurologic examination • behavior • antiretroviral agents • protease inhibitors

Abbreviations: CNS, central nervous system • NP, neuropsychological • ZDV, zidovudine • ddI, didanosine • PI, protease inhibitor • PACTG, Pediatric AIDS Clinical Trials Group • CDC, Centers for Disease Control and Prevention • NRTI, nucleoside reverse transcriptase inhibitor • 3TC, lamivudine • d4T, stavudine • RTV, ritonavir • NVP, nevirapine • NFV, nelfinavir • MDI, Mental Development Index • FSIQ, Full Scale Intelligence Quotient • STM, Short-Term Memory • CI, confidence interval

Developmental delays and neurologic complications, such as encephalopathy, have been identified in children who are infected with HIV since the earliest descriptions of the disease.1–19 HIV infects a variety of cell types in the brain, leading to damage of the central nervous system (CNS).20 Measures of cognitive, neurologic, and behavioral functioning, referred to jointly as neuropsychological (NP) functioning, serve as indirect measures to assess CNS functioning along with more direct measures such as computed tomography and magnetic resonance imaging scans. The pathogenesis of NP deficits in children with HIV is difficult to ascertain because these deficits may be associated with factors other than HIV infection, such as prenatal drug exposure, low level of maternal education, discordant mother-child interaction, changes in caregivers, and poverty.21–31

Some improvement in cognitive abilities was observed in children who were administered continuous parenteral zidovudine (ZDV),32,33 but improvements were not seen with oral administration of this agent.34 Subsequently, a study of 831 infants and children found that the combination ZDV/didanosine (ddI) was more effective for improvement of NP functioning in HIV-infected children than ZDV or ddI alone.35,36 This study also reported that the impact of antiretroviral drugs on the CNS differed from their overall clinical effects, as either ddI alone or ddI/ZDV treatment was equally effective in terms of lengthening the time to first clinical endpoint or death.

Before the development of antiretroviral drugs, many children who were infected with HIV died during infancy. The recent development of highly active antiretroviral therapy has dramatically prolonged the survival of HIV-infected children,37,38 thereby increasing the number of these children who enter adolescence and eventually adulthood. As HIV disease has moved from being a fatal to a chronic illness, cognitive, neurologic, and behavioral functioning of HIV-infected children has become a major concern.

To date, no large studies of NP functioning have been reported in children who receive antiretroviral treatment regimens that contain a protease inhibitor (PI). Pediatric AIDS Clinical Trials Group (PACTG) 338 was the first large study to investigate the role of PI-containing combination therapy in children with HIV disease.39 We have combined data from PACTG 338 and its companion study, PACTG 377,40,41 to determine the effectiveness of these regimens on NP measures and to assess the association of NP measures and viral load.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
PACTG 338 was a multicenter, randomized Phase II clinical trial that enrolled 297 children at 48 sites between February 6 and April 30, 1997. All patients had HIV infection, were 24 months to 17 years of age, had Centers for Disease Control and Prevention (CDC) immune category 1 or 2 disease, had experienced no new CDC clinical category C diagnosis in the previous 12 months, had not previously received PIs, and had been receiving continuous nucleoside reverse transcriptase (NRTI) antiretroviral therapy for the 16 weeks before study entry. Children were randomly assigned to receive either ZDV/lamivudine (3TC) (100 children), stavudine (d4T)/ritonavir (RTV) (97 children), or ZDV/3TC/RTV (100 children). At study week 12, 12% of the children in the ZDV/3TC group had undetectable HIV RNA levels (≤400 copies/mL) as compared with 52% and 54% in the 2- and 3-drug PI-containing treatment groups (P < .001) (see Nachman et al39 for additional information). Children who failed in the ZDV/3TC group with HIV RNA ≥10000 copies/mL were offered a switch to a PI-containing treatment combination as step 2 of this study, which was accepted by 46 children between their 7th and 12th months after initial study entry (see Yogev et al42 for additional information).

PACTG 377 used the same study design, sites, and similar subject entry criteria, except that the age range was extended to enroll children who were as young as 4 months. From December 29, 1997, to September 30, 1998, PACTG 377 randomly assigned 193 children to receive d4T/nevirapine (NVP)/RTV (41 children), d4T/3TC/nelfinavir (NFV) (63 children), d4T/NVP/NFV (44 children), or the 4-drug combination d4T/3TC/NVP/NFV (44 children). After 48 weeks of therapy, between 30% and 52% of the children on these 4 treatment arms had RNA suppression to ≤400 copies/mL (see Wiznia et al40 and Krogstad et al41 for additional information).

Although the primary objective of both of these clinical trials was to evaluate the safety, tolerability, and antiviral activity of these 7 regimens, a secondary objective of both studies was to evaluate NP response to treatment and to assess whether there was an association between changes in viral load and NP functioning. Both clinical trials had been reviewed by institutional review boards at all participating sites, and written informed consent was obtained from all patients, or their parents, or legal guardians.

NP Measures
NP testing was conducted by psychologists, neurologic examinations were conducted by clinicians, and behavior was evaluated by the caregiver who accompanied a child to the study visit. Most often the caregiver was the mother or foster mother. No one was blinded to the HIV status of the child. Although the study treatments were open label, the psychologists did not know which drug regimen the child was receiving.

Cognitive (All Children)
Children were examined on age-appropriate cognitive tests. As indicators of the overall cognitive functioning, we used the Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd Edition43 for ages up to 42 months and the Full Scale Intelligence Quotient (FSIQ) of the Wechsler intelligence tests for the older ages: the Wechsler Preschool and Primary Scales of Intelligence-Revised44 for ages 3.5 to 6 years; the Wechsler Intelligence Scale for Children, 3rd Edition45 for ages 6 to 17 years; and the Wechsler Adult Intelligence Scale, 3rd edition46 for those 17 years of age and older. The MDI and the FSIQ scores are standardized with a mean of 100 and an SD of 15. As children grew older, they were transitioned to the next age-appropriate test. However, when a child could not reach basal performance level on the age-appropriate test, a lower-level test was administered (eg, substituting the Bayley Scales of Infant Development, 2nd Edition, for the Wechsler Preschool and Primary Scales of Intelligence-Revised). For performance on the Bayley examination that was lower than the lowest score of 50, we assigned a score of 49.47 Scores were not corrected for gestational age. Children were examined at entry and on a study-specified age-dependent schedule thereafter. Children up to 3.5 years (42 months) of age were tested every 24 weeks; ages 3.5 to 6 years, every 24 weeks in the PACTG 338 study and every 48 weeks in the PACTG 377 study; and from the age of 6 years, every 48 weeks.

Short-Term Memory (PACTG 377 Only; From Age 3.5 Years)
As an indicator of short-term memory, we used the Short-Term Memory (STM) Area Standard Age Score of the Stanford-Binet Intelligence Scale, Fourth Edition.48 It has a mean of 100 and an SD of 16. For children 3.5 to <6 years, the Area score is based on 2 of the 4 STM subtests—Bead Memory and Memory for Sentences—and for older children on all 4 subtests, including Memory for Digits and Memory for Objects. From the age of 3.5 years, the STM task was administered every 24 weeks.

Vocabulary (PACTG 377 Only; From 6 Years of Age)
As an indicator of verbal skills, we used the Vocabulary subtest Standard Age Score of the Verbal Reasoning Area of the Stanford-Binet Intelligence Scale, Fourth Edition.48 It has a mean of 100 and an SD of 16. This subtest was administered to children from the age of 6 years every 24 weeks.

Fine Motor (PACTG 377 Only; From Age 3.5 Years)
As an indicator of fine-motor dexterity, we used the peg-insertion task of the Purdue Pegboard (Lafayette Instrument Co, Lafayette, IN). Children inserted thin 1-inch pegs into 2 vertical rows of holes, with right, left, and both hands, each trial for 30 seconds. Their scores were compared with 2 sets of norms, either of younger children, aged 2.5 to <6 years,49 or of older children, aged 5 to <16 years.50 The scores were converted into z scores with a mean of 0 and an SD of 1. This test was administered to children from the age of 3.5 years, every 24 weeks, but we present data only for children 5 years and older.

Behavioral (All Children From 3 Years of Age)
As an indicator of problematic behavior, we used the Conners' Parent Rating Scales.51 Parents or guardians rated the children on 48 descriptors of behavior that yielded 6 scores of problematic behavior: conduct problems, learning problems, psychosomatic symptoms, impulsivity-hyperactivity, anxiety, and a more general hyperactivity index, which has some of the items from the conduct, learning, and impulsivity-hyperactivity scales. Higher scores indicate more problematic behavior. Each of the 6 scales has a T score mean of 50 and an SD of 10. This measure was completed by parents or guardians of children from the age of 3 years every 24 weeks.

Neurologic (All Children)
Neurologic examinations were performed at study entry and as clinically indicated by loss of developmental milestones or neurologic or behavioral changes. As an indicator of problematic neurologic functioning, we used the presence of any neurologic symptoms or diagnoses, such as microencephaly, peripheral neuropathy, or hypertonia.

Viral Load
Plasma HIV-1 RNA was measured using Roche Amplicor Monitor Assay for PACTG 338 and using the NucliSens assay for PACTG 377 by laboratories that participated in the National Institute of Allergy and Infectious Diseases Virology Quality Assurance Program. Both assays have a lower limit of detection of 400 copies/mL (see Nachman et al39 and Krogstad et al41 for additional information).

Statistical Methods
NP results were not available for all children as a result of noninclusion of some measures in 1 of the 2 studies, child age outside the required range, missed tests, or invalid test results. Cognitive scores for 2% of the children were declared invalid primarily because of language barriers or uncooperative behavior. Fewer than 1% of the short-term memory and vocabulary measures were declared invalid.

NP scores were compared with means of the normative populations on which the tests were standardized using a 1-sample t test. Cognitive, STM, and vocabulary scores were compared with 100, fine-motor z scores were compared with 0, and behavior T scores were compared with 50. We quantify differences in the mean NP scores of this group of children compared with the means of the normative population using SDs from the means of the latter group.

The baseline HIV-1 RNA value for each patient was defined to be the geometric mean of the preentry and entry RNA values. An HIV-1 RNA assay result was categorized as less than the level of quantification (undetectable) when the result was ≤400 copies/mL. A child was said to have shown a viral response at week 48 when the child achieved an undetectable level of HIV-1 RNA at week 24 and maintained it through week 48 while staying on the initial drug treatment regimen.

Children who were assigned to the PACTG 338 treatment arm without a PI (the ZDV/3TC arm) were excluded from the analysis of week 48 data because of the inferior suppression of HIV-1 RNA on that arm and the subsequent transfer of some patients to the step 2 PI-containing combination regimen. A follow-up period of 48 weeks was selected for this analysis because of a sharp reduction in the number of patients who were followed beyond week 48. This sharp reduction was attributable to a delay in the initiation of a study extension and a reluctance of some study participants to continue on their assigned treatment as new combination therapies became available. Of the 489 children who initiated treatment, 86% were still on study at week 48.

When baseline HIV-1 RNA was analyzed as a continuous variable, it was first transformed to the log scale. Pearson’s coefficient of correlation was used to quantify the association between baseline viral load and NP measures. Associations involving NP measures were adjusted using ANCOVA to take into account tests or test transitions (cognitive only) as a result of aging of the children (eg, from Bayley at baseline to Wechsler at week 48), baseline NP score (week 48 only), baseline log-RNA (week 48 only), previous antiretroviral treatment, CD4%, CDC clinical classification, age, English language, and race/ethnicity (cognitive only).

All P values were 2 sided and were not adjusted for multiple comparisons. Because of the multiple NP measures evaluated in this analysis and the potential for false-positive results, caution should be exercised in the interpretation of P values, especially those of borderline significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population
Baseline characteristics of the 489 children from PACTG 338 and PACTG 377 are presented in Table 1. The median age of this group was 6.8 years, 46% were male, the majority (54%) were black non-Hispanic, 49% had previously received ZDV/ddI combination therapy, the median CD4 cell count/µL was 690, and the median plasma HIV-1 RNA copy number/mL was 17400.


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  		TABLE 1. Patient Characteristics at Study Entry

 
There was no difference between these 2 studies with respect to gender and CD4 cell count. PACTG 338 did not accept entry of children who were younger than 2 years, whereas 11% of the 192 children who entered PACTG 377 were younger than 2 years. At baseline, the median viral load was greater for PACTG 377 (24300 vs 13500 copies/mL; P < .001), attributable, in part, to the younger children permitted to enter PACTG 377. More children had received previous therapy with ZDV/ddI before entry onto PACTG 377 (58% vs 43%; P < .001). PACTG 338 enrolled proportionally fewer black children than did PACTG 377 (48% vs 64%; P = .004). Spanish was reported as the child's primary language for 102 (21%) of the children; 46 from mainland sites and 56 from Puerto Rico sites. At the Puerto Rico sites, testing was conducted in Spanish, so only 46 (9%) children were examined in their nonprimary language.

NP Functioning at Baseline
Table 2 gives the baseline mean values for the NP measures and reports the comparison of these with the means of national standardized samples of American children. Although each child had received 16 or more weeks of previous antiretroviral treatment, they showed significantly poorer skills on all of the administered NP performance measures, and their behavior was judged more problematic compared with established norms for their age. The mean cognitive (MDI or FSIQ), short-term memory, and vocabulary scores were ~1 SD (SD of the normative population) below those of established normative population means (all P < .001). The mean cognitive score was 83.5; only 13% were above the mean of 100, whereas 16% were 2 SD or more below the average. The children showed poorer hand dexterity than the norms for their age, with mean z scores between –1.01 and –0.81 (all P < .001).


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  		TABLE 2. NP Measures and Viral Load at Baseline

 
The children's behavior at baseline as rated by their parents or guardians was more problematic than established norms on 5 of the 6 scales (P < 0.001–0.004). Only the ratings on the Anxiety scale did not differ significantly from the norms.

Of the 473 children who had a neurologic examination at baseline, 63 (13%) had at least 1 abnormal neurologic symptom or diagnosis (a total of 88 different diagnoses). There are no established norms with which to compare these neurologic findings. The most frequently reported diagnoses were microencephaly (<5th percentile for gender and age; 16% of 88), hypertonic diplegia/diparesis (13%), and attention-deficit/hyperactivity disorder (10%). There were no significant differences in NP scores between PACTG 338 and 377 or among the 7 treatments at baseline.

Relationship Between NP Functioning and Viral Load at Baseline
Generally, a higher baseline viral load was correlated with poorer cognitive and fine-motor scores (see Table 2). There was no significant correlation between ratings of behavioral functioning and baseline viral load (all estimated correlation coefficients were ≤0.10). The difference in frequency of neurologic diagnoses for children with baseline viral load ≤50000 versus >50000 was not statistically significant (11.7% of 349 children vs 17.7% of 124 children; P = .092, {chi}2 test).

NP Functioning After Treatment With a PI
Treatment with a PI-containing regimen for 48 weeks did not show a significant positive effect on any of the NP measures, except for the vocabulary score (P = .043; see Table 3). For the vocabulary score, the degree of improvement was minimal and the mean score was still significantly lower than the established norm (P = .045). At week 48, the cognitive, short-term memory, vocabulary, and fine-motor score means were still between one third and 1 full SD below the norms for their age. For all of the NP measures, baseline scores were significant predictors of later NP outcomes even when adjusted for covariates.


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  		TABLE 3. NP Measures and Viral Load After Treatment

 
There were no significant differences among the 6 PI-containing treatment regimens with respect to changes in NP functioning from baseline to week 48 (data not shown), except for hand dexterity for the nonpreferred hand. However, the most likely explanation for the finding that nonpreferred hand dexterity was poorer for the ritonavir-containing treatment combination group (d4T/NVP/RTV) when compared with the other 2 treatment groups of PACTG 377 (P = .012) would be a false-positive result as a result of the multiple treatment group comparisons conducted.

Children who were already showing an abnormal neurologic diagnosis at baseline were more likely to develop new neurologic symptoms over the next 48 weeks than those who did not show any neurologic abnormalities at entry; those without any neurologic diagnoses at entry rarely received a diagnosis of any new neurologic problems by week 48. Of the 374 children who had a follow-up neurologic examination, 18 (5%; 95% confidence interval: 3%–8%) were identified with a new neurologic diagnosis by week 48: 2 of 325 of those without any diagnosis at baseline and 16 of 49 of those with at least 1 diagnosis at baseline (P < .001, Fisher’s exact test).

Viral Response and NP Functioning
It was hypothesized that the greatest improvement in NP functioning at week 48 would be seen for the children with the best virologic response. Approximately 44% of the children achieved and maintained a level of viral load below the limit of detection (≤400 copies/mL) from week 24 to 48 while staying on their initial treatment. The NP score means for this group of children are given in Table 3. However, the NP mean scores for this group did not show any clear improvement when compared with the overall results observed at week 48. All NP score means for the group of children with good viral load response at week 48 remained poorer than the means of established norms, many at a statistically significant level.

Predictive models were also used to investigate potential associations between changes in viral load and NP functioning (data not shown). We found that NP performance at baseline did not help predict virologic control through week 48 and that viral response 24 weeks after initiating PI-containing combination treatment was generally not a significant predictor of NP functioning at week 48.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
PACTG 338 was the first clinical treatment trial to introduce a PI as part of antiretroviral treatment of children who were infected with HIV. This trial and its subsequent companion study, PACTG 377, demonstrated high rates of suppression of viremia in clinically and immunologically stable children who were pretreated with antiretrovirals in the NRTI class. The PI combination therapies used in these studies were so effective that it was no longer feasible to use clinical outcomes such as time to an AIDS-defining event or survival for evaluation. Few AIDS-defining events and no deaths have been observed to date for the nearly 500 children who entered either PACTG 338 or 377. Instead, these and subsequent investigations have used the suppression of HIV-1 RNA to assess efficacy and thus have relegated clinical outcomes, including NP functioning assessments, to secondary roles.

Studies of HIV-infected children have consistently shown that they perform more poorly on tests of NP functioning. Our results corroborate these observations. We found that HIV-1-infected children showed poorer NP functioning compared with established norms for their age in virtually every domain that we studied, even after at least 16 weeks of previous antiretroviral treatment.

We found that higher viral load at baseline was associated with poorer cognitive and fine-motor functioning. However, baseline viral load was not significantly related to behavioral ratings by parents or guardians.

Although 48 weeks of PI combination therapy had dramatic virologic impact on the HIV-infected children, its effect on NP functioning was minimal. A statistically significant improvement was seen only for vocabulary scores of the Stanford-Binet. Score means for cognitive, short-term memory, vocabulary, and fine-motor scales still remained one third and 1 full SD poorer than the established norms for the general population of children. Our study showed less of an improvement in NP scores than PACTG 152, the earlier large study that had reported a modest but statistically significant improvement in cognitive performance with effective antiretroviral treatment.36 Perhaps 1 year is not a sufficiently long period of time for NP improvements to become large enough to be detected, or perhaps the NP damage occurs very early and is not easily corrected. It is important to look at long-term outcomes because changes in NP functioning may be slow to manifest themselves and plasma HIV-1 RNA is likely to be an incomplete surrogate for NP outcomes.

We did not find clear evidence of a difference among the 6 PI-containing treatment combinations with respect to NP functioning at 48 weeks. This may be attributable in part to the minor viral suppression differences that were observed among these PI-containing treatments. In contrast, PACTG 152 found that different drug treatments showed differential effects on NP outcomes.36

Direct comparisons of our findings with earlier published reports of NP functioning in HIV-infected children are difficult to make because earlier studies did not use PI combination therapies and they measured effectiveness using clinical endpoints such as time to disease progression or death rather than change in viral load, as used in current investigations. Differences between our results and the PACTG 152 results may also be attributable to the patient populations studied. PACTG 152 entered younger children (median: 2.2 years) and required patients to have <6 weeks of previous antiretroviral therapy, whereas our 2 studies required 16 or more weeks of therapy, clinically and immunologically stable disease, and no previous PI treatment.

Unlike the PACTG 152 trial52 and the Women and Infants Transmission Study,53 we did not find that baseline NP scores helped to predict the later course of HIV illness using viral load as a surrogate marker. PACTG 152 found that FSIQ at baseline helped to predict the time to disease progression or death, and FSIQ at week 48 added to such prediction beyond the prediction from the baseline biological markers of HIV and CD4 counts. The Women and Infants Transmission Study found that Bayley Scales MDI and Psychomotor Development Index scores in early infancy helped to predict mortality independent of other biological markers of HIV illness.

Because drug trials for HIV infection cannot recruit uninfected children of HIV-infected women, we did not have a direct comparison group to control for environmental factors. Environmental factors such as prenatal drug exposure, low level of maternal education, discordant mother-child interaction, changes in caregivers, and poverty are likely to affect children adversely, HIV infected or not. Thus, our study has inherent unavoidable limitations that must be considered in interpreting the data. Indirect information on this issue is available from PACTG 219 that reported NP functioning of 209 uninfected children who were born to HIV-infected women.54 Among other findings, this study showed that from early to late infancy, average cognitive scores declined from ~0.5 SD above to ~0.5 SD below the norms for the general population and by preschool age had declined to ~1 SD below the norms. This suggests a potential mounting detrimental effect of environment on cognitive development of children who are born to HIV-infected mothers, infected or not, starting in infancy. Still, in our study, HIV infection remained an additional detrimental factor; we found that already at baseline, higher viral load was significantly related to poorer cognitive performance. An additional limitation of our study is related to the natural variation associated with 6 different PI-containing treatment regimens, ~50 sites, and a wide range in ages, from 4 months to 17 years. Although detailed analyses of outcomes by specific treatment and age group or site were not feasible, our large group of uniformly treated and evaluated children with HIV disease permitted a more in-depth assessment of NP functioning than could be provided by a typical single-center study.

Until 1995, little or no antiretroviral therapy was routinely given to perinatally infected children immediately after birth. Consequently, unchecked viremia for an extended period during infancy was likely the major postnatal factor damaging these children's brain functioning, as suggested by the observed correlation between higher viral load and greater risk for encephalopathy.8 Even when initiated, early antiretroviral treatments were still not as effective in reducing viral load as have been the more recent PI-containing drug combinations. Effective drug combinations are now more likely to be initiated sooner after birth than before those studies. Consequently, with a more prompt reduction and lower maintained level of viral load in HIV-infected children, it is likely that the brain functioning of recently born perinatally infected children will be better preserved than it was in the past.

Our findings have important implications for the development of future strategies for antiretroviral treatment for HIV-infected children. We found that after at least 16 weeks of NRTI antiretroviral treatment (before starting PACTG 338 or 377 treatment), HIV-infected children showed significant deficits in their NP functioning. We also found that after 48 weeks of PI-containing combination therapy, which was effective in reducing the viral load to an undetectable level in ~44% of the children, there was still little or no improvement in NP functioning. It seems that although current antiretroviral therapy is effective in reducing viral load, it is relatively ineffective in remediating NP functioning, at least within a 1-year period. Therapeutic strategies that include not only suppression of viral load but also optimization of NP functioning need to be developed for HIV-infected children. Such strategies need to be based on improved understanding of the pathogenesis of NP dysfunction in HIV-infected children, including the contributions of direct HIV infection of the CNS as well as social and demographic risk factors. The provision of supportive services for young HIV-infected children and infants, such as special education, speech therapy, and counseling, may play a role in improvement of NP functioning. If NP dysfunction is primarily attributable to HIV infection, then modification of the initiation or the aggressiveness of currently available drugs or discovery of drugs that are more potent or have greater CNS efficacy may lead to treatment approaches in children that are different from those currently recommended for adults.


   ACKNOWLEDGMENTS
 
This work was supported by the Pediatric AIDS Clinical Trials Group 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), the Pediatric Clinical Research Center, University of California, San Francisco (funded by the National Center for Research Resources, 5 M01 RR-01271, US Public Health Service); Abbott Laboratories; Agouron Pharmaceuticals Inc; Boehringer-Ingelheim Pharmaceuticals, Inc; Bristol-Myers Squibb Company; and Glaxo-Wellcome, Inc. Dr Paul Krogstad is an Elizabeth Glaser Scientist of the Pediatric AIDS Foundation.

We thank the site staff for dedication and the children and their families for participating in the neuropsychological testing on these studies.


   FOOTNOTES
 
Accepted Jul 19, 2004.

Reprint requests to (R.J.J.) Pediatric Clinical Research Center, Department of Pediatrics, School of Medicine, University of California-San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0105. E-mail: jeremyr{at}peds.ucsf.edu

Conflict of interest: Drs Nachman, Pelton, Wiznia, and Yogev have served as ad hoc consultants or as speakers in programs sponsored by Abbott Laboratories, Agouron Pharmaceuticals Inc, Glaxo-Wellcome, or Bristol-Myers Squibb, pharmaceutical firms whose products were studied.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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