소아 만성 B형 간염 환아에서 라미부딘과 알파 인터페론의 치료효과 비교 : 치료 시작 후 2년 경과 시점 비교

Comparison of Therapeutic Efficacy between Lamivudine and Alpha-Interferon in Korean Children with Chronic Hepatitis B at Two Years after the Initiation of Treatment

  • 최병호 (경북대학교 의과대학 소아과학교실) ;
  • 장유철 (경북대학교 의과대학 소아과학교실) ;
  • 장창환 (경북대학교 의과대학 소아과학교실) ;
  • 오기원 (경북대학교 의과대학 소아과학교실) ;
  • 이준화 (경북대학교 의과대학 소아과학교실) ;
  • 고철우 (경북대학교 의과대학 소아과학교실)
  • Choe, Byung-Ho (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Jang, You Cheol (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Jang, Chang Hwan (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Oh, Ki Won (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Lee, Jun Hwa (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Ko, Cheol Woo (Department of Pediatrics, Kyungpook National University School of Medicine)
  • 투고 : 2004.08.16
  • 심사 : 2004.09.23
  • 발행 : 2005.01.15

초록

목 적 : 소아 만성 B형 간염 환아들에게 인터페론 또는 라미부딘으로 치료 후 그 치료효과를 치료 시작 후 2년 경과 시점에서 비교해 보고 소아에서 라미부딘의 장기 치료효과와 안정성에 대해 검증하고자 하였다. 방 법 : 1996년 9월부터 경북대학교병원 소아과에서 만성 B형 간염으로 치료를 시작한 후 2004년 6월까지 2년이 경과한 44명을 대상으로 하였다. 이중 23명은 알파 인터페론으로, 나머지 21명은 라미부딘으로 치료하면서 전향적 연구를 시행하였다. 인터페론 치료군과 라미부딘 치료군 사이에 성비, 나이, 치료 전 혈청 ALT 및 HBV DNA치에서는 유의한 차이가 없었다. 치료에 대한 효과는 치료 시작 2년 후 혈청 ALT 치의 정상화와 HBV DNA의 음전, HBsAg 소실 및 HBeAg 혈청전환 여부에 따라 결정하였다. 결 과 : 인터페론으로 치료한 23명 중 2년 경과 후 ALT치가 정상화된 환아는 10명(43%), HBV DNA치가 음전된 환아는 12명(52%), HBsAg이 소실된 환아는 1명(4%), HBeAg 혈청전환된 환아는 9명(39%)이었다. 이에 비해 라미부딘으로 치료한 21명에서는 각각 20명(95%), 19명(90%), 5명(24%), 13명(62%)이었다. 특히 라미부딘 치료군 중에서 7세 미만의 어린 환아 8명에서는 HBeAg 및 HBsAg 혈청전환이 각각 6명(75%)과 5명(63%)에서 일어나서 인터페론 치료군에 비해 좋은 치료효과를 보여주었다. 특히 유아기에 치료를 시작한 경우 7세 이상에 비해 HBsAg 소실이 유의하게 더 잘 일어났다. 결 론 : 한국의 소아 만성 B형 간염 환아에서 라미부딘의 장기 치료효과는 알파 인터페론에 비해 우수한 편이었고 부작용도 적었다.

Purpose : We compared the therapeutic efficacy of lamivudine and alpha-interferon in children with chronic hepatitis B two years after the initiation of treatment, so that we could verify the safety and long term efficacy of lamivudine in children. Methods : We prospectively studied 44 children(32 male and 12 female; age, 1-18 years, mean, 9 years) treated for chronic hepatitis B from September 1996 to June 2004 in Kyungpook National University Hospital in Korea. Twenty three children were treated with interferon, and 21 with lamivudine. Treatment efficacy was defined as the normalization of ALT and hepatitis B virus(HBV) DNA levels, loss of HBsAg and HBeAg seroconversion at two years after the initiation of treatment. Results : Among the 23 children treated with interferon, the ALT level normalized in 10 children(43 %) and HBV DNA was undetectable in 12 children(52%). HBsAg was undetectable in one child (4 %) and HBeAg seroconversion occurred in nine children(39%) two years after the initiation of treatment. In comparison, among the 21 children treated with lamivudine, ALT normalized in 20 children (95%), HBV DNA in 19(90%), HBsAg in 5(24%), and HBeAg seroconversion occurred in 13(62%). Above all, in the lamivudine treated group under the age of seven, HBeAg and HBsAg seroconversion occurred in six(75%) and five(63%) out of the eight children respectively, which showed superior HBsAg seroconversion rate if treated in preschool aged children. Conclusion : We believe that the therapeutic efficacy of lamivudine in children with chronic hepatitis B could be better than interferon with fewer side effects, especially in preschool aged children.

키워드

참고문헌

  1. Choe BH. Management of chronic hepatitis B in children. Proceedings of the 2003 Joint seminar of Korean gastroenterology society; 2003 Sep 21; Seoul. Seoul : The Korean Society of Gastroenterology, 2003:250-61
  2. Choe BH, Oh KW, Park WS, Lee JH, Kwon S, Ko CW, et al. Comparison of therapeutic efficacy between lamivudine and alpha-interferon in Korean children with chronic hepatitis B. J Pediatr Gastroenterol Nutr 2003;37:379 https://doi.org/10.1097/00005176-200309000-00040
  3. Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM, Goyens P, et al. Interferon alfa therapy for chronic hepatitis B in children : a multinational randomized controlled trial. Gastroenterology 1998;114:988-95. https://doi.org/10.1016/S0016-5085(98)70318-X
  4. Jonas MM, Kelley DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706-13 https://doi.org/10.1056/NEJMoa012452
  5. Jonas MM. Interferon-alpha for viral hepatitis. J Pediatr Gastroenterol Nutr 1996;23:93-106 https://doi.org/10.1097/00005176-199608000-00001
  6. Desmet VJ. Immunopathology of chronic viral hepatitis. Hepatogastroenterology 1991;38:14-21
  7. Hsu HY, Chang MH, Chen DS, Lee CY, Sung JL. Baseline seroepidemiology of hepatitis B virus infection in children in Taipei, 1984 : a study just before mass hepatitis B vaccination program in Taiwan. J Med Virol 1986;18:301-7 https://doi.org/10.1002/jmv.1890180402
  8. Hsu HY, Chang MH, Lee CY, Chen JS, Hsu HC, Chen DS. Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology 1992;15:382-6 https://doi.org/10.1002/hep.1840150304
  9. Kim Y, Baek S, Eom J, Chung K. Natural history of chronic hepatitis B in children. Korean J Pediatr 2004;47: 282-9
  10. Perrillo RP. Treatment of chronic hepatitis B with interferon : experience in western countries. Semin Liver Dis 1989; 9:240-8 https://doi.org/10.1055/s-2008-1040517
  11. Torre D, Tambini R. Interferon-alpha therapy for chronic hepatitis B in children : a meta-analysis. Clin Infect Dis 1996;23:131-7 https://doi.org/10.1093/clinids/23.1.131
  12. Conjeevaram HS, Di Bisceglie AM. Management of chronic viral hepatitis in children. J Pediatr Gastroenterol Nutr 1995;20:365-75 https://doi.org/10.1097/00005176-199505000-00001
  13. Jang CH, Lee KH, Hwang WK, Oh KW, Park WS, Lee JH, et al. The comparison of interferon-alpha treatment by dosages and retreatment for chronic hepatitis B in children. Korean J Pediatr Gastroenterol Nutr 2003;6:152-60
  14. Choe BH, Ko CW. Combined therapy of alfa-interferon and thymodulin on children with chronic active hepatitis B. Korean J Pediatr Gastroenterol Nutr 1998;1:79-89
  15. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Longterm beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29:971- 5 https://doi.org/10.1002/hep.510290312
  16. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Jr., Lindsay K, Payne J, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med 1990;323:295- 301 https://doi.org/10.1056/NEJM199008023230503
  17. Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998;102:968- 75 https://doi.org/10.1172/JCI3731
  18. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63 https://doi.org/10.1056/NEJM199910213411702
  19. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995;333:1657- 61 https://doi.org/10.1056/NEJM199512213332501
  20. Nevens F, Main J, Honkoop P, Tyrrell DL, Barber J, Sullivan MT, et al. Lamivudine therapy for chronic hepatitis B : a six-month randomized dose-ranging study. Gastroenterology 1997;113:1258-63 https://doi.org/10.1053/gast.1997.v113.pm9322520
  21. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339:61-8 https://doi.org/10.1056/NEJM199807093390201
  22. Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, et al. Lamivudine and 24 weeks of lamivudine/ interferon combination therapy for hepatitis B e antigen- positive chronic hepatitis B in interferon nonresponders. J Hepatol 2003;38:818-26 https://doi.org/10.1016/S0168-8278(03)00076-X
  23. Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouilleres O, Carbonell N, et al. Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone : results of a pilot study. Hepatology 2001;34:573-7 https://doi.org/10.1053/jhep.2001.26819
  24. Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002;36:1425-30
  25. Lee S, Han S, Cho S, Roh B, Sohn J, Kim D, et al. Distribution of HBV genotypes in patients with chronic HBV infection in Korea. Korean J Hepatol 2001;7:373-80
  26. Cha C, Sohn Y, Jang S, Lee H, Lee K, Shin E, et al. Genotype analysis of hepatitis B virus isolated from Korean hepatitis patients. Korean J Lab Med 2003;23:352-6
  27. Sakai T, Shiraki K, Inoue H, Okano H, Deguchi M, Sugimoto K, et al. Efficacy of long-term interferon therapy in chronic hepatitis B patients with HBV genotype C. Int J Mol Med 2002;10:201-4
  28. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates : results after 3 years of therapy. Hepatology 2001;33:1527-32 https://doi.org/10.1053/jhep.2001.25084
  29. Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32:803-6 https://doi.org/10.1053/jhep.2000.16665
  30. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology 2000;119:172-80 https://doi.org/10.1053/gast.2000.8559
  31. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998;27:1670-7 https://doi.org/10.1002/hep.510270628
  32. Melegari M, Scaglioni PP, Wands JR. Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. Hepatology 1998;27:628-33 https://doi.org/10.1002/hep.510270243
  33. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41 https://doi.org/10.1053/jhep.2001.29401
  34. Moraleda G, Saputelli J, Aldrich CE, Averett D, Condreay L, Mason WS. Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol 1997;71:9392-9
  35. Zeuzem S, de Man RA, Honkoop P, Roth WK, Schalm SW, Schmidt JM. Dynamics of hepatitis B virus infection in vivo. J Hepatol 1997;27:431-6 https://doi.org/10.1016/S0168-8278(97)80345-5
  36. Consensus statements on the prevention and management of hepatitis B and hepatitis C in the Asia-Pacific region. Core Working Party for Asia-Pacific Consensus on Hepatitis B and C. J Gastroenterol Hepatol 2000;15:825-41 https://doi.org/10.1046/j.1440-1746.2000.02324.x
  37. Zuccotti GV, Cucchi C, Gracchi V, D'Auria E, Riva E, Tagger A. A 1-year trial of lamivudine for chronic hepatitis B in children. J Int Med Res 2002;30:200-2 https://doi.org/10.1177/147323000203000214
  38. Selimoglu MA, Aydogdu S, Unal F, Zeytinoglu A, Yuce G, Yagci RV. Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children. Pediatr Int 2002; 44:404-8 https://doi.org/10.1046/j.1442-200X.2002.01589.x
  39. Lai CL, Lok AS, Lin HJ, Wu PC, Yeoh EK, Yeung CY. Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children. Lancet 1987;2:877-80
  40. Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med 1997;336:347-56 https://doi.org/10.1056/NEJM199701303360507