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Growth in Human Immunodeficiency Virus–Infected Children Receiving Ritonavir-Containing Antiretroviral Therapy
Sharon A. Nachman, MD;
Jane C. Lindsey, ScD;
Stephen Pelton, MD;
Lynne Mofenson, MD;
Kenneth McIntosh, MD;
Andrew Wiznia, MD;
Kenneth Stanley, PhD;
Ram Yogev, MD
Arch Pediatr Adolesc Med. 2002;156:497-503.
ABSTRACT
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Background Human immunodeficiency virus (HIV)–infected children often suffer
from impaired growth. Highly active antiretroviral therapy (HAART) successfully
reduces HIV 1 (HIV-1) RNA to 400 copies/mL or less in many children.
Objectives To determine if age- and sex-adjusted growth z
scores correlate with HIV-1 RNA level and if control of viral load for 48
and 96 weeks results in improved growth in children receiving highly active
antiretroviral therapy.
Design Secondary analysis of the cohort of children receiving ritonavir nested
in a randomized, open-label, clinical trial.
Subjects and Methods The Pediatric AIDS Clinical Trials Group Protocol 338 enrolled clinically
stable, antiretroviral therapy–experienced, HIV-infected subjects aged
2 through 17 years. Using data from subjects randomized to ritonavir-containing
regimens (n = 197), the association of growth z scores
and HIV-1 RNA levels were examined.
Main Outcome Measures Age- and sex-adjusted weight and height z scores.
Results Enrollment weights were comparable with age- and sex-adjusted norms,
but subjects receiving ritonavir-containing antiretroviral therapy were significantly
shorter (mean z score, -0.57 [29th percentile];
95% confidence interval, -0.73 to -0.40). Higher HIV-1 RNA levels
correlated with lower growth z scores (P<.01). Subjects achieving and maintaining HIV-1 RNA of 400 copies/mL
or less through 48 and 96 weeks experienced worse growth than subjects with
a less controlled viral load.
Conclusions In this pediatric cohort, a significant decline in height and weight z scores was found despite control of viral replication.
Further studies of growth are necessary to assess if nutritional and hormonal
adjuvants to highly active antiretroviral therapy should be considered to
improve growth in HIV-infected children.
INTRODUCTION
IMPAIRED SOMATIC growth is a well-documented complication of human immunodeficiency
virus 1 (HIV-1) infection in children.1-4
In perinatal infection, linear growth in particular seems to be affected more
than weight growth and can be apparent within the first few months of life.2, 4-5 Several studies have
documented that impaired growth is predictive of HIV-related disease progression,6-8 and in one study, disturbances
in linear (but not weight) growth correlated with high viral load in perinatally
infected infants.5 Antiretroviral therapy has
been shown to improve growth in some but not all studies.4-5,7
These studies, however, were primarily reported prior to the introduction
of highly active antiretroviral therapy and the use of protease inhibitors
(PIs), with which HIV-1 RNA levels in many children were brought to levels
beneath the quantification limits of current assays.9-10
The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 338 was designed
to evaluate the safety, tolerance, and virologic efficacy of changing antiretroviral
treatment to either dual nucleoside analogue therapy or a 2- or 3-drug regimen
containing the PI ritonavir in clinically and immunologically stable, PI-naive
children. Although this clinical trial was not designed to look at growth
as a primary outcome, it provides an opportunity to examine the correlation
of weight and height growth with HIV-1 RNA levels at study enrollment and
growth over time in children with persistent reductions in viral load for
1 and 2 years after the initiation of therapy with a PI.11
SUBJECTS AND METHODS
STUDY DESIGN AND DATA
The PACTG Protocol 338 enrolled 297 clinically and immunologically stable
subjects aged from 2 through 17 years (stable CD4 count or percentage in Centers
for Disease Control and Prevention immune category 1 or 2 during the 4 months
prior to study enrollment and with no new Centers for Disease Control category
C diagnoses in the 12 months prior to study enrollment). All had received
continuous antiretroviral therapy for at least 16 weeks before study enrollment
and had no exposure to combination therapy of zidovudine and lamivudine, non–nucleoside
reverse transcriptase inhibitors, or PIs. Participants were randomized to
1 of 3 treatment combinations: zidovudine and lamivudine; zidovudine, lamivudine,
and ritonavir; or stavudine and ritonavir. The primary objectives of the study
were to evaluate the safety and tolerance of the 3 regimens and to compare
the change in plasma HIV-1 RNA copy number between enrollment and study weeks
12 and 48. Follow-up was subsequently extended from the initially planned
48 to 120 weeks. Height and weight were measured every 4 weeks, following
standardized instructions outlined in PACTG manuals. Toxic effects were graded
according to the National Institute of Allergy and Infectious Diseases Division
of AIDS Standardized Toxicity Table for Grading Severity of Pediatric Adverse Experiences (April 1994). Gastrointestinal
tract grade 2 or higher toxic effect included appetite loss, weight loss,
nausea (moderately decreased intake to inability to ingest food or fluid for
>24 hours), vomiting (>1 episode per day for at least 3 days), and diarrhea
(liquid stools to dehydration requiring intravenous therapy or hypotensive
shock). The study was approved by the institutional review boards at the sites
and informed consent was obtained from all legal guardians and/or participants.
LABORATORY METHODS
The HIV-1 RNA copy number was assessed at preenrollment, enrollment,
and study weeks 4, 12, 24, 36, 44, 48, and every 12 weeks thereafter. The
HIV-1 RNA was measured using a nucleic acid sequence-based amplification assay
according to the manufacturer's instructions (NucliSens Assay; Organon Teknika,
Durham, NC). All assays were performed by a single laboratory participating
in the Divison of AIDS Virology Quality Assurance program.12
Assay results were adjusted using the Virology Quality Assurance program's
external standards as previously described.13
The lower limit of assay quantitation was 400 copies/mL. Lymphocyte subsets
were evaluated at preenrollment; enrollment; study weeks 4, 8, 12, and every
12 weeks thereafter. Assays were performed by clinical site laboratories participating
in the National Institute of Allergy and Infectious Diseases Flow Cytometry
Quality Assurance Program.14
STATISTICAL METHODS
The goal of this analysis was to assess the effect of highly active
antiretroviral therapy on height and weight growth over at least 48 weeks.
Subjects assigned to the dual non–nucleoside reverse transcriptase inhibitors
zidovudine and lamivudine arm, most of whom discontinued their assigned therapy
after 24 weeks of treatment, were excluded from this study. Weights and heights
were analyzed using age- and sex-adjusted z scores
based on norms derived from children not infected with HIV.15
A child with a z score of 0 is at the mean (equivalent
to the 50th percentile) for weight and height for his or her age and sex.
If a child was growing at a steady rate (tracking along their enrollment percentile),
their change in z score from baseline would be 0.
Positive changes in z scores would indicate improvements
in growth relative to their age and sex. Results are shown on the z score scale and transformed to the percentile scale for cross-sectional
summaries.
The association of HIV-1 RNA levels with growth z scores at study enrollment was examined using analysis of variance.16 To assess the effect of virologic suppression on
growth over 48 weeks, subjects were initially classified into the following
groups: (1) those who had achieved and maintained HIV-1 RNA levels of 400
copies/mL or less at weeks 24 and 48 and who had continued to take their originally
assigned therapy, (2) those receiving his or her original treatment with HIV-1
RNA levels between 401 copies/mL and 10 000 copies/mL at weeks 24 and
48, (3) subjects receiving his or her assigned treatment and with at least
one HIV-1 RNA level higher than 10 000 copies/mL, and (4) subjects who
discontinued his or her assigned treatment before week 48. Subjects could
have experienced dose reductions in groups 1 and 2, but they could not have
had their study treatment permanently discontinued to be in these groups.
Similar groupings were applied to subjects with 96 weeks of follow-up. Changes
in z scores were graphed by virologic response group.
Mixed-effects models17 were used to compare
the changes from baseline in age- and sex-adjusted weight and height z scores by virologic response group. In these models,
groups 3 and 4 were collapsed into 1 group since the profiles of changes were
similar and both groups reflected, in some sense, treatment failure (eg, toxic
effects, clinical end points, intolerance, or compliance problems). Models
included main effects for sex, race or ethnicity, treatment group, CD4 percentage,
height and weight z scores, HIV-1 RNA copy number,
Centers for Disease Control disease category, age (all measured at study enrollment),
whether the subject experienced any grade 2 or higher gastrointestinal tract
toxic effects during the first 24 weeks, or whether their dose was reduced
during the first 24 weeks. A stepwise procedure was used to find the most
parsimonious model. Least squares means were used to test for significant
changes from enrollment within the 3 HIV-1 RNA level response groups averaged
over the other covariates in the model. The groups were also compared with
respect to the rates of dose reductions and incidence of grade 2 or higher
gastrointestinal tract toxic effect using  2 tests.16 All significance levels are 2-sided and not adjusted
for multiple comparisons. All analyses were performed using SAS Version 6.12
(SAS Institute Inc, Cary, NC).
RESULTS
ENROLLMENT CHARACTERISTICS
One hundred ninety-seven subjects started 1 of the 2 PI-containing treatment
combinations while following PACTG Protocol 338. Distributions of treatment
group and demographic and laboratory characteristics at study enrollment are
given in Table 1. All subjects
were perinatally infected. Weight was within the normal range for age and
sex (mean z score, -0.04; 95% confidence interval
[CI], -0.20 to 0.12), which corresponds to the 48th percentile. Height
was significantly lower than age- and sex-adjusted norms (mean z score, -0.57; 95% CI, -0.73 to -0.40), which corresponds
to the 29th percentile.
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Table 1. Study Enrollment Characteristics*
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CORRELATION OF HIV-1 RNA LEVELS AND GROWTH z
SCORES AT STUDY ENROLLMENT
Enrollment height and weight z scores by enrollment
HIV-1 RNA copy number are given in Table
2. Significantly impaired age- and sex-adjusted weight was observed
only for subjects with enrollment HIV-1 RNA levels higher than 100 000
copies/mL (mean z score, -0.53; 95% CI, -0.90
to -0.17, which corresponds to the 30th percentile). In contrast, age-
and sex-adjusted height was significantly impaired in all subjects with detectable
HIV-1 RNA levels. A higher enrollment HIV-1 RNA copy number was significantly
correlated with lower height (P<.01) and weight z scores (P = .01).
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Table 2. Entry Height and Weight Age- and Sex-Adjusted z Scores by HIV-1 RNA*
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WEEK 48 CHANGES IN GROWTH z SCORES FROM STUDY
ENROLLMENT
The entire cohort (n = 197) showed significant declines in age- and
sex-adjusted weight from week 4 through 48. By week 12, the group had declined
on average by -0.08 (95% CI, -0.12 to -0.04) and they remained
at this level at week 48 (mean z score, -0.08;
95% CI, -0.15 to -0.01). No significant declines in height z scores were observed to week 48.
To assess if these changes depended on the level of virologic control,
the 197 subjects were divided into the 4 groups defined in the "Statistical
Methods" subsection of the "Subjects and Methods" section. Sixty subjects
achieved and maintained HIV-1 RNA levels of 400 copies/mL or less, 35 subjects
had HIV-1 RNA levels between 401 copies/mL and 10 000 copies/mL through
48 weeks of therapy, 47 subjects had observed HIV-1 RNA levels of higher than
10 000 copies/mL at either week 24 or 48, and 55 subjects discontinued
study treatment before week 48.
Mean (95% CIs) changes from baseline in weight and height z scores in the 4 cohorts defined by their HIV-1 RNA levels are shown
in Figure 1. Age- and sex-adjusted
weight declined in all 4 groups and remained below enrollment levels until
week 36 (Figure 1A). The largest
declines were seen in the subjects with the best virologic control, where
weight z scores remained below enrollment levels
through 48 weeks, with an average decline from enrollment of -0.20 (95%
CI, -0.30 to -0.09). The subjects who discontinued their original
treatment or who had no control of their viral load (groups 3 and 4) had very
similar profiles over the 48 weeks. Height z scores
(Figure 1B) showed a different pattern.
In the groups with moderate (group 2) or no (group 3) virologic control and
for those who discontinued their original treatment, height z scores remained relatively constant over time, but in the group with
the best virologic control (group 1), height z scores
declined after week 4. By week 48, this group had declined an average of -0.11
(95% CI, -0.19 to -0.02).
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Figure 1. Mean (95% pointwise confidence
intervals) indicate the changes from baseline in weight (A) and height (B) z scores by level of virologic control achieved through
48 weeks on study. HIV-1 indicates human immunodeficiency virus 1.
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The profiles for groups 3 and 4 were similar for both changes in weight
and height z scores. In addition, both groups represent
treatment failure, in the sense that group 3 had an inadequate response to
their antiretroviral treatment regimen and group 4 subjects had discontinued
the study treatment. The reasons for discontinuation in group 4 were toxic
effects (n = 14), clinical end points (n = 7), at the request of the subject
or investigator (n = 29), and miscellaneous other reasons (n = 5). These 2
groups were combined in the mixed-models stepwise regression. The most parsimonious
model for changes in weight z scores from baseline
included enrollment HIV-1 RNA levels (P = .05), whether
the subject experienced a gastrointestinal tract grade 2 or higher toxic effect
within the first 24 weeks (P<.001), and an interaction
term between group defined by level of virologic control and time (P = .04). Averaged over the 48 weeks, subjects experiencing a toxic
effect of the gastrointestinal tract declined -0.14 (95% CI, -0.07
to -0.21) z score units more than those not
experiencing this kind of toxic effect. Subjects with the best virologic control
showed significant declines from baseline from week 8 through week 48. By
week 48, the group with the best virologic control had declined a mean of -0.20
(95% CI, -0.30 to -0.10), the group with moderate control a mean
of -0.15 (95% CI, -0.28 to -0.02), and the group either
with no virologic control or who discontiued their original treatment had
no significant declines (mean z score, -0.02;
95% CI, -0.11 to 0.07).
The most parsimonious model for changes in height over time included
marginally significant interactions between time and age at enrollment (P = .03) and time and group defined by level of virologic
control (P = .03). By week 48 only children older
than 10 years at enrollment had significant declines (mean z score, -0.18; 95% CI, -0.29 to -0.06). The group
with the best virologic control showed significant declines in height growth
after week 36. By week 48 they had declined a mean of -0.12 (95% CI, -0.21
to -0.03), with the other 2 groups showing no significant declines from
baseline.
WEEK 96 CHANGES IN GROWTH z SCORES FROM STUDY
ENROLLMENT
Of the 197 subjects randomized to the ritonavir-containing arms, 37
achieved and maintained HIV-1 RNA levels of 400 copies/mL or less and 19 HIV-1
RNA levels between 401 copies/mL and 10 000 copies/mL through 96 weeks
of therapy. These represent subsets of the subjects defined in the week 48
analysis. In addition, fifty subjects had at least one HIV-1 RNA level higher
than 10 000 copies/mL and 91 subjects had discontinued their originally
assigned treatment by week 96. Profiles of the changes in weight and height z scores are shown in Figure 2. Changes in height z scores followed
similar patterns up to week 48 as for the week 48 cohorts discussed in the
"Week 48 Changes in Growth z Scores From Study Enrollment"
subsection of the "Results" section. Patterns were also similar for changes
in weight z scores with the exception of group 2,
which showed more improvement from week 36 than for the analogous week 48
group 2. With only 19 subjects, this group showed the greatest variability
and the differences are likely because of group selection factors.
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Figure 2. Mean (95% pointwise confidence
intervals) indicate the changes from baseline in weight (A) and height (B) z scores by level of virologic control achieved through
96 weeks on study. HIV-1 indicates human immunodeficiency virus 1.
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Age- and sex-adjusted weight remained relatively stable in all groups
except those with the best virologic control. This group showed significant
declines from baseline at both weeks 48 (mean z score, -0.27;
95% CI, -0.38 to -0.16) and 96 (mean z
score, -0.25; 95% CI, -0.42 to -0.08). Similar results were
seen for changes in height z scores, with week 48
and 96 changes in this group of -0.16 (95% CI, -0.25 to -0.07)
and -0.23 (95% CI, -0.38 to -0.09) respectively.
INFLUENCE OF THE TOXIC EFFECTS TO THE GASTROINTESTINAL TRACT AND DOSE
REDUCTIONS ON CHANGES IN WEIGHT AND HEIGHT GROWTH
One possible explanation for the decline in weight z scores (and subsequent decline in height z
scores) in the subjects with the best virologic control is that this group
managed to take the drug despite experiencing toxic effects that could influence
adequate caloric intake. To address this we compared the 3 groups (combining
groups 3 and 4) defined by virologic control at week 48 with respect to (1)
their rates of dose reductions during the first 24 weeks and (2) their rates
of gastrointestinal tract grade 2 or higher toxic effects. Of the 60 subjects
with the best virologic control, 10% had at least one dose reduction during
the first 24 weeks compared with 14% in the moderate virologic control group
and 26% in the third or other group. This difference was statistically significant
(P = .001, 2 test). In contrast,
there were no differences in the rates of grade 2 or higher toxic effects
in the 3 groups (28% vs 26% vs 34%, P = .55 for decreasing
levels of virologic control).
COMMENT
Several natural history studies have shown that children born to HIV-infected
women are shorter and weigh less than a comparison population of children
born to women who are not infected with HIV; however, those infants who are
ultimately shown to be uninfected "catch up" with their peers by the first
few years of life.2, 18-19
Infants who were infected with HIV had progressive decrements in growth compared
with uninfected infants born to HIV-infected women as well as uninfected control
children; the results of some studies (primarily in HIV-infected children
who do not receive antiretroviral therapy) suggest that height may be more
affected than weight growth.2-5
There have been mixed reports of the effect of zidovudine treatment on weight
and height growth of HIV-infected children.4-5,7
Carey et al6 found that height growth velocity
was more impaired than weight growth velocity in a cohort of participants
receiving antiretroviral therapy in 4 PACTG clinical trials. In the current
study, all subjects (median age, 7.2 years) had been exposed to therapy with
non–nucleoside reverse transcriptase inhibitors and had normal weight
relative to age- and sex-adjusted norms at study enrollment, but were significantly
shorter than their non–HIV-infected peers with an average height at
the 29th percentile. These data suggest that height growth continues to be
more affected than weight growth in the era of monotherapy or combination
therapy with non–nucleoside reverse transcriptase inhibitors. Weight
and height z scores were negatively correlated with
enrollment HIV-1 RNA level. However, significantly impaired height z scores were seen in all subjects with enrollment HIV-1 RNA levels
of 400 copies/mL or less but significantly impaired weight z scores were only observed in subjects with enrollment HIV-1 RNA levels
higher than 100 000 copies/mL at study enrollment, suggesting that height
may be more sensitive to virologic status than weight. These data are consistent
with those reported by Pollack et al,5 in which
linear but not weight growth was correlated with the level of postnatal viremia
in perinatally infected infants.
It is hoped that one benefit of achieving and sustaining low viral loads
with effective treatments will be improvement in weight and height growth.
Weight gain has been documented in some small studies in HIV-infected adults.20-21 However, this weight gain may be
secondary to changes in fat mass with no change in lean body mass.20 In addition, loss of body cell mass has continued
to be observed in infected adults receiving PIs.22
Data regarding the effects of PI-containing potent antiretroviral therapy
on the growth of HIV-infected children is limited. Of the 7 studies that mention
growth response to PI therapy, 5 reported some improvement in weight23-27;
however, 2 studies reported no change in weight and height growth.28-29 These individual studies involved
only a few patients, and it is difficult to compare them with the subjects
in our study because of the differences in design and patient populations
when evaluating growth changes. In the current study, contrary to expectation,
age- and sex-adjusted weight declined an average of -0.08 (95% CI, -0.15
to -0.01) units over the first 48 weeks. In the subgroup of subjects
who achieved and maintained virologic control with HIV-1 RNA levels of 400
copies/mL or less through 48 weeks, weight z scores
declined an average of -0.20 (95% CI, -0.30 to -0.09). Although
no significant declines in height z scores were observed
in the entire cohort during the first 48 weeks of the study, the subgroup
with the best virologic control did show declines of -0.12 (95% CI, -0.21
to -0.03). Since this subgroup showed significantly lower rates of dose
reductions during the first 24 weeks but comparable rates of toxic effects
of the gastrointestinal tract, it is possible that the decrements in weight z scores reflect an acute decrease in calorie intake caused
by the most common toxic reactions to ritonavir of nausea and vomiting in
children who were most compliant with therapy. Caloric intake was not collected
in this study, so we could not control for this factor in the analysis. Canani
et al24 suggested that ritonavir combination
therapy promptly restored and sustained gastrointestinal function and was
associated with viral load reduction.
Three recent articles describe changes in growth in children starting
or changing therapy with PIs. Miller et al30
found increases in weight and weight-for-height z
scores in 45 HIV-infected children initiating any type of PI therapy followed
up for a median of 2.4 years. Dreimane et al31
reported on 27 children who switched therapy and were followed up for an average
of 20.4 months. They observed increases in height z
scores and improvements in height velocity. Both studies included children
with advanced disease and did not differentiate between the type of PI therapy
used. Buchacz et al32 reported small but statistically
significant improvements in weight and height z scores
in a cohort study with children starting PI therapy in all stages of disease.
In our study we focused on relatively asymptomatic children initiating ritonavir
who achieved and maintained undetectable viral load for 48 or 96 weeks. In
both the 48- and 96-week analyses, the subgroup with the best virologic control
showed significant declines in weight z scores from
week 8, but significant declines in height growth only from week 36 onward.
It is unclear why relative weight loss stabilized after week 16 and height
loss did not (Figure 1). It is possible
that the initial decrease in weight z scores reflects
the ritonavir-related toxic effects of the gastrointestinal tract (eg, nausea)
in those children most compliant with their therapy (and thereby having the
best virologic response), with subsequent resolution of these toxic effects,
resulting in no further relative weight loss. The short-term effects on weight
growth and the longer-term effects on height growth are consistent with observations
in a WHO study in non–HIV-infected children, where investigators found
that wasting could develop but also recover rapidly, whereas height growth
represented the accumulated effect of wasting that might not be evident for
a longer period.33
Our conclusions are based on a small subset of subjects, and the study
was not designed to examine growth as a primary end point. Using changes from
baseline in z scores rather than calculating growth
velocities, which require minimum intervals of 24 weeks between measurements
(and for which we had no prestudy treatment values for comparison), allowed
us to identify both short- and long-term alterations in weight and height
growth. Since the study had no control group of untreated HIV-infected subjects
and since there is very little published in the literature on similarly aged-infected
children, it is unknown if the growth patterns shown in these subjects are
better or worse than would have been expected without treatment, and the changes
in growth factors we are reporting may not be generalizable to other highly
active antiretroviral therapy therapies or patient populations. It is clear,
however, that although the subjects with controlled viral load may not have
experienced very large declines in height growth, there was no evidence during
2 years of follow-up that they were catching up to growth levels in non–HIV-infected
children.
The cause of growth failure among HIV-infected children has not been
well delineated, and many factors including hypermetabolism, poor oral intake,
malabsorption, and/or hormonal changes may be involved.22
Fontana et al8 reported no preferential reduction
in fat-free body mass of HIV-infected children, suggesting that inadequate
caloric intake could be the main cause of growth failure rather than excess
catabolism. Similar results were reported by Henderson et al,34
who found that resting caloric expenditure was not significantly increased
in HIV-infected children compared with uninfected children, but the mean caloric
intake was significantly lower in HIV-infected children with growth failure
compared with uninfected children. These results supplement our findings and
suggest that further study of nutritional support and hormonal adjuvants in
addition to the use of highly active antiretroviral therapy therapy is warranted
in improving growth among HIV-infected children.
| What This Study Adds
Children infected with HIV often suffer from impaired growth. Highly
active antiretroviral therapy was administered in 2 treatment arms of the
PACTG Protocol 338, which effectively reduced viral load in a high proportion
of subjects. The hope was that control of viral replication would allow improved
growth in these children.
This secondary analysis of the cohort of children on ritonavir-containing
treatment regimens confirmed that at enrollment children with higher enrollment
viral loads were shorter and weighed less than children with more controlled
viral loads. Children who achieved the best virologic response during the
study, showed the worst growth profiles over 48 and 96 weeks. The results
show that further studies of growth are necessary even in children receiving
therapies that effectively bring viral replication under control.
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AUTHOR INFORMATION
Accepted for publication January 25, 2002.
This study 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
and the Statistical and Data Management Center of the PACTG (NIAID cooperative
agreement AI-41110).
This study was presented at the 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy, September 27, 1999, San Francisco, Calif.
We acknowledge the study participants, their parents and guardians.
Corresponding author and reprints: Sharon A. Nachman, MD, Department
of Pediatrics, State University of New York Health Science Center at Stony
Brook, Stony Brook, NY 11794-8111 (e-mail: snachman{at}notes.cc.sunysb.edu).
From the Department of Pediatrics, State University of New York Health
Science Center at Stony Brook (Dr Nachman); Center for Biostatistics in AIDS
Research, Harvard School of Public Health, Boston, Mass (Drs Lindsey and Stanley);
Department of Pediatrics, Boston Medical Center (Dr Pelton); Pediatric, Adolescent
and Maternal AIDS Branch, National Institute of Child Health and Human Development,
National Institutes of Health, Rockville, Md (Dr Mofenson); Department of
Pediatrics, Children's Hospital, Boston (Dr McIntosh); Department of Pediatrics,
Jacobi Hospital, Einstein Medical Center, Bronx, NY (Dr Wiznia); and the Department
of Pediatrics, Children's Memorial Hospital, Northwestern University, Chicago,
Ill (Dr Yogev).
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