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Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C
Recombinant Alfa-Interferon Plus Ribavirin Therapy in Children and Adolescents With Chronic Hepatitis C Stefan Wirth,1 Thomas Lang,2 Stephan Gehring,3 and Patrick Gerner1 Treatment with alfa-interferon alone yielded poor results in children with chronic hepatitis C and was not generally recommended. Owing to limited experience with combination therapy in children, the aim of the study was to evaluate the efficacy and tolerability of alfa-interferon 2b in combination with ribavirin in these patients with different routes of viral transmission. In an uncontrolled pilot study, 41 children and adolescents ranging from 3 to 16 years were treated with alfa-interferon at a dose of 3 or 5 MU/m2 3 times weekly in combination with oral ribavirin (15 mg/kg/d) for 12 months. The mode of infection was unknown in 4, parenterally transmitted in 16, and vertically transmitted in 21 children. Forty patients completed the study. Eleven children, who remained hepatitis C virus (HCV)RNA positive 6 months after the beginning, discontinued therapy. One boy stopped treatment because of side effects. At the end of treatment 25 patients were HCV-RNA negative (61%). All individuals remained HCV-RNA negative during the 6-month follow-up period. Nine of 15 children with parenteral (56.3%), 14 of 21 with vertical (66.6%), and 2 of 4 with unknown route of infection responded. Side effects included minor clinical signs such as fever, flu-like symptoms, anorexia, and more severe signs (21.4%) such as the development of thyroid autoantibodies and impairment of thyroid function. In conclusion, combination of alfa-interferon with ribavirin seems to be an important advance in the treatment of chronic hepatitis C in children and adolescents. This also is true for both vertically infected patients and for individuals with normal transaminase levels before therapy. (HEPATOLOGY 2002;36:1280-1284.)
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reatment with alfa-interferon yielded very inconstant results ranging between 5% and 45% sustained response in children with chronic hepatitis C.1-4 As in adults, genotype 1, which represents the most frequent genotype in Europe, has a low response rate by an average of 27% as reported by Jacobson et al.,5 who analyzed all relevant published trials in children. This led to the recommendation by some pediatric hepatologists not to treat chronically infected children without progressive disease. According to current knowledge the inflammatory activity in liver tissue is usually mild at the time of diagnosis and may remain at a low level over more than 10 to 15 years.6,7 The risk for developing cirrhosis probably Abbreviation: HCV, hepatitis C virus. From the 1Children’s Hospital Wuppertal, Affiliated Clinic to Witten-Herdecke University, Wuppertal; 2Children’s Hospital, Ludwig Maximilians University, Munich; and 3Children’s Hospital, University of Mainz, Mainz, Germany. Received February 20, 2002; accepted August 12, 2002. Address reprint requests to: Stefan Wirth, M.D., Children’s Hospital, Klinikum Wuppertal GmbH, Affiliated Clinic to Witten-Herdecke University, Heusnerstr. 40, D-42283 Wuppertal, Germany. E-mail: [email protected]; fax: (49) 202-8963834. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3605-0034$35.00/0 doi:10.1053/jhep.2002.36495 1280
will not exceed around 5% until adulthood.8,9 Nevertheless, in single cases progressive liver diseases will occur and besides that the majority of infected individuals remain infectious. Thus, because spontaneous remission of chronic hepatitis C is uncertain and cirrhosis and hepatocellular carcinoma are common complications in the long-term follow-up in adulthood,10 especially by children and adolescents who were infected very early in their lifetime, particularly by vertical transmission, these patients should be considered for therapy. Nevertheless, some early cognitive impairment also may exist even in patients with mild liver disease.11 A number of trials in adults with alfa-interferon in combination with ribavirin have shown that the response rate even in patients with genotype 1 could be significantly improved. For this reason the combination therapy has become standard treatment.12-16 In the meantime the response rate in adults with chronic hepatitis C has been further improved with pegylated alfa-interferon in combination with ribavirin.17,18 To date, none of these treatments has been approved for children and adolescents. Chronic hepatitis C in childhood includes some particular features in terms of mode of infection, immuno-
HEPATOLOGY, Vol. 36, No. 5, 2002
logic competence, and inflammatory activity. During the past years vertical infection has become the most important route of viral transmission.18-20 The children are infected in a phase of high immunotolerance. The scarce follow-up data suggest a relatively low disease progression during the first 15 to 20 years of life. A considerable number of young individuals display normal transaminase levels, reflecting a low inflammatory activity. For this reason the response rate has to be correlated with those different parameters to provide reliable treatment recommendations for this age group. Christensson et al.21 and Lackner et al.22 reported encouraging results in a small number of children and adolescents with malignant disease in remission and chronic hepatitis C. Sustained response rates were 64% and 50%. However, many of them harbored genotype 3. Because ribavirin has been proven to be a teratogen in animals, there may be some unknown risk and potential danger of administering this agent to the growing individual. Although to date there has been no evidence of teratogenic side effects in treated humans, careful monitoring is mandatory. The aim of this study was to evaluate the efficacy and tolerability of recombinant alfa-interferon-2b in combination with ribavirin in chronic hepatitis C virus (HCV)infected children and adolescents with different routes of viral transmission.
Patients and Methods Design of the Study Forty-one children and adolescents with chronic hepatitis C (19 girls; 22 boys; mean age, 10.8 years; range, 3-16 years) were included in an open-label pilot study. Three were less than 5 years of age. Mean age at diagnosis was 9 years and the duration of chronic infection was 2 to 12 years. Nine individuals had been treated unsuccessfully with recombinant alfa-interferon-2b. The patients’ characteristics are summarized in Table 1. They were included independent of mode of infection, levels of transaminases, HCV-RNA levels, and genotypes. Diagnosis Chronic hepatitis C infection was diagnosed on the basis of anti-HCV antibodies, quantitative serum HCVRNA determination, and genotyping. HCV RNA was determined by the Amplicor polymerase chain reaction method (Roche Diagnostics, Hoffmann-La Roche Ltd., Basel, Switzerland) and genotyping was performed referring to the Simmonds-Okamoto classification. Liver biopsy procedure was performed no more than 6 months before treatment. Thirty-eight patients underwent a liver biopsy procedure, 3 refused. Liver histology revealed mild
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Table 1. Characteristics and Results of 41 Children With Chronic Hepatitis C Before and After Treatment With Recombinant Alfa-Interferon Plus Ribavirin Treated Patients
Total Sex Women Men Alanine transaminase level Normal Elevated Route of transmission Parenteral Vertical Unknown Genotype 1 2 and 3 Alfa-interferon pretreatment
HCV-RNA Negative*
41
25 (61%)
19 22
12 (63.1%) 13 (59.1%)
12 29
8 (66.6%) 17 (58.6%)
16 21 4
9 (56.3%) 14 (66.6%) 2
34 7 9
18 (52.9%) 7 (100%) 6 (66.6%)
*6-month follow-up evaluation after end of treatment.
or moderate chronic inflammatory activity. There were no children with severe chronic hepatitis or cirrhosis. By using Knodell’s histology activity index one child had a score of 3, 35 had a score of 4 to 10, and only 2 had a score of 12. For ethical reasons, follow-up biopsy procedures after treatment were not intended. None of the patients had coinfection with other hepatotropic viruses or were human immunodeficiency virus seropositive. Tests for antibodies against liver kidney membrane 1 autoantibodies were negative and thyroid function was normal. At the beginning of treatment all patients were clinically asymptomatic. Treatment Schedule The children received subcutaneous recombinant alfainterferon-2b at the dosage of 3 (n ⫽ 10) or 5 MU/m2 (n ⫽ 30) of body surface 3 times weekly in combination with oral ribavirin (15 mg/kg/d in 2 doses) for 12 months. Patients who remained HCV-RNA seropositive 6 months after the beginning of treatment discontinued therapy. The criteria for inclusion were proven chronic hepatitis C with detection of HCV RNA and determination of genotype, 2 to 16 years of age of either sex and any race, and normal values for hemoglobin, platelets, white blood cells, bilirubin, glucose, and serum creatinine. Sexually active individuals had to practice adequate contraception. Criteria for exclusion were underlying systemic diseases with or without autoimmunity, metabolic liver disorders, prior immune suppressive therapy, and severe neurologic impairment. Each patient’s parents gave written consent and the study was approved by the University’s ethics committee. Monitoring. Blood and serum analyses as well as a physical examination were performed every 2 weeks for
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the first 4 weeks, then monthly until the end of treatment, and thereafter at the third and sixth months of posttherapy follow-up evaluation. Monitoring of side effects of treatment was performed at each visit by parent’s protocol. Response. Complete sustained virologic response was defined as normalization of serum transaminase levels and undetectable HCV RNA during the course of treatment and persistence during the entire posttherapy follow-up period. For statistic calculation t test was used.
Results Forty-one children and adolescents were enrolled in the study (Table 1). One boy stopped treatment after 2 months owing to severe hemolysis by decrease of the hemoglobin level from 11.8 g/dL to 6.6 g/dL and fever. At this time he was persistently HCV-RNA positive. Of the 40 patients completing the study, 12 remained HCVRNA positive at 6 months of therapy and discontinued treatment according to protocol owing to nonresponse. Three individuals experienced a breakthrough and became HCV-RNA positive again at 9, 10, and 11 months of therapy. They were also classified as nonresponders, as was the patient who stopped treatment owing to side effects. Overall, in intention-to-treat analysis, 25 patients were HCV-RNA negative after 12 months of treatment and remained negative for the entire 6-month follow-up period. Liver enzymes had normalized in all of those who had elevated levels before therapy. Thus, 25 of 41 treated children and adolescents (61%) showed sustained virologic response. Thirteen (59.1%) were boys and 12 (63.1%) were girls.
HEPATOLOGY, November 2002
Levels of Transaminases Before Treatment Patients were classified into 2 groups, one with normal transaminase levels and the second with elevated transaminase levels. Of 12 individuals with normal transaminase levels before treatment, 8 (66.6%) responded completely. In the group with elevated liver enzymes the response rate was 17 of 29 at 58.6%. Side Effects Transient flu-like symptoms with variable intensity including moderate fever were observed in all patients during the first weeks of treatment. In all of them the symptoms resolved or were negligible during the second 6 months. Febrile convulsions did not occur. Some patients had anorexia but no severe weight loss (⬍5%) was registered. No individual showed a lower growth rate than 4.5 cm/y. In 3 cases considerable hair loss and moderate dry skin was reported. One boy showed severe anemia, which finally led to withdrawal of treatment. No dose adjustment was required in any other patient. Six of 28 (21.4%) children who were treated longer than 6 months developed thyroid autoantibodies and in 3 (10.7%) thyroidstimulating hormone levels increased markedly, so thyroid hormone was supplemented for the remaining time of treatment. All side effects disappeared after the end of treatment. Hemoglobin Values Mean levels of hemoglobin and SD are presented in Fig. 1. Owing to hemolysis induced by ribavirin, hemoglobin levels were significantly lower at 6 and 12 months under treatment and increased to former values at the 6-month follow-up evaluation.
Dosage Six of 10 (60%) in the 3-MU group and 19 of 31 (61.3%) in the 5-MU group responded permanently. Genotype Eighteen of 34 (52.9%) patients with genotype 1 showed sustained virologic response. All individuals with genotype 2 or 3 (n ⫽ 7) responded permanently to treatment. Route of Infection Nine patients (56.3%) with parenteral and 14 patients (66.6%) with vertical viral transmission responded persistently. In the small group (n ⫽ 4) of unknown route of infection, 2 individuals responded.
Fig. 1. Documentation of the significant changes of hemoglobin values before, during, and after alfa-interferon plus ribavirin treatment (mean ⫾ SD).
HEPATOLOGY, Vol. 36, No. 5, 2002
Discussion The results of this study confirm that in children and adolescents with chronic hepatitis C treatment, recombinant alfa-interferon-2b plus ribavirin is well tolerated and yields a more than 50% overall sustained virologic response rate, which, however, depends on genotype. A recent study in otherwise healthy, chronically HCV-infected children reported an overall response rate of 45%23; another small study yielded 50%.24 Two studies in chronically infected children with malignancies in remission showed sustained virologic response in 64% and 50%.21,22 Thus, the reported response rates are much higher compared with the sustained virologic response of treatment with alfa-interferon monotherapy. Response to alfa-interferon monotreatment correlated with genotypes similar to those in adulthood and genotype 1 yielded poor results with an average response rate of 27%.5 Nongenotype-1–infected children responded in 70% of cases. Therefore, the magnitude of the improvement with combination therapy by doubling the response rate in genotype-1–infected children is important and may represent a major advance in the therapy of chronic hepatitis C in children. Concerning the response rate in relation to genotype it is particularly striking that all patients harboring non–1 genotypes did permanently respond. Moreover, a 53% response rate in children with genotype 1 is not less remarkable and, above that, is encouraging. Prospectively, the most important route of infection occurs by vertical transmission. Hepatitis C infection is inoculated in newborns with a relative high immunotolerance, leading to a chronic course in at least 50% to 60% of infected babies.19 Many of them do not develop progressive liver disease for many years and may have normal liver enzymes for a long period of time. That is the reason why the recommendation for alfa-interferon monotherapy in childhood and adolescence was, at most, halfhearted. Therefore, an important issue in terms of response rates is the question of whether children with vertical infection and/or normal transaminase levels do respond in the same way as parenterally infected individuals, who mainly have elevated liver enzyme levels. Our results did not reveal any difference between the mode of infection and the level of transaminases. In our view there is no longer a reason to withhold the treatment from those patients. Reports by Silverman et al.25 and Lee and Sherman26 confirm that adults with normal or near-normal alanine transaminase levels and predominantly genotype 1 also may achieve considerable sustained response rates (47%).
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The combination therapy was generally well tolerated. But all children and adolescents showed flu-like symptoms and some other signs of general indisposition. Psychologic impairment was not observed. Only one patient had to stop treatment owing to anemia and persisting fever. However, careful monitoring of autoimmunity, particularly of the thyroid gland, is mandatory because more than 20% developed thyroid autoantibodies under long-term treatment. The thyroid-stimulating hormone level also has to be checked on a regular basis. All side effects disappeared after the end of treatment. Detailed informing and careful contraceptive monitoring also is necessary to avoid pregnancies in adolescents of childbearing age. In conclusion, the results of this study are encouraging and combination of recombinant alfa-interferon with ribavirin may become standard therapy also for children and adolescents. In view of the presented response rates, recommendation for treatment in this age group should not be restricted to patients with progressive disease or markedly elevated liver enzyme levels. But, at least in the United States, this recommendation cannot be made until results of large-scale trials convince the Food and Drug Administration to approve a pediatric indication. For further studies it would be advisable to use pegylated interferon alone versus pegylated interferon in combination with ribavirin to evaluate if combination treatment is necessary in children with chronic hepatitis C or not to achieve improved sustained viral response. Acknowledgment: The authors are grateful to all colleagues taking part in the study: A. Ballauff, M.D., Essen; R. Behrens, M.D., Erlangen; T. Berger, M.D., Datteln; H. Girschick, M.D., Wu¨ rzburg; W. Kampmann, M.D., Osnabru¨ ck; D. Nolkemper, M.D., Hamburg; D. Paul, M.D, Ravensburg; M. Pohl, M.D., Frankfurt; P. Schirrmacher, M.D., Vechta; R. Wiesmann, M.D., Giessen; H. P. Zimmer, M.D., Mu¨ nster, Germany.
References 1. Bortolotti F, Giacchino R, Vajro P, Barbera C, Crivellaro C, Alberti A, Nebbia G, et al. Recombinant interferon-alfa therapy in children with chronic hepatitis C. HEPATOLOGY 1995;22:1623-1627. 2. Iorio R, Pensati P, Porzio S, Fariello I, Guida S, Vegnente A. Lymphoblastoid interferon alfa treatment in chronic hepatitis C. Arch Dis Child 1996; 74:152-156. 3. Matsuoka S, Mori K, Nakano O, Yuasa Y, Taguchi Y, Hayabuchi Y, Kuroda Y. Efficacy of interferons in treating children with chronic hepatitis C. Eur J Pediatr 1997;156:704-708. 4. Pensati P, Iorio R, Botta S, Tuccillo C, Donetto S, Vajor P, Ciarlo G, et al. Low virological response to interferon in children with chronic hepatitis C. J Hepatol 1999;31:604-611. 5. Jacobson KR, Murray K, Zellos A, Schwarz KB. An analysis of published trials of interferon monotherapy in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2002;34:52-58. 6. Garcia-Monzon C, Jara P, Fernandez-Bermejo M, Hierro L, Frauca E, Camarena C, Diaz C, et al. Chronic hepatitis C in children: a clinical and
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immunohistochemical comparative study with adult patients. HEPATOLOGY 1998;28:1696-1701. Locasciulli A, Testa M, Pontisso P, Benvegnu L, Fraschini D, Corbetta A, Noventa F, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997;11:3628-4633. Bortolotti F, Jara P, Diaz C, Vajro P, Hierrro L, Giacchino, de la Vega A, et al. Posttransfusion and community-acquired hepatitis C in childhood. J Pediatr Gastroenterol Nutr 1994;18:279-283. Vogt M, Lang T, Fro¨ sner G, Klingler C, Sendl A, Zeller A, Wiebecke B, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999;341:866-870. Forns X, Ampurdanes S, Sanchez-Tapias JM, Guilera M, Sans M, Sanchez-Fueyo A, Quinto L, et al. Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center. J Hepatol 2001;35: 265-271. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Wesnes KA, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. HEPATOLOGY 2002;35:433-439. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485-1492. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426-1432. Kjaergard LL, Krogsgaard K, Gluud C. Interferon alfa with or without ribavirin for chronic hepatitis C: systematic review of randomized trials. BMJ 2001;323:1151-1155. Schvarcz R, Glaumann H, Reichard O, Weiland O. Histological and virological long-term outcome in patients treated with interferon-alfa2b and ribavirin for chronic hepatitis C. J Viral Hepat 1999;6:237-242. Mangia A, Villani MR, Minerva N, Leandro G, Bacca D, Cela M, Caretta V, et al. Efficacy of 5 MU of interferon in combination with ribavirin for
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naive patients with chronic hepatitis C virus: a randomized controlled trial. J Hepatol 2001;34:441-446. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345:41-52. Manns MP, McHutchinson JG, Gordon SG, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-965. Bortolotti F, Iorio R, Resti M, Verucchi G, Giacchino R, Vegnente A, Vajro P, et al. An epidemiological survey of hepatitis C virus infection in Italian children in the decade 1990-1999. J Pediatr Gastroenterol Nutr 2001;32:562-566. Yeung LTF, King SM, Roberts EA. Mother-to-infant transmission of hepatitis C virus. HEPATOLOGY 2001;34:223-229. Christensson B, Wiebe T, Akesson A, Widell A. Interferon-alfa and ribavirin treatment of hepatitis C in children with malignancy in remission. Clin Infect Dis 2000;30:585-586. Lackner H, Moser A, Deutsch J, Kessler HH, Benesch M, Kerbl R, Schwinger W, et al. Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy. Pediatrics 2000; 106:E53. Kelly DA, Bunn SK, Apelian D, Baczkowski A, Gupta S, Laughlin M, Cohard M. Safety, efficacy, and pharmacokinetics of interferon alfa-2b plus ribavirin in children with chronic hepatitis C [Abstract]. HEPATOLOGY 2001;34:342A. ¨ D, Elkabes B, So¨ ku¨ cu¨ S, Saner G. Does interferon and ribavirin Su¨ oglu O combination therapy increase the rate of treatment response in children with hepatitis C? J Pediatr Gastroenterol Nutr 2002;34:199-206. Silverman AL, Ternes D, Comanor L, Gordon SC. Chronic HCV patients with normal ALT values respond well to Rebetron therapy [Abstract]. HEPATOLOGY 2001;34:339A. Lee SS, Sherman M. Pilot study of interferon-alfa and ribavirin treatment in patients with chronic hepatitis C and normal transaminase levels. J Viral Hepat 2001;8:202-205.
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reatment with alfa-interferon yielded very inconstant results ranging between 5% and 45% sustained response in children with chronic hepatitis C.1-4 As in adults, genotype 1, which represents the most frequent genotype in Europe, has a low response rate by an average of 27% as reported by Jacobson et al.,5 who analyzed all relevant published trials in children. This led to the recommendation by some pediatric hepatologists not to treat chronically infected children without progressive disease. According to current knowledge the inflammatory activity in liver tissue is usually mild at the time of diagnosis and may remain at a low level over more than 10 to 15 years.6,7 The risk for developing cirrhosis probably Abbreviation: HCV, hepatitis C virus. From the 1Children’s Hospital Wuppertal, Affiliated Clinic to Witten-Herdecke University, Wuppertal; 2Children’s Hospital, Ludwig Maximilians University, Munich; and 3Children’s Hospital, University of Mainz, Mainz, Germany. Received February 20, 2002; accepted August 12, 2002. Address reprint requests to: Stefan Wirth, M.D., Children’s Hospital, Klinikum Wuppertal GmbH, Affiliated Clinic to Witten-Herdecke University, Heusnerstr. 40, D-42283 Wuppertal, Germany. E-mail: [email protected]; fax: (49) 202-8963834. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3605-0034$35.00/0 doi:10.1053/jhep.2002.36495 1280
will not exceed around 5% until adulthood.8,9 Nevertheless, in single cases progressive liver diseases will occur and besides that the majority of infected individuals remain infectious. Thus, because spontaneous remission of chronic hepatitis C is uncertain and cirrhosis and hepatocellular carcinoma are common complications in the long-term follow-up in adulthood,10 especially by children and adolescents who were infected very early in their lifetime, particularly by vertical transmission, these patients should be considered for therapy. Nevertheless, some early cognitive impairment also may exist even in patients with mild liver disease.11 A number of trials in adults with alfa-interferon in combination with ribavirin have shown that the response rate even in patients with genotype 1 could be significantly improved. For this reason the combination therapy has become standard treatment.12-16 In the meantime the response rate in adults with chronic hepatitis C has been further improved with pegylated alfa-interferon in combination with ribavirin.17,18 To date, none of these treatments has been approved for children and adolescents. Chronic hepatitis C in childhood includes some particular features in terms of mode of infection, immuno-
HEPATOLOGY, Vol. 36, No. 5, 2002
logic competence, and inflammatory activity. During the past years vertical infection has become the most important route of viral transmission.18-20 The children are infected in a phase of high immunotolerance. The scarce follow-up data suggest a relatively low disease progression during the first 15 to 20 years of life. A considerable number of young individuals display normal transaminase levels, reflecting a low inflammatory activity. For this reason the response rate has to be correlated with those different parameters to provide reliable treatment recommendations for this age group. Christensson et al.21 and Lackner et al.22 reported encouraging results in a small number of children and adolescents with malignant disease in remission and chronic hepatitis C. Sustained response rates were 64% and 50%. However, many of them harbored genotype 3. Because ribavirin has been proven to be a teratogen in animals, there may be some unknown risk and potential danger of administering this agent to the growing individual. Although to date there has been no evidence of teratogenic side effects in treated humans, careful monitoring is mandatory. The aim of this study was to evaluate the efficacy and tolerability of recombinant alfa-interferon-2b in combination with ribavirin in chronic hepatitis C virus (HCV)infected children and adolescents with different routes of viral transmission.
Patients and Methods Design of the Study Forty-one children and adolescents with chronic hepatitis C (19 girls; 22 boys; mean age, 10.8 years; range, 3-16 years) were included in an open-label pilot study. Three were less than 5 years of age. Mean age at diagnosis was 9 years and the duration of chronic infection was 2 to 12 years. Nine individuals had been treated unsuccessfully with recombinant alfa-interferon-2b. The patients’ characteristics are summarized in Table 1. They were included independent of mode of infection, levels of transaminases, HCV-RNA levels, and genotypes. Diagnosis Chronic hepatitis C infection was diagnosed on the basis of anti-HCV antibodies, quantitative serum HCVRNA determination, and genotyping. HCV RNA was determined by the Amplicor polymerase chain reaction method (Roche Diagnostics, Hoffmann-La Roche Ltd., Basel, Switzerland) and genotyping was performed referring to the Simmonds-Okamoto classification. Liver biopsy procedure was performed no more than 6 months before treatment. Thirty-eight patients underwent a liver biopsy procedure, 3 refused. Liver histology revealed mild
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Table 1. Characteristics and Results of 41 Children With Chronic Hepatitis C Before and After Treatment With Recombinant Alfa-Interferon Plus Ribavirin Treated Patients
Total Sex Women Men Alanine transaminase level Normal Elevated Route of transmission Parenteral Vertical Unknown Genotype 1 2 and 3 Alfa-interferon pretreatment
HCV-RNA Negative*
41
25 (61%)
19 22
12 (63.1%) 13 (59.1%)
12 29
8 (66.6%) 17 (58.6%)
16 21 4
9 (56.3%) 14 (66.6%) 2
34 7 9
18 (52.9%) 7 (100%) 6 (66.6%)
*6-month follow-up evaluation after end of treatment.
or moderate chronic inflammatory activity. There were no children with severe chronic hepatitis or cirrhosis. By using Knodell’s histology activity index one child had a score of 3, 35 had a score of 4 to 10, and only 2 had a score of 12. For ethical reasons, follow-up biopsy procedures after treatment were not intended. None of the patients had coinfection with other hepatotropic viruses or were human immunodeficiency virus seropositive. Tests for antibodies against liver kidney membrane 1 autoantibodies were negative and thyroid function was normal. At the beginning of treatment all patients were clinically asymptomatic. Treatment Schedule The children received subcutaneous recombinant alfainterferon-2b at the dosage of 3 (n ⫽ 10) or 5 MU/m2 (n ⫽ 30) of body surface 3 times weekly in combination with oral ribavirin (15 mg/kg/d in 2 doses) for 12 months. Patients who remained HCV-RNA seropositive 6 months after the beginning of treatment discontinued therapy. The criteria for inclusion were proven chronic hepatitis C with detection of HCV RNA and determination of genotype, 2 to 16 years of age of either sex and any race, and normal values for hemoglobin, platelets, white blood cells, bilirubin, glucose, and serum creatinine. Sexually active individuals had to practice adequate contraception. Criteria for exclusion were underlying systemic diseases with or without autoimmunity, metabolic liver disorders, prior immune suppressive therapy, and severe neurologic impairment. Each patient’s parents gave written consent and the study was approved by the University’s ethics committee. Monitoring. Blood and serum analyses as well as a physical examination were performed every 2 weeks for
1282
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the first 4 weeks, then monthly until the end of treatment, and thereafter at the third and sixth months of posttherapy follow-up evaluation. Monitoring of side effects of treatment was performed at each visit by parent’s protocol. Response. Complete sustained virologic response was defined as normalization of serum transaminase levels and undetectable HCV RNA during the course of treatment and persistence during the entire posttherapy follow-up period. For statistic calculation t test was used.
Results Forty-one children and adolescents were enrolled in the study (Table 1). One boy stopped treatment after 2 months owing to severe hemolysis by decrease of the hemoglobin level from 11.8 g/dL to 6.6 g/dL and fever. At this time he was persistently HCV-RNA positive. Of the 40 patients completing the study, 12 remained HCVRNA positive at 6 months of therapy and discontinued treatment according to protocol owing to nonresponse. Three individuals experienced a breakthrough and became HCV-RNA positive again at 9, 10, and 11 months of therapy. They were also classified as nonresponders, as was the patient who stopped treatment owing to side effects. Overall, in intention-to-treat analysis, 25 patients were HCV-RNA negative after 12 months of treatment and remained negative for the entire 6-month follow-up period. Liver enzymes had normalized in all of those who had elevated levels before therapy. Thus, 25 of 41 treated children and adolescents (61%) showed sustained virologic response. Thirteen (59.1%) were boys and 12 (63.1%) were girls.
HEPATOLOGY, November 2002
Levels of Transaminases Before Treatment Patients were classified into 2 groups, one with normal transaminase levels and the second with elevated transaminase levels. Of 12 individuals with normal transaminase levels before treatment, 8 (66.6%) responded completely. In the group with elevated liver enzymes the response rate was 17 of 29 at 58.6%. Side Effects Transient flu-like symptoms with variable intensity including moderate fever were observed in all patients during the first weeks of treatment. In all of them the symptoms resolved or were negligible during the second 6 months. Febrile convulsions did not occur. Some patients had anorexia but no severe weight loss (⬍5%) was registered. No individual showed a lower growth rate than 4.5 cm/y. In 3 cases considerable hair loss and moderate dry skin was reported. One boy showed severe anemia, which finally led to withdrawal of treatment. No dose adjustment was required in any other patient. Six of 28 (21.4%) children who were treated longer than 6 months developed thyroid autoantibodies and in 3 (10.7%) thyroidstimulating hormone levels increased markedly, so thyroid hormone was supplemented for the remaining time of treatment. All side effects disappeared after the end of treatment. Hemoglobin Values Mean levels of hemoglobin and SD are presented in Fig. 1. Owing to hemolysis induced by ribavirin, hemoglobin levels were significantly lower at 6 and 12 months under treatment and increased to former values at the 6-month follow-up evaluation.
Dosage Six of 10 (60%) in the 3-MU group and 19 of 31 (61.3%) in the 5-MU group responded permanently. Genotype Eighteen of 34 (52.9%) patients with genotype 1 showed sustained virologic response. All individuals with genotype 2 or 3 (n ⫽ 7) responded permanently to treatment. Route of Infection Nine patients (56.3%) with parenteral and 14 patients (66.6%) with vertical viral transmission responded persistently. In the small group (n ⫽ 4) of unknown route of infection, 2 individuals responded.
Fig. 1. Documentation of the significant changes of hemoglobin values before, during, and after alfa-interferon plus ribavirin treatment (mean ⫾ SD).
HEPATOLOGY, Vol. 36, No. 5, 2002
Discussion The results of this study confirm that in children and adolescents with chronic hepatitis C treatment, recombinant alfa-interferon-2b plus ribavirin is well tolerated and yields a more than 50% overall sustained virologic response rate, which, however, depends on genotype. A recent study in otherwise healthy, chronically HCV-infected children reported an overall response rate of 45%23; another small study yielded 50%.24 Two studies in chronically infected children with malignancies in remission showed sustained virologic response in 64% and 50%.21,22 Thus, the reported response rates are much higher compared with the sustained virologic response of treatment with alfa-interferon monotherapy. Response to alfa-interferon monotreatment correlated with genotypes similar to those in adulthood and genotype 1 yielded poor results with an average response rate of 27%.5 Nongenotype-1–infected children responded in 70% of cases. Therefore, the magnitude of the improvement with combination therapy by doubling the response rate in genotype-1–infected children is important and may represent a major advance in the therapy of chronic hepatitis C in children. Concerning the response rate in relation to genotype it is particularly striking that all patients harboring non–1 genotypes did permanently respond. Moreover, a 53% response rate in children with genotype 1 is not less remarkable and, above that, is encouraging. Prospectively, the most important route of infection occurs by vertical transmission. Hepatitis C infection is inoculated in newborns with a relative high immunotolerance, leading to a chronic course in at least 50% to 60% of infected babies.19 Many of them do not develop progressive liver disease for many years and may have normal liver enzymes for a long period of time. That is the reason why the recommendation for alfa-interferon monotherapy in childhood and adolescence was, at most, halfhearted. Therefore, an important issue in terms of response rates is the question of whether children with vertical infection and/or normal transaminase levels do respond in the same way as parenterally infected individuals, who mainly have elevated liver enzyme levels. Our results did not reveal any difference between the mode of infection and the level of transaminases. In our view there is no longer a reason to withhold the treatment from those patients. Reports by Silverman et al.25 and Lee and Sherman26 confirm that adults with normal or near-normal alanine transaminase levels and predominantly genotype 1 also may achieve considerable sustained response rates (47%).
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The combination therapy was generally well tolerated. But all children and adolescents showed flu-like symptoms and some other signs of general indisposition. Psychologic impairment was not observed. Only one patient had to stop treatment owing to anemia and persisting fever. However, careful monitoring of autoimmunity, particularly of the thyroid gland, is mandatory because more than 20% developed thyroid autoantibodies under long-term treatment. The thyroid-stimulating hormone level also has to be checked on a regular basis. All side effects disappeared after the end of treatment. Detailed informing and careful contraceptive monitoring also is necessary to avoid pregnancies in adolescents of childbearing age. In conclusion, the results of this study are encouraging and combination of recombinant alfa-interferon with ribavirin may become standard therapy also for children and adolescents. In view of the presented response rates, recommendation for treatment in this age group should not be restricted to patients with progressive disease or markedly elevated liver enzyme levels. But, at least in the United States, this recommendation cannot be made until results of large-scale trials convince the Food and Drug Administration to approve a pediatric indication. For further studies it would be advisable to use pegylated interferon alone versus pegylated interferon in combination with ribavirin to evaluate if combination treatment is necessary in children with chronic hepatitis C or not to achieve improved sustained viral response. Acknowledgment: The authors are grateful to all colleagues taking part in the study: A. Ballauff, M.D., Essen; R. Behrens, M.D., Erlangen; T. Berger, M.D., Datteln; H. Girschick, M.D., Wu¨ rzburg; W. Kampmann, M.D., Osnabru¨ ck; D. Nolkemper, M.D., Hamburg; D. Paul, M.D, Ravensburg; M. Pohl, M.D., Frankfurt; P. Schirrmacher, M.D., Vechta; R. Wiesmann, M.D., Giessen; H. P. Zimmer, M.D., Mu¨ nster, Germany.
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