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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus. (HEPATOLOGY 2005;42:1010–1018.)

Hepatitis C virus (HCV) infection is a global health problem affecting an estimated 170 million individuals worldwide. Although our understanding about the natural history and pathobiology of HCV infection in children is incomplete, it has been associated with significant liver disease, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma in this population.1–4 Approximately 10% to 20% of adults5 and 36% of children6 treated with interferon alone achieve long-term virological remission. The addition of ribavirin to interferon-based regimens markedly improves virological responses in adults.7, 8 Limited data are available regarding the use of interferon alfa with ribavirin in children. Therefore, the aim of our studies was to evaluate the efficacy, safety, and pharmacokinetics of interferon alfa-2b in combination with ribavirin for the treatment of chronic HCV infection in children.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References

Study Design

A clinical program consisting of two studies was initiated to evaluate the efficacy, safety, and pharmacokinetics of interferon alfa-2b (Intron A, Schering-Plough, Kenilworth, NJ) plus ribavirin (Rebetol, Schering-Plough) in children with chronic HCV infection. The first study was a two-part phase 1 study to assess the efficacy, safety, and pharmacokinetics of interferon alfa-2b (3 million international units [MIU]/m2 subcutaneously 3 times weekly) plus ribavirin (8, 12, or 15 mg/kg/d orally in 2 divided doses). The dose of interferon alfa-2b used was based on safety data in children from a small pilot study.9 Cohort 1 of the phase 1 study was a dose-ranging study to select a ribavirin dose to use in combination with interferon alfa-2b for the second cohort of patients and future studies. Cohort 2 of the phase 1 study used the optimal ribavirin dose determined from cohort 1 of the phase 1 study. These results were combined with the subsequent phase 3 study. The phase 3 study used interferon alfa-2b (3 MIU/m2 subcutaneously 3 times per week, maximum 6MIU 3 times per week) and the selected optimal ribavirin dose from the phase 1 study, 15 mg/kg (maximum 1,200 mg/d). Both studies included a 48-week treatment period with a subsequent 24-week follow-up period. The studies were conducted in 29 centers in Europe, Canada, Israel, and the United States between January 1998 and November 2001, and 26 of them enrolled at least one subject in the trials. All studies were approved by each center's institutional review board, and all parents or legal guardians provided written informed consent; subject assent was also obtained when appropriate.

The endpoints for ribavirin dose selection were treatment week 4 pharmacokinetic assessments, levels of serum HCV RNA at treatment weeks 4 and 12, and safety through treatment week 12. In the first cohort of the phase 1 study, eligible subjects were randomly assigned to one of three treatments: interferon alfa-2b with ribavirin (8, 12, or 15 mg/kg/d) in equal proportion according to a computer-generated random code, supplied by the sponsor's biostatistics department to the central randomization center (Information Management Systems, Silver Spring, MD).

All subjects in cohort 2 of the phase 1 study and the phase 3 study received the same treatment regimen, interferon alfa-2b (3 MIU/m2 subcutaneously 3 times per week) with ribavirin (15 mg/kg/d); however, some subjects received the standard ribavirin capsule formulation and some received a new oral solution formulation in the phase 3 study.

Clinical evaluations occurred at treatment weeks 2 and 4 and then every 4 weeks during the treatment period and at follow-up weeks 4, 12, and 24 after treatment completion (and additionally for the phase 1 study at treatment weeks 1 and 6). All biochemical and hematological testing was performed at a central laboratory facility. Serum HCV RNA was measured before entry, at treatment weeks 2, 12, 24, 48, and follow-up weeks 4 and 24 in both studies. Serum HCV RNA in the phase 3 study was additionally evaluated at treatment weeks 4, 16, 20, 28, and 40 and follow-up week 12. The protocols allowed children who remained HCV RNA positive at week 24 to be discontinued from the study as treatment failures at the discretion of individual investigators.

Inclusion Criteria.

Children, 5 to 16 years old at time of entry for the phase 1 study (and 3 to 16 years old for the phase 3 study), were eligible if they were serum positive for HCV RNA by quantitative polymerase chain reaction (PCR). Previously interferon-treated patients with relapse were eligible for the phase 1 study but not the phase 3 study. Additional eligibility criteria included hemoglobin concentration >11 g/dL for girls and >12 g/dL for boys, white blood cell count >3,000/mm3, neutrophil count >1,500/mm3, platelet count >100,000/mm3, antinuclear antibody level ≤1:160, serum bilirubin concentration ≤3.0 mg/dL, and normal serum concentrations of albumin, creatinine, and thyroid-stimulating hormone (TSH). A liver biopsy consistent with chronic hepatitis C as reviewed at each center, obtained within 2 years (for phase 1 study) and within 1 year (for phase 3 study) before enrollment, was also required.

Exclusion Criteria.

Patients with decompensated cirrhosis, liver disease due to a cause other than HCV, human immunodeficiency and hepatitis B virus infection, hemoglobinopathies, hemophilia, malignancy (unless in remission for ≥5 years), preexisting neurological or psychiatric conditions (such as moderate or severe depression), substance abuse, chronic cardiopulmonary disease, immunologically mediated disorders, organ transplants, or serum alanine aminotransferase (ALT) >10 × upper limit of normal (for phase 1 study only) were excluded, as were girls of childbearing potential unable or unwilling to practice contraception.

Virological Assessment

The level of serum HCV RNA was initially measured by a quantitative PCR assay with a detection limit of 100 copies (29 IU)/mL (National Genetics Institute, Los Angeles, CA).10 During the phase 1 study, the initial test of quantitative HCV RNA was replaced by a comparable PCR assay with a detection limit of 100 copies (29 IU)/mL (Schering-Plough); range of linearity 100 to 2 × 109 copies/mL. Thereafter, all serum HCV RNA evaluations in the phase 1 and phase 3 studies were performed with the Schering-Plough assay. This assay is based on amplification of the HCV 5′ untranslated region using real-time PCR technology and is validated using HCV standards established by the World Health Organization (report on file with the Food & Drug Administration). The PCR assays were performed by technicians completely blinded to information about the clinical trial in laboratories distinctly separate from the offices where study data were processed and stored. HCV genotyping was performed by a line-probe assay11 for the phase 1 trial until it was replaced by one based on sequencing.12, 13

Efficacy and Safety Assessment

The primary efficacy end-point for all studies was sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after completing treatment. Laboratory variables were assessed at baseline and periodically during the 48-week treatment and 24-week follow-up periods. The protocols contained strict guidelines for dose reduction or discontinuation due to abnormalities in laboratory values. Adverse events were graded as mild, moderate, severe or life threatening, according to modified criteria of the World Health Organization14 and were managed by dose reductions except for life-threatening events, which resulted in permanent discontinuation of all study medications.

Patients with history of mild depression were considered for entry provided that pretreatment assessment of the subject's affective status by the enrolling investigator indicated that the subject was clinically stable. Psychological side effects were monitored by direct questioning at each protocol-specified treatment visit. Antidepressants were not used prophylactically in any of the treated children.

Pharmacokinetics and Measurements of Drug Concentration

Multiple-dose interferon alfa-2b and ribavirin pharmacokinetics were determined at week 4 in the phase 1 study by analyzing blood samples from 0, 2, 4, 6, 8, 10, 12, and 24 hours after dosing. In addition, trough serum or plasma concentrations of study medications were measured at treatment weeks 12, 24, 36, and 48. Ribavirin pharmacokinetics for capsule and oral solution formulations was determined in the phase 3 study at weeks 12, 24, 40, and 48. Serum interferon alfa-2b and plasma ribavirin concentrations were determined by validated electrochemiluminescent15 and mass spectrometry16 assays, respectively.

Assessment of Changes in Subject Height and Weight

Height and weight were measured at baseline, at the end of the 48-week treatment period, and at the end of the 24-week follow-up period. Each child's height and weight data were converted to an age- and gender-specific percentile for the baseline, end-of-treatment, and end-of-follow-up time points. Percentile assignments were performed independently by 2 pediatricians using the standard growth charts developed by the Centers for Disease Control and Prevention.17

Statistical Considerations

Efficacy and safety analyses were performed for all subjects who received at least one dose of study medication. The primary endpoint in the first cohort of the phase 1 study was to determine the incidence of adverse events, and the study was designed to have 60 patients, resulting in a 99.8% chance of at least one occurrence of any untoward event with a true underlying incidence rate of 10%. The chance was 95% if the underlying incidence rate was 5%.

The primary endpoint of the second cohort of the phase 1 study and the phase 3 study was the proportion of subjects who achieved SVR. A two-tailed Fisher's exact test was used to assess SVR between subgroups as a post hoc analysis.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References

In cohort 1 of the phase 1 study, the ribavirin treatment groups were similar with respect to baseline demographic, clinical, and virological features (data not shown). Four children had relapse after previous interferon treatment. Of 57 children assigned in parallel to receive interferon alfa-2b with ribavirin (8, 12, or 15 mg/kg/d), one patient (assigned to the 8 mg/kg/d ribavirin group) did not receive any study medication. This patient was therefore not included in the “intent to treat” analysis, which only included those who received at least one dose of study medications. Of the 56 patients who completed the study, 20, 19, and 17 subjects received ribavirin 8, 12, and 15 mg/kg/d, respectively. The mean reduction in serum HCV RNA (log10 copies/mL) per ribavirin group was 1.76, 1.74, and 2.07 at treatment week 4, and 2.76, 2.50, and 3.00 at treatment week 12 for ribavirin 8, 12, and 15 mg/kg/d, respectively. The mean reductions in levels of serum HCV RNA at treatment weeks 4 and 12 were not statistically different between the three ribavirin dosing regimens studied.

No significant differences were found in the nature or intensity of adverse events between the treatment groups of ribavirin 8, 12, or 15 mg/kg/d. In particular, the mean reductions (95% confidence interval) in hemoglobin concentration (g/dL) between baseline and treatment week 4 were 1.15 (0.62–1.69), 1.36 (0.90–1.82), and 1.57 (1.04–2.10) in the 8, 12, and 15 mg/kg/d groups, respectively. The mean hemoglobin drops (g/dL) between baseline and treatment week 12 were 1.04 (0.65–1.44), 1.01 (0.52–1.50), and 1.79 (1.25–2.34) in the 8, 12, and 15 mg/kg/d groups, respectively.

Based on its maximum reduction in levels of serum HCV RNA and comparably acceptable safety profile to the lower ribavirin regimens, the 15-mg/kg/d dose was selected as optimal. This ribavirin dose was used for further evaluation in cohort 2 of the phase 1 study and in the phase 3 study.

The phase 1 dose-finding study was not designed to establish statistical significance of serum viral suppression between the three ribavirin doses (8, 12, and 15 mg/kg/d). Given the small sample size of these groups, the highest viral load reduction at treatment weeks 4 and 12 in conjunction with an acceptable safety profile were used to define the “optimal” dose.

With this in mind, the virological response rates (proportion of patients who had undetectable serum HCV RNA) at treatment week 12 were 35%, 53%, and 59% in the 8, 12, and 15 mg/kg/d ribavirin dose groups, respectively. Similarly, the response rates at end of follow-up were 35%, 37%, and 47% for the 8, 12, and 15 mg/kg/d ribavirin groups, respectively. Of note, the mean reduction in hemoglobin concentration was 1.75 g/dL in children receiving 15 mg/kg/d ribavirin, which is less than that observed in adults (2.50 g/dL) treated with comparable doses of ribavirin (1,200 mg/d, which corresponds to approximately 15 mg/kg/d for an average 75-kg adult). This data further supported the 15 mg/kg/d dose of ribavirin as better than the others studied.

In all, 118 children received “optimal therapy” (interferon alfa-2b [3 MIU/m2 3 times per week] plus ribavirin [15mg/kg/d] in the phase 1 and phase 3 studies) and form the basis of this analysis. Baseline demographic and disease characteristics of these 118 subjects are shown in Table 1 and their disposition in Fig. 1. Of the 38 patients with treatment failure between treatment weeks 25 and 48, 37 were infected with HCV genotype 1, none with HCV genotype 2/3, and 1 with HCV genotype 4; 21 were children (≤12 years old), and 17 were adolescents (>12 years old). HCV RNA testing was performed in 30 of these patients at follow-up week 24, all of whom had detectable virus at this point.

Table 1. Baseline Demographic, Clinical and Virological Features of Treated Children
Total Number of Subjects118*
  • NOTE. Interferon alfa-2b (3 MIU/m2 subcutaneously 3 times per week) plus ribavirin (15 mg/kg orally every day).

  • *

    Includes all children given interferon alfa-2b (3 MIU/m2 subcutaneously 3 times per week) plus ribavirin (15 mg/kg orally once daily) in phase 1 (cohorts 1 and 2) and phase 3 studies.

  • Data missing for 1 subject.

  • Only 1 subject infected with HCV genotype 4.

Age (years) 
Median (range)11.0 (3–16)
Age range (years) 
 3–621 (18%)
 7–925 (21%)
 10–1229 (25%)
 13–1532 (27%)
 >1511 (9%)
Sex 
 Male/female67/51 (57%/43%)
Race 
 Caucasian94 (80%)
 Non-Caucasian24 (20%)
Body weight (kg) 
 Median (range, min-max)40.4 (10–95)
Weight range (kg) 
 ≤4673 (62%)
 >46–5513 (11%)
 >5532 (27%)
Source of HCV exposure 
 Transfusion associated49 (42)
 Vertical64 (54)
 Sporadic/other4 (3)
Estimated duration of infection (years) 
 Median (range)10.6 (0.8–17.0)
Number with previous malignancy9 (8%)
Number with preexisting mood disorder2 (2%)
Serum ALT (×ULN) 
 Median (range)1.2 (0.45–3.1)
 Number with normal values41 (35%)
HCV genotype 
 192 (78%)
 2/3/426 (22%)
Viral load (HCV RNA copies/mL) 
 Geometric mean2,037,747
 ≤2 million54 (46%)
 >2 million64 (54%)
Ribavirin formulation 
 Capsule63 (53%)
 Oral solution55 (47%)
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Figure 1. Number of patients at various stages of treatment and follow-up.

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Efficacy.

By intent-to-treat analysis, 59% (70/118) of “optimally treated” children 2b had undetectable levels of HCV RNA at treatment week 48 (end-of-treatment response), and 46% (54/118) achieved SVR. There was no significant difference between sustained response rates by ethnicity, body weight, sex, source of HCV exposure, estimated duration of infection, baseline serum ALT or ribavirin formulation. Among children with HCV genotype 1, SVR rates were higher in children who had viral levels ≤2,000,000 copies/mL than those with >2,000,000 copies/mL (48% vs. 26%, P < .05). No SVR differences were seen with respect to viral levels among those infected with HCV genotypes 2/3. Subjects with HCV genotype 2/3 had higher SVR rates (84%, 21/25) than those with HCV genotype 1 (36%, 33/92) (P < .001). The one subject with genotype 4 was a virological nonresponder.

The number of subjects is too small to make meaningful comparison with respect to age, but when categorized as children (5–12 years) and adolescents (>12 years), a significant difference was seen in SVR rates: 57% (43/75) versus 26% (11/43), respectively (P < .001). However, some of this difference in SVR may be explained by a high rate of missing follow-up PCR data in the older age group. Thirty-five percent (15/43) of the patients in the >12-year-old group are missing posttreatment PCR data, as compared with 7% (5/75) in the younger group (5–12 years). The adolescents had a similar percentage of patients with positive follow-up week 24 PCRs (40%, 17/43) to the younger children (36%, 27/75). Of note, 43 of 70 (61%) of children and 11 of 28 (39%) of adolescents who had follow-up at week 24 testing had undetectable serum HCV RNA. No meaningful differences were seen between children and adolescents with respect to frequency of adverse events, serious adverse events, early discontinuation because of treatment failure, protocol compliance, or HCV genotype distribution.

Levels of serum ALT normalized at the end of follow-up in 94% (31/33) of sustained responders with abnormal ALT at baseline. By contrast, ALT normalized in only 32% (9/28) of nonresponders with abnormal baseline ALT in whom end of follow-up ALT was available.

Safety.

All subjects had at least one adverse event during the treatment period, but more than 80% of them were considered to be mild or moderate in severity. All adverse events reported with a frequency of at least 10%, and those reported as severe are shown in Table 2. The most common adverse events were consistent with influenza-like syndrome, including fever, headache, and fatigue.

Table 2. Adverse Events
 All Grades* N (%)Severe N (%)
  • *

    Reported by at least 10% of subjects.

Total Subjects118 (100)118 (100)
Total reporting any adverse event118 (100)23 (19)
Headache81 (69)3 (3)
Fever72 (61)0
Fatigue68 (58)0
Anorexia60 (51)0
Abdominal pain46 (39)0
Vomiting50 (42)0
Nausea39 (33)0
Myalgia38 (32)2 (2)
Pharyngitis32 (27)0
Diarrhea30 (25)1 (<1)
Infection viral30 (25)0
Rigors29 (25)0
Weight decrease29 (25)0
Musculoskeletal pain25 (21)1 (<1)
Alopecia27 (23)0
Dizziness24 (20)1 (1)
Injection site reaction23 (19)1 (<1)
Rash20 (17)0
Emotional lability19 (16)0
Otitis media18 (15)0
Arthralgia18 (15)0
Injection site inflammation17 (14)0
Insomnia16 (14)0
Epistaxis15 (13)0
Depression15 (13)1 (<1)
Pruritus14 (12)0
Coughing13 (11)0
Malaise13 (11)0
Constipation12 (10)0
Irritability12 (10)1 (<1)

Severe adverse events were reported by 19% (23/118) of subjects. Neutropenia was the most common severe adverse event, and all but two cases were successfully managed by reducing the interferon dose. Depression was reported in 13% of children and was mild to moderate in severity in nearly all cases. However, of all children treated in these protocols, three had suicidal ideation, and one attempted suicide.

The one life-threatening adverse event reported was a suicide attempt in a 13-year-old female subject. After the suicide attempt, all treatment medications were discontinued, and antidepressants were initiated under psychiatric supervision, with resolution of suicidal ideation. Two additional subjects were hospitalized with serious psychiatric adverse events. One 9-year-old boy was hospitalized for depression, and a 14-year-old girl for suicidal ideation. Study medications were stopped in both of these subjects.

Dose Modification and Discontinuation Because of Adverse Events.

Dose modification was required in 31% (37/118) of subjects. The most common reasons for dose modification were anemia and neutropenia. In all, 8 subjects (7%) discontinued treatment because of adverse events, which included depression (n = 3), neutropenia (n = 2), and one case each of mild injection site pain, mild headache, and elevated aminotransferase level.No discontinuations resulted from anemia.

Clinical Laboratory Evaluation.

Hematological values decreased from baseline within the first 4 to 8 weeks of treatment then stabilized and returned to near-baseline or baseline levels by follow-up week 4 (Fig. 2). For all subjects, the mean change in hemoglobin from baseline to weeks 4 through 8 was −1.5 g/dL, followed by stabilization in association with reactive reticulocytosis. Decreases in levels of hemoglobin to <10g/dL occurred in nine subjects, all of whom were managed with dose reduction alone. Concomitant with decreases in hemoglobin, mild elevations in serum bilirubin (two cases) and uric acid (one case) were observed. A total of 23 of 118 (20%) subjects had grade 3 neutropenia (500–1,000 cells/L), and 3 of 118 (3%) experienced grade 4 neutropenia (<500 cells/L). None of the cases of severe neutropenia were associated with infectious complications. All but two cases were managed by dose modifications without discontinuation from therapy. No subject had a clinically significant decrease in platelet count. The proportion of subjects with normal TSH values by the end of treatment was 90% (56/62) and 100% (61/61) by follow-up week 24. None of the children with TSH abnormalities required reduction in dose or discontinuation of treatment. Three girls required L-thyroxine for hypothyroidism, two of whom had normal thyroid function with discontinuation of hormone treatment by treatment week 48 and by follow-up week 24, respectively. The third child subsequently developed insulin-dependent diabetes mellitus, and continues to take L-thyroxine.

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Figure 2. Hematological profile in pediatric subjects with chronic HCV treated with interferon alfa-2b (3 MIU/m2 3 times per week subcutaneously) with ribavirin (15 mg/kg/d by mouth). (A) Hemoglobin concentration and reticulocyte counts. (B) Neutrophil counts. (C) Mean platelet counts.

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Effects of Treatment on Height and Weight.

The changes in percentile from baseline to end of treatment and from end of treatment to end of follow-up are summarized in Fig. 3. The mean change in height percentiles in all subjects for the treatment period was −9.11 and +1.96 during follow-up. Similarly, mean weight percentile change during treatment and follow-up were −12.6 and +10.5, respectively. Generally, the mean data indicate that linear growth inhibition observed during treatment is not permanent, and a partially compensatory increase in linear growth rate is observed during posttreatment follow-up. A similar observation was made for weight, with a nearly compensatory “catch-up” weight gain noted after completion of treatment.

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Figure 3. Mean change in percentile in height and weight in pediatric subjects with chronic hepatitis C infection treated with interferon alfa-2b (3 MIU/m2 3 times per week subcutaneously) with ribavirin (15 mg/kg/d orally). A mean change in percentile of zero indicates that children were maintaining normal growth.

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Pharmacokinetics.

The multiple-dose pharmacokinetics of interferon alfa-2b and ribavirin in children at treatment week 4 are shown in Figs. 4 and 5. The multiple-dose pharmacokinetics of interferon alfa-2b in pediatric subjects were approximately twice that of corresponding adult values. This outcome is consistent with the fact that the pediatric dose is approximately twice that of adult subjects (Schering-Plough study, data on file) on a body surface area basis. Once these data are dose normalized, area under the curve (AUC(0–12h)) and maximum clearance (Cmax) are generally similar to the multiple-dose pharmacokinetics in adults. The pharmacokinetics of ribavirin showed general dose proportionality over the dose range studied. Mean plasma ribavirin Cmin values after administration of capsules or oral solution formulations were similar. Figure 5 shows the results of regression analyses carried out for ribavirin Cmax versus ribavirin dose and ribavirin AUC(0–12h) versus ribavirin dose. Linear dose/parameter relationships were demonstrated for each comparison. The pediatric ribavirin pharmacokinetic parameters at 8, 12, and 15 mg/kg/d corresponded to adult pharmacokinetic parameters at doses of 800, 1,000, and 1,200 mg/d, respectively.

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Figure 4. Mean serum interferon alfa-2b concentrations in adult and children with chronic HCV infection after 4 weeks of treatment. Adults were treated with interferon alfa-2b (3MIU 3 times per week subcutaneously) and ribavirin (1.0–1.2 g/d orally) and children (cohort 1 of our phase 1 trial) with interferon alfa-2b (3 MIU/m2 3 times per week subcutaneoulsy) and ribavirin (8, 12, or 15 mg/kg/d PO).

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Figure 5. Regression analyses in adult and pediatric subjects. Adults were treated with interferon alfa-2b (3MIU 3 times per week subcutaneously) and ribavirin (1.0–1.2 g/d orally) and children (cohort 1 of our phase 1 trial) with interferon alfa-2b (3 MIU/m2 3 times per week subcutaneouly) and ribavirin (8, 12, or 15 mg/kg/d orally). (A) Ribavirin Cmax versus ribavirin dose (orally). (B) Ribavirin AUC0–12h versus ribavirin dose (orally).

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Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References

The importance of HCV infection in adults lies in its propensity to cause insidiously progressive liver damage. Based on our current understanding of the pathobiology of HCV, it is reasonable to assume that the virus behaves in the same manner in children as in adults. Although childhood HCV infection is generally associated with mild liver damage, it has been associated with significant liver disease,1–4 including chronic hepatitis, cirrhosis, and hepatocellular carcinoma, in this population. Our studies demonstrate that interferon alfa-2b in combination with oral ribavirin is effective and reasonably safe for the treatment of childhood chronic hepatitis C. Infection with HCV genotypes 2 or 3, and lower level of serum HCV RNA at baseline in HCV genotype 1, are associated with higher virological response rates. These results are consistent with those reported in small pediatric pilot18–21 and large adult studies.7, 8

SVR rates in children with chronic HCV given interferon alfa-2b with ribavirin in these studies are higher than in those using interferon alone (46% vs. 36%, respectively).6 The use of different patient populations and treatment regimens in the small, previously published pediatric clinical studies of interferon as monotherapy makes direct comparisons between these treatment regimens difficult.

African-American adults have lower rates of SVR to interferon alfa-2b plus ribavirin than do Caucasian adults.22 In our studies, none of the African-American subjects (0/5) had a SVR to combination therapy. The number of African-American children studied was too small to draw firm conclusions but this observation suggests that African Americans, both children and adults, have lower response rates than Caucasians.

Combination therapy was generally well tolerated by children in these studies. The overall pattern of adverse events, hematological changes, and discontinuations from treatment is consistent with that seen in pediatric subjects treated with interferon alone or in combination with ribavirin.18–21 The adverse event profile in children is also similar to that seen in adults treated with comparable regimens.7, 8 The most common adverse events consisted of influenza-like symptoms and gastrointestinal complaints, including fever, headache, anorexia, vomiting, abdominal pain, myalgia, and nausea. These side effects were generally mild to moderate in severity, not treatment limiting, and improved over time. Of note, 19% of optimally treated children in our trials had a serious adverse event, and adverse events led to dose modification in 31% and discontinuation in 7%. The most common reasons for dose adjustment were anemia and neutropenia, which were managed by dose reductions in most cases; there were no discontinuations for anemia, and only two children discontinued therapy for neutropenia. Of note, treatment-related mean reductions in hemoglobin level and neutrophil counts were less pronounced in children than in similarly treated adults.7, 8 Importantly, severe infections did not occur in any of the children who developed neutropenia in these studies.

Neuropsychiatric adverse events were common, occurring in approximately 50% of treated children. Most events, such as insomnia, irritability, and somnolence, were mild to moderate in severity. In addition, depression, a side effect not previously reported in children with chronic HCV infection given interferon alone23 or with ribavirin,18–21 occurred in 13% of subjects. This may reflect the fact that the protocols were designed to identify and monitor depressive symptoms. The overall incidence of depression in children (13%) was lower than in adults treated with combination therapy (36%).7, 8 Although depression was mild to moderate in severity in most cases, three children had suicidal ideation (one during follow-up after completion of the treatment period), and one attempted suicide. This rate of suicidal ideation or attempt (3.4%) is generally consistent with the published prevalence in surveys of high school students24 but higher than that reported in similarly treated adults with hepatitis C (1%).7, 8 Of note, 3 of the 4 subjects who had suicidal ideation or attempt were adolescents, one of the most “at-risk” populations.24 The presence of chronic illness and a history of depression or behavior disorder are also associated with an increased risk of suicide.24, 25 It is therefore possible that study medications were not directly responsible for suicidal ideation, but rather uncovered underlying psychological problems in predisposed individuals. Nevertheless, this highlights the importance of carefully monitoring children and adolescents given interferon and ribavirin for the development of depressive symptoms, particularly in those with “at-risk” comorbid conditions. It should be noted that suicidal ideation resolved with prompt reduction or discontinuation of study medications, and in some cases, initiation of appropriate antidepressant treatment.

In agreement with published pediatric data,18–21 decreases in mean linear growth and weight associated with treatment were observed in these studies. However, after discontinuation of treatment, compensatory increases were noted in both height and weight, reaching near-baseline pretreatment values by the end of follow-up. Thus, the changes in growth parameters observed with combination interferon alfa-2b and ribavirin treatment appear to be transient in children. Compensatory increase in height and weight were incomplete at the last follow-up visit. Ongoing follow-up studies are evaluating the longer-term effects of combination therapy on growth in children with chronic HCV infection.

These studies evaluate the multiple-dose pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV infection. The pharmacokinetic profiles of interferon alfa-2b and ribavirin were similar between children and adults with respect to Cmax, Cmin and AUC(0–12h). Ribavirin doses of 8, 12, and 15 mg/kg/d in children were pharmacologically equivalent to daily doses of 800, 1,000, and 1,200 mg in adults, respectively. Single-dose pharmacokinetics of interferon also appear to be similar between children and adults.26 These pharmacokinetic similarities suggest that interferon alfa-2b and ribavirin metabolism are similar in children and adults, and that appropriately weight-adjusted doses of both may be safely used in children. In general, ribavirin capsule and oral solution formulations were comparable with respect to pharmacokinetic profiles, suggesting that either formulation is suitable for use in children.

In conclusion, these phase 1 and phase 3 studies show that interferon alfa-2b in combination with ribavirin is effective and reasonably safe for the treatment of chronic pediatric HCV infection. The pediatric safety data, pharmacokinetic profiles, and efficacy for the combination are similar to that reported in adults for the treatment of HCV infection.

APPENDIX

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References

John Bradley, M.D., Children's Hospital of San Diego, San Diego, CA; Robert S. Brown, M.D., Columbia Presbyterian Medical Center, New York, NY; Thomas W. Faust, M.D., University of Pennsylvania Philadelphia, PA; Fadi G. Haddad, M.D., Driscoll Children's Hospital-Specialty Clinic, Corpus Christi, TX; David Kimberlin, M.D., The University of Alabama at Birmingham, Birmingham, AL; Andrea Kovacs, M.D., Children's Hospital of Los Angeles, Los Angeles, CA; Alain Lachaux, Hopital Edouard Herriot, Lyon, France; Karen Lindsay, M.D., Maternal Child Research Program, Los Angeles, CA; Steven J. Lobritto, M.D., Columbia Presbyterian Medical Center, New York, NY; Parvathi Mohan, M.D., Children's National Medical Center, Washington, DC; Michael R. Narkewicz, M.D., Children's Hospital Research Institute, Denver, CO; April L.Palmer, University of Mississippi Medical Center, Jackson, MS; Henry Pollack, M.D., New York University Medical Center, New York, NY; Mobeen H. Rathore, M.D., University of Florida Health Science Center, Jacksonville, FL; Eve Roberts, M.D., The Hospital for Sick Children, Toronto, Canada; Benjamin Shneider, M.D., Mount Sinai Medical Center, New York, NY; Richard Whitley, M.D., The University of Alabama at Birmingham, Birmingham, AL; Stefan Wirth, Klinikum Wuppertal GmbH, Wuppertal, Germany.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. APPENDIX
  7. References
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