PEDIATRICS Vol. 106 No. 3 September 2000, pp. 540-546

Effects of Negative Life Events on Immune Suppression in Children and Youth Infected With Human Immunodeficiency Virus Type 1

Lois C. Howland, DrPH, RN, Steven L. Gortmaker, PhD, Lynne M. Mofenson, MD, Cathie Spino, ScD, Jane D. Gardner, ScD, Heather Gorski, MA, Mary Glenn Fowler, MD, MPH^§, and James Oleske, MD, MPH^¶

From the ^* Department of Maternal and Child Health, Harvard School of Public Health, Boston, Massachusetts;  Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts; ^§ Efficacy Trials Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland;  Pediatric, Adolescent and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; and the ^¶ Department of Pediatrics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey.

	ABSTRACT

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Objectives.  To evaluate the association of negative stressful life events experienced over 12 months and the risk of moderate to severe immune suppression among children and youth infected with human immunodeficiency virus type 1 (HIV-1).

Methods.  Longitudinal study of 618 HIV-1-infected children, baseline ages 1 to 20 years (mean age: 6.4 years), who completed 52 weeks of participation in the Pediatric Late Outcomes Study (Pediatric AIDS Clinical Trials Group Protocol 219). Severity of immune suppression was indicated by the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System, based on CD4 percentages. The total number of negative life eventscategorized as none, 1, or >1 life event reported as having occurred in the previous 12 months (previous 6 months for children <3 years of age)was the predictor variable. Multiple logistic regressions were estimated to assess the relationship of negative life events and immune suppression at outcome, controlling for baseline measures of immune suppression, continuous CD4%, negative life events, age, race/ethnicity, gender, primary caretaker, education level of caretaker, and acquired immunodeficiency syndrome status.

Results.  At week 52, 379 subjects (61% of total study population) had moderate to severe immune suppression. Of 275 children with normal immune function at baseline, 68 (24.7%) subsequently developed moderate to severe suppression levels by week 52 of follow-up. Of 343 children with immune suppression at baseline, 32 (9.2%) had recovered to normal CD4% levels by week 52. More than 1 negative life event was associated with an increased risk (prevalence) of immune suppression (odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.44,5.31), controlling for baseline CD4%, total life events, and other covariates. Children without immune suppression at baseline who experienced >1 negative life event had an increased incidence of immune suppression (OR: 2.93; 95% CI: 1.34,6.39), controlling for baseline covariates.

Conclusions.  Results indicate that negative stressful life events increase the risk of children with HIV-1 infection having impaired immune function. Further research is needed to identify potential mechanisms of the relationship between stressful life events and impaired immune function. These mechanisms include psychoneuroendocrinologic response and difficulties in adherence to therapy after exposure of a child to major negative life events.  Key words:  CD4 percentile, life events, pediatric human immunodeficiency virus disease.

CD4 cell counts are important surrogate markers of disease progression in children infected with the human immunodeficiency virus type 1 (HIV-1).^1,2 It is important to identify non-HIV-related factors that can affect CD4 cell count to more effectively plan interventions to maintain or improve the health of these children. Although some research has suggested a link between negative stressful life events and subsequent CD4 cell counts in adults,^3,4 to date no research has examined prospectively the relationship of negative stressful life events and CD4 cell counts in children infected with HIV-1.

The prevalence of children with HIV-1 infection in the United States is currently unknown, but it was estimated that there were 12 240 children living with HIV infection in the United States at the end of 1993.⁵ An estimated 6000 infected women give birth annually. If an 8% transmission rate is assumed since 1994, the year it was shown that zidovudine reduced prenatal transmission by two thirds, a conservative estimate is that 15 000 HIV-infected children are currently alive in the United States.⁶ Use of zidovudine prophylaxis to reduce perinatal transmission promises to markedly reduce, but not eliminate, incident cases of perinatally acquired pediatric HIV-1 infections.^7,8 Additionally antiretroviral and adjunctive therapies are now available that can improve and preserve immune status for children with HIV-1 infection.^9,10 As a result, the number of children living with HIV infection in the United States has continued to increase.

Although newer surrogate markers such as plasma HIV-1 RNA copy numbers are being used to monitor HIV-1 disease progression, CD4 cell count remains an important indicator of immune function. Studies in adult and pediatric HIV-infected individuals have shown that CD4 cell count and percent are independently predictive of disease progression and mortality, even after adjustment for plasma HIV RNA copy number.^1,2,11,12

Previous research has demonstrated that negative stressful life events are associated with a subsequent apparent increase in infectious diseases and other medical conditions in children, including streptococcal infection,¹³ respiratory infections,¹⁴ insulin-dependent diabetes mellitus,¹⁵ excess bleeding in children with hemophilia,¹⁶ behavioral¹⁷ and psychiatric problems,¹⁸ and a variety of other morbid conditions.¹⁹ Research in psychoneuroimmunology has strongly suggested stress attributable to negative life events is a contributing factor in immune dysfunction and, specifically, in adult HIV-1 disease progression.^4,20 Children with HIV-1 disease are more likely to come from families that experience significant and frequent negative life events. These families often experience poverty, problems with substance abuse, and frequent home disruption attributable to changes in housing and household composition.^21-23 It is not known what effects stressful negative life events may have on HIV-1 disease progression in infected children.

The primary purpose of this prospective study was to examine the association of negative stressful life events with the risk of immune suppression (as defined by the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System in 1994)²⁴ among children with HIV-1 infection followed longitudinally over 1 year.

	METHODS

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Patient Population

We analyzed data collected as part of the Pediatric Late Outcomes Study-Pediatric AIDS Clinical Trials Group Protocol 219 (PACTG 219). PACTG 219 began enrollment of subjects April 1, 1993, with the primary objective to identify late outcomes in children previously or currently enrolled in pediatric acquired immunodeficiency syndrome (AIDS) clinical trials conducted under the auspices of the PACTG. The investigational review board of each research institution approved this research protocol, and formal written consent from the child's parent or guardian and, when appropriate, the assent of the child was obtained before study enrollment of children in PACTG 219. Longitudinal data from the Pediatric Late Outcomes Study were used to analyze the association between reported negative stressful life events and immune suppression.

Children were enrolled in this study through Pediatric AIDS Clinical Trials Units located in major clinical research centers across the United States and Puerto Rico. Children eligible for enrollment into PACTG 219 include HIV-infected children previously or currently enrolled in a PACTG-sponsored clinical trial. Also eligible were HIV-exposed infants enrolled in neonatal treatment or vaccine studies or born to HIV-infected women enrolled in a PACTG perinatal trial. In the latter case both children who were eventually diagnosed as uninfected as well as those children who were infected were included in PACTG 219.

Enrolled children were followed with periodic assessments of immunologic and other laboratory parameters, and clinical and neuropsychologic evaluations through 21 years of age. PACTG 219 study participants were seen for study visits at entry to the study and at follow-up visits at either 6-month (for children <3 years old) or 12-month (children 3 years old) intervals until the child's 21st birthday or until the child was lost to follow-up. Children eligible for the current analysis were HIV-infected children enrolled in PACTG 219 who were between the ages of 12 months and 20 years of age and who had completed at least 1 year of study follow-up. Children classified as either not HIV-1-infected or of indeterminate HIV-1 infection status, and children with duplicate or missing critical enrollment data were not included in the analysis.

Between April 1993 and April 1996, 801 HIV-1-infected children between 12 months and 20 years of age had completed at least 52 weeks of PACTG 219 participation. Fifty-five children (6.8%) were missing CD4% subset data at week 52 and were excluded from the analysis. Approximately 16% of children (n = 128) were further excluded from the analysis attributable to missing important covariate data at either baseline or week 52; therefore, a total of 618 children were included in the analysis cohort.

Children with missing data excluded from the final study sample were more likely to have primary caretakers who were someone other than their biological parent (P = .001) and to have a caretaker who had a higher mean education level (P = .04). Otherwise, the children excluded in the analysis sample did not vary significantly from the final sample. It is possible that those children with missing data represent children more likely to be in the care of a foster parent or other family member who had limited information on the child, but we were unable to determine this from available data.

All children in the analysis sample had HIV-1 infection confirmed by an AIDS Clinical Trials Group (ACTG)-certified laboratory. HIV-1 status was determined to when the child was older than 18 months and had been shown to be HIV-1-antibody-positive by enzyme-linked immunosorbent assay and confirmatory Western blot analysis on 2 separate determinations. Children under 18 months old were considered HIV-1-infected if they had 2 or more positive virologic assays on peripheral blood samples: HIV coculture of peripheral blood mononuclear cells, HIV DNA polymerase chain reaction, or p24 antigen testing.

Laboratory Methods

CD4 Lymphocyte Percentage Venous blood samples were collected at each study visit to measure CD4 and other lymphocyte subsets. Samples for lymphocyte subset enumeration were collected in test tubes containing ethylene diamine tetraacetic acid, kept at room temperature and analyzed by flow cytometry within 24 hours by laboratories participating in the ACTG Flow Cytometry Quality Assurance Program.²⁵ The process of direct immunofluorescence with fluorescein isothiocyanate or phycoerythrin-conjugated mouse monoclonal antibodies (Becton Dickinson, Mountain View, CA) determined percentages of CD4 lymphocytes. Because CD4% is less subject to intrapatient variation and age-related change than absolute CD4 count, the analyses used CD4% as the measure of immune function.²⁶ Immunologic status was categorized by the severity of immunosuppression according to the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System in 1994.²⁴ Immune suppression at baseline and week 52 of the study was coded as a dichotomous outcome of interest in this analysis. CD4% was analyzed as both a continuous variable as well as a dichotomous variable (no immune suppression [CD4%: >24] vs moderate [CD4%: 15-24] or severe [CD4%: <15] immune suppression).

Data Collection and Definitions

Negative Stressful Life Events At entry and at each follow-up visit, parents or guardians were asked to report specific major negative life events that occurred since the child's last visit. For those participants who were 3 years of age and older (86%), this meant events recalled over the past 12 months. For those children <3 years old (14% of subjects), this meant events recalled over the past 6 months. We calculated a total event score for both the week 0 and week 52 visits; this was an unweighted sum of reported negative life events. Previous research has demonstrated that weighted (life events assigned varying relative weights) and unweighted sums of stressful life events are closely correlated.^27,28 Each event was coded 1 if the event occurred 1 or more times since the last study visit and 0 if otherwise. For example, a change in housing may have occurred more than once in a 6- to 12-month period, but the child's total event score would only be increased by 1 for this type of event.

Other Covariates Other potentially confounding baseline covariates measured at week 0 included: total event score, age in years, sex, race/ethnicity, primary caretaker, education level of the primary caretaker, AIDS diagnosis, continuous CD4% count, and immune suppression category for percent CD4 cell counts. We included AIDS diagnosis at baseline because a child with AIDS diagnosis at baseline is assumed to have a more advanced stage of disease that may affect the rate of CD4 cell depletion. An AIDS diagnosis is conferred if a child experiences 1 or more AIDS-defining events or conditions, such as Pneumocystis carinii pneumonia or HIV encephalopathy.³² The baseline total event score was included to control for the preexisting level of major life events occurring within a household.

Statistical Methods

Proportional differences were compared using ² tests; differences in means of continuous variables were evaluated with t tests. Logistic regressions were calculated to estimate the relationship between the number of negative life events reported at week 52 and immune suppression category at week 52, controlling for baseline covariates delineated above. All analyses were performed with the SAS Statistical Program (SAS, Cary, NC).³³ All P values reported are 2-tailed.

	RESULTS

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The mean age of the 618 children in the study cohort was 6.4 years, sex distribution was approximately equal, and the racial/ethnic distribution was similar to that observed for reported pediatric AIDS cases nationally in 1996.³⁴ Table 1 summarizes the baseline demographic and HIV-1-related characteristics of the sample. The associations of baseline characteristics with prevalence of immune suppression (those children with CD4% levels in the moderate to severe immune suppression range) at week 52 are also provided in Table 1. Baseline variables associated with immune suppression at week 52 included older age (P = .001), an AIDS diagnosis (P = .001), immune suppression (P = .001), and lower mean CD4% level (P = .0001).

In the analysis cohort there were 343 children (56%) at baseline with CD4% levels <25 (moderate to severe immune suppression). Of the 275 children with normal CD4% levels at baseline, 68 (25%) subsequently developed moderate to severe immune suppression levels. There were 32 children (9%) who initially had moderate to severe immune suppression levels of CD4% who recovered to normal CD4% levels by week 52.

We calculated logistic regressions to examine the association of reported categories (none, 1, and 2 or more) of negative life events over 52 weeks and the odds of prevalent immune suppression at week 52 (Table 2). Crude odds indicate an increased risk of 2.11 (95% confidence interval [CI]: 1.38,3.23) of immune suppression at week 52 if a child had reported 2 or more life events compared with children reporting no life events. After controlling for the baseline immune suppression category and other potential confounders, the risk increased to 2.76 (95% CI: 1.44,5.31; P = .002).

Among those children without immune suppression at baseline, we calculated logistic regressions to examine the association of negative life events with the incidence of immune suppression that developed over the 1-year follow-up. These results indicated a crude odds of 2.91 (95% CI: 1.5,5.64) for developing suppressed CD4% levels over 52 weeks if a child reported 2 or more negative life events. Adjusting for above-mentioned covariates using multiple logistic regression resulted in odds of 2.93 (95% CI: 1.34,6.39; P = .007) of developing immune suppression for children with 2 or more versus no events.

There was no evidence that negative life events were related to immune recovery among children with impaired immune function at baseline (n = 32). We also estimated multiple logistic regressions using continuous total negative life event score (0-8 events), controlling for the covariates mentioned above. The odds of developing immune suppression by week 52 were 1.38 (95% CI: 1.1,1.7; P = .003) for each negative life event. In other words, a child's risk of developing immune suppression increased by 38% for each additional negative life event reported over the 12-month follow-up period.

	DISCUSSION

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The purpose of this study was to prospectively examine the association of negative stressful life events with the risk of immune suppression in HIV-infected children. Among the 618 children followed in the prospective Pediatric Late Outcomes Study with complete data for at least 52 weeks, we have shown that >1 negative stressful life event was associated with a significantly increased risk of the prevalence of immune suppression at week 52, controlling for baseline measures of CD4%, total life event score, and other potentially confounding covariates. Similar results were found in predicting incidence of immune suppression over this 12-month follow-up.

These data are consistent with the theoretical model proposed by Antoni et al,²⁰ in which perceived stress begins a cascade of neurohormonal responses affecting immune response in HIV-infected individuals. Specifically, perceived stress, particularly stressful situations that the individual is unable to control or modify, results in increased circulating corticosteroid levels leading to subsequent immune suppression. Dunn³⁵ cites experimental and empirical stress research that documents significant associations between the presence of stress and increased levels of stress hormones (glucocorticoids [cortisol, adrenocorticotropin hormone], corticotropin-releasing factor, catecholamines [epinephrine, norepinephrine]) and immune suppression (increased CD8 cell count, decreased CD4 cell count, decreased naturalkiller cell count and activity). Although individual children may have differential responses to specific events (eg, children in foster care may sustain more or less stress from the death of a parent depending on the age of the child and the length of time in foster care), the events studied have been shown to contribute stress to children's lives.^17,29-31

This study is limited in its ability to fully characterize the relationship of stress from negative life events and moderate to severe immune suppression. Our statistical power to detect significant differences was diminished by the loss of ~23% of the original analysis sample attributable to missing key data.

Further, because we were analyzing data collected for purposes different from our analysis objectives, we were only able to examine those negative life events recorded on the PACTG 219 data collection instrument. Important other stressful negative life events that could occur in the lives of children with HIV-1 infection, such as change of caretaker, parental incarceration, the addition of adults to the household, the birth of a sibling, or the separation of parents, were not recorded. A more exhaustive list of possible negative life events may have revealed an even more substantial association with risk of immune suppression. We had initially included hospitalization as one of the reported negative life events; however, this event is closely correlated with disease progression. Hospitalization potentially also serves as an important source of stress in a child's life. Because hospitalization could be collinear with both the predictor and outcome variables, we decided against including this event in the event measure.

Research has indicated that social support can significantly modify a child's response to stress by improving their ability to cope.³⁶ An important source of social support to the child is their primary caretaker. If the primary caretaker has fallen ill or is hospitalized, the impact of the event may be compounded by the loss of a primary source of social support. Our study is limited by the lack of data on social support within the household, which could be an important mediating factor in determining the impact of stressful life events and health outcomes.

One possible alternative explanation for the observed relationship between increased negative stressful life events and immune suppression is that family disruption caused by major life events may lead to lowered adherence to a therapeutic regimen. Missed doses of antiretroviral medication may cause rebound in viral activity, a subsequent increase in viral load, and eventual further destruction of CD4 cells. Measures of therapy adherence or of viral load were not available and, hence, we could not explore this potential mediating mechanism. Although the clinical research sites attempt to closely monitor adherence to medication protocols, more valid and reliable measures of therapeutic compliance by individual study subjects are currently under study. Adherence measures are being developed within the PACTG to attempt to document difficulties occurring in compliance and possible factors that may affect this important factor. This is a topic of future study. Stored specimens will be used in the future to evaluate HIV RNA copy number in these patients. Future studies should, therefore, allow for a more complete analysis of the relationship between a child's exposure to stressful negative life events and that child's subsequent immune function.

Previous research examining the relationship of stressful life events in individuals with HIV-1 infection has been limited to adult cohorts using cross-sectional and convenience samples. Limited prospective studies with children demonstrating significant relationships between negative life events and subsequent disease have not included children with HIV-1 disease. Although limited in its scope, this study provides evidence to suggest that children with HIV-1 infection may, like children with other chronic disease conditions, sustain an increased risk for more rapid disease progression when they experience stressful negative life events. The influence of negative life events on immune function may be a confounding covariate in clinical trial studies. Further study involving more sensitive measures of HIV disease progression (such as RNA copy number), a more complete description of stressful events and measurement of important potential mediating factors, such as social support measures and therapy adherence, is needed. This will allow for a clearer understanding of the stress-disease progression relationship in children infected with HIV-1.

	CONCLUSION

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Children who are infected with HIV-1 are often exposed to many negative stressful life events. For some children, negative stressful life events may be an important potential cofactor in HIV disease progression. Nondisease factors that may influence immune suppression are important to understand as strategies are developed to support and enhance the child's overall health status. Social support and supportive therapy in the form of increased home visits, provision of counseling, assignment of case managers, and assistance for families with adherence to antiretroviral therapies have been recommended by the Pediatric Supportive Care/Quality of Life Committee of the PACTG to improve the quality of life for children with HIV-1 disease.³⁷ These activities may also act to mediate effects of stress when children and their families experience major negative life events. Increased social support to HIV-1-infected children and their families when major negative life events occur may be a noninvasive intervention that can sustain a child's immunologic status.

	APPENDIX

The following institutions and individuals participated in PACTG 219:

University of Rochester: F. Gigliotti, B. Murante; Columbus Children's Hospital: M. Brady, J. Hunkler; Case Western Reserve: M. Chance; Children's Hospital of New Jersey: G. McSherry, D. Storm; Children's Hospital of Boston: K. McIntosh, E. Cooper, N. Karthas; Boston Medical Center: S. Pelton, A. Regan; University of North Carolina: W. Lim, E. Pitkin; University of California Los Angeles: Y. Bryson, M. Dillon; Children's Hospital of Los Angeles: J. Goldsmith, Z. O'Keefe; Long Beach Memorial: A. Deveikis; Harbor University of California Los Angeles Medical Center: M. Keller; Johns Hopkins University: R. Livingston, N. Hutton; University of Maryland: P. Fink, J. Farley; Baylor: W. Shearer, C. Hanson; Chicago Children's Hospital: R. Yogev, D. Fonken; Cook County Hospital: K. Boyer, C. Booth; University of Chicago Children's Hospital: D. Johnson, P. Lofton; Columbia Presbyterian Medical Center: J. Pitt, M. Donahue; Incarnation Children's Center: S. Nicholas, L. Nielson; University of Miami: G. Scott, C. Goldberg; Mount Sinai Medical Center: H. Sacks, E. Chusid; Beth Israel Medical Center: R. Bonforte, A. Marshak; New York University-Bellevue Hospital: W. Borkowsky, S. Deygoo; University of California San Francisco: D. Wara, D. Trevithick; University of California San Diego: S. Spector, C. McIvor; Duke University: R. McKinney, Jr, L. Ferguson; Saint Jude's Children's Research Hospital: P. Flynn, W. Hughes; University of Puerto Rico: L. Flores, Z. Rivera; Children's Hospital of Philadelphia: R. Rutstein, C. Vincent; Children's Hospital of Seattle: M. O'Hara, K. Mohan; Bronx Lebanon Hospital Center: A. Wiznia, W. Biernick; Children's Hospital of Washington, DC: T. Rakusan, S. Zamer; Tulane University: R. Van Dyck, M. Silio Post; University of Massachusetts: K. Luzuriaga, J. L. Sullivan, D. Christian; Baystate Medical Center: B. Stechenberg, M. Toye; University of Connecticut/Connecticut Children's Medical Center: P. Krause, G. Karas; University of Texas-Houston Health Science Center: M. Cantini; Los Angeles Children's Hospital: T. Coates; Schneider Children's Hospital: S. Schuval, C. Colter; Metropolitan Hospital Center; M. Bamji, K. Novita; Harlem Hospital: E. Abrams, M. Frere; State University of New York-Brooklyn: S. Fikrig, D. Swindell; North Shore University Hospital: S. Bakshi, L. Rodriquez; Saint Christopher's Hospital: H. Lischner, A. Kamrin; Cornell University: J. Cervia, K. O'Keefe; University of Illinois: K. Rich, J. Camacho; Emory University Hospital: S. Nesheim, L. Meadows; San Juan City Hospital: E. Jimenez, M. Rivera; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson: S. Gaur, P. Whitley-Williams; Ramon Ruiz Arnau University Hospital: R. Aguayo, E. Reyes; Kings County Hospital Center: H. Mendez, H. Bergin; Medical University of South Carolina: G. Johnson, E. Matters; Yale University School of Medicine: W. Andiman, D. Schroeder; State University of New York Health Science Center at Syracuse: L. Weiner, K. Contello; State University of New York-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. Lepow; Children's Hospital of Dallas: D. Ramirez, A. Winborn; Howard University Hospital: S. Rana, H. Fink; University of Alabama at Birmingham: R. Pass, R. Bagely; Los Angeles County Medical Center/University of Southern California: A. Kovacs, E. Fillingim; Montefiore Medical Center: D. Monte; University of Florida Health Science Center: M. Rathore, C. Martin; University of Mississippi: H. Gay, S. Sadler; Virginia Commonwealth University: S. Lavoie, T. Smith; Denver Children's Hospital: B. McFarland, J. Kappius; North Broward Hospital District: A. Puga, P. Munger; University of Florida-Gainesville: J. Sleasman, K. Klubektanz; Palm Beach County Health Department: G. Stiebel-Chin, P. Vann; PACTG Statistical and Data Analysis Center (Harvard School of Public Health): R. Gelber; and Data Management Center (Frontier Science Technology Research Foundation, Inc): B. Cunningham.

	ACKNOWLEDGMENTS

This work was supported under the auspices of the PACTG of the National Institute of Allergy and Infectious Diseases and the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

The members of PACTG 219 are gratefully acknowledged for their support of this research: Sophia Lee, MS; Bethanne Cunningham, BA, MS; Mary Culnane, MS, CRNP; and Jennifer Post, RN, BSN.

	FOOTNOTES

Dr Howland is currently affiliated with the Graduate School of Nursing, University of Massachusetts, Worcester, Massachusetts.

Dr Spino is currently affiliated with Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan.

Dr Fowler is currently affiliated with the Centers for Disease Control and Prevention, Atlanta, Georgia.

Received for publication Feb 1, 1999; accepted Jan 20, 2000.

Reprint requests to (L.C.H.) Graduate School of Nursing, University of Massachusetts, 55 Lake Ave N, Worcester, MA 01655-0115. E-mail: lois.howland{at}umassmed.edu

	ABBREVIATIONS

HIV-1, human immunodeficiency virus type 1; PACTG 219, Pediatric AIDS Clinical Trials Group Protocol 219; AIDS, acquired immunodeficiency syndrome; ACTG, AIDS Clinical Trials Group; CI, confidence interval; OR, odds ratio.

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