Lamivudine plus Adefovir Combination Therapy versus Entecavir Monotherapy for Lamivudine-resistant Chronic Hepatitis B: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 LIYu ¹ , MANing ¹ , DENGJiao ² ,  CHENGGang ¹

1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China;
2. Department of Pharmacy General Hospital of Shenyang Military Region, Shengyang 110016, China;

Corresponding author：

CHENGGang, Email: chenggang63@hotmail.com

Keywords：

Chronic hepatitis B; Lamivudine-resistant; Lamivudine; Adefovir; Entecavir; Systematic review; Meta-analysis; Randomized controlled trial; Cohort study

DOI：

10.7507/1672-2531.20150095

Video：

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Objective To systematically review the efficacy of lamivudine (LAM) plus adefovir (ADV) versus entecavir (ETV) monotherapy for LAM-resistant chronic hepatitis B patients. Methods We electronically searched databases including PubMed, The Cochrane Library (Issue 12, 2013), CBM, CNKI, VIP, WanFang Data from their inception to December 2013, to collect randomized controlled trials (RCTs) or cohort studies of LAM+ADV versus ETV for LAM-resistant chronic hepatitis B. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and assessed the methodological quality of included studies. Then, meta-analysis was performed using RevMan 5.2 software. Results A total of 13 RCTs and 5 cohort studies involving 1 336 patients were included. The results of meta-analyses of RCTs showed that:there were no significant differences between the LAM+ADV group and the ETV group in the negative rates of serum HBV-DNA (RR=1.00, 95%CI 0.91 to 1.10, P=0.94), HBeAg (RR=0.90, 95%CI 0.70 to 1.17, P=0.43), serum ALT recovery rate (RR=0.97, 95%CI 0.90 to 1.05, P=0.45) and serum HBeAg conversion rate (RR=0.71, 95%CI 0.40 to 1.24, P=0.22) at the 48^th week. The results of meta-analyses of cohort studies showed that:there were no significant differences between the two groups in the negative rates of serum HBV-DNA (RR=1.37, 95% CI 0.91 to 2.06, P=0.13) and serum ALT recovery rate (RR=0.99, 95%CI 0.87 to 1.12, P=0.87), but the ETV group had higher serum HBeAg conversion rate (RR=0.24, 95% CI 0.07 to 0.79, P=0.02). Conclusion Current evidence shows that the efficacy of LAM+ADV is similar to ETV at the 48^th week for LAM-resistant chronic hepatitis B patients. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.

Citation： LIYu, MANing, DENGJiao, CHENGGang. Lamivudine plus Adefovir Combination Therapy versus Entecavir Monotherapy for Lamivudine-resistant Chronic Hepatitis B: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2015, 15(5): 573-580. doi: 10.7507/1672-2531.20150095 Copy

1.	Fact sheets:hepatitis B. World Health Organization. Updated March 2015. Available at:http://www.who.int/mediacentre/factsheets/fs204/en/.
2.	Pawlotsky JM, Dusheiko G, Hatzakis A, et al. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice:recommendations for a standardized approach. Gastroenterology, 2008, 134(2):405-415.
3.	Westland CE, Yang H, Delaney WE, et al. Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients. J Viral Hepat, 2005, 12(1):67-73.
4.	赵树山, 范学工, 陈立章, 等. 阿德福韦酯联合胸腺肽α-1与单用阿德福韦酯比较治疗慢性乙肝的系统评价. 中国循证医学杂志, 2010, 10(8):972-977.
5.	Yuen MF, Fung J, Wong DKH, et al. Prevention and management of drug resistance for antihepatitis B treatment. Lancet Infect Dis, 2009, 9(4):256-264.
6.	Higgins JPT, Altman DG (editors). Chapter 8:Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration,2011. Available at:www.cochrane-handbook.org.
7.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metananlysis. Eur J Epidemiol, 2010, 25(9):603-605.
8.	王君萍. 拉米夫定联合阿德福韦酯或恩替卡韦治疗慢性乙型肝炎患者的疗效评价. 健康大视野, 2013, 21(1):6.
9.	刘爱平, 耿爱文, 李阳. 拉米夫定耐药慢性乙型肝炎患者应用拉米夫定联合阿德福韦酯或恩替卡韦治疗的疗效评价. 吉林医学, 2013, 34(2):246-246.
10.	杨庆文. 拉米夫定联合阿德福韦酯治疗拉米夫定和阿德福韦酯序贯治疗耐药40例. 中国中医药现代远程教育, 2012, 10(22):36-38.
11.	龚菁, 郭风彩, 李大春, 等. 联合阿德福韦酯或换用恩替卡韦治疗拉米夫定耐药慢性乙型肝炎患者的临床观察. 中国医药指南, 2012, 10(27):23-24.
12.	曹民. 拉米夫定耐药后的治疗选择. 现代医药卫生, 2012, 28(9):1439-1439.
13.	高冬梅. 中心拉米夫定耐药的慢性乙型肝炎治疗策略. 中国医药指南, 2012, 10(8):146-148.
14.	邰立慧. 阿德福韦联合拉米夫定与恩替卡韦治疗耐药性慢性乙肝疗效比较. 中国血液流变学杂志, 2011, 21(2):298-299.
15.	Ryu HJ, Lee JM, Ahn SH, et al. Efficacy of adefovir add-on lamivudine rescue therapy compared with switching to entecavir monotherapy in patients with lamivudine-resistant chronic hepatitis B. J Med Virol, 2010, 82(11):1835-1842.
16.	骆晓霞, 陈康鉴. 拉米夫定联合阿德福韦酯或恩替卡韦治疗拉米夫定和阿德福韦酯序贯治疗耐药患者的研究. 齐齐哈尔医学院学报, 2010, 20(20):3286-3287.
17.	邱源旺, 蒋祥虎, 黄利华, 等. 乙型肝炎病毒 YMDD 变异的治疗对策. 中华肝脏病杂志, 2009, 17(3):171-174.
18.	Pellicelli AM, Barbarini G, Romano M, et al. Entecavir therapy for Lamivudine resistant HBV cirrhotic patients waiting for olt:Viral and biochemical outcomes at one year. Hepatology, 2009, 50(SUPPL.4):514A.
19.	Lee SJ, Yim HJ, Hwang SG, et al. Treatment of lamivudine-resistant chronic hepatitis B infection:a multicenter retrospective study. Scand J Gastroenterol, 2013, 48(2):196-204.
20.	Heo NY, Lim YS, Lee HC, et al. Lamivudine plus adefovir or entecavir for patients with chronic hepatitis B resistant to lamivudine and adefovir. J Hepatol, 2010, 53(3):449-454.
21.	Lee HW, Kim HJ, Choi CH, et al. Entecavir rescue therapy versus adefovir combination therapy in lamivudine-refractory patients with chronic hepatitis B. Hepatol Int, 2010. 4(1):132-133.
22.	Chung GE, Kim W, Lee KL, et al. Add-on adefovir is superior to a switch to entecavir as rescue therapy for lamivudine-resistant chronic hepatitis B. Dig Dis Sci, 2011, 56(7):2130-2136.
23.	Kim HJ, Park JH, Park DI, et al. Rescue therapy for lamivudine-resistant chronic hepatitis B:Comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J Gastroenterol Hepatol, 2010, 25(8):1374-1380.
24.	刘昕, 刘宇. 阿德福韦酯和恩替卡韦治疗拉米夫定耐药慢性乙肝临床疗效和成本评价. 中国现代药物应用, 2013, 7(16):153-154.
25.	吴杭源. 肾移植乙肝患者使用拉米夫定出现YMDD变异的治疗. 现代中西医结合杂志, 2013, 22(4):367-368.
26.	Huang ZB, Zhao SS, Huang Y, et al. Comparision of the efficacy of lamivudine plus adefovir versus entecavir in thetreatment of lamivudine-resistant chronic hepatitis B:a systematic review and meta-analysis. Clin Ther, 2013, 35(12):1997-2006.
27.	Sheng YJ, Liu JY, Tong SW, et al. Lamivudine plus adefovir combination therapy versus entecavir monoherapy for lamivudine-resistan chronic hepatitis B:a systematic review and meta-analysis. Virol J, 2011, 8:393-403.

1. Fact sheets:hepatitis B. World Health Organization. Updated March 2015. Available at:http://www.who.int/mediacentre/factsheets/fs204/en/.
2. Pawlotsky JM, Dusheiko G, Hatzakis A, et al. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice:recommendations for a standardized approach. Gastroenterology, 2008, 134(2):405-415.
3. Westland CE, Yang H, Delaney WE, et al. Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients. J Viral Hepat, 2005, 12(1):67-73.
4. 赵树山, 范学工, 陈立章, 等. 阿德福韦酯联合胸腺肽α-1与单用阿德福韦酯比较治疗慢性乙肝的系统评价. 中国循证医学杂志, 2010, 10(8):972-977.
5. Yuen MF, Fung J, Wong DKH, et al. Prevention and management of drug resistance for antihepatitis B treatment. Lancet Infect Dis, 2009, 9(4):256-264.
6. Higgins JPT, Altman DG (editors). Chapter 8:Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration,2011. Available at:www.cochrane-handbook.org.
7. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metananlysis. Eur J Epidemiol, 2010, 25(9):603-605.
8. 王君萍. 拉米夫定联合阿德福韦酯或恩替卡韦治疗慢性乙型肝炎患者的疗效评价. 健康大视野, 2013, 21(1):6.
9. 刘爱平, 耿爱文, 李阳. 拉米夫定耐药慢性乙型肝炎患者应用拉米夫定联合阿德福韦酯或恩替卡韦治疗的疗效评价. 吉林医学, 2013, 34(2):246-246.
10. 杨庆文. 拉米夫定联合阿德福韦酯治疗拉米夫定和阿德福韦酯序贯治疗耐药40例. 中国中医药现代远程教育, 2012, 10(22):36-38.
11. 龚菁, 郭风彩, 李大春, 等. 联合阿德福韦酯或换用恩替卡韦治疗拉米夫定耐药慢性乙型肝炎患者的临床观察. 中国医药指南, 2012, 10(27):23-24.
12. 曹民. 拉米夫定耐药后的治疗选择. 现代医药卫生, 2012, 28(9):1439-1439.
13. 高冬梅. 中心拉米夫定耐药的慢性乙型肝炎治疗策略. 中国医药指南, 2012, 10(8):146-148.
14. 邰立慧. 阿德福韦联合拉米夫定与恩替卡韦治疗耐药性慢性乙肝疗效比较. 中国血液流变学杂志, 2011, 21(2):298-299.
15. Ryu HJ, Lee JM, Ahn SH, et al. Efficacy of adefovir add-on lamivudine rescue therapy compared with switching to entecavir monotherapy in patients with lamivudine-resistant chronic hepatitis B. J Med Virol, 2010, 82(11):1835-1842.
16. 骆晓霞, 陈康鉴. 拉米夫定联合阿德福韦酯或恩替卡韦治疗拉米夫定和阿德福韦酯序贯治疗耐药患者的研究. 齐齐哈尔医学院学报, 2010, 20(20):3286-3287.
17. 邱源旺, 蒋祥虎, 黄利华, 等. 乙型肝炎病毒 YMDD 变异的治疗对策. 中华肝脏病杂志, 2009, 17(3):171-174.
18. Pellicelli AM, Barbarini G, Romano M, et al. Entecavir therapy for Lamivudine resistant HBV cirrhotic patients waiting for olt:Viral and biochemical outcomes at one year. Hepatology, 2009, 50(SUPPL.4):514A.
19. Lee SJ, Yim HJ, Hwang SG, et al. Treatment of lamivudine-resistant chronic hepatitis B infection:a multicenter retrospective study. Scand J Gastroenterol, 2013, 48(2):196-204.
20. Heo NY, Lim YS, Lee HC, et al. Lamivudine plus adefovir or entecavir for patients with chronic hepatitis B resistant to lamivudine and adefovir. J Hepatol, 2010, 53(3):449-454.
21. Lee HW, Kim HJ, Choi CH, et al. Entecavir rescue therapy versus adefovir combination therapy in lamivudine-refractory patients with chronic hepatitis B. Hepatol Int, 2010. 4(1):132-133.
22. Chung GE, Kim W, Lee KL, et al. Add-on adefovir is superior to a switch to entecavir as rescue therapy for lamivudine-resistant chronic hepatitis B. Dig Dis Sci, 2011, 56(7):2130-2136.
23. Kim HJ, Park JH, Park DI, et al. Rescue therapy for lamivudine-resistant chronic hepatitis B:Comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J Gastroenterol Hepatol, 2010, 25(8):1374-1380.
24. 刘昕, 刘宇. 阿德福韦酯和恩替卡韦治疗拉米夫定耐药慢性乙肝临床疗效和成本评价. 中国现代药物应用, 2013, 7(16):153-154.
25. 吴杭源. 肾移植乙肝患者使用拉米夫定出现YMDD变异的治疗. 现代中西医结合杂志, 2013, 22(4):367-368.
26. Huang ZB, Zhao SS, Huang Y, et al. Comparision of the efficacy of lamivudine plus adefovir versus entecavir in thetreatment of lamivudine-resistant chronic hepatitis B:a systematic review and meta-analysis. Clin Ther, 2013, 35(12):1997-2006.
27. Sheng YJ, Liu JY, Tong SW, et al. Lamivudine plus adefovir combination therapy versus entecavir monoherapy for lamivudine-resistan chronic hepatitis B:a systematic review and meta-analysis. Virol J, 2011, 8:393-403.

Chinese Journal of Evidence-Based Medicine

Lamivudine plus Adefovir Combination Therapy versus Entecavir Monotherapy for Lamivudine-resistant Chronic Hepatitis B: A Meta-analysis

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