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PEDIATRICS Vol. 109 No. 6 June 2002, pp. 1144-1152

The Prevalence of Pain in Pediatric Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome as Reported by Participants in the Pediatric Late Outcomes Study (PACTG 219)

Denise M. Gaughan, MPH*, Michael D. Hughes, PhD*, George R. Seage, III, DSc, MPH*,{ddagger}, Peter A. Selwyn, MD, MPH§, Vincent J. Carey, PhD*, Steven L. Gortmaker, PhD*,|| and James M. Oleske, MD, MPH PACTG 219 Team

* Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
{ddagger} Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
§ Department of Family Medicine and Community Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
|| Department of Health & Social Behavior, Harvard School of Public Health, Boston, Massachusetts
Department of Pediatrics, University of Medicine and Dentistry of New Jersey Medical School, Newark, New Jersey

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 STATISTICAL METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objectives. As the life expectancy of children with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) increases, quality-of-life outcomes are of increasing concern. The prevalence of pain in adults with AIDS ranges from 40% to 60%, depending on stage of illness. There is limited research concerning pain in HIV-infected children and youth.

Design. The General Health Assessment for Children was administered to caregivers of HIV-infected children and youth enrolled in the Pediatric Late Outcomes Study (PACTG 219), a prospective cohort study. Pain is assessed over the previous month with 7 questions. For the purpose of this analysis, we defined pain as the presence of pain of at least moderate intensity. Participants were observed from January 1, 1996, to December 31, 1999.

Results. A total of 985 HIV-positive participants had a baseline pain evaluation in 1995. The prevalence of pain remained relatively constant during each year of observation, averaging 20%. Lower CD4+ T-lymphocyte percentage, female gender, and an HIV/AIDS-related diagnosis were highly associated with an increased risk of reported pain. Pain was also independently associated with increased risk of death. After adjusting for CD4 percentage, use of combination therapy including protease inhibitors, comorbid diagnoses, and other sociodemographic characteristics, individuals reporting pain were over 5 times more likely to die than those not reporting pain (hazard ratio = 5.07; 95% confidence interval = 3.23–7.95).

Conclusions. Pain is a frequently encountered symptom in children and youth with HIV disease and is also associated with increased mortality. These findings emphasize the importance of pain management in this population.

Key Words: pain • HIV/AIDS • pediatrics • protease inhibitors • generalized estimating equations • proportional hazards regression

Abbreviations: HIV, human immunodeficiency virus • AIDS, acquired immunodeficiency syndrome • PI, protease inhibitor • PACTG, Pediatric AIDS Clinical Trials Group • GHAC, General Health Assessment for Children • OR, odds ratio • CI, confidence interval


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 STATISTICAL METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As new therapies dramatically extend the lives of people with human immunodeficiency virus (HIV), quality-of-life outcomes, such as pain and psychological distress have become increasingly important indicators of disease manifestation.1 Studies have estimated that the prevalence of pain in adults with acquired immunodeficiency syndrome (AIDS) ranges from 40% to 60%, with pain more frequently reported as the disease progresses.2–5

The prevalence and duration of pain in HIV has been found to be comparable with that of cancer patients.6 In pediatric cancer, pain is mainly attributed to treatment interventions and procedures as opposed to the tumor itself.7–9 Conversely, the cause of pain in HIV is complex and has been attributed to the disease; complications of secondary infections, treatment interventions, and procedures; and non–AIDS-related conditions, such as disk disease and diabetic nephropathy.6,10,11 Oleske et al10 conducted a chart review of 150 children with HIV and found reports of both acute and chronic pain, with only one-third receiving appropriate analgesia. Pain was only managed adequately in the terminal phase of disease. Strong parental denial of the disease, and consequently their child’s pain, was also described. Hirschfeld et al6 found that among 61 children infected with HIV, 59% of the children reported pain related to the disease had adversely impacted their lives. This prevalence rate was supported by the caregivers of whom 55% stated that their children had pain. However, a recent study of the correlation of parent and child’s perception of pain among children undergoing surgery in a tertiary care setting found that caregivers tended to underestimate their child’s pain.12

In the adult population, HIV/AIDS-associated pain is undertreated.3,12,13 Opioids in particular are rarely prescribed.14,15 Breitbart et al5 reported that even in the presence of severe pain, only 6% of patients were prescribed a strong opioid, as recommended by the World Health Organization’s Analgesic Ladder.16,17 Physician and patient barriers to pain management have been identified and include potential side effects and common opioid phobias, such as respiratory depression, constipation from the opioid, lethargy or stupor, nausea or vomiting, and iatrogenic addiction or renewed addiction if the individual has a history of substance abuse.18

Immune suppression has been associated with increased pain.12,19 Among 2650 HIV-infected adults enrolled in the HIV Outpatient Study, pain of unknown cause was observed in those with severe immune suppression (CD4+ <50 cells/uL) as well as increased duration of painful episodes.20 The investigators were unable to attribute pain to specific diagnoses and suggested that the pain was a unique complication of HIV disease.

Uncontrolled pain may also complicate an individual’s clinical course, resulting in an increase of morbidity and mortality. Among 458 adults with AIDS, severe acute abdominal pain was associated with reduced survival.21 Median survival with AIDS among individuals reporting abdominal pain was 180 days compared with 540 days for those without abdominal pain (P < .05). Although in most cases, the authors were able to attribute the patient’s pain to a specific clinical diagnosis, the cause of this pain remained unclear for 8% of the study population.

Since the introduction of protease inhibitors (PIs) in 1996, HIV/AIDS has been rapidly transformed from an imminently terminal disease to a chronic one.22 PIs have succeeded in markedly decreasing the level of HIV RNA virus in many children.23 It is believed that as PI use increases, a decrease in the incidence of opportunistic infections and other common diagnoses often associated with pain etiology will be observed. However, PI use may be associated with pain-related side effects including gastrointestinal symptoms, paresthesia, weakness, and nephrolithiasis.24–27 The study reported here was initiated to evaluate whether there had been a consequent decline in pain reports among HIV-infected children followed since before PIs became available. This study also identifies other factors associated with increased risk of pain and the association of pain and survival.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
STATISTICAL METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Pediatric AIDS Clinical Trials Group’s Late Outcomes Study (PACTG 219) is a prospective cohort study designed to examine the long-term effects of exposure in utero and/or postnatally to HIV and antiretroviral therapies. Children were eligible to enroll in PACTG 219 if they were previously enrolled in a PACTG treatment study. The cohort used in this analysis was restricted to HIV-infected participants enrolled before January 1, 1996, who were still in follow-up on that date. This restriction assured a pre-PI evaluation of pain and allowed up to 4 years of follow-up for each individual. Participants were also required to have a baseline evaluation of pain (the observation taken closest but before January 1, 1996). Participants were observed from January 1, 1996, to December 31, 1999. Pain was assessed biannually until the age of 24 months and then yearly until the participant reached 21 years. The study protocol was approved by each site’s Human Subjects Committee, and informed formal written consent was obtained from the child’s parent or guardian.

Pain is assessed over the previous month using 7 questions from the disease related symptoms section of the General Health Assessment for Children (GHAC).28 The GHAC has been shown to have good psychometric properties as reported by Gortmaker et al.28 The questions addressed the following areas of pain: physical or bodily pain; abdominal pain; headache; mouth or throat pain; chest pain; joint bone pain; and neuritis (defined as pain, numbness or tingling in hands or feet). Caregivers of participants are asked to grade the child’s level of distress over the past 4 weeks using 1 of 6 possible responses: "not at all," " very mildly," "mildly," "moderately," "very much," and "extremely." For the purposes of this analysis, participants with distress reported as moderate or greater to any of the 7 pain-related symptom questions were classified as having pain. We also examined the 7 subtypes individually.

The relationship between opportunistic infections and other common diagnoses and reported pain was also investigated. The most common diagnoses (defined as affecting at least 30 individuals during the period 1995–1999) for PACTG 219 participants were retrieved from the database. Two of us (J.M.O. and P.A.S.) identified whether the diagnosis had painful manifestations. In the absence of a resolution date for the diagnosis, a 30-day duration was assumed for bacterial and viral infections.


   STATISTICAL METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 STATISTICAL METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Demographic and clinical variables including gender, race/ethnicity (white, non-Hispanic, black, non-Hispanic, or Hispanic), and birth weight (under vs over 2500 g), and time varying values for CD4 percentage (categorized as CD4 percentage <15%, 15%–24%, and >=25%), PI exposure, maternal intravenous (IV) drug use (past or current vs none), caregiver (biological mother vs other), comorbid diagnoses, and age (categorized as < years, 5–11 years, and 12–21 years) were examined to investigate their association with overall pain and subtypes.

Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to identify trends in reported pain. Indicator variables were created for each of the 11 diagnoses identified as having painful manifestations. Unadjusted ORs and their corresponding 95% CIs were obtained using logistic regression methods to investigate associations with overall pain at baseline (1995).29 Generalized estimating equation models were used to identify manifest trends in pain as well as each of the 7 pain subtypes.30 Generalized estimating equation methods take into account the intrasubject correlation between successive pain evaluations within a patient over time. The autoregressive working correlation structure was used.

The log rank test was used to compare Kaplan-Meier estimates of survival distributions for groups defined in terms of baseline pain and other covariate values.31 Proportional hazards regression models were used to examine longitudinal associations between survival and pain as well as other time varying covariates.32 The choice of time-varying covariates reflects the intent of our original hypothesis examining the association between pain and survival while adjusting for, rather than examining, the predictive value of these variables.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 STATISTICAL METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 985 HIV-positive children had a baseline pain evaluation (1995) and were in follow-up on January 1, 1996. The proportion of participants having a pain report was very similar in each year between 1995–1999 and varied from 18% to 21%. The GHAC questionnaire was completed for 649 (72%) of the 899 living participants in 1999; 124 (14%) had refused further participation or had moved. The remaining 126 (14%) individuals declined to complete the questionnaire (a common reason given was insufficient time during the clinic visit). Among these individuals, there was no association between a report of pain at baseline and subsequent dropout.

Among the 449 individuals with pain reported at some time during the observation period, 258 had a report at 1 assessment (59%), 109 at 2 assessments (24%), and 82 at 3 or more assessments (17%).

Of the 35 diagnoses observed to occur in at least 30 children in our cohort, 11 were identified as having painful manifestations (Table 1). The proportion of children with each of the diagnoses who had a report of pain varied from 11% for parotitis to 53% for peripheral neuropathy.


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  		TABLE 1. Specified Painful Diagnoses and Their Relation to Pain as Reported by Cohort Participants

 
The proportion of participants who had taken PIs increased over time, increasing to 76% during the 4-year observation period. The occurrence of pain-related diagnoses also decreased significantly throughout follow-up, from 46% to 29% over the 4-year observation period.

Predictors of Pain at Baseline (1995)
The association between pain and selected patient characteristics at baseline are given in Table 2. The odds of a report of pain among participants with severe immune suppression (CD4 percentage <15%) were more than tripled compared with those with minimal or no suppression (CD4 percentage >=25%; OR = 3.14). However, the odds of a report of pain for individuals with mild to moderate suppression (CD4 percentage 15%–24%) were not significantly elevated compared with those with minimal or no suppression (OR = 1.08; 95% CI: 0.65–1.79).


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  		TABLE 2. Association Between Pain and Patient Characteristics at Baseline (1995) (ORs and 95% CIs)

 
The odds of a report of pain for females were 66% greater than for males (OR = 1.66). Increasing age was significantly associated with increased reports of pain. The odds of a report of pain for children age 5 to 11 were increased 69% compared with those under age 5 (OR = 1.69). Among adolescents (age 12 and older) the odds of a report of pain were doubled compared with those for participants under the age of 5 (OR = 2.21). Finally, the odds of a report of pain for black, non-Hispanic participants were 37% lower than for white, non-Hispanic participants (OR = 0.63).

A pain-related diagnosis, caregiver type, maternal history of IV drug use, and low birth weight were not significantly associated with increased reports of pain at baseline among members of this cohort.

Repeated Measures Analysis of Pain
The association between the odds of pain and selected patient characteristics using the repeated pain evaluations obtained through the period 1995–1999 are provided in Tables 3 and 4. As the percentage of CD4 T lymphocyte cells decreased, reports of pain increased. After adjustment for other patient characteristics, those participants with severe or moderate immune suppression were more likely to have a pain report than those with little or no immune suppression (OR = 2.37 and OR = 1.55, respectively). For all 7 pain subtypes, the odds of a pain report increased as the CD4 percentage decreased (Table 4).


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  		TABLE 3. Association Between Pain and Patient Characteristics Over Time (ORs and 95% CIs)

 

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  		TABLE 4. Predictors of Pain Subtypes (ORs and 95% CIs)*{dagger}{ddagger}

 
Females had a report of pain more frequently than males (OR = 1.49). This trend was seen for all 7 pain subtypes (Table 4). There was a marginally significant trend in the cohort for Hispanic and black, non-Hispanic participants to have fewer pain reports than their white, non-Hispanic peers. However, there was no consistent pattern across the 3 race/ethnicity groups for the different pain subtypes. Pain reports were more frequent among older children. Participants aged 12 and over were 60% more likely to report pain than those under the age of 5. There were generally similar trends for each of the 7 pain subtypes.

The odds of a pain report were increased among those with a pain-related diagnosis than among those without (OR = 1.39). This trend was seen for all of the subtypes.

Low birth weight was not significantly associated with overall pain report. It was, however, significantly associated with increased reports of most of the pain subtypes specifically, physical or bodily pain (OR = 1.40), mouth or throat pain (OR = 1.78), and joint bone pain (OR = 1.51). A child cared for by his or her biological mother was 33% less likely to report abdominal pain than those in the care of another family member or person (OR = 0.67).

PI or maternal IV drug use were not associated with increased reports of pain among members of this cohort.

Association Between Survival and Pain
A total of 86 participants died during the observation period (January 1, 1996-December 31, 1999). Of the 180 individuals having a report of pain at baseline, 33 died during follow-up (18%) compared with 53 (7%) of the 805 individuals who did not have a report of pain at baseline. Among the 86 individuals who died, 56 had a report of pain at the last assessment preceding death (65%). A report of pain at baseline was associated with decreased length of survival (P = .001; Fig 1A). Survival was also poorer for participants with CD4 percentage below 15% compared with individuals with higher CD4 percentage (P = .001). Figure 1B details survival probabilities for baseline values of pain and CD4 percentage. Survival was not significantly associated with any other patient characteristics at baseline.



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  		Fig 1. Survival probability curves by (A) baseline pain and (B) baseline pain and CD4 percentage.

 
A multivariate proportional hazards regression model was developed that included race/ethnicity, birth weight, and gender, with time varying covariates for pain, CD4 percentage category, age group, caregiver type, maternal IV drug use, PI use, and comorbid diagnosis as possible predictors of the hazard of death (Table 5). There was a significant association between poorer survival and both the presence of pain and lower CD4 percentage after adjustment for other variables. Individuals with pain were over 5 times more likely to die compared with those who did not report pain (hazard ratio = 5.07). Older children also had better survival. Gender, race/ethnicity, caregiver type, birth weight, and maternal IV drug use were not significantly associated with survival.


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  		TABLE 5. Proportional Hazards Multivariate Regression of Mortality

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 STATISTICAL METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pain is a frequently encountered symptom in HIV-infected children and adolescents. Children infected with HIV are living longer,33 presumably attributable to advances in antiretroviral therapy, and improved prophylaxis therapies. The stated hypothesis predicted that a PI-inclusive therapy might help preserve immune function and delay opportunistic infections by suppressing viral replication and consequently reduce pain. However, although the use of PIs increased, the incidence of both painful diagnoses and mortality decreased significantly during follow-up, the percentage of children having a report of pain remained relatively constant at 20% throughout the observation period.

Immune suppression was highly predictive of the frequency with which patients reported moderate or greater pain. In repeated measures analysis, participants with mild to moderate immune suppression were more likely to have a report of pain than those with minimal or no immune suppression. Individuals with severe immune suppression had even higher odds of a report of pain; 137% higher than those with intact immune systems.

Pain was also more commonly reported for females than males; a finding observed previously in the adolescent literature.34,35 Symptom data from the PRIME-MD study, a cross-sectional analysis of 1000 individuals treated at 4 primary care sites, showed that after adjusting for psychiatric comorbid illness, females were 50% more likely to report symptoms than males.36 The authors attributed their finding to gender differences in social roles and responsibilities as well as differences in the prevalence of depressive and anxiety disorders, which are more common in females. Future studies should examine these issues as well as emotional and behavioral symptoms and disorders and their relationship to pain more closely as they are a potentially important predictor of pain among children with HIV/AIDS.

In our study, as observed in others,35 pain reports also increased with age. However, whether this finding might be explained by the ability of youth and adolescents to articulate adequately the pain they are experiencing compared with younger children is unclear. Future analysis should examine the effects of age on a child’s ability to self-report pain and compare these results to caregiver reports. In addition, given the established associations between gender, age, and increased pain reports in the general pediatric population, evaluation of how much higher the prevalence of somatic pain is in HIV-infected children would be useful.

The association between pain and survival persisted in multivariate analyses adjusted for extent of immune suppression, comorbid illness, PI use, and other factors. This finding further supports the hypothesis that pain may be a unique complication of HIV infection.

A biological explanation for the hypothesis that pain is a unique manifestation of HIV disease may be that these children are oversensitized to pain as a result of neuronal damage during development. Much research has been devoted to the effects of pain on the developing nervous system. It was previously held that because of the plasticity of the developing nervous system in infants, the effects of pain, if felt at all, were temporal.37 Research over the past decade has challenged this belief. Taddio et al38 reported that males circumcised without proper analgesia reported a heightened sensitivity to vaccinations at 4 and 6 months later when compared with males who had received adequate analgesia. More recent animal data suggests that exposure to noxious stimuli during development of the nociceptive neuronal circuitry (the pain pathway) results in a permanent rewiring of the central nervous system.39 The study reported that infant rats whose feet were made sore were hypersensitive to pain as adults. On necropsy, the authors observed that additional neurons had grown in the area surrounding the damaged tissue, resulting in an overrepresentation of the affected area in the central nervous system. Given the similarity between pain system development in rats and humans,39,40 the authors’ speculated that similar deleterious effects may be seen in humans and emphasized the importance of analgesia in neonates undergoing repeated venipuncture or other medical procedures associated with pain. This recommendation was formally put forth in September 2001 in a joint statement from the American Academy of Pediatrics and the American Pain Society on the assessment and management of acute pain in infants, children, and adolescents.41

Infants with vertically acquired HIV infection, who constitute 93% of this cohort, are subjected to a variety of medical procedures including repeated blood draws in the neonatal period. This is particularly true of infants born prematurely, a frequent complication of perinatal HIV infection, averaging 22% across PACTG studies.42 Although evidence exists supporting an association between preterm delivery and alterations in the pain threshold in the general population,43–45 this data were not routinely collected in earlier versions of PACTG 219. However, a review of birth weights indicated that 1 in 5 children in the cohort (N = 195) weighed <2500 g at the time of delivery. Although low birth weight does not always denote preterm delivery, it is the most accurate marker we have to support this phenomenon and was significantly associated with increased reports in most of the pain subtypes, specifically, physical or bodily pain, mouth or throat pain, joint bone pain and neuritis, among members of this cohort. This theory of a neurodevelopmental insult lowering the pain threshold however was not part of the original study design. Future research should examine this relationship in greater detail.

In addition, children exposed to opiates or other illicit substances in utero may require supplementary analgesia to achieve pain palliation. Although analgesia is now recommended for infants undergoing pain-related medical procedures, analgesia administered in the absence of a stress response (pain) may have injurious effects on the developing neuronal circuitry. Newborn rats exposed to morphine when not in pain needed greater amounts of morphine later in life to achieve adequate analgesia.46 The prevalence of exposure to opiates or other illicit substances in utero among PACTG study participants is about 22% .42

Pain management in pediatric HIV infection is complex; psychosocial issues surrounding the use of potent analgesia may exist. Clinicians may be less forthcoming with narcotic prescriptions to children of illicit substance users (current or former) resulting in inadequate analgesia of the child’s pain.47 This aversion on the part of the clinician may transfer to the affected child. Parents with a history of narcotic abuse may be wary of opiate analgesia and subconsciously underestimate the child’s pain. Oleske et al10 reported a strong resistance to the use of narcotics among parents of HIV-infected children. A study of adults who became infected with HIV through intravenous drug use found that these individuals were less likely to receive adequate pain analgesia, reported lower levels of pain relief and a greater degree of psychological distress when compared with patients from other risk factor groups.48 Future research should examine current illicit drug use among caregivers, which may provide additional insight into this association.

As with most observational studies, there is a degree of confounding by indication or severity as sicker children were more likely to receive combination therapy with protease inhibitors earlier.33 We have tried to adjust for this fact by including markers for disease severity, such as CD4 percentage and painful diagnoses.

Our study relied exclusively on caregiver interpretation of the child’s pain as opposed to self-report. Also, our study only evaluates pain over the month before the scheduled study visit and consequently is unable to differentiate between acute and chronic pain (pain of 3 months duration or greater). Although acute pain may become chronic pain, it lacks the psychological manifestations seen in chronic pain and consequently demands a different treatment strategy.

Given the subjective nature of pain, our efforts to classify pain-related diagnoses might have resulted in accurate yet imprecise estimates and impaired our ability to adjust for painful opportunistic infections. A diagnosis was determined to be pain-related based on the clinical experience of the 2 clinicians. Although it is true that pain can come from multiple sources, the clinicians were looking specifically at the relationship with particular diagnoses. The decreased occurrence of pain-related diagnoses might not be observed for other common diagnoses, which alone do not have painful manifestations but may cumulatively contribute to disease progression and consequently to increased pain reports.

Despite enormous therapeutic advances, most notably PIs, pain remains a frequent symptom in pediatric HIV disease. As this population lives longer with this disease in a chronic state, pain management will become an increasingly important issue.


   ACKNOWLEDGMENTS
 
This work was supported by the National Institute of Allergy and Infectious Diseases Pediatric AIDS Clinical Trials Group, the National Institute of Child Health Pediatric and Perinatal HIV Clinical Trials Network, and National Institute of Allergy and Infectious Diseases cooperative agreement AI-41110 for the Statistical and Data Management Center of the PACTG.

The following institutions and individuals participated in PACTG 219:

University of Medicine and Dentistry of New Jersey University Hospital: P. Palumbo, M. J. Hoyt; St Joseph’s Hospital and Medical Center: N. Hutchcon, A. Townley; Cooper Hospital—University Medical Center: A. Feingold, S. Burrows-Clark; University of Rochester: F. Gigliotti, B. Murante; Columbus Children’s Hospital: M. Brady, J. Hunkler; Children’s Hospital of Boston: K. McIntosh, K. Bertelsen; Boston Medical Center: S. Pelton, A. Regan; University of North Carolina: T. Belhorn, E. Pitkin; UCLA: Y. Bryson, M. Dillon; Children’s Hospital of Los Angeles: J. Church, C. Salata; Long Beach Memorial: A. Deveikis, L. Melton; Harbor-UCLA Medical Center: M. Keller, J. Hayes; Johns Hopkins University: N. Hutton, S. Marvin; University of Maryland: P. Vink, K. Fore; Baylor College of Medicine/Texas Children’s Hospital: W. Shearer, K. Owl; Chicago Children’s Hospital: R. Yogev, D. Fonken-Cloutier; Cook County Hospital: K. Boyer, E. Gliwa; University of Chicago Children’s Hospital: J. Englund, P. Lofton; Women and Children’s HIV Program: D. Johnson, B. Wolfe; Columbia Presbyterian Medical Center: A. Gershon, M. Donahue; Incarnation Children’s Center: A. Gershon, P. Miller; Cornell University-New York Presbyterian Hospital: A. Gershon, A. Monroe; University of Miami: G. Scott, P. Bryan; Jackson Memorial Hospital: MJ. O’Sullivan, P. Bryan; New York University-Bellevue Hospital: W. Borkowsky, N. Deygoo; University of California San Francisco -Moffitt Hospital: D. Wara, D. Trevithick; San Francisco General: D. Wara, M. Shannon; Children’s Hospital, Oakland: A. Petru, T. Courville; Pheonix Children’s Hospital: J. Platt, L. Clarke-Steffen; University of California San Diego: S. Spector, M. Caffery; Duke University: R. McKinney, Jr, J. Swetnam; St. Jude’s Children’s Research Hospital: P. Flynn, J. Utech; University of Puerto Rico: I. Febo Rodriguez, S. Nieves; Children’s Hospital of Philadelphia: S. Starr, C. Vincent; Children’s Hospital of Seattle: L. Frenkel, K. Mohan; Bronx Lebanon Hospital Center: A. Wiznia, W. Biernick; Children’s Hospital of Washington, DC: H. Spiegel, J. Ziegler; Tulane University: R. Van Dyke, M. Cowie; University of Massachusetts: K. Luzuriaga, D. Christian; Baystate Medical Center: B. Stechenberg, M. Toye; University of Connecticut/Connecticut Children’s Medical Center: J. Salazar, G. Karas; Schneider Children’s Hospital: V. Bonagura, C. Colter; Metropolitan Hospital Center; M. Bamji, K. Novita; Harlem Hospital: E. Abrams, D. Calo; University of Cincinnati: J. Mrus, N. Boosveld; SUNY-Brooklyn: E. Handelsman, D. Swindell; North Shore University Hospital: S. Pahwa, L. Rodriquez; St. Christopher’s Hospital: M. Bagarazzi, R. Buie; Oregon Health Sciences University: Lewis P, Croteau R; Bronx Lebanon Hospital Center: S. Bakshi, C. Nubel; St Luke’s/Roosevelt Hospital Center: S. Arpadi, R. Warford; Cornell University: R. Johan-Liang, K. O’Keefe; University of Illinois: K. Rich, J. Camacho; Emory University Hospital: S. Nesheim, R. Dennis; San Juan City Hospital: E. Jimenez, M. Thurin; Children’s Hospital of the King’s Daughters: T. Rubio, D. Sandifer; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson: S. Gaur, L. Cerrachio; Ramon Ruiz Arnau University Hospital: W. Figueroa, E. Reyes; Medical College of Georgia: W. Foshee, S. Cobb; University of South Alabama: M. Mancao, J. Bebawy; The Medical Center: R. Stauffer, D. Barnes; Medical University of South Carolina: G. Johnson, A. Cope; Yale University School of Medicine: W. Andiman, D. Schroeder; SUNY Health Science Center at Syracuse: C. Cunningham, K. Contello; SUNY-Stony Brook: S. Nachman, M. Davi; Children’s Hospital of Michigan: E. Moore, C. Cromer; Children’s Hospital at Albany Medical Center: N. Wade, M. Adams; Children’s Hospital of Dallas: J. Squires, D. Perry; Howard University Hospital: S. Rana, P. Yu; University of Alabama at Birmingham: R. Pass, T. Byars; Los Angeles County Medical Center/University of Southern California: A. Kovacs, E. Operskalski; Montefiore Medical Center/Albert Einstein College of Medicine: A. Rubinstein, G. Krienik; University of Florida Health Sciences Center: M. Rathore, M. Eagle; University of Mississippi: H. Gay, S. Sadler; Medical College of Virginia: S Lavoie, T Smith; Denver Children’s Hospital: E. McFarland, C. Salbenblatt; North Broward Hospital District: A. Puga, D. Cruz; University of Florida-Gainesville: J. Sleasman, C. Delaney; Palm Beach County Health Department: G. Stiebel-Chin, P. Vann; Case Western Reserve University: M. Chance; Children’s Hospital of New Jersey: G. McSherry, D. Storm; University of Texas Health Sciences Center, Houston: M. Cantini; Los Angeles Children’s Hospital: T. Coates; Kings County Hospital Center: H. Mendez, H. Bergin; Mount Sinai Medical Center: H. Sacks, E. Chusid; and Beth Israel Medical Center: R. Bonforte, A. Marshak.


   FOOTNOTES
 
Received for publication Oct 3, 2001; Accepted Feb 20, 2002.

Reprint requests to (D.M.G.) Center for Biostatistics in AIDS Research, Harvard School of Public Health, 655 Huntington Ave, FXB 553, Boston, MA 02115. E-mail: gaughan{at}sdac.harvard.edu


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 STATISTICAL METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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