• 四川大學華西醫(yī)院感染性疾病中心,教育部人類疾病生物治療重點實驗室,成都,610041;

目的 　系統(tǒng)評價與拉米夫定相關的乙型肝炎病毒YMDD區(qū)變異后不同抗病毒治療方法的療效和安全性.
方法 　計算機檢索MEDLINE (1989～2004.4)、EMBASE (1989～2004.4)和中國生物醫(yī)學文獻數(shù)據(jù)庫(1989～2004.4);手工檢索未發(fā)表的中文學術會議文獻.收集與拉米夫定相關的乙型肝炎病毒YMDD區(qū)變異后不同抗病毒療法的臨床隨機與半隨機對照試驗,由兩名評價者獨立評價和提取資料,并采用Cochrane協(xié)作網(wǎng)專用軟件RevMan 4.2進行統(tǒng)計分析.
結果 　共納入5篇隨機和半隨機對照研究,包括6個試驗組284例病人.Meta分析結果顯示,拉米夫定+阿德福韋治療對HBVDNA、HBeAg轉陰率及ALT復常率的效果明顯優(yōu)于單獨應用拉米夫定,其RR和95%CI分別為16.61(2.29,120.71),6.66(1.23,35.88)和6.26(2.29,17.12).氧化苦參堿+胸腺肽對HBVDNA、HBeAg轉陰率明顯優(yōu)于單獨應用拉米夫定,其RR和95%CI分別為2.96(1.26,6.93),2.51(1.05,5.98).試驗組單獨使用阿德福韋與拉米夫定比較,兩者在HBVDNA及HBeAg轉陰率方面差異無統(tǒng)計學意義[RR 11.00,95%CI(0.65,186.02);RR 7.00,95%CI(0.39,126.92)];干擾素+拉米夫定對HBVDNA轉陰率、HBeAg轉陰率、ALT復常率優(yōu)于單獨應用拉米夫定,其RR和95%CI分別為3.50(0.90,13.58),4.90(0.70,35.10)和2.80(0.91,8.12);拉米夫定+中藥與拉米夫定比較,其HBVDNA轉陰率的差異無統(tǒng)計學意義[RR 1.16,95%CI(0.89,1.51)].在治療過程中出現(xiàn)的副作用主要有:干擾素組產(chǎn)生流感樣癥狀,阿德福韋組有輕度腎臟損傷,拉米夫定組有少數(shù)病例出現(xiàn)一過性病情加重.
結論 　乙肝病毒YMDD變異后,阿德福韋+拉米夫定、氧化苦參堿聯(lián)合胸腺肽等療法的抗病毒作用及生化指標改善均優(yōu)于繼續(xù)單獨使用拉米夫定.但由于樣本量偏少,隨機對照試驗的質量普遍較低,對此尚不能得出肯定性的結論,有待擴大樣本進一步研究.

引用本文： 王甦,趙連三. 乙肝病毒YMDD區(qū)變異后不同抗病毒療法效果的系統(tǒng)評價. 中國循證醫(yī)學雜志, 2004, 04(11): 783-788. doi: 復制

1. ［10］Wu GX, Cha YQ, Zheng J, Wang YZ, Zhou GP. Effect of interferon combined with lamivudine in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD[J]. Chin J Hepatol, 2003; 11(12): 752753.
2. 吳國祥, 查雁生, 鄭劍, 王永忠, 周國平. 干擾素聯(lián)合拉米夫定治療YMDD變異株慢性乙型肝炎[J]. 中華肝臟病雜志, 2003; 11(12):752～753.
3. ［11］Guo P, Kong W. Effect of yi gan jie du tang in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD[J]. Journal of Shandong University of Traditional Chinese. 2003; 27(3):203204.
4. 郭朋, 孔偉. 乙肝解毒湯抗乙肝病毒YMDD變異的臨床觀察[J]. 山東中醫(yī)藥科大學學報, 2003; 27(3):203～204.
5. ［12］Fang GQ, Fu GQ. Effect of oxymatrine combined with Thymothin in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD. Infect Dis Info, 2002; 15(3):139140.
6. 方廣強, 甄中蜂. 氧化苦參堿聯(lián)合胸腺肽治療拉米夫定所致YMDD變異后的慢性乙型肝炎療效觀察[J]. 傳染病信息, 2002; 15(3):139～140.
7. ［13］Gutfreund KS, Wijjiams M, George R, Bain VG, Ma MM, Yoshida EM, Villeneu JP, Fischer KP, Tyrrek DL. Gentypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance[J]. J Hepatology, 2000; 33(3):469-475.
8. ［14］Allen MI, Deslauriers.M, Andrens CM, Tipples GA, Walters KA, Tyrrell DLJ, Brown N, Condreay LD. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine[J]. J Hepatology, 1998; 27(6):1 670-1 677.
9. ［15］Ling R, Mutime D, Ahmed M, Boxall EH, Ellas E, Dusheiko GM, Harrison TJ. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine[J]. Hepatology, 1996; 24(3):711-713.
10. ［16］Yao GB, Yang MY, JI YY, Zhu M, Xu B. Clinical influence and management after emergence of HBVDNA motif mutation during lamivudine treatment[J]. Chinese Hepatology, 1999; 4(4):194196.
11. 姚光弼, 揚敏燕, 計焱焱, 朱枚, 徐蓓. 拉米夫定治療乙型肝炎時其病毒發(fā)生YMDD變異的臨床影響處理[J]. 肝臟, 1999; 4(4):194～196.
12. ［17］Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edumdson S, Lai CL. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B[J]. Gasteroenterology, 2000; 119(1):172-180.
13. ［18］Yao GB, Wang BE, Cui ZY, Yao JL, Zeng MD. The long-term efficacy of lamivudine in chronic hepatitis B: interim analysis of 3-years clinic course[J]. Chin J Interm Med, 2003; 42(6):382387.
14. 姚光弼, 王寶恩, 崔振宇, 姚集魯, 曾民德. 拉米夫定治療慢性乙型肝炎三年療效觀察[J]. 中華內(nèi)科雜志, 2003; 42(6):382～387.
15. ［1］Lee WM. Medical progress:hepatitis B virus infection[J]. N Engl J Med, 1997; 337(24):1 733-1 745.
16. ［2］Lok ASF. Chronic hepatitis B. N Eng J Med, 2002; 346(22):1 682-1 683.
17. ［3］Pramoolsinsup C. Management of viral hepatitis B[J]. J Gastroentero & Hepato, 2002;17(Suppl): s125-s145.
18. ［4］Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, Moorat A, Barber J, Gray DF. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial[J]. Gut, 2000; 46(4):562-568.
19. ［5］Chang TT, Lai CL, Liaw YF, Guan R, Kim SG, Lee CM, Ng KY. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV patients treated with lamivudine for four years[J]. Antiviral Therapy, 2000; 5:44.
20. ［6］Guan R ,Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5 years lamivudine treatment of Chinese patients with chronic hepatitis B[J]. J Gastroenterol hepatol, 2001; 16:A60.
21. ［7］Leung NW, Lai CL, Guan R, Liaw YF. The effect of longer duration of harbouring lamivudine-resistant hepatitis B virus (YMDD mutants) on live histology during 3 years lamivudine therapy in Chinese patients[J]. Hepatology, 2001; 34:348A.
22. ［8］Perrillo R, Hann HI, Mutimer D, Willems B, Leung N, William M.LEE, Moorat A, Gardner S, Woessner M, Bourne E, Carol L and Schiff E. Adefovir dipivixil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus[J]. Gasteroenterology, 2004;126(1):81-90.
23. ［9］Peters M, Hann HW, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourkire M, Kowdley K, Trepo C, Gray DF, Sullivan M, Kieber K, Ebrahimi r, Xiong S and Brosgart CL. Adefovir dipivixil alone or combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B[J]. Gasteroenterology, 2004;126(1):91-101.
  1. 1. ［10］Wu GX, Cha YQ, Zheng J, Wang YZ, Zhou GP. Effect of interferon combined with lamivudine in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD[J]. Chin J Hepatol, 2003; 11(12): 752753.
  2. 2. 吳國祥, 查雁生, 鄭劍, 王永忠, 周國平. 干擾素聯(lián)合拉米夫定治療YMDD變異株慢性乙型肝炎[J]. 中華肝臟病雜志, 2003; 11(12):752～753.
  3. 3. ［11］Guo P, Kong W. Effect of yi gan jie du tang in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD[J]. Journal of Shandong University of Traditional Chinese. 2003; 27(3):203204.
  4. 4. 郭朋, 孔偉. 乙肝解毒湯抗乙肝病毒YMDD變異的臨床觀察[J]. 山東中醫(yī)藥科大學學報, 2003; 27(3):203～204.
  5. 5. ［12］Fang GQ, Fu GQ. Effect of oxymatrine combined with Thymothin in treatment of chronic hepatitis B patients infected with HBV with mutation of YMDD. Infect Dis Info, 2002; 15(3):139140.
  6. 6. 方廣強, 甄中蜂. 氧化苦參堿聯(lián)合胸腺肽治療拉米夫定所致YMDD變異后的慢性乙型肝炎療效觀察[J]. 傳染病信息, 2002; 15(3):139～140.
  7. 7. ［13］Gutfreund KS, Wijjiams M, George R, Bain VG, Ma MM, Yoshida EM, Villeneu JP, Fischer KP, Tyrrek DL. Gentypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance[J]. J Hepatology, 2000; 33(3):469-475.
  8. 8. ［14］Allen MI, Deslauriers.M, Andrens CM, Tipples GA, Walters KA, Tyrrell DLJ, Brown N, Condreay LD. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine[J]. J Hepatology, 1998; 27(6):1 670-1 677.
  9. 9. ［15］Ling R, Mutime D, Ahmed M, Boxall EH, Ellas E, Dusheiko GM, Harrison TJ. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine[J]. Hepatology, 1996; 24(3):711-713.
  10. 10. ［16］Yao GB, Yang MY, JI YY, Zhu M, Xu B. Clinical influence and management after emergence of HBVDNA motif mutation during lamivudine treatment[J]. Chinese Hepatology, 1999; 4(4):194196.
  11. 11. 姚光弼, 揚敏燕, 計焱焱, 朱枚, 徐蓓. 拉米夫定治療乙型肝炎時其病毒發(fā)生YMDD變異的臨床影響處理[J]. 肝臟, 1999; 4(4):194～196.
  12. 12. ［17］Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edumdson S, Lai CL. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B[J]. Gasteroenterology, 2000; 119(1):172-180.
  13. 13. ［18］Yao GB, Wang BE, Cui ZY, Yao JL, Zeng MD. The long-term efficacy of lamivudine in chronic hepatitis B: interim analysis of 3-years clinic course[J]. Chin J Interm Med, 2003; 42(6):382387.
  14. 14. 姚光弼, 王寶恩, 崔振宇, 姚集魯, 曾民德. 拉米夫定治療慢性乙型肝炎三年療效觀察[J]. 中華內(nèi)科雜志, 2003; 42(6):382～387.
  15. 15. ［1］Lee WM. Medical progress:hepatitis B virus infection[J]. N Engl J Med, 1997; 337(24):1 733-1 745.
  16. 16. ［2］Lok ASF. Chronic hepatitis B. N Eng J Med, 2002; 346(22):1 682-1 683.
  17. 17. ［3］Pramoolsinsup C. Management of viral hepatitis B[J]. J Gastroentero & Hepato, 2002;17(Suppl): s125-s145.
  18. 18. ［4］Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, Moorat A, Barber J, Gray DF. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial[J]. Gut, 2000; 46(4):562-568.
  19. 19. ［5］Chang TT, Lai CL, Liaw YF, Guan R, Kim SG, Lee CM, Ng KY. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV patients treated with lamivudine for four years[J]. Antiviral Therapy, 2000; 5:44.
  20. 20. ［6］Guan R ,Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5 years lamivudine treatment of Chinese patients with chronic hepatitis B[J]. J Gastroenterol hepatol, 2001; 16:A60.
  21. 21. ［7］Leung NW, Lai CL, Guan R, Liaw YF. The effect of longer duration of harbouring lamivudine-resistant hepatitis B virus (YMDD mutants) on live histology during 3 years lamivudine therapy in Chinese patients[J]. Hepatology, 2001; 34:348A.
  22. 22. ［8］Perrillo R, Hann HI, Mutimer D, Willems B, Leung N, William M.LEE, Moorat A, Gardner S, Woessner M, Bourne E, Carol L and Schiff E. Adefovir dipivixil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus[J]. Gasteroenterology, 2004;126(1):81-90.
  23. 23. ［9］Peters M, Hann HW, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourkire M, Kowdley K, Trepo C, Gray DF, Sullivan M, Kieber K, Ebrahimi r, Xiong S and Brosgart CL. Adefovir dipivixil alone or combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B[J]. Gasteroenterology, 2004;126(1):91-101.