SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Weight loss and changes in growth are noted in children treated with interferon alpha (IFN-α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha-2a (Peg-IFN-α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS-C) trial underwent anthropometric measurements, dual-energy X-ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5-unit decrement in height-for-age z (HAZ) score. Though weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long-treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. Conclusions: Peg-IFN-α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV. (HEPATOLOGY 2012)

Chronic hepatitis C virus (HCV) infection in childhood is usually a mild, slowly progressive disease. The extended natural history has not been clearly elucidated, but some children develop progressive liver disease with cirrhosis1 and even cancer.2 Pegylated interferon alpha (Peg-IFN-α) with ribavirin (RBV), until recently, was the standard treatment for chronic HCV in adults and is approved for children as young as 3 years of age. There may be significant benefit to treating HCV infection in children, while liver disease is mild, confounding factors are few, and IFN-α is usually well tolerated.3

Potential side effects of IFN-α in children have been a concern in the decision to use this agent. Weight loss, slow weight gain, and changes in linear growth have been reported in children treated with IFN-α for either chronic hepatitis B or HCV.4, 5 Some reversibility of these effects has been documented after cessation of treatment, but few details are known about this side effect. In particular, the question of whether and how changes in weight represent changes in body composition has never been studied. In addition, the long-term effects, especially on linear growth, have not been fully elucidated.

The Pediatric Study of Hepatitis C (PEDS-C) was a randomized, controlled, multicenter trial of the safety and efficacy of Peg-IFN-α2a (PEGASYS, Roche Pharmaceuticals, Nutley, NJ) with and without RBV (COPEGUS, Roche Pharmaceuticals) in children and adolescents with chronic hepatitis C. The results regarding safety and efficacy of this treatment have been previously reported.6 Subjects were followed longitudinally for up to 2 years after treatment to ascertain changes in anthropometric status in children treated with Peg-IFN-α2a and to determine whether these changes were associated with other factors, including dietary intake and physical activity, during and after treatment. Additional analyses were planned to investigate changes in weight, growth, and body composition in relation to type of antiviral therapy and receipt of at least 80% of total calculated dose of Peg-IFN-α2a. Informed consent was obtained from parents or guardians of all subjects, and the study was approved by the institutional review boards of all participating institutions.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Patients.

Eligible subjects included treatment-naïve children 5-18 years of age with chronic HCV infection documented by the presence of HCV RNA in plasma on two occasions at least 6 months apart. Details of the trial were previously published,7 and the study was registered at www.ClinicalTrials.gov (NCT00100659). Subjects were enrolled by investigators at 11 North American centers from December 2004 until May 2006. All 2-year off-therapy follow-up visits were completed by February 2010.

All children received Peg-IFN-α2a. Although some children also received RBV, Peg-IFN-α2a is the agent considered responsible for weight loss commonly observed in treated patients. In a generalized estimating equations model adjusted for baseline age and sex, we found no statistical difference in weight, growth, or body-composition outcomes between subjects who received RBV and those who did not, so the groups were combined for the current analysis. The cohort was divided into three groups based on duration of Peg-IFN-α2a treatment (24, 48, or 72 weeks), regardless of RBV treatment. Post-treatment follow-up continued for up to 96 weeks.

Virologic Testing.

Qualitative HCV RNA was assessed with Roche COBAS AMPLICOR HCV qualitative polymerase chain reaction v2.0, with a lower limit of detection of 60 IU/mL. HCV viral genotyping was performed at entry using a line-probe assay (Innogenetics, Ghent, Belgium). Sustained virologic response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment.

Treatment.

Subjects were randomly assigned with equal allocation to receive either Peg-IFN-α2a and RBV or Peg-IFN-α2a and placebo. Peg-IFN-α2a was administered in a dose of 180 μg/1.73 m2 body-surface area (maximum, 180 μg) subcutaneously once-weekly. RBV was administered in a dose of 15 mg/kg/day orally in two doses (maximum, 1,200 mg/day if ≥75 kg and 1,000 mg if <75 kg), using 100-mg tablets. Placebo tablets were supplied in the same dosing regimen as RBV. Patients without detectable HCV RNA at 24 weeks were continued on treatment for another 24 weeks, whereas those who had detectable HCV RNA at 24 weeks were considered treatment failures. Treatment was stopped in those subjects who had been given Peg-IFN-α2a with RBV and were still viremic. Patients who failed treatment with Peg-IFN-α2a plus placebo were offered “open-label” therapy with Peg-IFN-α2a plus RBV for another 48 weeks (stopping after 24 weeks if HCV RNA remained positive). This strategy led to three groups based on duration of Peg-IFN-α2a treatment of 24, 48, or 72 weeks (Fig. 1). Further details of the study design have been previously reported.7 Drug dose reductions were instituted for toxicities according to protocol.

thumbnail image

Figure 1. Derivation and definitions of the study population demonstrating the three therapy duration groups.

Download figure to PowerPoint

Growth, Body Composition, and Nutritional Status.

Body weight was measured by an electronic digital scale accurate to 0.1 kg. Standing height was measured by stadiometer to the nearest 0.1 cm. Triceps, biceps, iliac, and subscapular skinfold thicknesses were measured to the nearest 0.5 mm using Lange skin calipers. Midarm circumference (MAC) was measured to the nearest 0.1 cm using a flexible, nonstretchable plastic tape, and midarm muscle area (MAMA) was calculated (MAC2/4π). All measurements were made by a single observer at each site, who had been trained in the standardized measurement procedures. Anthropometric measurements were performed in duplicate and reported as the mean of the two measurements. Weight-for-age z (WAZ) score, height-for-age z (HAZ) score, body mass index (BMI) z score (BMIZ), and triceps skinfold (TS) z (TSFZ) score8 were calculated using the 2000 U.S. National Center for Health Statistics reference values (www.cdc.gov/nchs). Anthropometric data were measured at baseline and weeks 24, 48, and 72 of treatment, as well as up to 96 weeks post-treatment.

Dual-energy X-ray absorptiometry (DXA) scans were performed using either Hologic, Inc. (QDR4500A and QDR4500W models; Bedford, MA) or GE Lunar Prodigy (GE Medical Systems, Fairfield, CT) bone densitometers. Scans were performed on a single densitometer at each center. Data were standardized across sites and read at a central site. The software versions used for acquisition varied from version 11.2 to 12.7.3.1 (APEX 2.2) on Hologic machines and from 8.10 to 11.20 on Lunar machines. Whole body scans were performed according to manufacturer's specific procedures. Quality control for these measures included cross-calibration of all devices as well as longitudinal monitoring of each site scanner's accuracy and stability. Hologic DXA longitudinal quality control was carried out by scanning, either daily or no less than three times per week, the Hologic Spine phantom, and by performing a weekly table top radiographic uniformity test (Airscan). GE Lunar DXA longitudinal quality control was provided by scanning, either daily or no less than three times per week, the Lunar calibration block, and the Lunar aluminum spine phantom. Intramanufacturer cross-calibration was performed by scanning a set of European Spine, Hologic Block, and Whole Body Phantoms (QRM GmbH, Mohrendorf, Germany) at the beginning of the study period. For intermanufacturer cross-calibration of the whole body bone mineral density, standardization equations were used.9 A “gold standard” site was chosen, to which other sites were calibrated. No intermanufacturer cross-calibration was performed for the whole body soft tissue measurements, because there was no standardization equation or converting formula available to use. All subject and cross-calibration scans were analyzed centrally by the DXA Core Laboratory (University of California, San Francisco, San Francisco, CA) using Hologic software release 12.3 and Lunar software release 11.4. Data were expressed as grams of fat, grams of fat-free mass, and total body weight. Percent body fat (%BF) was defined as total grams of fat/body weight x 100). Percent body fat z score (%BFZ) and fat-free mass z score (FFMZ) were calculated using the Pediatric Body Composition Reference Charts of the Children's Nutrition Research Center at USDA/Baylor College of Medicine (Houston, TX) (http://www.bcm.edu/bodycomplab/Flashapps/AllDXArefsChartpage.html).10

Dietary intake assessment was obtained using 3-day food records.11 Each 3-day record consisted of a 2-day patient/parent-completed food diary and a 24-hour diet recall with the assistance of a study-designated site dietitian during an interview with the subject and parent. Detailed instructions were provided to each subject at the baseline visit. Each 3-day record included at least one weekday and one weekend day. Total intake of calories from each 3-day period was determined using the Food Processor SQL Nutrition Analysis Software (ESHA Research, Salem, OR). Dietary energy intake (kcal/day) was calculated as the average intake over the 3 days for each visit. Energy intake was expressed as a percentage of the subject's resting energy expenditure (REE), as calculated by Schofield's equations.12

Physical activity was assessed by parent responses to questions designed to determine changes in the amount and strenuousness of activity during each month before the protocol-defined study visit.13 In one question, parents were asked to compare the child's level of activity to other children of the same age and sex on a 5-point scale. In a second question, parents estimated the percent of time the child spent in activities of varying strenuousness during weekdays and weekend days. Week estimates of each activity level were calculated based on 5 × weekday measure + 2 × weekend measure.

The study was conducted under an Investigational New Drug application and was approved by the institutional review boards of the participating sites. All parents and guardians provided written informed consent, and children over 12 years provided written assent before enrollment. The Data Coordinating Center was the Maryland Medical Research Institute (Baltimore, MD).

Statistical Analysis.

Baseline characteristics were described using mean ± standard deviation (SD) for continuous data and N (%) for categorical data. Physical activity data that were continuously distributed were highly skewed and were described by median and interquartile range (IQR). Outcomes of interest included change from baseline for WAZ, HAZ, BMIZ, TSFZ, %BFZ, and FFMZ, all of which were approximately normally distributed. Subjects were treated with Peg-IFN-α2a for either 24, 48, or 72 weeks and then followed thereafter for up to 96 weeks post-therapy. The analysis of changes in weight, height, and body composition over time was performed with a repeated-measures, generalized linear model assuming a normal distribution with an identity link function. The within-subjects correlation was modeled as autoregressive (AR1). Changes in outcome from baseline were assessed with an interaction term of weeks on study drug (24, 48, or 72) by weeks off study drug (0, 24, 48, or 96), adjusted for baseline age and sex. The effect of several independent variables, including duration of Peg-IFN-α2a treatment, SVR, energy intake during and after treatment, change in physical activity during and after treatment, receipt of RBV, and receipt of at least 80% of total dose of Peg-IFN-α2a, were explored, but not retained, in the final model, because none were statistically significant modifiers. All tests were two-sided, with P < 0.05 used to indicate statistical significance. Results and plots were generated using SAS/STAT and SAS/GRAPH software (version 9.2) of the SAS System for Windows (SAS Institute Inc., Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Patients.

One hundred and fourteen children were eligible for treatment and randomized to receive Peg-IFN-α2a with either RBV (N = 55) or placebo (N = 59) (Fig. 1). Six subjects were either lost to follow-up or withdrew before completing at least 24 weeks of therapy, and 1 subject in the 72-week treatment group was omitted after a sensitivity analysis showed this subject to have highly influential anthropometry z scores. This resulted in a final study cohort of 107 subjects. Twelve subjects in the RBV arm had no virologic response (VR) at week 24, at which point treatment was discontinued, and 2 from the placebo arm were lost to follow-up at 24 weeks, resulting in 14 children who had only 24 weeks of Peg-IFN-α2a. Children who had VR at week 24 (N = 66) received 24 more weeks of treatment, as did those who crossed over from placebo to RBV (N = 27). Among these 93 children, 82 (16 from the crossover group) were treated for a total of 48 weeks, whereas the remaining 11 children in the crossover group had VR at week 48 and received a total of 72 weeks of Peg-IFN-α2a. Follow-up visits occurred at 24, 48, and 96 weeks after discontinuation of therapy. Because of attrition, loss of contact, or retreatment, not all subjects were available at all follow-up visits.

Subjects at baseline were, on average, 11 years of age (range, 5-17), 45% female, mostly Caucasian (82%), and of normal weight, height, BMI, %BF, and fat-free mass. A majority of subjects had no more than mild disease (82% no more than mild histologic activity, 100% with no more than mild steatosis, and 96% with no more than portal-periportal fibrosis). Additional baseline characteristics are shown in Table 1.

Table 1. Baseline Characteristics for 107 Subjects
 N (%) or Mean ± SD
Patient characteristics 
 Age (years)11.1 ± 3.5
  5-1159 (55)
  12-1748 (45)
 Female gender48 (45)
 Non-Caucasian race (n = 97)17 (18)
 WAZ (n = 106)0.56 ± 1.17
 HAZ (n =1 06)0.17 ± 1.05
 BMIZ (n = 106)0.60 ± 1.11
  BMIZ >2.0010 (9)
 %BFZ (n = 77)0.00 ± 1.15
 FFMZ (n = 80)0.01 ± 0.92
 Mode of acquisition (n = 90) 
  Maternal infant80 (89)
  Transfusion8 (9)
  Sexual contact, intravenous drug use2 (2)
 Genotype (n = 106) 
  185 (80)
  27 (7)
  313 (12)
  61 (1)
Histology results (n = 104) 
 Histology activity index 
  None0 (0)
  Minimal (1-3)33 (32)
  Mild (4-6)52 (50)
  Moderate (7-9)17 (16)
  Marked (10-12)2 (2)
 Steatosis 
  None59 (57)
  Minimal (≤5% of tissue)36 (35)
  Mild (6%-33%)9 (9)
 Fibrosis score 
  None13 (13)
  Portal-periportal fibrosis (Ishak 1-2)86 (83)
  Bridging fibrosis (Ishak 3-4)4 (4)
  Cirrhosis (Ishak 5-6)1 (1)

VRs.

Primary efficacy and safety of treatment in this study has been reported.6 In the 107 subjects included in this study cohort, the SVR rate was 56% among 52 children who received Peg-IFN-α2a and RBV and 22% among 55 who received Peg-IFN-α2a with placebo (P = 0.0003).

Weight, Stature, and BMI.

Table 2 shows the change from baseline for WAZ, HAZ, and BMIZ for the three treatment duration groups (24, 48, and 72 weeks of Peg-IFN-α2a), after adjusting for baseline age and sex. Significant decreases were observed in age-adjusted weight, height, and BMIZ scores while on therapy, with longer treatment associated with greater decreases. The most marked decreases for WAZ and HAZ were observed in the 11 children who received therapy for 72 weeks (mean ± standard error [SE] decrease: −0.50 ± 0.13 and −0.50 ± 0.07, respectively; P < 0.0001 versus baseline for each), whereas for BMIZ, the greatest decrease occurred for subjects receiving 48 weeks of therapy (−0.40 ± 0.04; P < 0.0001). Thereafter, z scores rebounded toward baseline levels, especially among the largest treatment group (48 weeks of therapy) (Fig. 2). This group, at 96 weeks post-treatment, was not statistically different from baseline for any of the three z scores. In the small group of children treated for 72 weeks, HAZ score was still significantly different from baseline at the end of follow-up (Supporting Fig. 1).

Table 2. Change in WAZ, HAZ, and BMIZ From Baseline, Adjusted for Baseline Age and Sex (n = 106)*
Weeks onWeeks off Change in WAZChange in HAZChange in BMIZ
Peg-IFN-α2aPeg-IFN-α2aNMean ± SEPΔ=0Mean ± SEPΔ=0Mean ± SEPΔ=0
  • *

    One subject was missing WAZ, HAZ, and BMIZ at baseline.

240106−0.31 ±0.03<0.0001−0.14 ± 0.02<0.0001−0.33 ± 0.04<0.0001
 2411−0.15 ± 0.070.03−0.11 ± 0.050.05−0.16 ± 0.070.03
 489−0.05 ± 0.100.63−0.03 ± 0.120.81−0.10 ± 0.090.28
 967−0.08 ± 0.180.650.14 ± 0.180.43−0.21 ± 0.150.15
48088−0.43 ± 0.04<0.0001−0.28 ± 0.02<0.0001−0.40 ± 0.04<0.0001
 2473−0.08 ± 0.040.06−0.22 ± 0.03<0.0001−0.01 ± 0.050.77
 4863−0.01 ± 0.050.88−0.16 ± 0.04<0.00010.00 ± 0.050.94
 96530.02 ± 0.070.81−0.08 ± 0.060.18−0.03 ± 0.070.66
72011−0.50 ± 0.13<0.0001−0.50 ± 0.07<0.0001−0.35 ± 0.140.01
 2411−0.04 ± 0.120.76−0.42 ± 0.09<0.00010.14 ± 0.140.35
 48110.03 ± 0.120.77−0.39 ± 0.110.00040.18 ± 0.120.14
 9670.01 ± 0.140.92−0.41 ± 0.190.030.13 ± 0.090.16
thumbnail image

Figure 2. Change from baseline in WAZ, HAZ, and BMIZ among subjects treated with Peg-IFN-α2a for 48 weeks. Error bars indicate 95% confidence interval. Shaded regions indicate time on Peg-IFN-α2a. Results are from a generalized linear model, adjusted for baseline age and sex.

Download figure to PowerPoint

Further analysis was performed in the largest group: subjects treated for 48 weeks. In this group, 29 subjects (33%) had greater than a 0.5-unit decrement in HAZ score at one or more time points during the study. In particular, 10 (34%) subjects crossed this threshold during treatment, but rebounded to within a 0.5-unit decrease in HAZ by the end of the trial, 7 (24%) continued to have more than a 0.5-unit decrement in HAZ score by the end of the trial, and 12 (41%) exceeded a 0.5-unit decrease only after therapy was discontinued. Among subjects <12 years of age at baseline, 19 (41%) experienced a drop in HAZ score of 0.5 or larger, compared with 10 (24%) among subjects 12 years or older (P = 0.11 by Fisher's exact test). The multivariate model described above was rerun for the 48-week treatment group by including WAZ score changes, specifically to examine the effect of weight loss on HAZ score. The data suggest that subjects who experienced more than a 0.50-decrement in WAZ had an additional mean decrement of 0.15 units in HAZ score at all follow-up periods. Those with an <0.50 WAZ decrement rebounded at 48 and 96 weeks post-treatment to near baseline levels, whereas those with an >0.50 WAZ decrement remained below baseline levels (data not shown).

Body Composition.

Serial measures of body composition, as measured by DXA, are presented in Table 3 for the whole cohort and Fig. 3 for the group treated for 48 weeks. Significant reductions in %BFZ were noted during treatment. After 24 or 48 weeks of Peg-IFN-α2a, %BFZ was lower than baseline by 0.12 ± 0.05 and 0.14 ± 0.06 units, respectively (P = 0.02 for both comparisons). After discontinuation of therapy, %BFZ returned to baseline levels in all subjects, except for a mean increase of 0.33 ± 0.08 units (P < 0.0001) at 48 weeks post-therapy among subjects in the 24-week therapy group.

Table 3. Change in %BFZ and FFMZ From Baseline, Adjusted for Baseline Age and Sex
Weeks onWeeks offChange in %BFZChange in FFMZ
Peg-IFN-α2aPEG-IFN-α2aNMean ± SEPΔ=0NMean ± SEPΔ=0
24068−0.12 ± 0.050.0270−0.33 ± 0.05<0.0001
 2460.02 ± 0.050.606−0.26 ± 0.080.001
 4850.33 ± 0.08<0.00015−0.46 ± 0.200.02
 9640.31 ± 0.340.373−0.28 ± 0.080.0003
48056−0.14 ± 0.060.0256−0.37 ± 0.05<0.0001
 2444−0.02 ± 0.060.79450.02 ± 0.060.75
 4840−0.01 ± 0.070.91400.06 ± 0.070.36
 96280.04 ± 0.120.7130−0.02 ± 0.090.81
7204−0.24 ± 0.220.2930.11 ± 0.210.60
 244−0.14 ± 0.400.7430.33 ± 0.300.27
 484−0.11 ± 0.450.8030.47 ± 0.270.08
 9610.37 ± 0.260.1610.61 ± 0.200.002
thumbnail image

Figure 3. Change from baseline in %BFZ and FFMZ among subjects treated with Peg-IFN-α2a for 48 weeks. Error bars indicate 95% confidence interval. Shaded regions indicate time on Peg-IFN-α2a. Results are from a generalized linear model, adjusted for baseline age and sex.

Download figure to PowerPoint

Concurrent with these changes in body fat, significant decrements in FFMZ were observed during treatment in all groups (Supporting Figs. 2 and 3). After 24 or 48 weeks of Peg-IFN-α2a, FFMZ was lower than baseline by 0.33 ± 0.05 and 0.37 ± 0.05 units, respectively (P < 0.0001 for both comparisons). Variable trends in FFMZ were observed after the discontinuation of treatment. In the group treated for 24 weeks, FFMZ was still lower than baseline at 24 weeks post-therapy (−0.26 ± 0.08; P = 0.001), 48 weeks post-therapy (−0.46 ± 0.20; P = 0.02), and 72 weeks post-therapy (−0.28 ± 0.08; P = 0.0003). In the larger group treated for 48 weeks, FFMZ returned to baseline levels after treatment was stopped. In the smaller group treated for 72 weeks, FFMZ rebounded to levels surpassing baseline levels.

Measures of peripheral body composition mirrored these DXA trends (Supporting Table 1). TSFZ scores were significantly lower than baseline in subjects treated for either 24 or 48 weeks (−0.17 ± 0.07, P = 0.01, and −0.27 ± 0.09, P = 0.002, respectively) (Supporting Fig. 4). MAC and MAMA were not different from baseline during antiviral therapy, suggesting no accretion of peripheral lean mass. After therapy ceased, expected increments in MAC and MAMA were observed.

Dietary Intake.

Mean (± SD) dietary energy intake was 139% (± 43%) of estimated REE at baseline, 148% (± 54%) of resting REE while on antiviral therapy, and 133% (± 51%) when subjects were off treatment (P = 0.06; data not shown).

Physical Activity.

Assessment of physical activity at baseline, as well as during and after treatment, is shown in Table 4. No effect of treatment on either comparison of treated children to peers or distribution of level of activity, as assessed by parent questionnaires, was observed.

Table 4. Physical Activity (107 Subjects)
 BaselineOn TherapyOff TherapyP Value
  • *

    Response categories scored: 1 = a lot less active; 2 = a little less active; 3 = about average; 4 = a little more active; and 5 = a lot more active.

  • Physical activity measures were collected on a single weekday and a single weekend day. Week estimates were based on the following equation: (5 × weekday measure) + (2 × weekend day measure).

Physical activity    
Subjects (n)10610792
In comparison to other children the same age and sex, the subject is… (%)0.56
 A lot less active0 (0)0 (0)1 (1) 
 A little less active9 (9)26 (13)9 (9) 
 About average62 (59)105 (54)56 (54) 
 A little more active23 (22)48 (25)28 (27) 
 A lot more active11 (10)14 (7)9 (9) 
 Median score (IQR)*3 (3-4)3 (3-4)3 (3-4)0.59
Percent of week spent…    
 Sleeping39 (36-43)39 (35-42)39 (35-42)0.63
 Sedentary or seated activities52 (42-70)56 (42-70)51 (36-67)0.20
 Light or casual activities16 (11-21)15 (8-22)15 (10-21)0.76
 Moderate or stop/start activities8 (4-12)7 (3-11)8 (4-13)0.17
 Intense or sustained activities2 (0-7)2 (0-5)4 (0-8)0.09

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

In this large cohort of children with chronic HCV infection treated with antiviral therapy, we observed significant changes in weight, height, and body composition, some of which persisted after discontinuation of treatment. The nature and timing of these effects were not explained by reductions in dietary intake or energy expenditure.

There has long been a concern about effects of prolonged treatment with IFN-α or its pegylated counterpart on the nutritional status of children. The mechanism of weight loss, slow weight gain, or decreased growth velocity associated with this cytokine has not been elucidated. Some patients report nausea, anorexia, early satiety, or diarrhea while being treated with these agents, but these symptoms are often short-lived and are not universal.

A number of studies have evaluated this potential safety concern in children with chronic viral hepatitis. In 1996, weight loss was noted in children treated for 6 months for chronic hepatitis B or chronic hepatitis C. Among 11 children with hepatitis B virus or HCV infection, treatment with recombinant IFN-α2a and 2b for at least 24 weeks was associated with a mean WAZ score decrement of 0.81 units after 3 months of therapy (P < 0.001) and a decrement of 0.45 units after 6 months of treatment (P < 0.05). Mean weight-for-height z scores were reduced from +0.18 to −0.74 after 3 months of therapy (P < 0.01); BMI was not reported.5 In that study, children returned to baseline WAZ values by 1 year after treatment and height was not affected by antiviral therapy. Mean energy intake was recorded in only 2 of the 11 subjects. It was reported to be normal at baseline, but reduced by 13% and 26%, respectively, after 3 months of antiviral therapy.

Temporary effects on weight and height were noted in children with chronic hepatitis B treated for only 24 weeks with IFN-α with or without lamivudine.14 As treatment durations increased for chronic hepatitis C in children, especially those with genotype 1 infection, additional data regarding this effect has accumulated. In 56 children treated with IFN-α2b and RBV for 48 weeks, changes in both weight and height percentiles were reported.15 Although compensatory weight gain was noted after treatment was discontinued, the linear growth catch-up was only partial after the 24-week follow-up period, and longer follow-up of that cohort is under way. These effects were observed with the use of Peg-IFNs as well. In a multinational study of 65 HCV-infected children treated with Peg-IFN-α2a and RBV for 24 (N = 18) or 48 (N = 47) weeks, weight and height z scores were not different from baseline at the end of treatment.16 However, in another European study, this time with Peg-IFN-α2b and RBV, weight loss was recorded in 19% of children and was noted to be regained after 24 weeks of follow-up.17 In that cohort, linear growth velocity decreased during treatment in the majority (70%) of subjects and increased during off-treatment follow-up. Decrease in mean height percentile at the end of 24 weeks of follow-up was greater in those children who had received a longer duration of therapy. None of these studies included analysis of body composition, to determine the body compartment(s) that were compromised during IFN-α treatment, and none included assessment of energy intake and physical activity during and after therapy.

Possible etiologies of growth delay in patients with chronic hepatitis include increased energy requirements, decreased energy intake, or gastrointestinal malabsorption, but the medical literature contains few systematic studies of the nutritional status of patients undergoing antiviral therapy.18 Among adults with HCV treated with Peg-IFN and RBV, 14 of 15 patients lost weight during treatment, with a mean weight loss of 3.1 kg at 24 weeks.19 This weight loss was associated with lower dietary energy intake—on average, 9.7% lower than baseline at week 1 and persisting through week 12. Data from the current study do not demonstrate a similar change in dietary intake in this group of children, because in our sample there was actually a trend to an increase in energy intake while on treatment.

Our data demonstrate that weight and height z scores declined in tandem, as opposed to sequential changes, as might be expected if nutritional factors, such as decreased intake or increased energy losses, were responsible for the slower linear growth velocity. These findings implicate an alternative mechanism for these constitutional effects, such as direct effects of the IFN on somatic growth. In addition, whole body DXA data suggested that both body fat and fat-free mass components were affected by this growth-arresting effect. Arm anthropometric data also suggested a reduction in peripheral fat mass that returned to baseline after therapy was completed. It is important to note that baseline liver histology and response to therapy did not affect these growth outcomes, indicating that neither underlying liver disease nor uncontrolled viral replication contributed to the observed changes in weight, growth, or body composition.

Many children with chronic HCV infection are good candidates for treatment. Successful therapy will substantially decrease long-term risk for serious complications, such as cirrhosis and hepatocellular carcinoma. Less measurable, but no less significant, benefits include mitigation of concern about later perinatal transmission and real or perceived social stigmatization and fewer risks for liver disease cofactors, such as obesity and alcohol consumption, in infected children and adolescents. IFN-based therapies are the mainstay of HCV treatment in both children and adults. However, growth disruption is a uniquely pediatric concern. We have demonstrated significant effects on weight, BMI, and body composition in a large cohort of children treated with Peg-IFNα2a, including measurable effects on linear growth and body composition, that persisted after the treatment was discontinued in some groups. There was no difference in HAZ score effects in preadolescent, compared to adolescent, children. It is critical that longer term growth and metabolic data are gathered to determine the ultimate effect of this therapy, so that informed decisions can be made about optimal timing of treatment in this vulnerable population.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

The authors would like to acknowledge the contribution of Dr. Roman Shypailo, Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston TX, for assistance with calculating body composition z scores.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information
  • 1
    Bortolotti F, Verucchi G, Cammà C, Cabibbo G, Zancan L, Indolfi G, et al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology 2008; 134: 1900-1907.
  • 2
    González-Peralta R, Langham MR, Jr., Andres JM, Mohan P, Colombani PM, Alford MK, Schwarz KB. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009; 48: 630-635.
  • 3
    Rodrigue JR, Balistreri W, Haber B, Jonas MM, Mohan P, Molleston JP, et al. Peginterferon with or without ribavirin has minimal effect on quality of life, behavioral/emotional, and cognitive outcomes in children. HEPATOLOGY 2011; 53: 1468-1475.
  • 4
    Comanor L, Minor J, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM, et al. Impact of chronic hepatitis B and interferon-alfa therapy on growth of children. J Vir Hepat 2001; 8: 139-147.
  • 5
    Gottrand F, Michaud L, Guimber D, Ategbo S, Dubar G, Turck D, Farriaux JP. Influence of recombinant interferon alpha on nutritional status and growth pattern in children with chronic viral hepatitis. Eur J Pediatr 1996; 155: 1031-1034.
  • 6
    Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas MM, et al. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology 2011; 140: 450-458.e451.
  • 7
    Murray KF, Rodrigue JR, González-Peralta RP, Shepard J, Robuck PR, Schwarz KB; for the PEDS-C Clinical Research Network. Design of the PEDS-C trial: pegylated interferon ± ribavirin for children with chronic hepatitis C viral infection. Clin Trials 2007; 4: 661-673.
  • 8
    Addo OY, Himes JH. Reference curves for triceps and subscapular skinfold thicknesses in US children and adolescents. Am J Clin Nutr 2010; 91: 635-642.
  • 9
    Hui SL, Gao S, Zhou XH, Johnston CC, Jr., Lu Y, Glüer CC, et al. Universal standardization of bone density measurements: a method with optimal properties for calibration among several instruments. J Bone Miner Res 1997; 12: 1463-1470.
  • 10
    Kelly TL, Wilson KE, Heymsfield SB. Dual energy X-ray absorptiometry body composition reference values from NHANES. PLoS ONE 2009; 4: e7038.
  • 11
    Burrows TL, Martin RJ, Collins CE. A systematic review of the validity of dietary assessment methods in children when compared with the method of doubly labeled water. J Am Diet Assoc 2010; 110: 1501-1510.
  • 12
    Schofield W. Predicting basal metabolic rate, new standards, and review of previous work. Hum Nutr Clin Nutr 1985; 39C( Suppl 1): 5-41.
  • 13
    Sallis JF, Haskell WL, Wood PD, Fortmann SP, Rogers T, Blair SN, et al. Physical activity assessment methodology in the Five-City Project. Am J Epidemiol 1985; 121: 91-106.
  • 14
    Kuloğlu Z, Kansu A, Demirçeken F, Arici ZS, Berberoğlu M, Ocal G, Girgin N. The influence of interferon-alpha and combination interferon-alpha and lamivudine therapy on height and weight in children with chronic hepatitis B infection. J Pediatr Endocrinol Metab 2007; 20: 615-620.
  • 15
    González-Peralta R, Kelly DA, Haber B, Molleston J, Murray KF, Jonas MM, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. HEPATOLOGY 2005; 42: 1010-1018.
  • 16
    Sokal EM, Bourgois A, Stéphenne X, Silveira T, Porta G, Gardovska D, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. J Hepatol 2010; 52: 827-831.
  • 17
    Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010; 52: 501-507.
  • 18
    Piche T, Schneider SM, Tran A, Benzaken S, Rampal P, Hebuterne X. Resting energy expenditure in chronic hepatitis C. J Hepatol 2000; 33: 623-627.
  • 19
    Hamer C. The impact of combination therapy with peginterferon alpha-2a and ribavirin on the energy intake and body weight of adult hepatitis C patients. J Hum Nutr Diet 2008; 21: 486-493.

Supporting Information

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
HEP_25690_sm_SuppFig1.ppt103KSupporting Information Figure 1.
HEP_25690_sm_SuppFig2.ppt87KSupporting Information Figure 2.
HEP_25690_sm_SuppFig3.ppt103KSupporting Information Figure 3.
HEP_25690_sm_SuppFig4.ppt94KSupporting Information Figure 4.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.