Growth as a prognostic indicator in children with human immunodeficiency virus infection treated with zidovudine

Growth as a prognostic indicator in children with human immunodeficiency virus infection treated with zidovudine Ross E. M c K i n n e y , Jr., MD, C a t h e r i n e Wilfert, MD, a n d t h e AIDS Clinical Trials G r o u p Protocol 043 Study G r o u p ~ From the Departments of Pediatrics and Microbiology, Duke University Medical School, Durham, North Carolina, and the Pediatric AIDS Clinical Trials Group

Objective: To assess measures of growth as prognostic indicators in response to zidovudine treatment in children with symptomatic human i m m u n o d e f i c i e n c y virus infection. Methods: We retrospectively assessed data from AIDS Clinical Trials Group Protocol 043, an open-label, phase II study of oral zidovudine therapy (180 m g / m 2 per dose every 6 hours) in children with human i m m u n o d e f i c i e n c y virus who have severe symptoms. Several variables were e v a l u a t e d for their prognostic significance: CD4 + lymphocyte percentage; rates of weight gain and linear growth; entry weight, height, and weight-for-height z scores for age; race; gender; age; and route of transmission. Results: The overall survival rate as of April I, 1992 (4 years after study initiation), was 44%, with a median survival of 37.9 months. The risk of death was greatest in children with CD4 + lymphocyte p e r c e n t a g e s <20% (relative risk, 3.49), but was also increased in children who had a weight-for-age z s c o r e < - 2 on entry to the study (relative risk, 1.53) and in those who failed to gain weight at the 25th percentile rate or greater during the first 6 months of therapy (relative risk, 2.03). These three factors, as well as race and gender, were found to be significant predictors in a multivariate, proportional-hazards model of survival. Entry height-for-age and height growth rates did not have predictive value for survival in univariate or multivariate analyses. Conclusions: Weight-for-age and rate of weight gain are important, easily obtained, and inexpensive prognostic indicators in children with symptomatic human i m m u n o d e f i c i e n c y virus treated with zidovudine. Both were less predictive of survival than the entry CD4 + lymphocyte percentage. (J PEDIATR1994;125:728-

33)

Supported in part by the AIDS Clinical Trials Group, National Institute of Allergy and Infectious Diseases, and the Burroughs Wellcome Co. Presented in part in abstract form at the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La., Oct. 18, 1993, and at the Society for Pediatric Research Meeting, Seattle, Wash., May 4, 1994. Submitted for publication March 7, 1994; accepted June 3, 1994. Reprint requests: Ross McKinney, Jr., MD, Box 3461, Duke University Medical Center, Durham, NC 27710.

728

aThe nine study sites and their lead investigators were as follows: Johns Hopkins School of Medicine (John F. Modlin, MD), Duke University Medical Center (Catherine Wilfert, MD), New Jersey Children's Hospital (Edward M. Connor, MD), Children's Hospital Medical Center, Boston (Kenneth Mclntosh, MD), New York University School of Medicine (William Borkowsky, MD), University of Miami School of Medicine (Gwendolyn Scott, MD), University of California, San Francisco (Peggy Weintrub, MD), Children's Hospital of Los Angeles (Edward Gomperts, MD), and the National Cancer Institute (Philip A. Pizzo, MD). 9/20/58225

The Journal o f Pediatrics Volume 125, Number 5, Part 1

Young infants with human immunodeficiency virus infection usually have growth delay. Within the first few months of life the typical child with HIV infection is shorter and weighs less than an uninfected control subject. 1 In contrast, children in the later stages of infection often have a progressive pattern of absolute weight loss, frequently associated with diarrhea and anorexia, and a decrease in their weight-for-height. Administration of zidovudine appears to have a beneficial effect on weight gain despite the initially poor weight status of the children .2 Subsequent studies have also suggested that weight gain may be an indicator of antiretroviral therapeutic efficacy.3, 4 Anecdotal cases suggest that for children with zidovudine-resistant virus, changing therapy to an antiviral agent to which their virus is susceptible may improve the rate of growth. 3 Other studies have suggested that growth is a relatively insensitive short-term predictor of survival.4 The following three hypotheses were tested in this investigation: (1) the rate of weight gain of symptomatic HIV-infected children in response to zidovudine therapy predicts the probability of survival; (2) CD4 + lymphocyte counts and percentages are more important than growth rates as predictors of survival; and (3) the additional information gained by assessing growth is a useful prognostic indicator. METHODS

The AIDS Clinical Trials Group Protocol 043 was a phase II study of zidovudine administered orally at 180 m g / m 2 per dose every 6 hours. 2 A total of 88 patients were enrolled between April 1988 and January 1989. By entry criteria, the children were between 3 months and 13 years of age and had severe, symptomatic HIV disease. Sixtyeight children (77%) were infected perinatally. Height and weight measurements were obtained every 4 weeks for 1 year. The study concluded in May 1990. Follow-up data regarding survival status and dates of death were obtained as of April 1992 for all 88 patients. The study was performed at nine sites. The protocol did not specify a method for height and weight measurements. The height and weight values were converted to age-specific z scores by using the anthropomorphy unit of Epi Info, version 5 (Centers for Disease Control and Prevention, Atlanta, Ga.). The z scores are equivalent to a standard deviation unit. A height-for-age z score of - 1 means that a child's height is 1 SD below the age- and gender-specific mean height for the normal population. Approximately 98% of normal children are taller than a height-for-age z score of - 2 . Growth rate (velocity) calculations were made by standard incremental growth charts. 5 Growth velocity percentiles were calculated for the 70 children who had 20 or more

M c K i n n e y et al.

729

weeks of follow-up, and were divided into 8 percentile ranges (<3, 3 to <10, 10 to <25, 25 to <50, 50 to 75, >75 to 90, >90 to 97, and >97). The sensitivity and specificity of each growth measure for the mortality rate were calculated with the following formulas: Sensitivity = Number of children who died with an abnormal measure/Number who died

(1)

Specificity = Number of children who lived with a normal measure/Number who lived

(2)

Relative risk calculations for entry variables were performed by using Epi Info for all 88 children and for growth rates on the 70 patients with adequate time of study enrollment. Only 87 patients were included in the weight-forheight analyses because one girl was too old for the weightfor-height charts (>120 months of age). The CD4 + lymphocyte counts and percentages were obtained by standard flow cytometric methods. Both the CD4 + lymphocyte counts and percentages were analyzed statistically, but because the results of both measures were similar, only the CD4 + lymphocyte percentages are reported. An additional benefit to the use of CD4 + lymphoHIV

Human immunodeficiency virus

[

cyte percentages instead of counts is the smaller amount of age-dependent change, particularly after the first year of life.6 Most statistical calculations were performed with the Statistical Analysis Systems software version 6.08 (SAS Institute, Inc., Cary, N.C.). Group correlations between CD4 + lymphocyte percentages and growth measures were performed with the Spearman rank test. Comparisons of survival times were made with the Kaplan-Meier method and the Wilcoxon Test (SAS procedure LIFETEST). Multivariate analysis of factors predicting the time of survival was performed with the Cox proportional hazards model (SAS procedure PHREG). Backward exclusion was used to select for variables significantly contributing to the model. The proportional hazards calculations were performed twice, with the included values considered as either continuous variables or as variables dichotomized on either side of a threshold and assigned values 0 (low risk) or 1 (higher risk). Because the results of the two methods were essentially the same, only the dichotomized results are reported. The variables included in the model and their thresholds were as follows: percentage CD4 + lymphocyte (10%); sex, race, weight-for-age z score ( - 2 ) ; heightfor-age z score ( - 2 ) ; weight-for-height z score ( - 1); weight growth rate percentile (<25th percentile); and height growth rate percentile (<25th percentile). Age was also considered, but because it did not correlate with

730

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The Journal of Pediatrics November 1994

Table I. Sensitivity of measurements to lethal outcome

Criteria

Sensitivity

Specificity

Entry weight-for-age z score < - 2 Entry height-for-age z score < - 2 Entry weight-for-height z score < - 1 Entry CD4 + lymphocyte percentage <10 Entry CD4 ÷ percentage <20 Female sex White or Hispanic race/ethnicity 6-month weight-growth <25th percentile

0.43 0.57 0.37 0.61 0.90 0.53 0.59 0.53

0.79 0.56 0.79 0.79 0.51 0.67 0.59 0.83

Relative risk (95% Cl)* 1.53 (1.08, 1.27 (0.87, 1.36 (0.95, 2.08 (1.41, 3.49 (1.57, 1.42 (0.98, 1.39 (0.94, 2.03 (1.27,

2.17) 1.87) 1.94) 3.07) 7.78) 2.06) 2.04) 3.22)

N = 88 except for weight growth rate (n = 70) and weight-for-height(n = 87). *The relativerisk is for the risk of dying if the criteria are met versus if they are not. survival time in the analysis of continuous variables, it was not included as a dichotomized variable. RESULTS

Population characteristics. The basic demographic characteristics of the population were published previously. 2 The median age at entry was 3:1 years. There were 39 girls (44%). Forty-nine patients (56%) died. The median survival (by the method of Kaplan and Meier) was 37.9 months (95% confidence interval: 27.8, 47.8). Among children for whom follow-up was adequate for calculation of growth rates, 34 (49%) of the 70 children died. The children were small in both height (98%, <50th percentile) and weight (90%, <50th percentile), similar to data in infants with HIV infection, and as a result the weight-for-height value s were distributed almost normally (Figure). Sensitivity of growth as a predictor of survival. The most sensitive predictor of death was a low CD4 + lymphocyte percentage. Of the patients who died, 90% had a CD4 + lymphocyte percentage <20% on entry to the study. The relative risk of death was significantly increased in children with low CD4 + lymphocyte percentages, in those who had a weight growth rate below the 25th percentile for age, and in those who had an entry weight-for-age z score less than - 2 (Table I). Growth and immunologic correlates at entry. Spearman rank correlation coefficients were calculated to investigate the relationships between growth and CD4 + lymphocyte percentages. The percentage of CD4 + lymphocytes had a significant correlation with entry height-for-age z score (r = 0.32; p = 0.007) and 6-month weight growth rate percentile (r = 0.25; p = 0.03). It was not significantly correlated with weight (r = 0.06) or weight-for-height z scores (r = - 0 . 1 7 ; p = 0.17), or with the height growth rate percentile (r = 0.02). Measures of growth were compared with each other to characterize the growth abnormalities seen at the time of entry and during the first 6 months of study. The weight growth rate percentiles were inversely related to the entry weight-for-length z score (i.e., leaner children gained

weight at a faster rate during zidovudine therapy) (r = -0.33; p = 0.006). Entry weight and height z scores were not significantly correlated with the weight or height growth rates. The entry weight-for-age and height-for-age z scores were strongly correlated (r = 0.52; p = 0.0001) (i.e., shorter patients also weighed less). Survival analysis. A higher entry weight-for-age z score was associated with longer survival, as was a weight-forlength z score of "1 or better (Table II). The stratification by weight-for-length z score better or worse than - 2 was not significant, possibly because of the small number of children (11) with entry z scores < - 2 . There was a significant difference by gender, with boys having a survival advantage. The largest single survival disadvantage was seen in children with less than 10% CD4 + lymphocytes. Multivariate analysis. Cox proportional hazard modeling was performed to assess the relative effects of gender, percentage of CD4 + lymphocytes, and abnormalities of growth on time of survival (Table III). In univariate models of survival outcome, CD4 + percentage, weight gain rate, and gender were all significant. Five variables contributed significantly to the multivariate model: weight-for-age z score at entry, CD4 + lymphocyte percentage, weight growth rate percentile, gender, and race. Height-for-age z score at entry, height growth rate percentile, weight-for-height z score at entry, and age at entry did not contribute significantly. DISCUSSION Suppression of HIV infection through the use of an effective antiretroviral drug such as zidovudine has a positive effect on the growth rate of children with symptoms of the disease. 2 In this investigation, rates of weight gain for children with symptoms were also predictive of outcome. The proportion of children with weight gain rates below the 25th percentile who died during the study was significantly higher and their survival time was shorter. In relative terms, the number and percentage of CD4 + lymphocytes were a better predictor of survival than growth. The prognostic value of changes in CD4 + lymphocyte counts has recently been controversial, 7' 8 bug we con-

The Journal of Pediatrics Volume 125, Number 5, Part 1

sidered only the entry CD4 + lymphocyte percentages and counts (the latter were not presented). In children with advanced disease, CD4 + lymphocyte counts seem to improve less in response to zidovudine than in adults. 2 We found that CD4 + lymphocyte percentages were very sensitive predictors of death: 90% of the patients who died entered with a CD4 + lymphocyte percentage <20. Children who entered with a CD4 + lymphocyte percentage <20 had a 3.5-fold greater chance of dying relative to peers with better CD4 + lymphocyte percentages. The Cox multivariate analyses were designed to determine whether measurements of growth and size contribute additional information beyond the CD4 + lymphocyte percentage. The CD4 + values, entry weight, weight growth rate, race, and gender all contributed significant information to the mathematic model predicting survival time. Age did not prove to be a significant variable, probably because all the children began with relatively advanced disease, regardless of their age. This lack of an association with age means that the use of CD4 + lymphocyte percentages without age adjustment did not seem to be an important omission. The effect of gender was unexpected. Life expectancy was shorter in the girls than in the male enrollees by more than 11A years. In addition, female gender was a significant contributor to the Cox survival model, even after control for the effect of CD4 + lymphocyte percentages (data not shown). No significant differences in growth, age, or entry CD4 + lymphocyte percentage could be identified between female and male patients. However, all but two girls acquired their HIV infection vertically, whereas 13 boys acquired their infection through blood or blood-product infusion. Patients with hemophilia have generally had a slower rate of HIV progression than children with vertically acquired infection, and this may have contributed to the difference in survival by gender. 8 As described recently in HIV-infected children younger than 2 years of age, 1 at entry these children were symmetrically small in weight and height and were not particularly lean. Those children who were on the lower end of the weight-for-height scales tended to gain weight at a faster rate than patients who were less lean at study entry. They also had a higher mortality rate. Absolute weight status and weight loss have proved to be important prognostic indicators for adult patients. 9-11 A critical difference in children is the anticipation of growth. Measurement of absolute individual weight loss identifies only the most severely affected patients, particularly in young infants and adolescents, in whom the rate of growth is most rapid. Growth velocity charts can be used to provide a more sensitive and age-specific indicator of an individual child's progress relative to expectations. Ongino et al. 3 proposed an association between changes

McKinney et al.

40

7 31

Weight

30

20

10

0

40

Height

30

20

10

0

40

30

Weight for Height

.........................................................................................................................................

20

10

0

<-3

-2 to -1 -3 to -2

0 to 1 -1 to 0 1 to 2 Z-Score Range

>2

Figure. Percentage of 88 children who were within weight-for-age (top chart), height-for-age (middle chart), and weight-for-height (bottom chart) z score ranges at study entry. Weight and height

distributions demonstrate the negative effects of HIV on growth in children before antiretroviral therapy; the normal weight-forheight distribution demonstrates the symmetry of the effects on both height and weight.

in growth rates and zidovudine resistance. Our study did not obtain resistance data, but none of the patients had received zidovudine at the time of enrollment, and it seems unlikely that drug resistance was a major contributor to the short-

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McKinney et al.

The Journal of Pediatrics November 1994

Table II. Survival analysis: categoric Survival rate*

M e d i a n survival timet (too) (95*/. C!)

Category

No. alive/total

%

Overall >--6 Months in study By entry characteristics Weight z Score < - 2 z Score >--2 Height z Score < - 2 z Score >--2 Weight-for-height z Score < - 1 z Score >--1 z Score < - 2 z score >--2 CD4 + lymphocyte percentage <10 _>10 <20 -->20 Gender Female Male Race Black White or Hispanic Growth 6-mo Weight growth percentile <25 Weight growth >-25%

39/88 36/70

44 51

8/29 31/59

28 53

0.03

15.9 (9.0, 30.7) 44.7 (37.0, NA)

0.0003

17/45 22/43

38 51

0.21

29.7 (20.3, NA) 44.7 (31.4, NA)

0.10

8/26 30/61 4/11 34/76

31 49 36 45

0.11

22.8 42.7 15.4 39.0

0.008

8/38 31/50 19/63 20/25

21 62 30 80

0.0001

13/39 26/49

33 53

23/43 16/45 7/25 29/45

P

P

37.9 (27.8, NA)

0.60

(9.0, 38.3) (31.4, NA) (4.2, NA) (28.7, NA)

0.14

22.4 (9.9, 29.7) NA (42.7, NA) 26.3 (20.3, 32.6) NA (NA, NA)

0.0001

0.06

26.3 (15.4, 42.7) 44.7 (32.1, NA)

0.01

53 36

0.09

44.7 (28.7, NA) 31.4 (23.1, 41.7)

0.18

28 64

0.003

30.7 (25.4, 41.7) NA (39.7, NA)

0.02

0.00002

0.0001

N = 88 except for weight growth (n = 70), and weight-for-height (n = 87) groups. CI, Confidenceinterval; NA, not applicable (generally because survival time is too great). *Probability calculations for survival rates computed with chi-square analysis. tCalculations for time of survival computed with Kaplan-Meier analysis with Wilcoxon Test.

Table III. Cox proportional hazards regression Multivariate

Univariate Variable

Risk ratio*

pt

Risk ratio

p

Entry weight-for-age z score < - 2 Entry CD4 + lymphocyte percentage <20% 6-mo Weight growth rate percentile <25 Female gender White or Hispanic race/ethnicity

1.85 3.13 2.51 2.15 1.96

0.09 0.001 0.008 0.03 0.06

2.79 3.06 3.01 5.73 4.75

0.01 0.005 0.007 0.0003 0.0006

N = 70. *Risk ratio is the relative risk of dying if the variable criteria are met. tP Value is computed with Wald chi-square analysis. t e r m p h e n o m e n a described. However, it will be i m p o r t a n t in the future to d e t e r m i n e the effectiveness of weight gain as a m a r k e r of antiviral resistance, given the high expense and technical difficulty of resistance assays. W e conclude t h a t m e a s u r e m e n t of growth is an inexpensive m a r k e r t h a t helps characterize the clinical status of HIV-infected children. It appears to be less predictive of the

mortality rate t h a n C D 4 + lymphocyte values in advanced disease, but still contributes i m p o r t a n t clinical data. In addition, the weight gain rate of children after initiation of zidovudine therapy appears to act as a m a r k e r of t h e r a p e u t i c efficacy. T h e rate of weight gain is currently being used as an end point in a large A I D S Clinical Trials G r o u p Protocol ( A I D S Clinical Trials G r o u p 152), and its validity as a

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M c K i n n e y et al.

surrogate marker predictive of survival may be further defined. We are grateful to the patients and investigators who participated in AIDS Clinical Trial Group Protocol 043. The study coordinator at Burroughs Wellcome was Mary Maha Elkins, RN, and the supervising investigator was Sandra Nussinoff Lehrman, MD. REFERENCES

1. McKinney RE, Robertson JWR, Duke Pediatric AIDS Clinical Trials Unit. Effect of human immunodeficiency virus infection on the growth of young children. J PEDIATR 1993; 123:579-82. 2. McKinney RE, Maha MA, Connor EM, et al. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. N Engl J Med 1991;324:101825. 3. Ongino MT, Dankner WM, Spector SA. Development and significance of zidovudine resistance in children infected with human immunodeficiency virus. J PEDIATR 1993;123:1-8. 4. Mofenson L, Moye J, Nugent R, Bethel J, Korelitz J. Relation of mortality risk to selected pediatric HIV disease progression endpoints (DPE) used in pediatric HIV therapeutic trials [Abstract 1123]. Proceedings of the 33rd Interscience Convention on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, New Orleans, October 20, 1993.

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5. Roche AF, Himes JH. Incremental growth charts. Am J Clin Nutr 1980;33:2041-52. 6. McKinney RE, Wilfert CM. Lymphocyte subsets in children less than 2 years old: normal values in a population at risk for human immunodeficiency virus infection and diagnostic and prognostic application to infected children. Pediatr Infect Dis J 1992;11:639-44. 7. Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994;343:871-81. 8. Eyster EM. Continuing issues regarding transfusion and coagulation factor acquired HIV infection in children. In: Pizzo PA, Wilfert CM. Pediatric AIDS: the challenge of HIV infection in infants, children, and adolescents. 2nd ed. Baltimore: Williams & Wilkins, 1994:51-69. 9. Guenter P, Muurahainen N, Simons G, et al. Relationships among nutritional status, disease progression, and survival in HIV infection. J Acquir Immun Defic Syndr 1993;6:1130-8. 10. Chlebowski RT, Grosvenor MB, Bernhard NH, Morales LS, Bulcavage LM. Nutritional status, gastrointestinal dysfunction, and survival in patients with AIDS. Am J Gastroenterol 1989;84:1288-93. 11. Lindan CP, Allen S, Serufilira A, et al. Predictors of mortality among HIV-infected women in Kigali, Rwanda. Ann Intern Med 1992;116:320-8.

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