Efficacy and Safety of Interferon-alpha Combined with Enticavir for Treatment-naïve Chronic Hepatitis B Patients: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

 JIAFan ,  WUXia , KANGPeng , GAOJie , XUChun-lin , LIUWen-juan , JIANGGui-hua

Department of Infectious Diseases, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China;

Corresponding author：

WUXia, Email: wuspot@163.com

Keywords：

Chronic hepatitis B; Treatment-naï; ve; Interferon-alpha; Enticavir; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20160050

Video：

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Objective To systematically review the efficacy and safety of interferon-alpha (IFN-α) combined with enticavir (ETV) for treatment-naïve chronic hepatitis B (CHB) patients, so as to provide references for clinical practice. Methods We electronically searched databases including PubMed, EMbase, The Cochrane Library (Issue 7, 2015), Web of Science, WanFang Data, CNKI, CBM and VIP from inception to July 20^th, 2015, to collect randomized controlled trials (RCTs) about IFN-α combined with ETV versus IFN-α or ETV monotherapy for treatment-naïve CHB patients. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software. Results A total of 10 RCTs involving 964 patients were included. The results of meta-analysis showed that:For HBV-DNA loss rate, HBeAg loss rate and HBeAg seroconversion rate, there were no significant differences between the combination therapy group and the monotherapy group at 12-week of treatment, but the combination therapy group was significantly superior to the monotherapy group at 24-and 48-week of treatment except that there was no significant difference between the combination therapy group and the IFN-α monotherapy group in HBeAg seroconversion at 48-week of treatment. For rate of ALT normalization, the combination therapy group was superior to the IFN-α monotherapy group at 12-and 24-week of treatment, but there were no significant differences between the combination therapy group and the ETV monotherapy group at 12-, 24-, and 48-week of treatment. For safety, no pooled analysis was performed because different outcomes were reported by included studies. Conclusion IFN-α combined with ETV is superior to IFN-α or ETV monotherapy in decreasing viral load, and promoting HBeAg loss and HBeAg seroconversion for treatment-naïve CHB patients, but the evidence of safety is insufficient. Due to the limited quantity and quality of included studies, the aforementioned conclusions still need to be further verified by conducting more large-scale, high quality RCTs.

Citation： JIAFan, WUXia, KANGPeng, GAOJie, XUChun-lin, LIUWen-juan, JIANGGui-hua. Efficacy and Safety of Interferon-alpha Combined with Enticavir for Treatment-naïve Chronic Hepatitis B Patients: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2016, 16(3): 319-324. doi: 10.7507/1672-2531.20160050 Copy

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2.	Ott JJ, Stevens GA, Groeger J, et al. Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine, 2012, 30(12):2212-2219.
3.	Zarski JP, Marcellin P, Leroy V, et al. Characteristics of patients with chronic hepatitis B in France:predominant frequency of HBe antigen negative cases. J Hepatol, 2006, 45(3):355-360.
4.	Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology, 2007, 45(2):507-539.
5.	Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med, 2004, 350(11):1118-1129.
6.	Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis, 2003, 23(1):47-58.
7.	Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B:summary of a clinical research workshop. Hepatology, 2007, 45(4):1056-1075.
8.	McMahon BJ. The natural history of chronic hepatitis B virus infection. Semin Liver Dis, 2004, 24 (Suppl 1):17-21.
9.	Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis:incidence and risk factors. Gastroenterology, 2004, 127:S35-S50.
10.	Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B:natural history and treatment. Semin Liver Dis, 2006, 26(2):130-141.Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology, 2007, 45(2):507-539.
11.	Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva:World Health Organization; 2015. Available at:http://www.who.int.
12.	尹炽标, 张复春, 冼建中, 等. 乙型肝炎病毒载量及ALT水平与干扰素应答关系的研究. 临床肝胆病杂志, 2004, 20(2):97-98.
13.	陈新月, 于岩岩, 张文瑾, 等. 慢性乙型肝炎抗病毒治疗疗效及因素研究. 首都医科大学学报, 2006, 27(2):166-170.
14.	张复春. 乙型和丙型肝炎病毒载量与干扰素疗效关系的研究. 广州:中山大学, 2003.
15.	Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8:Assessing risk of bias in included studies. In:Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011, Available at:www.cochrane-handbook.org.
16.	Tangkijvanich P, Chittmittraprap S, Poovorawan K, et al. A randomized study comparing efficacy of peginterferon alpha 2b monotherapy versus combination with entecavir in HBeAg negative chronic hepatitis B. Hepatol Int, 2015, 9(1):S204.
17.	Xie Q, Zhou H, Bai X, et al. A randomized, open-label clinical study of combined pegylated interferon alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B. Clin Infect Dis, 2014, 59, 1714-1723.
18.	Brouwer WP, Xie Q, Sonneveld MJ, et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B:A multicenter randomized trial (ARES study). Hepatology, 2015, 61(5):1512-1522.
19.	Liu CJ, Wang CC, Yang SS, et al. entecavir plus peginterferon alfa-2a vs. entecavir alone in the treatment of hepatitis B e antigen-positive chronic hepatitis B:an interim report. J Hepatol, 2013, 58:S308.
20.	Kim HI, Kim SG, Kim YS, et al. The analysis of virologic response in combination treatment with pegylated interferon and nucleoside analogue in patients with chronic hepatitis B. Hepatology, 2011, 54:1050A-1051A.
21.	葛迎春. 恩替卡韦联合长效干扰素治疗乙肝的临床研究. 中国卫生标准管理, 2015, 6(9):202-203.
22.	张志敏, 季宝玉, 李琳, 等. 恩替卡韦联合a-2b干扰素治疗慢性乙型肝炎的疗效观察. 蚌埠医学院学报, 2014, 39(5):621-623.
23.	李瑞芝, 谢小花. 聚乙二醇干扰素联合恩替卡韦治疗慢性乙肝的疗效观察. 医药前沿, 2014, (31):147-148.
24.	曾文, 袁静, 刘映霞, 等. 聚乙二醇干扰素alpha-2a联合恩替卡韦治疗高病毒载量HBeAg阳性慢性乙型肝样的临床研究. 中华实验和临床病毒学杂志, 2013, 27(2):115-118.
25.	阿衣枯力·托乎提. 聚乙二醇化α-2a干扰素联合恩替卡韦治愈慢性乙肝18例分析. 世界最新医学信息文摘, 2014, (11):150-151.
26.	Peters MG, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology, 2004, 126(1):91-101.
27.	Reijnders JG, Perquin MJ, Zhang N, et al. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology, 2010, 139(2):491-498.
28.	Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology, 2011, 140(1):132-143.
29.	Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med, 2008, 359(23):2442-2455.
30.	Chang TT, Chao YC, Gorbakov VV, et al. Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat, 2009, 16(11):784-789.
31.	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(10):1001-1010.
32.	Ha NB, Ha NB, Garcia RT, et al. Medication nonadherence with long-term management of patients with hepatitis B e antigen-negative chronic hepatitis B. Dig Dis Sci, 2011, 56(8):2423-2431.
33.	Peters M. Actions of cytokines on the immune response and viral inter-actions:an overview. Hepatology, 1996, 23(4):909-916.
34.	Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol, 2003, 77(1):68-76.

1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat, 2004, 11(2):97-107.
2. Ott JJ, Stevens GA, Groeger J, et al. Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine, 2012, 30(12):2212-2219.
3. Zarski JP, Marcellin P, Leroy V, et al. Characteristics of patients with chronic hepatitis B in France:predominant frequency of HBe antigen negative cases. J Hepatol, 2006, 45(3):355-360.
4. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology, 2007, 45(2):507-539.
5. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med, 2004, 350(11):1118-1129.
6. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis, 2003, 23(1):47-58.
7. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B:summary of a clinical research workshop. Hepatology, 2007, 45(4):1056-1075.
8. McMahon BJ. The natural history of chronic hepatitis B virus infection. Semin Liver Dis, 2004, 24 (Suppl 1):17-21.
9. Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis:incidence and risk factors. Gastroenterology, 2004, 127:S35-S50.
10. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B:natural history and treatment. Semin Liver Dis, 2006, 26(2):130-141.Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology, 2007, 45(2):507-539.
11. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva:World Health Organization; 2015. Available at:http://www.who.int.
12. 尹炽标, 张复春, 冼建中, 等. 乙型肝炎病毒载量及ALT水平与干扰素应答关系的研究. 临床肝胆病杂志, 2004, 20(2):97-98.
13. 陈新月, 于岩岩, 张文瑾, 等. 慢性乙型肝炎抗病毒治疗疗效及因素研究. 首都医科大学学报, 2006, 27(2):166-170.
14. 张复春. 乙型和丙型肝炎病毒载量与干扰素疗效关系的研究. 广州:中山大学, 2003.
15. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8:Assessing risk of bias in included studies. In:Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011, Available at:www.cochrane-handbook.org.
16. Tangkijvanich P, Chittmittraprap S, Poovorawan K, et al. A randomized study comparing efficacy of peginterferon alpha 2b monotherapy versus combination with entecavir in HBeAg negative chronic hepatitis B. Hepatol Int, 2015, 9(1):S204.
17. Xie Q, Zhou H, Bai X, et al. A randomized, open-label clinical study of combined pegylated interferon alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B. Clin Infect Dis, 2014, 59, 1714-1723.
18. Brouwer WP, Xie Q, Sonneveld MJ, et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B:A multicenter randomized trial (ARES study). Hepatology, 2015, 61(5):1512-1522.
19. Liu CJ, Wang CC, Yang SS, et al. entecavir plus peginterferon alfa-2a vs. entecavir alone in the treatment of hepatitis B e antigen-positive chronic hepatitis B:an interim report. J Hepatol, 2013, 58:S308.
20. Kim HI, Kim SG, Kim YS, et al. The analysis of virologic response in combination treatment with pegylated interferon and nucleoside analogue in patients with chronic hepatitis B. Hepatology, 2011, 54:1050A-1051A.
21. 葛迎春. 恩替卡韦联合长效干扰素治疗乙肝的临床研究. 中国卫生标准管理, 2015, 6(9):202-203.
22. 张志敏, 季宝玉, 李琳, 等. 恩替卡韦联合a-2b干扰素治疗慢性乙型肝炎的疗效观察. 蚌埠医学院学报, 2014, 39(5):621-623.
23. 李瑞芝, 谢小花. 聚乙二醇干扰素联合恩替卡韦治疗慢性乙肝的疗效观察. 医药前沿, 2014, (31):147-148.
24. 曾文, 袁静, 刘映霞, 等. 聚乙二醇干扰素alpha-2a联合恩替卡韦治疗高病毒载量HBeAg阳性慢性乙型肝样的临床研究. 中华实验和临床病毒学杂志, 2013, 27(2):115-118.
25. 阿衣枯力·托乎提. 聚乙二醇化α-2a干扰素联合恩替卡韦治愈慢性乙肝18例分析. 世界最新医学信息文摘, 2014, (11):150-151.
26. Peters MG, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology, 2004, 126(1):91-101.
27. Reijnders JG, Perquin MJ, Zhang N, et al. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology, 2010, 139(2):491-498.
28. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology, 2011, 140(1):132-143.
29. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med, 2008, 359(23):2442-2455.
30. Chang TT, Chao YC, Gorbakov VV, et al. Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat, 2009, 16(11):784-789.
31. 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(10):1001-1010.
32. Ha NB, Ha NB, Garcia RT, et al. Medication nonadherence with long-term management of patients with hepatitis B e antigen-negative chronic hepatitis B. Dig Dis Sci, 2011, 56(8):2423-2431.
33. Peters M. Actions of cytokines on the immune response and viral inter-actions:an overview. Hepatology, 1996, 23(4):909-916.
34. Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol, 2003, 77(1):68-76.

Chinese Journal of Evidence-Based Medicine

Efficacy and Safety of Interferon-alpha Combined with Enticavir for Treatment-naïve Chronic Hepatitis B Patients: A Systematic Review

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