The Korean Journal of Medicine

  • 제85권2호
  • /
  • Pages.157-166
  • /
  • 2013
  • /
  • 1738-9364(pISSN)
  • /
  • 2289-0769(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지
DOI QR코드

DOI QR Code

초치료 만성 B형간염 환자에서 엔테카비어의 장기 치료 효과 및 그 예측인자

Clinical Efficacy of Entecavir and Factors Predicting Long-Term Treatment Response in Nucleoside-Na$\ddot{i}$ve Patients with Chronic Hepatitis B

  • 김범희 (충남대학교 의학전문대학원 내과학교실) ;
  • 윤범용 (충남대학교 의학전문대학원 내과학교실) ;
  • 박대화 (충남대학교 의학전문대학원 내과학교실) ;
  • 이엄석 (충남대학교 의학전문대학원 내과학교실) ;
  • 김석현 (충남대학교 의학전문대학원 내과학교실) ;
  • 이병석 (충남대학교 의학전문대학원 내과학교실) ;
  • 이헌영 (충남대학교 의학전문대학원 내과학교실)
  • Kim, Beom Hee (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Yoon, Beom Yong (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Park, Dae Wha (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Lee, Eaum Seok (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Kim, Seok Hyun (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Lee, Byung Seok (Department of Internal Medicine, Chungnam National University School of Medicine) ;
  • Lee, Heon Young (Department of Internal Medicine, Chungnam National University School of Medicine)
  • 투고 : 2012.10.29
  • 심사 : 2012.12.31
  • 발행 : 2013.08.01
⟨ 이전 논문 다음 논문 ⟩

초록

목적:초치료 만성 B형간염 환자들에서 엔테카비어의 치료 효과와 그 예측인자에 대해 분석하였다. 방법:2007년 3월부터 2011년 5월까지 과거 항바이러스제 치료 경험이 없는 만성 B형간염 환자로서 엔테카비어 0.5 mg을 매일 최소 48주 이상 복용한 환자 77명을 후향적으로 조사하였다. 엔테카비어 투여 중 혈청 HBV DNA치가 116 copies/mL 이하로 감소하여 검출되지 않는 경우인 바이러스 반응과 혈청 ALT치의 정상화되는 경우인 생화학적 반응, HBeAg의 혈청 소실과 혈청전환을 각각 평가하였다. 결과:치료 12, 24, 48, 96, 144주에 대한 누적 바이러스 반응률은 각각 59.7%, 82%, 88.3%, 89.6%, 93.1%였다; 누적 생화학적 반응률은 각각 51.9%, 74%, 84.4%, 94.8%, 98.3%였다; HBeAg의 누적 혈청 소실률은 10.5%, 18.4%, 28.9%, 36.8, 47.4%였다; 누적 HBeAg 혈청 전환율은 7.9%, 18.4%, 21.1%, 28.9%, 39.5%였다. 다변량 분석을 시행한 결과 혈청 HBV DNA 음전과 관련된 독립적 예측인자는 기저 HBeAg 음성(p = 0.006)과 치료 12주 후 바이러스 반응인 초기 바이러스 반응(p = 0.027)이었다. 또한 HBeAg 혈청 소실과 관련된 독립적 예측인자도 초기 바이러스 반응(p = 0.001)이었다. 결론:엔테카비어는 초치료 만성 B형간염 환자에서 뛰어난 생화학적 반응과 바이러스 반응을 보였다. 초기 바이러스 반응은 혈청 HBV DNA 음전과 HBeAg 혈청 소실을 예측할 수 있는 독립적 인자로 확인되어 치료 중 초기 바이러스 반응이 엔테카비어의 장기적인 치료 반응을 예측하는 데 유용할 것으로 생각된다.

Background/Aims: The aims of this study were to characterize the treatment response to entecavir and to examine factors affecting that response. Methods: A total of 77 nucleoside-na$\ddot{i}$ve patients with chronic hepatitis B who had received entecavir (0.5 mg daily) for at least 48 weeks were consecutively enrolled between March 2007 and March 2011. The rates of virological response (hepatitis B virus [HBV] DNA < 116 copies/mL), biochemical response (alanine aminotransferase ${\leq}$ upper limit of normal), hepatitis B e antigen (HBeAg) loss, and seroconversion were retrospectively analyzed. Results: The cumulative rates of virological response at 12, 24, 48, 96, and 144 weeks were 59.7%, 82%, 88.3%, 89.6%, and 93.1%, respectively; biochemical response rates were 51.9%, 74%, 84.4%, 94.8%, and 98.3%, respectively; HBeAg loss rates were 10.5%, 18.4%, 28.9%, 36.8%, and 47.4%, respectively; and HBeAg seroconversion rates were 7.9%, 18.4%, 21.1%, 28.9%, and 39.5%, respectively. In multivariate analysis, independent predictors associated with HBV DNA polymerase chain reaction (PCR) negativity were the absence of HBeAg at baseline (p = 0.006) and early virological response (HBV DNA < 2,000 copies/mL after 12 weeks of therapy; p = 0.027). In univariate analysis, early virological response was an independent factor predicting HBeAg loss (p = 0.001). Conclusions: Entecavir induced excellent biochemical and virological responses in nucleoside-na$\ddot{i}$ve patients with chronic hepatitis B. Early virological response was an independent factor predicting HBV PCR negativity and HBeAg loss, and can be used to predict long-term treatment response to entecavir.

키워드

참고문헌

  1. Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006;28:112-125. https://doi.org/10.1093/epirev/mxj009
  2. Korea centers for disease control and prevention: the fourth Korea National Health and Nutrition Examination Survey 2007. 2008.
  3. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-686. https://doi.org/10.1053/j.gastro.2005.11.016
  4. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73. https://doi.org/10.1001/jama.295.1.65
  5. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001-1010. https://doi.org/10.1056/NEJMoa051285
  6. Leung N, Peng CY, Hann HW, et al. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir. Hepatology 2009;49:72-79. https://doi.org/10.1002/hep.22658
  7. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 2009;49:1503-1514. https://doi.org/10.1002/hep.22841
  8. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125:1714-1722. https://doi.org/10.1053/j.gastro.2003.09.033
  9. The Korean Association for the Study of the Liver (KASL). KASL Clinical Practice Guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2012;18:109-162. https://doi.org/10.3350/cmh.2012.18.2.109
  10. Song BC, Chae HB, Kim YN, Lee BS, Cho YK. Pretreatment levels of HBV DNA and early virological response during entecavir therapy predicts HBeAg loss in HBeAgpositive chronic hepatitis B patients. Korean J Hepatol 2009;15(Supp1 3):S42. https://doi.org/10.3350/kjhep.2009.15.1.42
  11. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011-1020. https://doi.org/10.1056/NEJMoa051287
  12. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123-129. https://doi.org/10.1016/S0140-6736(05)17701-0
  13. Perrillo RP, Schiff ER, Davis GL, 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
  14. Lok AS, Wu PC, Lai CL, et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology 1992;102:2091-2097. https://doi.org/10.1016/0016-5085(92)90337-X
  15. Tseng TC, Liu CJ, Wang CC, et al. A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine-treated chronic hepatitis B patients. Liver Int 2008;28:1034-1041. https://doi.org/10.1111/j.1478-3231.2008.01766.x
  16. Westland C, Delaney W 4th, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology 2003;125: 107-116. https://doi.org/10.1016/S0016-5085(03)00700-5
  17. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44:283-290. https://doi.org/10.1016/j.jhep.2005.10.018
  18. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis 2006;26:130-141. https://doi.org/10.1055/s-2006-939751
  19. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 2005;42:121-129.
  20. Zarski JP, Marcellin P, Cohard M, Lutz JM, Bouche C, Rais A. Comparison of anti-HBe-positive and HBe-antigenpositive chronic hepatitis B in France: French Multicentre Group. J Hepatol 1994;20:636-640. https://doi.org/10.1016/S0168-8278(05)80352-6
  21. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother 2004;48:3498-3507. https://doi.org/10.1128/AAC.48.9.3498-3507.2004
  22. Degertekin B, Lok AS. Monitoring antiviral resistance in patients receiving nucleos(t)ide analog therapies for hepatitis B: which method should be used? J Hepatol 2008;48:892-894. https://doi.org/10.1016/j.jhep.2008.03.010
  23. Lok AS, Zoulim F, Locarnini S, et al. Antiviral drugresistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007; 46:254-265. https://doi.org/10.1002/hep.21698
  24. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960-967. https://doi.org/10.1111/j.1572-0241.2003.07486.x
  25. Adams LA, Knuiman MW, Divitini ML, Olynyk JK. Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption. J Gastroenterol Hepatol 2008;23(7 Pt 1):1089-1093. https://doi.org/10.1111/j.1440-1746.2008.05451.x