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Neurodevelopmental Functioning in HIV-Infected Infants and Young Children Before and After the Introduction of Protease Inhibitor–Based Highly Active Antiretroviral Therapy

^a Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
^b Chicago Children's Memorial Hospital, Northwestern University, Chicago, Illinois
^c Center for Mental Health Research on AIDS, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. The purpose of this work was to examine the effects of HIV infection and the impact of highly active antiretroviral treatment with protease inhibitors on neurodevelopmental functioning during the first 3 years of life.

PATIENTS AND METHODS. Pediatric AIDS Clinical Trials Group 219/219C is a longitudinal cohort study that has enrolled HIV-infected (HIV⁺) and HIV-exposed but uninfected (HIV^–) infants and children since 1993. Longitudinal profiles of neurodevelopmental functioning as measured by the Bayley Scales of Infant Development were compared by HIV-infection status before and after the availability of highly active antiretroviral therapy with a protease inhibitor and within infants with Bayley tests available before and after initiating protease inhibitor therapy.

RESULTS. In the pre–protease inhibitor era, mean mental and motor scores in HIV⁺ (n = 54) infants <1 year of age were significantly lower than those among HIV^– infants (n = 221) and remained lower up to 2 years of age. After protease inhibitors became available, mean mental and motor functioning of HIV⁺ infants (n = 91) <1 year of age were still significantly lower than those of HIV^– infants (n = 838). However, against a background of declining scores among the HIV^– infants, there was evidence of limited improvement in the HIV⁺ infants relative to their uninfected peers. Among infants who had Bayley II evaluations before and after starting a protease inhibitor, there was a trend to improved mental and motor scores after initiation of protease inhibitor therapy.

CONCLUSIONS. The suppression of systemic viral replication and subsequent substantial improvements in survival and immunologic status brought about by highly active antiretroviral therapy have been followed by limited improvements in neurodevelopmental functioning in young children. Additional longitudinal research is needed to better understand the role of antiretroviral therapy as well as the impact of genetic and environmental factors on neurodevelopmental functioning in children affected by HIV.

Key Words: HIV • neurodevelopmental functioning • cohort study

Abbreviations: CNS—central nervous system • HIV⁺—HIV-infected • HAART—highly active antiretroviral therapy • PI—protease inhibitor • HIV^–—HIV-exposed but uninfected • PACTG—Pediatric AIDS Clinical Trials Group • ART—antiretroviral therapy • B-I—Bayley Scales of Infant Development • B-II—Bayley Scales of Infant Development, Second Edition • CDC—Centers for Disease Control and Prevention • GEE—generalized estimating equation • NRTI—nucleotide reverse transcriptase inhibitor

Infection with HIV is associated with an increased risk for central nervous system (CNS) disease, primarily because of HIV infection in the brain.^1–3 Early in the epidemic, 50% to 90% of children with HIV infection exhibited severe and often progressive CNS manifestations,^4,5 reflected in deficits in cognitive, language, motor, and behavioral functioning.⁶ In the absence of treatment, the greatest risk for HIV-associated encephalopathy occurs during the first year of life and may be the initial AIDS-defining symptom,^7,8 but CNS manifestations of HIV may also first present years later.^9,10

Recent investigations have suggested a reduced prevalence of encephalopathy in HIV-infected (HIV⁺) children.^7,8,11 However the differential impact of factors responsible for this decline remains unclear. Use of highly active antiretroviral therapy (HAART) in children has dramatically improved survival,¹² immunologic status,¹³ and growth.^14,15 Suppression of systemic viral replication may reduce the number of HIV-infected cells entering the CNS and potentially reduce the incidence of severe CNS damage. However, many antiretroviral agents, including some protease inhibitors (PIs), are not equivalent in their ability to penetrate the blood brain barrier,^16,17 which may allow the CNS to serve as a reservoir for latently infectious virus.¹⁸ Since HAART became available, a proportional increase in the AIDS dementia complex compared with other AIDS-defining illnesses has been observed in HIV⁺ adults.¹⁹ Therefore, HAART may have less impact on HIV-related CNS dysfunction²⁰ and neurodevelopmental functioning.²¹ A recent small case series described significant cognitive decline among children treated with HAART in the context of immunologic, virologic, and clinical stability.²²

The purpose of this investigation was to examine the effects of HIV infection on neurodevelopmental functioning during the first 3 years of life and to evaluate the impact of PI-containing HAART regimens. We report on neurodevelopmental functioning of HIV-exposed but uninfected (HIV^–) and HIV⁺ infants and young children, regardless of treatment regimen, before and after PIs became available. We also examine the within-subject effects of initiation of a PI before 3 years of age.

	METHODS

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Study Design
These analyses used data from Pediatric AIDS Clinical Trials Group (PACTG) Late Outcomes Protocol 219/219C. This prospective cohort study, which opened to accrual in 1993, was designed to assess long-term outcomes of in utero exposure to HIV and antiretroviral drugs in infants and children, as well as the long-term effects of antiretroviral therapy (ART) among children with HIV infection.^12–14,23 Until 2000, only children enrolled in PACTG clinical trials or children born to HIV-infected mothers enrolled in PACTG or Adult AIDS Clinical Trials Group trials were eligible. In 2000, eligibility criteria for PACTG 219 were expanded (PACTG 219C) to include all perinatally exposed infants and HIV⁺ children, regardless of previous participation in a clinical trial. Human subject research review boards at participating sites in the United States, including Puerto Rico, approved the research protocol. Before enrollment, written informed consent was obtained from participants' parents or legal guardians.

Developmental Measures
The Bayley Scales of Infant Development²⁴ (B-I) and the Bayley Scales of Infant Development, Second Edition,²⁵ (B-II) were used to assess the developmental functioning of infants. The B-I was used in PACTG 219 predominantly in the pre-PI era, before 1997, and can be administered to infants and children 1 month and 24 days of age to 30 months and 15 days. PACTG 219 transitioned to the B-II starting in March of 1996, and its use continued in PACTG 219C. The B-II can be administered to infants and children 16 days of age to 42 months and 15 days. As sites transitioned to using the B-II, they were encouraged to continue using the B-I test in infants who had already completed a B-I test to avoid test transition effects. Tests were administered at entry to the study and then every 6 months until 2 years of age and, for the B-II, at 3 years. Only tests completed by infants within the age limits of the test were included in our analyses.

Results from both Bayley tests were recorded as raw scores and then transformed using the normative tables in the manuals to age-adjusted scaled scores with no adjustment for prematurity. Each test is standardized to have a mean of 100 and SD of 16 (B-I) and 15 (B-II). Mental development and psychomotor development indices were obtained at each testing occasion. When infants obtained raw scores too low to derive a scaled score, the lowest possible scaled score minus 1 (ie, 49) was imputed. This is a common technique for addressing floor effects²⁶ but may result in overestimation of a child's performance. Also, if the administering neuropsychologist indicated that the child was unable to complete the test under standardized test conditions, a value of 49 was imputed. Such tests were included because they have been found to be predictive of HIV disease progression.²⁷

Patient Populations
Three cohorts of perinatally exposed infants were identified. Cohort I included infants born between October 1992 and June 1997 (when the first PACTG study using a PI started enrollment) having 1 B-I evaluation before 1 year of age and was used to compare the profiles of HIV^– and HIV⁺ infants before HAART with PIs became available. Any evaluations completed after a child started PIs were excluded. Cohort II included infants born after June 1997 having 1 B-II evaluation before 1 year of age. This cohort was used to describe and compare profiles of HIV⁺ (regardless of actual treatment regimen) and HIV^– infants in the era of PI-based HAART and included follow-up until October 2005. Cohort III included infants having 1 B-II evaluation before and 1 after they started PIs (before or after 1 year of age and regardless of date of birth). Some infants in cohort III were also part of cohort II.

Sociodemographic, Health, and ART Covariates
Sociodemographic variables included age, gender, and race/ethnicity. Birth characteristics included birth weight, maternal history of intravenous drug use, and any maternal ART use. Primary caregiver and maximum years of schooling completed by the primary caregiver were used as surrogates for family status and socioeconomic status, respectively. CD4 lymphocyte percentage (<25% or 25%) and Centers for Disease Control and Prevention (CDC) disease category at the time of the first Bayley evaluation were used to characterize HIV health status. HIV-1 RNA levels were not collected in PACTG 219 before 2000 and, thus, were not included in this analysis. As a surrogate for general health, ratings (0%–100%) were calculated from 3 scales measuring overall health, physical, and emotional well-being. The number of stressful life events since the previous study visit (0–9: caregiver lost job, family member left home, loss of housing, entitlement or health insurance, family member hospitalized or very sick, change in caregiver, death in the family) was used as a surrogate for general well-being.²⁸ Using an intent-to-treat approach, subjects were classified as being on PI-based HAART after their first exposure to PIs, regardless of subsequent treatment changes.

Statistical Methods
The response variable was the Bayley scaled score, grouped into 6-month age intervals 24 months and at 36 months using the protocol-specified testing schedule: 6 (lower age limit of test to 9 months), 12 (>9 to 15 months), 18 (>15 to 21 months), 24 (>21 to 30 months), and 36 (>30 to 42 months). Fisher's exact tests and t tests were used for univariate comparisons of categorical and continuous variables. Random-effects models fitting separate intercepts and slopes to each subject's scaled scores were used to compare profiles between HIV^– and HIV⁺ infants adjusting for other covariates.²⁹ To test for changes in slopes before and after the initiation of PIs in cohort III, a random-effects model with a change point was used.³⁰ Generalized estimating equations (GEEs) were used to compare proportions of HIV⁺ and HIV^– infants with significant mental or motor delays (scaled scores <70) as they aged.³¹ To assess the influence of potentially informative missingness patterns, analyses were replicated using only observed results and then using the last observed value carried forward to missing time points. Because conclusions were similar, only results using the observed data are presented.

	RESULTS

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Patient Populations
Cohort I included 275 (221 HIV^– and 54 HIV⁺) infants, and cohort II included 929 (838 HIV^– and 91 HIV⁺) infants. There were a further 656 (558 HIV^– and 98 HIV⁺) infants enrolled in PACTG 219/219C before 1 year of age who did not have the necessary B-I or B-II test before 1 year of age for inclusion in cohorts I or II. To assess whether those included in the 2 cohorts were different from those not included, we compared sociodemographic characteristics, birth characteristics, and health variables at entry to PACTG 219/219C. The variables that differed significantly were the proportion of mothers with a history of IV drug use (9% among those in cohort I/II vs 14%; P < .01) and, among the HIV⁺ subjects, higher CD4 percentage (means of 46% vs 31%; P = .03).

Cohort I: Cognitive Functioning in HIV^– and HIV⁺ Infants and Young Children 2 Years of Age in the Pre-PI Era
Subject Characteristics
Characteristics of infants in cohort I at the time of their first B-I test are shown in Table 1. HIV^– infants were younger than the HIV⁺ infants (mean of 6.7 months vs 7.6 months; P = .03). Their mothers had higher rates of ART use during pregnancy (79% vs 48% of known; P < .01) and lower rates of previous IV drug use (11% vs 25% of known; P = .02). HIV^– infants were also more likely to be born after January 1, 1995, reflecting the increased use of ART and the success of zidovudine to reduce mother-to-child transmission.³² Significantly more HIV^– subjects had birth weights 2500 g than HIV⁺ infants (91% vs 67%; P < .01). More HIV^– infants were living with a biological parent (96% of known vs 83%; P < .01), and they had higher mean health ratings (89% vs 73%; P < .01) and CD4 percentages (46% vs 31%; P < .01).

Both mental (P = .04) and motor (P = .06) scores of HIV⁺ infants were positively correlated with CD4 percentages. Mean mental scores for infants with CD4 percentages <15%, 15% to 25%, and 25% were 66, 79, and 90, and mean motor scores were 53, 78, and 82. Mean mental scores were also associated with CDC disease category (A [93], B [79], and C [76]; P = .05). Mean motor scores by CDC disease category were 85, 73, and 69 (P = .17).

Comparison of Trajectories of B-I Scores 2 Years of Age
Data completeness at the upper age limit of the B-I is shown in Table 3. Up until the last B-I test, 7 (13%) of the HIV⁺ infants and young children had received no antiretroviral treatment, 45 (83%) had taken only nucleoside reverse transcriptase inhibitors (NRTIs) and 2 (4%) had taken NRTIs and non-NRTIs.

View larger version (11K): [in this window] [in a new window]   FIGURE 1 A, Cohort I: mean B-I mental scaled scores according to age. B, Cohort I: mean B-I motor scaled scores according to age. The bars show 95% confidence intervals. The dashed lines show the HIV+ cohort divided into 2 groups, defined by the infants’ CD4 percentages measured at the time of first test before 1 year of age.

Cohort II: Cognitive Functioning in HIV^– and HIV⁺ Infants and Young Children 3 Years of Age in the PI Era

Comparison of Trajectories of B-II Scaled Scores 3 Years of Age

Figure 2 A and B and Table 6 show mean (95% confidence intervals) scaled scores by age and HIV status. Numbers of tests in each age group and the percentage of mental floor scores are shown in Table 4. At 6 months, the HIV⁺ infants had significantly lower mean mental and motor scores than the HIV^– infants regardless of immunologic status (CD4 percentage < or 25%). By 24 and 36 months, these differences were no longer statistically significant. Random-effects models showed that mental scores declined at a significantly greater rate in the HIV^– infants (–6.2 [SE: 0.4] points per year) than the HIV⁺ infants (–3.2 [SE: 1.0] points per year; P = .01). The same pattern was observed for motor scores, with the HIV^– infants and young children changing by an average of –1.4 (SE: 0.4) points per year, whereas the HIV⁺ infants and young children showed improvements of 1.3 (SE: 1.2) points per year (P = .03). Models were then fit including 2-way interactions of the study under which the infant had enrolled (219 or 219C), each sociodemographic, birth characteristic, and health covariate with age. Although the statistical significance of the effect of HIV status on the rates of change varied, the direction was consistent (HIV⁺ infants improved relative to HIV^– infants over time), and the effect remained at least marginally significant (P .07). As with mental score models, the trend for motor scores by HIV status was consistently for the HIV⁺ infants and young children to improve relative to the HIV^– infants and young children with statistical significance for this effect ranging from P = .04 to P = .15. There was no evidence that any of these factors were affecting the rates of change differently in the HIV⁺ or HIV^– infants.

View larger version (12K): [in this window] [in a new window]   FIGURE 2 A, Cohort II: mean B-II mental scaled scores according to age. B, Cohort II: mean B-II motor scaled scores according to age. The bars show 95% confidence intervals. The dashed lines show the HIV+ cohort divided into 2 groups, defined by the infants’ CD4 percentages measured at the time of first test before 1 year of age.

Random-effects models were fit to compare slopes in mental and motor scores before and after PIs. Before starting a PI, mental scores declined an average of –8.4 (SE: 1.8) points per year (P < .01; reference rate of decline in HIV^– infants was –6.2 [SE: 0.4] points per year from cohort II), and after starting PIs, this rate of decline was significantly reduced to –1.1 (SE: 2.2) points per year (P = .02). A similar trend for motor scores was observed. The average rate of decline before starting a PI was –3.1 (SE: 2.1) points per year, and after starting, there was a mean increase of ⁺0.7 (SE: 2.5) points per year, but the difference was not significant (P = .26). Sensitivity analyses using the sociodemographic and health covariates did not influence these findings.

	DISCUSSION

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The use of HAART for HIV⁺ children has reduced mortality and morbidity during recent years. The efficacy of HAART with respect to distal outcomes, such as neurodevelopmental functioning, has not been well described, despite the fact that HAART is now a standard of care in pediatric HIV infection. The results of this investigation are consistent with investigations during the pre-HAART era that identified compromised mental and motor functioning among infants with HIV infection.^33,34 The results also extend our understanding of the effects of PI-based HAART showing a positive but limited impact on neurodevelopmental trajectories and the rate of significant cognitive and motor impairment in HIV⁺ infants and young children during the first 3 years of life, despite substantial effects on survival¹² and immunologic status.¹³ This limited positive effect of HAART may be partly because infants and young children with compromised CNS now survive the more severe early manifestations of the disease but may have persistent neurobehavioral difficulties.³⁵

The observed differences in neurodevelopment between HIV⁺ and HIV^– infants in cohort I may be related to genetic, health, disease, treatment, and/or psychosocial factors. For example, HIV^– infants were significantly more likely than HIV⁺ infants to have been exposed to ART in utero and to weigh more at birth. They were less likely to have mothers with a history of IV drug use and more likely to live with a biological parent. HIV⁺ infants, on the other hand, had lower mean health ratings and CD4 percentages, notwithstanding ART that may have been provided during infancy. Infants with immune suppression (CD4 percentages <25%) seemed to be most vulnerable with respect to neurodevelopmental functioning, demonstrating mental and motor scores lower than those of the HIV^– infants, as well as HIV⁺ infants with less immune suppression (CD4 percentages 25%). As Tardieu³⁶ suggests, these very young children may experience a specific form of HIV-associated CNS disease related to prenatal HIV infection of the brain. Similar results have been shown in a recent study comparing McCarthy Scales of Children's Abilities neurodevelopmental scores for HIV⁺ children with and without an early AIDS-defining illness and HIV-exposed but uninfected children aged 3 to 7 years.³⁵ It is worth noting that the difference between HIV⁺ and HIV^– infants was already present in all of the cohorts at the earliest measurement point, before 1 year of age. This finding is similar to the results from Llorente et al,³⁷ who found significant developmental differences at 4 months of age that were predictive of survival and also illustrated the significant neurobehavioral effects of HIV in the prenatal and early postnatal period.

Both HIV^– and HIV⁺ infants and young children in cohort I displayed a negative developmental trajectory, with indices declining at similar rates from birth to 2 years of age. These results may reflect the relative detrimental impact of genetic susceptibility³⁸ and a psychosocial environment often characterized by poverty and other risk factors known to influence cognitive development^39,40 and often observed in HIV-affected families. Declines of similar magnitude on the Bayley over the first years of life have been reported for non–HIV-affected groups from comparable socioeconomic backgrounds.^41,42

HAART has a substantial impact on the immunologic status of HIV⁺ children.¹³ In our study, HIV⁺ infants in cohort II had higher mean CD4 percentages at 6 months relative to those in cohort I and their CD4 percentages improved relative to the natural rate of decline in HIV^– infants and young children 3 years of age (data not shown). This group also showed limited but positive trends in neurodevelopmental functioning relative to their HIV^– peers, both in analyses looking at changes in test scores and in the proportion of infants with severe impairment, about which we may be cautiously optimistic. Initial differences in mental functioning between HIV^– and HIV⁺ infants in the post-PI era (cohort II) diminished with age, reflecting the more positive trajectory in scores in HIV⁺ versus HIV^– infants and the small improvement in the trajectories before and after starting a PI in cohort III. The trends over age in cohort II were observed in the context of gradually declining mental and motor scores in HIV^– infants and young children, as also observed among infants in cohort I. Again, the impact of poverty and other psychosocial factors on neurodevelopmental functioning is powerful and must continue to be considered as we attempt to understand the role of HAART in the health and development of children with HIV infection.

There are a number of limitations to this analysis, including the confounding in calendar time of the transition from the B-I to B-II in the parent study, which occurred as PIs were introduced in children. "Transforming" scores from 1 neurodevelopmental test onto an updated version is not feasible in this population because many infants score well below the normed mean of 100, and there are no published data on the differences in test scores at the lower end of the scale. We cannot, therefore, directly compare scores in cohorts I and II. However, we believe the within-subject changes in scores over time may be comparable in the 2 test versions. In the HIV^– infants and young children, the rate of decline in mental scores was –6.4 (SE 1.1) points per year on the B-I and –6.2 (0.4) points per year on the B-II, but only in cohort II were the rates of decline smaller in the HIV⁺ infants and young children, providing evidence that neurodevelopmental status was better in the post-PI era. In addition, the scores obtained by infants on the B-I, published in 1969, may be subject to the Flynn effect, which is the systematic increase in intelligence quotient scores that causes test norms to become obsolete over time.^43,44 B-II results likely provide a more valid assessment of the developmental status of infants and young children in cohort II, because they are based on recently updated norms from a contemporary sample.

With the small number of HIV⁺ infants in cohort III, we used a simple classification of starting PI-based HAART, not allowing for variability in treatment regimens and switches over time. This "intent-to-treat" approach is not unrealistic, however, because once infants start PIs, in general they stay on PIs, albeit with occasional interruptions. Our ability to observe the true effects of PIs on cognitive scores may also have been reduced because of confounding by indication, in which newer treatments are accessed first by children with more advanced disease and reduced potential for normal development, thus underestimating the effect of starting a PI-based HAART.

Another potential limitation concerns selection effects if test scores were more likely to be missing because the infants were neurologically impaired. To enter the analysis cohorts, neurodevelopmental evaluation with a Bayley scale was required at 1 year of age. If impaired infants were more likely not to have a test administered, the cohorts would not be representative of the broader PACTG 219/219C population. There was some evidence that this was the case, because those in cohorts I and II had higher mean CD4 percentages and a lower proportion of mothers with a history of intravenous drug use than those not evaluated. There were also missing test results at the upper age limits of the scales. Reasons included loss to follow-up from the study, not having a test in the required window, and transitioning to the next age-appropriate test. If HIV⁺ infants with more advanced impairment or HIV^– infants with normal functioning were more likely to be lost to follow-up, miss visits, or be more or less likely to be evaluated with the test aimed at younger infants, then the trajectories we observed over the first 3 years are likely to be biased. There was some evidence that the higher-functioning infants and young children were more likely to move on to the next age-appropriate test at the test transition ages (results not shown). However, we repeated the analyses imputing the last nonmissing score at each testing window for infants lost to follow-up (not including those who transitioned to the next age-appropriate test), and qualitatively the results did not change. Additional but unmeasurable factors, such as use of early intervention services and the effects of repeated testing using the same instrument, were not controlled for and may have affected the results. However, practice effects may be less likely when developmental testing is completed with infants and young children, because item sets vary according to the age of the child.

Finally, the random-effects models were fit using the imputed value of 49 for the floor scores, potentially violating the assumptions of normality. Because the results from the GEE analyses were consistent with the analyses using the continuous data, we do not believe that the imputed scores greatly influenced the results.

	CONCLUSIONS

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The etiology and natural history of neurodevelopmental impairments associated with HIV infection in young children remain difficult to identify and predict, because neurodevelopment in these children is determined by the interaction of multiple genetic, health, disease, treatment, and psychosocial factors that may vary in their impact during infancy and childhood. Further analyses focusing on the impact of maternal risk factors and ARV use with this cohort would be of interest. However, this study provides evidence of limited beneficial effects of PI-based HAART on neurodevelopment in the first years of life. The effects of HAART may become more apparent as the children reach school age and beyond and as differential and characteristic patterns of strengths and weakness in domains of development are identified. Results observed in our investigation necessarily require confirmation and elaboration in other studies.

	ACKNOWLEDGMENTS

 
This work was supported by the Statistical and Data Analysis Center of the PACTG at the Harvard School of Public Health under the National Institute of Allergy and Infectious Diseases cooperative agreement 5U01 AI41110, the National Institute of Child Health and Human Development, and the National Institute of Mental Health.

The following institutions were involved in the design, data collection, and conduct of PACTG 219C but were not involved in the present analysis, the interpretation of the data, the writing of the article, or the decision to submit the article for publication: Baylor Texas Children's Hospital: F. Minglana, M.E. Paul, and C.D. Jackson; University of Florida, Jacksonville: M.H. Rathore, A. Alvarez, M. Scites, and M. Tucker; San Juan City Hospital: M. Acevedo, M. Gonzalez, L. Fabregas, and M.E. Texidor; Chicago Children's Memorial Hospital: R. Yogev, E. Chadwick, and A. Talsky; University of Puerto Rico, University Children's Hospital AIDS Program: I. Febo-Rodriguez, L. Lugo, R. Santos, and I. Sallabarria; Bronx Lebanon Hospital Center: M. Purswani, S. Hagmann, and E. Stuard; University of Miami: G.B. Scott, C.D. Mitchell, L. Taybo, and S. Willumsen; University of Medicine and Dentistry of New Jersey: S. Adubato, L. Bettica, J. Johnson, and P. Palumbo; University of California San Diego Mother, Child and Adolescent HIV Program: S.A. Spector, R. Viani, M. Caffery, and L. Proctor; Children's Hospital at State University of New York Downstate: E. Handelsman, H.J. Moallem, D.M. Swindell, and S. Bewley; New York University School of Medicine/Bellevue Hospital: W. Borkowsky, S. Chandwani, N. Deygoo, and S. Akleh; Charity Hospital of New Orleans and Earl K. Long Early Intervention Clinic: M. Silio, T. Alchediak, C. Boe, and M. Cowie; Children's Hospital Boston: S. Burchett and N. Karthas; Children's Hospital of Michigan: E. Moore and C. Cromer; St Christopher's Hospital for Children, Philadelphia: J. Chen, J. Foster, D. Conway, and R. Laguerre; Howard University: S. Rana, P.H. Yu, H. Finke, and S.B. Wilson; Los Angeles County Medical Center/University of Southern California: J. Homans, M. Neely, L.S. Spencer, and A. Kovacs; St Jude Children's Research Hospital, Memphis: P.M. Flynn, N. Patel, K. Knapp, and P. Garvie; Baystate Medical Center Children's Hospital: B.W. Stechenberg, D.J. Fisher, S. McQuiston, and M. Toye; Jacobi Medical Center: M. Donovan, R. Serrano, M. Burey, and R. Auguste; Columbia Presbyterian Medical Center and Cornell University New York Presbyterian Hospital: A. Higgins, M. Foca, P. LaRussa, and C. Mellins; University of California San Francisco, Moffitt Hospital: D. Wara, D. Trevithick, R. Jeremy, and N. Tilton; University of Massachusetts Medical School: K. Luzuriaga and D. Smith; Children's Hospital of Philadelphia: R.M. Rutstein, C.A. Vincent, S.D. Douglas, and G.A. Koutsoubis; Johns Hopkins University, Pediatrics: N. Hutton, B. Griffith, S. Marvin, and A. Anderson; Children's Hospital of Oakland: A. Petru, T. Courville, R. Jeremy, and K. Gold; Children's Hospital, University of Colorado, Denver: R. McEvoy, J. Maes, M. Abzug, and E. Barr; North Broward Hospital District: A. Puga; Boston Medical Center: S.I. Pelton and A.M. Reagan; Duke University: F. Wiley, K. Whitfield, O. Johnson, and R. Dizney; Harlem Hospital: S. Champion, M. Frere, and E.J. Abrams; Schneider Children's Hospital: V.R. Bonagura, S.J. Schuval, and C. Colter; University of Alabama at Birmingham: R. Pass, M. Crain, N. Beatty, and H. Charlton; State University of New York Stony Brook: S. Nachman, D. Ferraro, S. Madjar, and M. Kelly; University of Illinois: K.C. Rich, K. Hayani, and M. Bicchinella; University of Maryland Medical Center: V. Tepper, K. Peery, C. Hilyard, and K. Klipner; Metropolitan Hospital Center: M. Bamji, I. Pathak, S. Manwani, and E. Patel; Children's Hospital and Regional Medical Center, Washington: M. Acker, A. Melvin, C. McLellan, and K. Mohan; Children's National Medical Center: H. Spiegel and V. Amos; Ramon Ruiz Arnau University Hospital: W. Figueroa and E. Reyes; University of North Carolina at Chapel Hill: T. Belhorn, B. Pitkin, and J. Eddleman; Children's Medical Center of Dallas; Connecticut Children's Medical Center: J. Salazar, G. Karas, L. Wells, and T. George; University of South Alabama: M. Mancao; University of Chicago Children’s Hospital; Cook County Hospital: J.B. McAuley, K.M. Boyer, M. Haak, and N. Mourikes; Children's Hospital at Albany Medical Center: A.D. Fernandez, P.A. Hughes, N. Wade, and M.E. Adams; State University of New York Upstate Medical University: L.B. Weiner, K.A. Contello, W.A. Holz, and M.J. Famiglietti; University of Florida at Gainesville: R.M. Lawrence, J.F. Lew, C. Delaney, and C. Duff; University of Rochester Medical Center: G.A. Weinberg, F. Gigliotti, B. Murante, and S. Laverty; Mount Sinai Medical Center: D. Johnson, D. Kowalski, and B. Wolfe; Public Health Unit of Palm Beach County: J. Sleasman and C. Delaney; Children's Hospital and Medical Center, Seattle; Yale University School of Medicine: W.A. Andiman, S. Romano, L. Hurst, and D. Schroeder; St Josephs Hospital and Medical Center, Patterson: N. Hutchcon and A. Townley; Harbor-University of California Los Angeles Medical Center: M. Keller, C. Mink, S. Wettgen, and N. Redjal; Long Beach Memorial: A. Deveikis, L. Melton, S. Marks, and K. Elkins; Children's Hospital of Los Angeles: J. Church and T. Dunaway; Lincoln Medical and Mental Health Center; Medical College of Georgia: C.S. Mani; Phoenix Children's Hospital: J.P. Piatt, J. Foti, and L. Clarke-Steffen; Robert Wood Johnson Medical School: S. Gaur, P. Whitley-Williams, A. Malhotra, and L. Cerracchio; Vanderbilt University Medical Center: G. Wilson; University of Mississippi Medical Center: H. Gay and S. Sadler; Emory University Hospital: S. Nesheim and R. Dennis; Columbus Children's Hospital: M. Brady, J. Hunkler, and K. Koranyi; University of South Florida: P. Emmanuel, J. Lujan-Zilberman, C. Graisberry, and S. Moore; Children's Hospital of the King's Daughters: R.G. Fisher, V. Van de Water, T.T. Rubio, and D. Sandifer; Incarnation Children's Center, New York: A. Gershon and P. Miller; Medical University of South Carolina: G.M. Johnson and A. Hutto; San Francisco General Hospital: D. Wara, A. Kamrin, and S. Farrales; Mt Sinai Children's Hospital: M. Dolan, J. D'Agostino, and R. Posada; Beth Israel Medical Center; Medical College of Virginia: S.R. Lavoie and T.Y. Smith; The Medical Center, Pediatric, Columbus: C. Mani and S. Cobb; Children's Hospital of Los Angeles: A. Kovacs and E. Operskalski; Cooper Hospital-University Medical Center: A. Feingold and S. Burrows-Clark; Sacred Heart Children's Medical Services of Florida: W. Albritton; St Luke's/Roosevelt Hospital Center: R. Warford and S. Arpadi; University of Cincinnati: J. Mrus, R. Beiting, and N. Boosveld; North Shore University Hospital: S. Pahwa and L. Rodriquez; Westchester Hospital; Metropolitan Hospital; Montefiore Medical-Albert Einstein College of Medicine: A. Rubinstein and G. Krienik; Cedar's/Sinai Medical Center; Case Western/Rainbow Babies & Children's Hospital; Hermann Hospital; Lincoln Hospital; King's County Hospital Center; St Louis Children's Hospital: K.A. McGann, L. Pickering, and G.A. Storch; Georgetown University Hospital; Oregon Health and Science University: P. Lewis and R. Croteau.

We thank the children and their families, the study team, and the individuals and institutions involved in the conduct of PACTG 219C for contributing to this research.

	FOOTNOTES

 
Accepted Sep 28, 2006.

Address correspondence to Kathleen M. Malee, PhD, Chicago Children's Memorial Hospital, Northwestern University, 2300 Children's Plaza, Box 155, Chicago, IL 60614. E-mail: kmalee{at}childrensmemorial.org

The views expressed in this article do not necessarily represent the views of the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, or the US government.

Part of these data were presented at the XVI International AIDS Conference; August 14, 2006; Toronto, Ontario, Canada (abstract MOAB0301).

Financial Disclosure: During the course of the study, Dr Hughes received grant support from Roche and has had honoraria or consultancies with Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Chiron, Roche, and Tibotec. These companies all manufacture antiretroviral drugs or other therapy for HIV infection.

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