Does Interferon and Ribavirin Combination Therapy Increase the Rate of Treatment Response in Children With Hepatitis C?
Corresponding Author
Özlem D. Süoğlu
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Address correspondence and reprint requests to Özlem D. Süoğlu, Tepegoz sok Tamiş çik 49/12, Göztepe Istanbul 81060, Turkey (e-mail: [email protected]).Search for more papers by this authorBerna Elkabes
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorSemra Sökücü
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorGünay Saner
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorCorresponding Author
Özlem D. Süoğlu
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Address correspondence and reprint requests to Özlem D. Süoğlu, Tepegoz sok Tamiş çik 49/12, Göztepe Istanbul 81060, Turkey (e-mail: [email protected]).Search for more papers by this authorBerna Elkabes
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorSemra Sökücü
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorGünay Saner
Pediatric Gastroenterology and Hepatology Department, Istanbul School of Medicine, Istanbul University, Turkey
Search for more papers by this authorABSTRACT
Background
Interferon-α was the first accepted treatment of chronic hepatitis C. In recent years, adding ribavirin has produced better response rates in adult patients than monotherapy with interferon-α. Whether adding ribavirin also improves treatment results in pediatric patients remains unclear.
Methods
Twelve patients were given 3 million U/m2 subcutaneous interferon-α three times weekly and 15 mg/kg oral ribavirin daily, and 10 patients were given only 3 million U/m2 subcutaneous interferon-α three times weekly for a total of 12 months.
Results
The dropout rate was 22.8% (25% for patients receiving combination treatment versus 20% for those receiving monotherapy). At the end of treatment, viral clearance was achieved in 50% of the patients who received combination treatment versus 30% of those who received monotherapy. After 12 months of posttreatment follow-up, sustained response rates were 30% and 41.7%, respectively. Of those who responded to treatment, 66.7% had received ribavirin whereas 37.5% of nonresponders had received ribavirin therapy.
Conclusion
Adding ribavirin to interferon treatment improved end-of-treatment response rates in children with chronic hepatitis C. Tolerance of treatment was similar to tolerance of monotherapy. However, studies of greater numbers of pediatric patients with longer follow-up periods are necessary to determine prolonged sustained response.
REFERENCES
- 1Di Bisceglie AM, Hepatitis C. Lancet 1998; 351: 351–5.
- 2Carithers RL, Emerson SS. Therapy of hepatitis C: meta-analysis of interferon 2b trials. Hepatology 1997; 26(suppl 1): 83–8.
- 3Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778–89.
- 4Fujisawa T, Inui A, Ohkawa T, et al. Response to interferon therapy in children with chronic hepatitis C. J Pediatr 1995; 127: 660–2.
- 5Pensati P, Iorio R, Botta S, et al. Low virological response to interferon in children with chronic hepatitis C. J Hepatol 1999; 31: 604–11.
- 6Weiland O. Treatment of naive patients with chronic hepatitis C. J Hepatol 1999; 31: (suppl 1):168-73.
- 7McHutchinson JG, Gordon SC, Schiff ER, et al. Interferon alfa 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339: 1485–92.
- 8Brillanti S, Garson J, Foli M, et al. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology 1994; 107: 812–17.
- 9Barbaro G, Di Lorenzo G, Belloni G, et al. Interferon alpha 2B and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial. Am J Med 1999; 107: 112–8.
- 10Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa 2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339: 1493–9.
- 11 World Medical Association. Declaration of Helsinki: adopted by 18th WMA, 1964; revised by 48th WMA, 1996.
- 12Abacioğlu YH, Davidson F, Tuncer S, et al. The distribution of hepatitis C virus genotypes in Turkish patients. J Viral Hepatol 1995; 2: 297–301.
- 13Kilic H, Taskapan H, Sahin I, et al. Hepatitis C virus genotypes in chronic hemodialysis patients. Nephron 2000; 84: 379–80.
- 14Fang JWS, Chow V, Johnson YNL. Virology of Hepatitis C Virus. Clin Liver Dis 1997; 1: 493–514.
- 15Lefkowitch JH, Schiff ER, Davis GL, et al. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group. Gastroenterology 1993; 104: 595–603.
- 16Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19: 1513–20.
- 17Craxi A, Camma C, Giunata M. Definition of response to antiviral therapy in chronic hepatitis C. J Hepatol 1999; 31(suppl 1): 160–7.
- 18 World Health Organisation. Hepatitis C: global prevalence. Wkly Epidemiol Rec 1997; 72: 341–8.
- 19Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology 2000; 31: 1014–8.
- 20Fujisawa T, Komatsu H, Inui A, et al. Spontaneous remission of chronic hepatitis C in children. Eur J Pediatr 1997; 156: 773–6.
- 21Bortolotti F, Giacchino R, Vajro P, et al. Recombinant interferon alpha therapy in children with chronic hepatitis C. Hepatology 1995; 22: 1623–7.
- 22Iorio R, Pensati P, Porzio S, et al. Lymphoblastoid interferon alfa treatment in chronic hepatitis C. Arch Dis Child 1996; 74: 152–6.
- 23Fujisawa T, Inui A, Komatsu H, et al. Long term efficacy of interferon alfa therapy for chronic hepatitis C in children. J Pediatr Gastroenterol Nutr 2000: 31(suppl 2): 269.
- 24Clemente MG, Congia M, Lai ME, et al. Effect of iron overload on the response to recombinant interferon alfa treatment in transfusion dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 1994; 125: 123–8.
- 25Zancan L, Strafella MS, Brugiolo A, et al. Chronic hepatitis C infection in childhood and early cirrhosis: It is possible? J Pediatr Gastroenterol Nutr 2000; 30: 350–1.
- 26Gonzalez-Peralta RP. Hepatitis C virus infection in pediatric patients. Clin Liver Dis 1997; 1: 691–705.
- 27Guido M, Rugge M, Jara P, et al. Chronic hepatitis C in children: the pathologic and clinical spectrum. Gastroenterology 1998; 115: 1525–9.
- 28Garcia-Monzon C, Jara P, Fernandez-Bermejo, et al. Chronic hepatitis C in children: a clinical and immunohistochemical comparative study with adult patients. Hepatology 1998; 28: 1696–701.
- 29Badizadegan K, Jonas MM, Ott MJ, et al. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998; 28: 1416–23.
- 30Bunn SK, Hubscher SG, Kelly DA. The progression of hepatic inflammation and fibrosis in children with hepatitis C [abstract]. J Pediatr Gastroenterol Nutr 2000; 31(suppl 2): 53.
- 31Ruiz-Moreno M, Rua MJ, Castillo I, et al. Treatment of children with chronic hepatitis C with recombinant interferon-α: a pilot study. Hepatology 1992; 16: 882–5.
- 32Cesaro S, Rosetti F, De Moliner L, et al. Interferon for chronic hepatitis C in patients cured of malignancy. Eur J Pediatr 1994; 153: 659–62.
- 33Komatsu H, Fujisawa T, Inui A, et al. Efficacy of interferon in treating chronic hepatitis C in children with a history of acute leukemia. Blood 1996; 87: 4072–5.
- 34Zwiener RJ, Fielman BA, Cochran C, et al. Interferon alpha2b treatment of chronic hepatitis C in children with hemophilia. Pediatr Infect Dis J 1996; 15: 906–8.
- 35Matsuoka S, Mori K, Nakano O, et al. Efficacy of interferons in treating children with chronic hepatitis C. Eur J Pediatr 1997; 156: 704–8.
- 36Marcellini M, Kondili LA, Comparcola D, et al. High dosage alpha-interferon for treatment of children and young adults with chronic hepatitis C disease. Pediatr Infect Dis J 1997; 16: 1049–53.
- 37Sawada A, Tajiri H, Kozaiwa K, et al. Favorable response to lymphoblastoid interferon-alpha in children with chronic hepatitis C. J Hepatol 1998; 28: 184–8.
- 38Di Marco V, Lo lacono O, Almasio P, et al. Long-term efficacy of α-interferon in β-thalassemics with chronic hepatitis C. Blood 1997; 90: 2207–12.
- 39Jonas M, Ott MJ, Nelson SP, et al. Interferon alpha treatment of chronic hepatitis C virus infection in children. Pediatr Infect Dis J 1998; 17: 241–6.
- 40Yüce A, Koçak N, Gürakan F, et al. Interferon alpha treatment for chronic hepatitis C in children. Turk J Pediatr 2000; 42: 34–8.
- 41Ko JS, Choe YH, Kim EJ, et al. Interferon alfa treatment of chronic hepatitis C in children with hemophilia [abstract]. J Pediatr Gastroenterol Nutr 2000; 31(suppl 2): 271.
- 42Jacobson KR, Murray KF, Zellos A, et al. Analysis of interferon monotherapy trials in children with HCV [abstract]. J Pediatr Gastroenterol Nutr 2000; 31(suppl 2): 123.
- 43Nakashima E, Yamato Y, Kimura A, et al. Efficacy of interferon alpha treatment in Japanese children with chronic hepatitis C [abstract]. J Pediatr Gastroenterol Nutr 2000; 31(suppl 2): 116.
- 44Baggio VL, Pugliese RPS, Miura IK, et al. Treatment of chronic hepatitis C with recombinant interferon α2b in childhood [abstract]. J Pediatr Gastroenterol Nutr 2000; 31(suppl 2): 52.
- 45Mabbe CL, Crippin JS, Lee WM. Interferon and hepatitis C--factors predicting therapeutic outcome. Aliment Pharmacol Ther 1998; 12: 509–18.
- 46Girelli CM, Mirata C, Lesinigo E, et al. Iron overload and response to α-interferon in chronic hepatitis C. Am J Gastroenterol 1995; 90: 170–1.
- 47Kaserer K, Fiedler R, Steindl P, et al. Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C. Histopathology 1998; 32: 454–61.
- 48Akiyoshi F, Sata M, Uchimura Y, et al. Hepatic iron stainings in chronic hepatitis C patients with low HCV RNA levels: a predictive marker for IFN therapy. Am J Gastroenterol 1997; 92: 1463–6.
- 49Olynk JK, Reddy KR, Di Bisceglie AM, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995; 108: 1104–9.
- 50Izumi N, Enomoto N, Uchihara M, et al. Hepatic iron contents and response to interferon-α in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus. Dig Dis Sci 1996; 41: 989–94.
- 51Barbaro G, Di Lorenzo G, Ribersani M, et al. Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype. J Hepatol 1999; 30: 774–82.
- 52Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology 1999; 30: 787–93.
- 53 EASL International Consensus Conference on Hepatitis C. Paris, 26-27 February 1999. Consensus statement. J Hepatol 1999; 31:(suppl 1):3-8.
- 54Bruchfeld A, Stahle L, Schvarchz R, et al. Ribavirin treatment in combination with interferon alfa in dialysis patients with chronic hepatitis C infection [abstract]. Hepatology 2000; 32: 351A.
- 55Pol S, Zylberberg H, Fontaine H, et al. Treatment of hepatitis C in special groups. J Hepatol 1999; 31(suppl 1): 205–9.
- 56Telfer PT, Garson JA, Whitby K, et al. Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients. Br J Haematol 1997; 98: 850–5.
- 57Christensson B, Wiebe T, Akesson A, et al. Interferon-α and ribavirin treatment of hepatitis C in children with malignancy in remission. Clin Infect Dis 2000; 30: 585–6.
- 58Lackner H, Moser A, Deutsch J, et al. Treatment of chronic hepatitis C with interferon and ribavirin in children surviving pediatric malignancy [abstract]. J Pediatr Gastroenterol Nutr 2000: 31(suppl 2): 114.
- 59Bunn S, Kelly D, Murray KF, et al. Safety, efficacy and pharmacokinetics of interferon alfa-2b and ribavirin in children with hepatitis C [abstract]. Hepatology 2000; 32: 350A.
- 60Kaji K, Nakanuma Y, Harada K, et al. Hemosiderin deposition in portal endothelial cells is a histologic marker predicting poor response to interferon-α therapy in chronic hepatitis C. Pathol Int 1997; 47: 347–52.
- 61Fiel MI, Schiano TD, Guido M, et al. Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin. Am J Clin Pathol 2000; 113: 35–9.
- 62Hannley JP, Haydon GH. The biology of interferon-α and the clinical significance of anti-interferon antibodies. Leuk Lymphoma 1998; 29: 257–68.
- 63Milella M, Antonelli G, Santantonio T, et al. Neutralizing antibodies to recombinant alpha-interferon and response to therapy in chronic hepatitis C virus infection. Liver 1993; 13: 146–50.
- 64Hanley J, Jarvis LM, Simmonds P, et al. Development of anti-interferon antibodies and breakthrough hepatitis during treatment for HCV infection in haemophiliacs. Br J Haematol 1996; 94: 551–6.
- 65Antonelli G, Currenti M, Turriziani O, et al. Neutralizing antibodies to interferon-α: relative frequency in patients treated with different interferon preparations. J Infect Dis 1991; 163: 882–5.
- 66Leroy V, Baud M, De Traversay C, et al. Role of anti-interferon antibodies in breakthrough occurrence during alpha 2a and 2b therapy in patients with chronic hepatitis C. J Hepatol 1998; 28: 375–81.