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.	趙樹山, 范學工, 陳立章, 等. 阿德福韋酯聯合胸腺肽α-1與單用阿德福韋酯比較治療慢性乙肝的系統評價. 中國循證醫學雜志, 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. 拉米夫定聯合阿德福韋酯或恩替卡韋治療慢性乙型肝炎患者的療效評價. 健康大視野, 2013, 21(1):6.
9.	劉愛平, 耿愛文, 李陽. 拉米夫定耐藥慢性乙型肝炎患者應用拉米夫定聯合阿德福韋酯或恩替卡韋治療的療效評價. 吉林醫學, 2013, 34(2):246-246.
10.	楊慶文. 拉米夫定聯合阿德福韋酯治療拉米夫定和阿德福韋酯序貫治療耐藥40例. 中國中醫藥現代遠程教育, 2012, 10(22):36-38.
11.	龔菁, 郭風彩, 李大春, 等. 聯合阿德福韋酯或換用恩替卡韋治療拉米夫定耐藥慢性乙型肝炎患者的臨床觀察. 中國醫藥指南, 2012, 10(27):23-24.
12.	曹民. 拉米夫定耐藥后的治療選擇. 現代醫藥衛生, 2012, 28(9):1439-1439.
13.	高冬梅. 中心拉米夫定耐藥的慢性乙型肝炎治療策略. 中國醫藥指南, 2012, 10(8):146-148.
14.	邰立慧. 阿德福韋聯合拉米夫定與恩替卡韋治療耐藥性慢性乙肝療效比較. 中國血液流變學雜志, 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.	駱曉霞, 陳康鑒. 拉米夫定聯合阿德福韋酯或恩替卡韋治療拉米夫定和阿德福韋酯序貫治療耐藥患者的研究. 齊齊哈爾醫學院學報, 2010, 20(20):3286-3287.
17.	邱源旺, 蔣祥虎, 黃利華, 等. 乙型肝炎病毒 YMDD 變異的治療對策. 中華肝臟病雜志, 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.	劉昕, 劉宇. 阿德福韋酯和恩替卡韋治療拉米夫定耐藥慢性乙肝臨床療效和成本評價. 中國現代藥物應用, 2013, 7(16):153-154.
25.	吳杭源. 腎移植乙肝患者使用拉米夫定出現YMDD變異的治療. 現代中西醫結合雜志, 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. 趙樹山, 范學工, 陳立章, 等. 阿德福韋酯聯合胸腺肽α-1與單用阿德福韋酯比較治療慢性乙肝的系統評價. 中國循證醫學雜志, 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. 拉米夫定聯合阿德福韋酯或恩替卡韋治療慢性乙型肝炎患者的療效評價. 健康大視野, 2013, 21(1):6.
9. 劉愛平, 耿愛文, 李陽. 拉米夫定耐藥慢性乙型肝炎患者應用拉米夫定聯合阿德福韋酯或恩替卡韋治療的療效評價. 吉林醫學, 2013, 34(2):246-246.
10. 楊慶文. 拉米夫定聯合阿德福韋酯治療拉米夫定和阿德福韋酯序貫治療耐藥40例. 中國中醫藥現代遠程教育, 2012, 10(22):36-38.
11. 龔菁, 郭風彩, 李大春, 等. 聯合阿德福韋酯或換用恩替卡韋治療拉米夫定耐藥慢性乙型肝炎患者的臨床觀察. 中國醫藥指南, 2012, 10(27):23-24.
12. 曹民. 拉米夫定耐藥后的治療選擇. 現代醫藥衛生, 2012, 28(9):1439-1439.
13. 高冬梅. 中心拉米夫定耐藥的慢性乙型肝炎治療策略. 中國醫藥指南, 2012, 10(8):146-148.
14. 邰立慧. 阿德福韋聯合拉米夫定與恩替卡韋治療耐藥性慢性乙肝療效比較. 中國血液流變學雜志, 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. 駱曉霞, 陳康鑒. 拉米夫定聯合阿德福韋酯或恩替卡韋治療拉米夫定和阿德福韋酯序貫治療耐藥患者的研究. 齊齊哈爾醫學院學報, 2010, 20(20):3286-3287.
17. 邱源旺, 蔣祥虎, 黃利華, 等. 乙型肝炎病毒 YMDD 變異的治療對策. 中華肝臟病雜志, 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. 劉昕, 劉宇. 阿德福韋酯和恩替卡韋治療拉米夫定耐藥慢性乙肝臨床療效和成本評價. 中國現代藥物應用, 2013, 7(16):153-154.
25. 吳杭源. 腎移植乙肝患者使用拉米夫定出現YMDD變異的治療. 現代中西醫結合雜志, 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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