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Treatment-Mediated Changes in Human Immunodeficiency Virus (HIV) Type 1 RNA and CD4 Cell Counts as Predictors of Weight Growth Failure, Cognitive Decline, and Survival in HIV-Infected Children

  1. Jane C. Lindsey1,
  2. Michael D. Hughes2,
  3. Ross E. McKinney4,
  4. Mary K. Cowles5,
  5. Janet A. Englund6,7,a,
  6. Carol J. Baker6,7,
  7. Sandra K. Burchett3,
  8. Mark W. Kline7,
  9. Andrea Kovacs8 and
  10. Jack Moye9
  1. 1Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
  2. 2Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
  3. 3Children's Hospital, Harvard Medical School, Boston, Massachusetts
  4. 4Pediatric AIDS Clinical Trials Unit, Duke University Medical Center, Durham, North Carolina
  5. 5Department of Statistics and Actuarial Science, University of Iowa, Iowa City
  6. 6Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas
  7. 7Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  8. 8Maternal Child Program, University of Southern California Medical Center, Los Angeles
  9. 9National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland
  1. Reprints or correspondence: Dr. J. C. Lindsey, Center for Biostatistics in AIDS Research, Harvard School of Public Health, 651 Huntington Ave., Boston, MA 02115 (lindsey{at}sdac.harvard.edu).

  1. Presented in part: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2000 (abstract N32e).

  • ↵a Present affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois.

 
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Abstract

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression—HIV-1 RNA level, CD4 cell count, and CD4 percentage—for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.

The value of human immunodeficiency virus (HIV) type 1 RNA levels and CD4 cell counts as prognostic markers for progression to AIDS or death is clearly established in HIV—infected adults in natural history studies [1, 2] and clinical trials [3, 4]. Unlike adults, who are developmentally stable and in whom changes in immunologic status are predominantly caused by the HIV infection, children experience changes in growth and in central nervous system (CNS) and immune function. Disease progression manifests itself differently in children, and markers of immunologic function [5], virus load [6], and rates of disease progression [7] are associated with age. This often makes it inappropriate to extrapolate findings in adult studies to children. Cohort studies in HIV-infected infants and children [6, 8] have reported the predictive value of HIV-1 RNA levels, CD4 cell counts, and CD4 percentages on disease progression (defined as incidence of a new Centers for Disease Control and Prevention category C diagnosis [9] or death). However, there has been limited study of the association between treatment-mediated changes in these parameters and disease progression in children. One study reported the prognostic value of these predictors at baseline and after 24 weeks of therapy on a composite clinical outcome (weight growth failure, neurologic/neuropsychologic decline, development of significant new HIV-related diagnoses, and death [10, 11]). Mofenson et al. [12] described the effect of treatment-mediated changes in CD4 percentage and HIV-1 RNA level on survival.

We report the results of a meta-analysis of studies of the Pediatric AIDS Clinical Trials Group (PACTG), undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in HIV-1 RNA levels, CD4 cell counts, and CD4 percentages on weight growth failure, cognitive decline, and survival in children. Although the drug combinations used in these studies did not include protease inhibitors, nucleoside reverse-transcriptase inhibitors (NRTIs) are the backbone of current highly active antiretroviral combinations and may be useful in countries with no or limited access to protease inhibitors. Our results provide important information concerning the association between treatment-mediated virologic and immunologic marker changes and disease progression in children, how these associations vary with age, and how they might differ from results in HIV-1—infected adults. Our findings may be useful in designing future clinical trials and for the management of HIV-infected infants and children.

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Methods

Studies and evaluations

Studies eligible for inclusion in the meta-analysis (PACTG 152 [7], PACTG 239 [13], PACTG 240 [14], PACTG 245 [15], and PACTG 300 [16]) were randomized clinical trials of NRTIs and the nonnucleoside RTI (NNRTI) drug nevirapine, conducted by the PACTG. All studies had ⩾24 weeks of follow-up and HIV-1 RNA measurements in at least some children before the start of therapy and after 24 weeks of study. Lymphocyte subsets were measured at baseline and at 24 weeks. Weights were measured every 4 weeks, and cognitive test scores were recorded at age-appropriate intervals (every 24 weeks in children <30 months old and at least every year in older children).

The focus of the analysis was on baseline and week 24 marker values. The baseline value was the marker measurement closest to and within 30 days before the start of study treatment. Because of the variation in clinic visits in different studies, the week 24 measurement was defined as the value closest to week 24 within a window of time between 16 and 32 weeks after the start of treatment. Only children with HIV-1 RNA levels and CD4 cell counts at both baseline and week 24 were included in the analysis. Children also had to have started ⩾1 new agent to which they had never been previously exposed. If a subject participated in >1 of the 5 studies, data from the first enrollment were used. Although different assays for quantifying HIV-1 RNA levels were used, the same assay was used for all measurements within each study; thus, stratifying the analyses by study controlled for this source of variation. Values below the limit of quantification of an assay were replaced by the limit. Only 3% of values were below the limit, so this practice had minimal effect on the results.

Outcome measurements

Because the definition of disease progression varied between studies, 3 end points with objective definitions were used. The first was death occurring >24 weeks after the initiation of study antiretroviral therapy. Weight growth failure, which could only occur >32 weeks after initiation of treatment, was defined as the third of 3 consecutive 6-month weight growth velocities less than the third percentile for age and sex [17], with weight at the third time point less than the 10th percentile for age and sex. Cognitive decline, which could occur >24 weeks after baseline, was defined as a decline in scaled score >30 points within the Bayley I [18] or II [19] tests; a decline in scaled score >30 points from a Bayley I or II to any other test; a decline in scaled score >15 points from any previous McCarthy [20], Wechsler preschool and primary scale of intelligence [21], Wechsler intelligence scale for children, third edition [22], or Wechsler intelligence scale for children, revised [23]; or no increase in raw score from the previously administered test of the same type for >12 weeks for the Bayley or McCarthy tests. Weight growth failure and cognitive decline are part of the composite clinical end points used in PACTG trials and have similar definitions to those used in ongoing trials.

Statistical methods

Analysis of variance, adjusting for study, was used to compare baseline, week 24, and changes from baseline to week 24 marker levels, by age group [24]. To assess the prognostic value of the markers, proportional hazards models [25] were used to evaluate associations between marker levels and time from the week 24 HIV-1 RNA measurement to each clinical end point. HIV-1 RNA levels and CD4 cell counts were analyzed as continuous variables on the base 10 logarithmic (log10) scale because this gave good satisfaction of the assumptions required for the proportional hazards models. All models were stratified by treatment and study. This allows the hazard for the outcome to be different for each study and treatment, but assumes that the association between outcome and differences in marker levels at baseline or week 24 is the same across studies. Initial exploratory models were run to see whether sex, race/ethnicity, or prior treatment influenced the associations of the markers with the risk of any of the clinical outcomes. None were found. Results were illustrated by categorizing HIV-1 RNA levels and CD4 cell counts. Tests for interaction were used to evaluate whether any associations varied between the different treatments used in the studies. Comparisons of differences in likelihoods from nested proportional hazards models were used to assess the relative strength of the association between the 2 CD4 measures and the clinical end points. Follow-up for survival was censored at the time of study closure or at loss to follow-up. Follow-up for weight growth failure and cognitive decline was censored at the time of the last weight or neuropsychologic test score measurement, respectively.

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Results

Patient population

Five studies were included in the analysis. Children started treatment between August 1991 (PACTG 152) and June 1997 (PACTG 239 and 300); follow-up was completed between August 1995 (PACTG 152) and September 1997 (PACTG 239). A total of 2081 children started treatment on ⩾1 study, but only 1089 are included in this analysis: 150 did not receive a new antiretroviral, 166 had <24 weeks of follow-up, and 676 had incomplete baseline or week 24 virologic or immunologic data. Three hundred eleven of the 676 subjects were enrolled in older studies, in which RNA testing was done only on a subset of subjects. There were no statistically significant differences between the study population and those not included in the analysis in the distributions of sex, race/ethnicity, age, CD4 cell count, or source of infection. There was a slightly higher proportion of treatment-naive subjects in the analysis subset (73% vs. 67%), which was a function of the eligibility criteria requiring ⩾1 new antiretroviral treatment.

Table 1 shows the treatments evaluated in the 5 studies and baseline characteristics of the 1089 infants and children. All studies used either monotherapy (47% of patients) or combination therapy with NRTIs. Two treatment arms of PACTG 245 included the NNRTI nevirapine in combination with 1 or 2 NRTIs. Among the 1089 children, 50% were boys and 55% were black (non-Hispanic). The studies targeted different age groups with varying histories of prior antiretroviral use. Overall, 73% of the children had no previous treatment. In the 4 studies that collected data on source of infection, 90%–100% of the children were perinatally infected. There was a wide range of HIV-1 RNA levels and immunologic values before initiation of study treatment across studies. In all studies, the median weight-for-age z-score was <0, (i.e., <50th percentile of weight for age and sex in children without HIV infection). In all, 25% of the children recorded cognitive scaled scores <70 on the age-appropriate measures of cognitive functioning: 9% were <50.

Figure 1
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Figure 1

Cumulative proportion of deaths, by week 24 human immunodeficiency virus (HIV)—1 RNA level, among 1089 subjects participating in 5 Pediatric AIDS Clinical Trials Group trials.

Figure 2
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Figure 2

Cumulative proportion of weight growth failures, by week 24 human immunodeficiency virus (HIV)—1 RNA level, among 1089 subjects participating in 5 Pediatric AIDS Clinical Trials Group trials.

Figure 3
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Figure 3

Cumulative proportion of cognitive declines, by week 24 human immunodeficiency virus (HIV)—1 RNA level, among 1089 subjects participating in 5 Pediatric AIDS Clinical Trials Group trials.

Table 1
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Table 1

Baseline characteristics of 1089 participants in 5 Pediatric AIDS Clinical Trial Group (PACTG) clinical trials.

Median follow-up from the week 24 HIV-1 RNA measurement for survival varied from a median of 0.7 years in PACTG 239 to 2.2 years in PACTG 152 (overall median, 1.2 years; table 2). Follow-up for the weight growth and cognitive end points was slightly shorter, with overall medians of 1.0 and 0.9 years, respectively, reflecting that evaluations were only obtained at defined clinic visits and were less likely to occur after discontinuation of study treatment prior to the end of study. All follow-up was used to maximize the number of events.

Table 2
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Table 2

Clinical end point rates in Pediatric AIDS Clinical Trials Group (PACTG) studies.

The number of end points occurring on each study is shown in table 2. Some children were not included in the weight growth failure analyses because they had to stay in the study for ⩾32 weeks to satisfy the end point definition. Similarly, since cognitive decline was defined as a decline in scores, only children with ⩾2 valid tests could meet the end point. Overall, weight growth failure and cognitive decline occurred more frequently (12% and 13%) than death (5%). The rates showed variability over studies, reflecting, in part, the different disease status and ages of the study populations.

Associations of markers and disease progression with age

Median marker values at baseline, after 24 weeks, and changes from baseline to week 24 are summarized in table 3 for each of 5 age groups. Similar to previous reports, HIV-1 RNA levels and CD4 cell counts and percentages were significantly lower in older children (P < .01) at baseline and at week 24 (P < .01). There were no statistically significant associations between the changes in any of these markers from baseline to week 24 and age.

Table 3
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Table 3

Median marker levels, median changes from baseline to week 24, and event rates 18 months after week 24, by age.

Eighteen-month event rates (estimated from Kaplan-Meier curves) for the 3 clinical end points are also shown in table 3. There were significant differences in the rates of death, weight growth failure, and cognitive decline end points across ages (P < .01), with older children tending to have lower rates. Differences between rates among age groups >1 year old tended to be small, compared with the difference between children >1 year and ⩽1 year old. Therefore, results concerning the evaluation of the prognostic value of markers focused primarily on whether any of the associations found varied between these 2 age groups.

Prognostic value of the markers for survival

Of the 1089 infants and children, 55 (5%) died during a median follow-up of 1.2 years after their week 24 HIV-1 RNA measurement (table 2). Among infants ⩽1 year old at baseline, the estimated Kaplan-Meier percentages for death within 1 and 2 years after week 24 were 6% and 12%. This compares with 1% and 7% among children >1 year old.

In age-adjusted analyses, there was a significant association between the risk of death and higher HIV-1 RNA level at week 24 (P < .001) and between the risk of death and lower log10 CD4 cell counts (P < .001) and CD4 percentages (P < .001). There was no evidence that either CD4 measure was more highly associated with the risk of death. These associations between the risk of death and HIV-1 RNA level and CD4 cell counts (categorized into 2 groups) are illustrated in table 4 (rows and columns labeled “Total”) and were apparent in children ⩽1 and >1 year old. The association of risk of death and categorized HIV-1 RNA level is shown graphically in figure 1. The graphs portray clear differentiation with HIV-1 RNA level in both age groups.

Table 4
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Table 4

Clinical end point rates by 18 months after human immunodeficiency virus (HIV)—1 RNA measurement.

In multivariate proportional hazards models that included age, HIV-1 RNA, and 1 of the 2 CD4 measures at week 24 (modeled as continuous variables), the associations with each marker were both significant (P < .01). The association of HIV-1 RNA level and CD4 cell count by age group is illustrated in table 4. Children with both higher HIV-1 RNA level (⩾5 log10 copies/mL) and lower CD4 cell count (<500 cells/mm3) had the highest risk of death. Event rates were lower among children with HIV-1 RNA level <5 log10 copies/mL and/or ⩾500 CD4 cells/mm3.

When we included baseline HIV-1 RNA levels and CD4 measures in the multivariate model, these were also significant or marginally significant predictors of the risk of death in addition to values at week 24 (table 5). Thus, it is not only the level of these markers after 24 weeks of treatment that is important for assessing progression but also their baseline marker values.

Table 5
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Table 5

Risk ratios (95% confidence intervals) from multivariate proportional hazards models describing the association between human immunodeficiency virus (HIV)—1 RNA, immunologic function (log10 CD4 cell count or CD4 percentage), and death.

Age was not a significant predictor of the hazard of death in the multivariate model (table 5). Furthermore, the inclusion of age by marker interaction terms showed there was no significant evidence that the associations of any of the markers with the hazard of death varied by age. Hence, the differences in mortality between the 2 age groups are largely explained by the differences in HIV-1 RNA and CD4 cell levels at baseline and week 24. Thus, the risk ratio for death comparing 2 children whose HIV-1 RNA levels differ by 1 log10 copies/mL or whose CD4 cell counts differ by 1 log10 cells/mm3 does not depend on whether the 2 children are <1 or >1 year old.

Prognostic value of the markers for weight growth failure

The associations between the risk for weight growth failure and HIV-1 RNA and CD4 measures were quite different from the associations of the risk of death and these markers. As with death, there were significantly increased risks for weight growth failure with higher HIV-1 RNA levels and lower levels of each CD4 measure at week 24 (P < .001, univariate analyses adjusted for age). However, although the association with HIV-1 RNA was clear among children >1 year old, it was not apparent among younger infants (P < .001 for difference in association between age groups). This is illustrated in figure 2, which shows a clear separation between event rates defined by level of HIV-1 RNA at week 24 in children >1 year old at baseline, but no separation among those ⩽1 year old. For CD4 cell count, the association was not significantly different between the 2 age groups. These trends are also seen in table 4. There is a much smaller difference in 18-month event rates between the 2 categories of HIV-1 RNA level in the ⩽1-year-old age group than in the older group, but there is a clear separation in the event rates between the categories of CD4 cell count in both age groups. In addition, on the basis of differences in the log likelihood between models with log10 CD4 cell count and CD4 percentage relative to those with only 1 immunologic parameter, there was strong evidence that the log10 CD4 cell count was more highly associated with the risk of weight growth failure than was CD4 percentage.

In multivariate proportional hazards models, these results persisted: there was a significant difference between age groups in the association between HIV-1 RNA level at week 24 and the risk for weight growth failure, with no apparent effect in infants ⩽1 year old. Lower CD4 cell count at week 24 was still significantly associated with an increased risk of weight growth failure independently of HIV-1 RNA level. Week 24 CD4 percentage was no longer prognostic with HIV-1 RNA already in the model. There was no evidence of differences in the association of the immunologic end points and outcome by age group. In contrast to the results for death, adding either baseline HIV-1 RNA level or CD4 cell count into a model that already had the week 24 levels of these markers did not add significantly to the model. Therefore, marker values observed at week 24 and not the baseline values are most important in determining the risk of weight growth failure. However, after taking into account the week 24 HIV-1 RNA levels and CD4 cell counts, the risk of weight growth failure was 2.1 times greater in infants ⩽1 year old than in older infants and children >1 year old (P = .01). Thus, the difference in risk of weight growth failure between the younger and older children is not fully explained by differences in marker levels.

Prognostic value of the markers for cognitive decline

Overall, cognitive decline had the highest event rates (table 2). Children ⩽1 year old had an 18-month event rate of 36% versus 12% in children >1 year old at baseline (table 4). In univariate models that controlled for age, only week 24 HIV-1 RNA level was strongly predictive of cognitive decline (P < .001). There was marginally significant evidence that the association was weaker in infants ⩽1 year old than in older children (P = .06 for difference in association between 2 age groups). This can be seen in table 4, where the difference in event rates in the ⩽1-year-old age group between those with week 24 HIV-1 RNA levels <5 versus ⩾5 log10 copies/mL (33% vs. 39%) is smaller than the difference in the older age group (8% vs. 23%). Cumulative proportions of cognitive decline according to category of week 24 HIV-1 RNA level showed more separation in children >1 year old, compared with the younger children (figure 3). CD4 measures at week 24 were only marginally significant (log10 CD4 cell count, P = .09; CD4 percentage, P = .11).

In the multivariate model that included age, HIV-1 RNA level, and each of the 2 CD4 measures, week 24 CD4 measures were not significant. Furthermore, neither HIV-1 RNA levels nor the CD4 measures at baseline were significant when added to a model that included the week 24 values. Age remained a significant predictor with week 24 HIV-1 RNA levels in the model; thus, as with weight growth failure, the increased event rates in the younger children are not fully explained by the higher HIV-1 RNA levels.

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Discussion

This study demonstrates the independent value of HIV-1 RNA and CD4 measures obtained 24 weeks after initiation of new antiretroviral treatment for predicting survival of HIV-infected children. It also shows that associations between these surrogate markers and the risk of weight growth failure or cognitive decline differs from their association with the risk of death and may differ by age.

By combining data across 5 pediatric trials, we gained greater power to assess the prognostic value of the marker levels across types of clinical outcomes and across age groups. Conclusions did not vary by treatment or study, although there was little power to address this question directly. For survival, both HIV-1 RNA and CD4 levels after 24 weeks of antiretroviral therapy were independently predictive, which is consistent with previous findings combining clinical end points or death [10] and for survival alone [12]. Our results also show that these marker values before initiation of antiretroviral treatment provide additional predictive power. This confirms the findings by Palumbo et al. [11] for PACTG 152 and suggests that clinicians need to consider both baseline and during-treatment HIV-1 RNA level and CD4 marker levels when making patient care decisions. For example, more aggressive therapies in children with poorer baseline marker levels could be considered. In adult patients, there have been conflicting reports regarding the importance of baseline HIV-1 RNA values after adjusting for levels achieved after initiation of treatment [2, 3, 26]. This difference between children and adults may reflect the fact that, in children, marker values change with age, even in the absence of treatment [6].

Another important finding regarding survival in infants and children is the lack of a significant age effect once HIV-1 RNA and CD4 levels (CD4 cell count or percentage) at week 24 and baseline are considered. Thus, the higher mortality rates in infants ⩽1 year old, compared with older children, appear to be explained by differences in marker values with age. This finding has implications for clinical practice, because it suggests that the difference in risk of death approximately doubles with each 1 log10 copy/mL increase in HIV-1 RNA level at week 24 and at baseline (table 5). This observation was also found when differences in rates of a composite clinical end point across age groups were analyzed [10].

The association between weight growth failure and cognitive decline and HIV-1 RNA and CD4 levels in HIV-infected children has not been well studied. In our analysis, because of the large sample size, we were able to evaluate associations with weight growth failure and cognitive decline as separate clinical outcomes. For both, we found associations between higher HIV-1 RNA levels at week 24 and the risk of weight growth failure and cognitive decline, and these associations were particularly apparent in children >1 year old (figures 2 and 3). However, among infants ⩽1 year old, there appeared to be no association between HIV-1 RNA levels and weight growth failure and only a weak association with risk of cognitive decline.

We did additional analyses to assess the impact of the differential data collection schedules after children discontinued the antiretroviral study treatment and the potential informative censoring of the clinical end points by death and whether either might cause the different associations between risk and HIV-1 RNA levels between age groups. Weight was recorded every 12 weeks, and collection of weight and cognitive tests became less reliable after children discontinued treatment, making it less likely that a weight growth failure or cognitive decline end point would be identified. However, altering the weight growth failure definition to require only 2 or 1 weight growth velocity measurements below the third percentile did not influence the magnitude of the differences between age groups. Also, using a combined weight growth failure, cognitive decline, or death end point did not eliminate the difference. Relying only on HIV-1 RNA levels and CD4 cell counts as end points in clinical trials in young infants may not be optimal, because they do not seem to capture important effects on weight growth and cognitive failure. In children >1 year old, marker levels had similar effects on weight growth failure, cognitive decline, and survival, and, although it would be important to control for age in an analysis, marker values at week 24 could be interpreted in an age-independent manner.

The prognostic value of the CD4 measures depended on the clinical end point. When used in combination with HIV-1 RNA level, both were equally prognostic for survival, but only the CD4 cell count was predictive of weight growth failure, and neither was predictive of cognitive decline, suggesting that the CD4 cell count is the most useful immunologic marker when evaluating treatment efficacy. The fact that neither CD4 measure was predictive of cognitive decline may reflect a direct effect of HIV-1 on the CNS, rather than being a consequence of immunosuppression. This would support the use of therapeutic agents that cross into the CNS, especially when HIV-1 RNA levels exceed 5.5 log10 copies/mL (∼30,000 copies/mL), because the risk of cognitive decline was markedly increased above this level (figure 3). This might be particularly important in infants ⩽1 year old, because we also found that younger age was predictive of the greater absolute risk of cognitive decline even after adjustment for HIV-1 RNA level.

Although these 5 studies included children from 3 months to 18 years old, with a wide range of HIV-1 associated clinical findings, they were conducted when the standard of care was changing rapidly. Antiretroviral treatment-mediated changes in HIV-1 RNA and CD4 cell levels were much smaller than those observed during the protease inhibitor era, so it is not possible to extrapolate our conclusions to children who are currently enrolled in clinical trials. Our analysis population included a subset of subjects with a slightly higher proportion of treatment-naive subjects who had tolerated treatment and had not experienced disease progression for ⩾24 weeks. However, with these caveats, it is clear that age is an important factor and that conclusions about associations of surrogate markers with clinical outcomes in adult studies cannot be universally applied to the pediatric population, especially to infants ⩽1 year old. The differential impact of these markers on the 3 clinical end points of death, weight growth failure, and cognitive decline is also important because treatments aimed at altering marker levels may improve prognosis for one outcome but have less impact on another aspect of the disease directly affecting quality of life [27]. This emphasizes the need for continued investigation of treatment effects on all aspects of disease progression in the pediatric population.

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Acknowledgments

We thank K. O'Donnell (Duke University Medical Center, Durham, NC) and P. Brouwers (Texas Children's Cancer Center, Baylor College of Medicine, Houston) for helping to define the cognitive end points, Shirley Traite (Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston) for creating the analysis data sets, the children and families who participated in the Pediatric AIDS Clinical Trials Group clinical trials, and the reviewers for their helpful comments.

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Footnotes

  • Informed consent was obtained from children or their parents and guardians, and human experimentation guidelines of the US Department of Health and Human Services were followed in the conduct of this clinical research.

  • Financial support: Statistical and Data Management Center of the Pediatric AIDS Clinical Trials Group (National Institute of Allergy and Infectious Diseases cooperative agreement AI-41110).

  • Received March 24, 2000.
  • Revision received July 17, 2000.
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  1. J Infect Dis. (2000) 182 (5): 1385-1393. doi: 10.1086/315865
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