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Abstract

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

Peginterferon plus ribavirin is standard therapy for adults with chronic hepatitis C. As no data are available for children, the aim of the study was to evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in chronically infected children. Genotypes, alanine aminotransferase levels, and different routes of viral transmission were considered. In an open-labeled, uncontrolled pilot study, 62 children and adolescents (range, 2–17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 μg/kg body weight once per week plus oral ribavirin (15 mg/kg × day) for 48 weeks. Sixty-one patients completed the study. Twenty-three children discontinued therapy after 6 months according to study protocol. Sustained viral response was documented in 22 (47.8%)of 46 patients with genotype 1, in 13 (100%) of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 (70.4%) of 27 children with parenteral, in 12 (48%) of 25 with vertical, and in 5 of 9 with unknown route of infection. Overall, treatment was well tolerated. Nevertheless, some side effects were present in all treated patients. Eighty-three percent had leucopenia, but only 3 individuals required dose reduction and 10.3% developed thyroid autoantibodies and thyroid dysfunction. In conclusion, combination treatment of peginterferon alfa-2b with ribavirin showed encouraging results and was well tolerated in children and adolescents with chronic hepatitis C. Weekly dosing of peginterferon alfa-2b is a considerable advance for this age group. The treatment is not approved for children. Further controlled trials are needed. (HEPATOLOGY 2005.)

Peginterferon alfa and ribavirin is established as standard treatment in adults with chronic hepatitis C (HCV). International studies have yielded sustained viral response rates (SVR) between 44% and 75% according to the genotype.1, 2 Whereas interferon alfa-2b and ribavirin has been approved for individuals between 3 and 18 years of age in the United States, the indication for therapy in children and adolescents is still debated in many countries. One reason may be that ribavirin has teratogenic or embryocidal effects in animals. The risk of ribavirin as a carcinogen in humans has not been established. For more than 20 years, the substance has been used in infants for other indications, such as respiratory syncytial virus infection.

The usage of peginterferon has improved response rates in adults by approximately 10% compared with a treatment regimen with interferon-alfa and ribavirin. Moreover, dosing of peginterferon once per week is another considerable advantage. No treatment study with peginterferon-alfa and ribavirin in children and adolescents with chronic HCV has been published so far.

Chronic HCV in childhood features particular issues regarding mode of infection, immunological competence, and inflammatory activity. Vertical infection is the most important route of viral transmission.3 These children are infected at a phase of high immune tolerance. A considerable number of young individuals display normal aminotransferases, reflecting a low inflammatory activity. Despite a relatively low disease progression during the first 15 to 20 years of life, severe liver disease occasionally occurs during childhood. In vertically infected patients, long-term spontaneous clearance of chronic HCV is low, and both liver cirrhosis and hepatocellular carcinoma are common late complications in adulthood.4–6 Furthermore, potential infectivity and a substantial social burden during the entire childhood remain, which may lead to social disintegration in some cases.

Several studies have been performed on the treatment of chronic HCV with interferon-alfa and ribavirin in this age group,7–12 most reporting a SVR of approximately 50%. However, in most papers stratification of results referring to genotype and mode of transmission was insufficient. Many of the patients were infected with genotype 3 and via parenteral transmission. Because treatment at an early age is better tolerated than in adulthood, individuals who were infected very early in their lifetime, particularly by vertical transmission, should be offered treatment. The aim of the current study was to evaluate the efficacy and tolerability of recombinant peginterferon alfa-2b in combination with ribavirin in chronic HCV infected children and adolescents with different routes of viral transmission.

Patients and Methods

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

Design of the Study.

62 children and adolescents with chronic HCV were included in an open label uncontrolled pilot study. Mean age at diagnosis was 7.9 years and the duration of chronic infection 1 to 15 years. Patients' baseline characteristics are reported in Table 1. Five individuals had been unsuccessfully treated with recombinant interferon alfa-2b. The patients were included independent of mode of infection, levels of transaminases, HCV RNA levels, and genotypes. The study was coordinated by the author. The protocol was agreed on by all participating centers. The clinical and laboratory data as well as adverse effects were evaluated and reviewed by the coordinator according to the case report forms. Each patient's parents and each child over 12 years of age agreed by written consent. The study was approved by the ethics committee of Witten-Herdecke University, which is experienced in dealing with clinical studies involving children and adolescents.

Table 1. Baseline Characteristics of 62 Children and Adolescents With Chronic Hepatitis C Before Treatment
CharacteristicsN
  1. Abbreviations: HCV, hepatitis C virus; ALT, alanine aminotransferase.

Sex 
 Female33 (53%)
 Male29 (47%)
Age, yrs2–17 (mean, 10.6)
Mode of infection 
 Parenteral28 (45.1%)
 Vertical25 (40.3%)
 Unknown9 (14.6%)
Genotype 
 147 (75.8%)
 24 (6.5%)
 39 (14.5%)
 42 (3.2%)
Anti-HCV positive62
HCV RNA (IU/mL)0.32–62 × 105 (mean, 6.3)
ALT ≤ 30 U/L36 (58%)
ALT > 30 U/L26 (42%)
Interferon pretreatment5

Diagnosis.

Chronic HCV infection was diagnosed on the basis of anti-HCV antibodies, quantitative serum HCV RNA determination and genotyping. HCV RNA was determined by the Amplicor polymerase chain reaction method (Roche Diagnostics, Basel, Switzerland), and genotyping was performed according to the Simmonds-Okamoto classification. HCV RNA testing was performed at each of the locations. Liver biopsy was not mandatory for inclusion in the study and was performed in 37 patients. Histological examination showed mild or moderate chronic inflammatory activity and low degree of fibrosis. No children had severe chronic hepatitis or cirrhosis. In all liver specimens, Knodell's histology activity index was below 10.

None of the patients had coinfection with other hepatotropic viruses, and none were human immunodeficiency virus seropositive. Pretreatment antibodies against liver kidney membrane autoantibodies were negative, and thyroid function was normal. Before therapy, all patients were clinically asymptomatic.

Treatment Schedule.

The children received subcutaneous recombinant peginterferon alfa-2b at a dosage of 1.5 μg/kg body weight once per week in combination with oral ribavirin (15 mg/kg × day in 2 doses) for 48 weeks. According to the study protocol, patients who remained HCV RNA seropositive 6 months after the beginning of treatment discontinued therapy and were characterized as non-responders. Knowing the adult experience that only 6 months' therapy is required for genotypes 2 and 3, the parents of individuals infected with these genotypes were allowed to decide whether they wanted to complete therapy for 48 weeks or to stop after 6 months. Thus, 8 of 13 children with genotype 2 or 3 were treated for 48 weeks, and 5 discontinued after 6 months.

Criteria for inclusion were proven chronic HCV with detection of HCV-RNA and determination of genotype, 2 to 17 years of age, both genders and all races, and normal values for hemoglobin, platelets, white blood cells, bilirubin, glucose, and serum creatinine. Sexually active male subjects and female individuals of childbearing potential committed themselves to practicing adequate contraception during the treatment period and for 6 months after discontinuation of therapy. Criteria for exclusion were underlying systemic diseases with or without autoimmunity, metabolic liver disorders, and severe neurological impairment.

Monitoring.

Blood and serum analyses as well as physical examination were performed 2, 4, and 8 weeks after starting therapy, then every 3 months until the end of treatment and thereafter at 3 and 6 months during post-therapy follow-up. A pregnancy test was performed in females with reproductive potential before the start of medication. Monitoring of treatment side effects and exclusion of pregnancy during treatment was done by parent's and patient's report at each visit.

Response.

Complete SVR was defined as normalization of serum alanine aminotransferase (ALT) and undetectable HCV RNA during the course of treatment and persistence during the entire 6 months' post-therapy follow-up period. Fisher's exact test was used for statistical calculation.

Results

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

Of 62 children and adolescents, 61 completed the study. One individual stopped treatment after 10 weeks because of a local allergic reaction at the injection site. Of the 61 patients, 17 infected with genotype 1 and one with genotype 4 were HCV RNA positive at 6 months of therapy and 5 of 13 responders with genotypes 2 and 3 discontinued treatment according to protocol. During therapy, 6 patients (9.8%) experienced a breakthrough and became HCV RNA positive again. They were also classified as non-responders.

Three months after starting treatment, 20 (91%) of 22 patients with genotype 1 and SVR and 12 (92.3%) of 13 with genotype 2 or 3 and SVR were HCV RNA negative.

Overall, on a per-protocol analysis, 39 patients (63.9%) were HCV RNA negative 12 months after starting treatment, and 36 (59%) remained negative for the entire 6-month follow-up period. Three (7.7%) of thirty-nine, all of them infected by genotype 1, had a relapse with detectable HCV RNA during the 6-month follow-up period. Liver enzymes had normalized in all responders who had elevated levels before therapy. All individuals infected with genotypes 2 and 3 who were treated for 24 weeks remained HCV RNA negative 12 months after discontinuation. The results are summarized in Table 2. In terms of response, there was no age-related difference. Seventeen (54.8%) of thirty-one children younger than 11 years and 19 (63.3%) of 30 older than 12 years of age showed SVR.

Table 2. Viral Response Rates of 61 Children and Adolescents With Chronic Hepatitis C During and After Peginterferon-alfa-2b Plus Ribavirin Treatment in Relation to Mode of Infection, ALT Levels, and Genotype
 NHCV-RNA Negative
3 Months6 Months12 Months18 Months (SVR)
  • Abbreviations: SVR, sustained viral response rate; ALT, alanine aminotransferase.

  • *

    Breakthrough 6 (9.8%).

  • Relapse 3 (7.7%).

  • P = .087.

  • §

    P = .11.

  • P = .0003.

Total6138 (62.3%)43 (70.5%)39 (63.9%)*36 (59%)
Mode of infection     
 Parenteral2719 (70.4%)22 (81.5%)21 (77.8%)19 (70.4%)
 Genotype 121   13 (61.9%)
 Vertical2514 (56%)16 (64%)13 (52%)12 (48%)
 Genotype 120   7 (35%)
 Unknown95 (55.5%)5 (55.5%)5 (55.5%)5 (55.5%)
 Genotype 15   2 (40%)
ALT levels     
 Normal3628 (77.7%)31 (86.1%)27 (75%)24 (66.6%)§
 Elevated >30 U/L2510 (40%)12 (48%)12 (48%)12 (48%)§
Genotype     
 14624 (52.1%)29 (63%)25 (54.3%)22 (47.8%)
 2, 31312 (92.3%)13 (100%)13 (100%)13 (100%)
 421111
 Interferon pretreatment52332

Genotype.

Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (P = .0003). One of 2 patients with genotype 4 had SVR.

Route of Infection.

Of 27 patients, 19 (70.4%) with parenteral and 12 (48%) of 25 with vertical viral transmission persistently responded. In the smaller group (n = 9) of unknown route of infection, 5 individuals responded. Multivariate analysis did not show any statistical significance (P = .28). However, a comparison of the parenteral and vertical infected group showed a tendency for the parenteral group to respond better (P = .087).

ALT Levels Before Treatment.

Patients were classified in 2 groups, one with normal and the second with elevated transaminases. Of 36 individuals with normal ALT before treatment, 24 (66.6%) responded completely. In the group with elevated liver enzymes, 12 (48%) of 25 showed SVR. Both groups did not differ significantly (P = .11).

Interferon-Alfa Pretreatment.

Two of 5 patients with prior interferon-alfa monotherapy had SVR; 1 relapsed 3 months after ceasing treatment.

Side Effects.

In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, was observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions did not occur. The frequency of adverse events is summarized in Table 3. Twelve patients had significant weight loss during treatment, but none of them lost more than 10% of their weight before therapy. Nine individuals showed temporary phases with mood swings or behavioral changes with sometimes more aggressive attitude than before therapy, as documented by their parents. Dose reduction by 20% to 30% of peginterferon was performed because of considerable leukopenia in 3 patients (1.5–1.7/nL) and in 1 because of general weakness. Three of them were sustained responders; 1 girl discontinued treatment after 10 weeks due to local allergic reaction at the injection site. One girl developed diabetes mellitus after 9 months of treatment. Therapy was continued without changing dosage, and the patient showed SVR. The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment was significant. Five individuals received a weight-adjusted dose of L-thyroxine until the end of treatment. In 3 of them, L-thyroxine could be stopped during follow-up and in 2 thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and peg-interferon. Because of hemolysis induced by ribavirin, mean hemoglobin levels were lower at 6 and 12 months under treatment and rose to former values at 6 months' follow-up. No severe hemolysis was observed. The data are reported in Table 4. With the exception of diabetes mellitus, all other side effects disappeared after the end of treatment.

Table 3. Frequency of Side Effects During Peginterferon-alfa-2b Plus Ribavirin Treatment
Laboratory FindingsN (%)
Leucopenia 
 <5/nL46 (75.4)
 <2/nL5 (8.2)
Neutropenia (<40%)34 (55.7)
Hemoglobin <10 mg/dL3 (4.9)
Thrombopenia (<100/nL)1 (1.6)
Clinical findings 
 Flu-like symptoms50 (82)
 Fever (>38°C)31 (51)
 Anorexia13 (21.3)
 Weight loss (>5%–<10%)12 (19.7)
 Temporary mood swings or dumpishness9 (14.8)
 Hair loss9 (14.8)
 Redness at the injection site8 (13.1)
 Weight gain (>5%)7 (11.5)
 Dose reduction3 (4.9)
Table 4. Mean Hemoglobin Values and Percentage of TSH Elevation and Emergence of Thyroid Antibodies Before, During, and After Peginterferon-alfa-2b Plus Ribavirin Treatment
MonthsHemoglobin (mean; g/dL)TSH ElevatedThyroid Antibodies Positive
013.201/62 (1.6%)
3 2/61 (3.3%)3/61 (4.9%)
611.66/61 (9.8%)7/61 (11.5%)
9 1/39 (2.6%)5/39 (12.8%)
1212.24/39 (10.3%)6/39 (15.4%)
1813.603

Discussion

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

Peginterferon-alfa plus ribavirin treatment has been established as standard therapy in adults with chronic HCV. The sustained viral response rates for patients infected by genotype 1 ranged between 39% and 46%.1, 2, 13, 14 Moreover, individuals with genotype 2 or 3 were cured in at least 80%.15 The route of infection in adults is usually associated with intravenous drug use or transfusion of blood products. To date, except for a letter to the editor,16 no published data regarding peginterferon-alfa plus ribavirin therapy in children and adolescents are available. Some studies using interferon-alfa and ribavirin yielded overall response rates between 41.7% and 61%.7–12 Most treated children in these studies had been infected by parenteral transmission. Because treatment with peginterferon-alfa and ribavirin yielded a further increase by approximately 10% compared with combination therapy with non-pegylated interferon-alfa in adults, it was obvious to offer the treatment to children and adolescents as well. Moreover, weekly dosing was more acceptable than thrice-weekly dosing.

The data of this uncontrolled study confirm that treatment with recombinant peginterferon alfa-2b plus ribavirin in children and adolescents with chronic HCV was well tolerated and yielded an encouraging result with 59% SVR. However, compared with the response rates in studies with non-pegylated interferon-alfa plus ribavirin, no substantial increase of the SVR could be documented.9, 11 Concerning the response rate in relation to genotype, it is particularly remarkable that all patients infected by genotypes 2 and 3 showed permanent response. Because there was no difference in relation to the duration of therapy (24 vs. 48 weeks), it is very likely that treatment for 24 weeks is sufficient, as in adults.15 The overall response rate of 47.8% in individuals with genotype 1 was certainly high but may have been influenced by the response in parenterally infected patients. Children with parenteral infection showed a slight but not significantly better response compared with those with vertical infection. Vertically infected individuals with genotype 1 had a comparatively moderate response rate (35%). These results would be comprehensible with the knowledge of spontaneous viral elimination on long-term follow-up, which is much less in vertically infected children, reflecting a higher immune tolerance to the virus.4, 5, 17 However, further studies with larger numbers of patients have to elucidate whether there is a different response rate in relation to mode of transmission.

A result of interest is the fact that patients with normal ALT levels had a slight tendency to respond better than those with elevated values (66.6% vs. 48%; P = .11). Recent studies in adults showed that the response rates seem to be independent of the liver enzyme levels.18–20 This issue is important insofar as there is no reason to exclude children with normal ALT levels from treatment.

The therapy was generally well tolerated, and compliance was good, even in the group of adolescents. Almost all patients showed flu-like symptoms and some other signs of indisposition. Severe psychological impairment was not observed. One patient stopped treatment because of local allergic reaction at the injection site, and 1 girl developed type 1 diabetes mellitus, which is a rare but well-described side effect under interferon treatment.21 Also, careful monitoring of autoimmunity regarding the thyroid gland is mandatory, because in 15% thyroid antibodies emerged under long-term treatment. Thyroid-stimulating hormone levels also have to be controlled on a regular basis. All patients continued to attend kindergarten or school.

In conclusion, the results of this open-labeled, uncontrolled study are encouraging, and the combination of peginterferon-alfa with ribavirin as standard therapy also should be considered for children and adolescents. Recommendations for treatment in this age group should not be restricted to patients with progressive liver disease or elevated liver enzymes. Nevertheless, because ribavirin is potentially teratogenic, the necessity for adding it to peginterferon should be proven. Individuals infected by genotypes 2 and 3 have an excellent response rate. Although in genotype 1 patients it is uncertain whether a better response rate than non-pegylated interferon-alfa exists, the considerable advantage of peginterferon is the dosing once per week. Further studies should focus on treatment duration for genotypes 2 and 3 patients and particularly on vertically infected children with genotype 1.

Acknowledgements

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

The authors thank all colleagues involved in the study: R. Adam, Düsseldorf, G. Auerswald, Bremen, M. Ahaus, Aachen, B. Block, Braunschweig, R. Behrens, Nürnberg, T. Berger, Datteln, A. Enninger, Stuttgart, A. Findeisen, Greifswald, G. Fröhlich, Memmingen, B. Gruhn, Jena, G. Kliemann, Giessen, E. v. Kries, Karlsruhe, G. Koch, Hagen, H. Köhler, Erlangen, G. Laske, Berlin, R. Link, Offenburg, W. Marg, Bremen, D. Marsan, Krefeld, R. Melchior, Kassel, M. Melter, Hannover, H. Morf, Flensburg, R. Mühlenberg, Krefeld, A. Näke, Dresden, T. Pabst, Köln, D. Paul, Ravensburg, E. D. Pfister, Hannover, A. Schmidt-Choudury, Bochum, H. Schaub, Wetzikon, T. Schneider, Hamburg, W. v. Schwerin, Otterndorf, M. Stern, Tübingen, F. Walther, Rostock, G. Stursberg, Günzburg, and K. Terwolbeck, Heilbronn

References

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