Efficacy of Antiviral Drugs for Hepatitis B with YMDD Motif Variant: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Su , ZHAO Liansan

Department of Infectious Disease; West China Hospital; Sichuan University; Division of Molecular Biology of Infectious Disease; Key Laboratory of Biotherapy of Human Disease; Ministry of Education of China; Chengdu 610041; China;

Corresponding author：

Keywords：

Lamivudine; Hepatitis B virus; YMDD motif variant; Antiviral therapy; Systematic review

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Objective 　To evaluate the efficacy and safety of antiviral drugs for hepatitis B with YMDD motif variant.
Methods 　We electronically searched MEDLINE (1989-April, 2004), EMBASE (1989-April, 2004), CBMdisc (expand) (1989-April, 2004), and handsearched unpublished Chinese conference proceedings. Randomized and quasi-randomized trials in patients with chronic hepatitis B with YMDD motif variant correlative to lamivudine were collected. Two reviewers extracted the data and assessed the quality of literature independently. The data were then analyzed by RevMan 4.2 software.
Results 　Five studies involving 6 trials and 284 patients were included. According to the results of meta-analysis, antiviral therapy with adefovir plus lamivudine showed significantly better effects on the clearance of serum HBV-DNA and HBeAg and normalization of ALT than that of lamivudine alone (RR 16.61, 95%CI 2.29 to 120.71; RR 6.66, 95%CI 1.23 to 35.88 and RR 6.26, 95%CI 2.29 to 17.12 respectively); also, oxymatrine plus thymothin showed obviously better effects on the clearance of serum HBV-DNA and HBeAg (RR 2.96, 95%CI 1.26 to 6.93 and RR 2.51, 95%CI 1.05 to 5.98 respectively).But adefovir alone showed no better effects on clearance of serum HBV-DNA and HBeAg than that of lamivudine alone (RR 11.00, 95%CI 0.65 to 186.02 and RR 7.00, 95%CI 0.39 to 126.92 respectively); interferon plus lamivudine showed no better effects on the clearance of serum HBV-DNA, HBeAg and the normalization of ALT (RR 3.50, 95%CI 0.90 to 13.58; RR 4.90, 95%CI 0.70 to 35.10 and RR 2.80, 95%CI 0.91 to 8.12 respectively). Chinese herbs plus lamivudine showed no better effects on the clearance of serum HBV-DNA (RR 1.16, 95%CI 0.89 to 1.51). There were no significant side effects in the groups, except flu like symptom in the interferon group, slight kidney impairment in the adefovir group, and aggravation of rare cases in lamivudine group.
Conclusions 　Antiviral therapy with adefovir plus lamivudine, or oxymatrine plus thymothin, shows better effects than with lamivudine alone in terms of antiviral therapy and clinical outcome improvement. However, the evidence is too weak to draw a definite conclusion in this systematic review. Larger sample size and rigorously designed randomized, double blind, placebo control trials are required for future study.

Citation： WANG Su,ZHAO Liansan. Efficacy of Antiviral Drugs for Hepatitis B with YMDD Motif Variant: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2004, 04(11): 783-788. doi: Copy

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.	吴国祥, 查雁生, 郑剑, 王永忠, 周国平. 干扰素联合拉米夫定治疗YMDD变异株慢性乙型肝炎[J]. 中华肝脏病杂志, 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, 孔伟. 乙肝解毒汤抗乙肝病毒YMDD变异的临床观察[J]. 山东中医药科大学学报, 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.	方广强, 甄中蜂. 氧化苦参碱联合胸腺肽治疗拉米夫定所致YMDD变异后的慢性乙型肝炎疗效观察[J]. 传染病信息, 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, 扬敏燕, 计焱焱, 朱枚, 徐蓓. 拉米夫定治疗乙型肝炎时其病毒发生YMDD变异的临床影响处理[J]. 肝脏, 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, 王宝恩, 崔振宇, 姚集鲁, 曾民德. 拉米夫定治疗慢性乙型肝炎三年疗效观察[J]. 中华内科杂志, 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. ［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. 吴国祥, 查雁生, 郑剑, 王永忠, 周国平. 干扰素联合拉米夫定治疗YMDD变异株慢性乙型肝炎[J]. 中华肝脏病杂志, 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, 孔伟. 乙肝解毒汤抗乙肝病毒YMDD变异的临床观察[J]. 山东中医药科大学学报, 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. 方广强, 甄中蜂. 氧化苦参碱联合胸腺肽治疗拉米夫定所致YMDD变异后的慢性乙型肝炎疗效观察[J]. 传染病信息, 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, 扬敏燕, 计焱焱, 朱枚, 徐蓓. 拉米夫定治疗乙型肝炎时其病毒发生YMDD变异的临床影响处理[J]. 肝脏, 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, 王宝恩, 崔振宇, 姚集鲁, 曾民德. 拉米夫定治疗慢性乙型肝炎三年疗效观察[J]. 中华内科杂志, 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.

Chinese Journal of Evidence-Based Medicine

Efficacy of Antiviral Drugs for Hepatitis B with YMDD Motif Variant: A Systematic Review

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