Efficacy and Safety of Interferon-alpha Combined with Enticavir for Treatment-na?ve 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-na?; 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-na?ve 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-na?ve 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-na?ve 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-na?ve 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

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.	尹熾標, 張復春, 冼建中, 等. 乙型肝炎病毒載量及ALT水平與干擾素應答關系的研究. 臨床肝膽病雜志, 2004, 20(2):97-98.
13.	陳新月, 于巖巖, 張文瑾, 等. 慢性乙型肝炎抗病毒治療療效及因素研究. 首都醫科大學學報, 2006, 27(2):166-170.
14.	張復春. 乙型和丙型肝炎病毒載量與干擾素療效關系的研究. 廣州:中山大學, 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. 恩替卡韋聯合長效干擾素治療乙肝的臨床研究. 中國衛生標準管理, 2015, 6(9):202-203.
22.	張志敏, 季寶玉, 李琳, 等. 恩替卡韋聯合a-2b干擾素治療慢性乙型肝炎的療效觀察. 蚌埠醫學院學報, 2014, 39(5):621-623.
23.	李瑞芝, 謝小花. 聚乙二醇干擾素聯合恩替卡韋治療慢性乙肝的療效觀察. 醫藥前沿, 2014, (31):147-148.
24.	曾文, 袁靜, 劉映霞, 等. 聚乙二醇干擾素alpha-2a聯合恩替卡韋治療高病毒載量HBeAg陽性慢性乙型肝樣的臨床研究. 中華實驗和臨床病毒學雜志, 2013, 27(2):115-118.
25.	阿衣枯力·托乎提. 聚乙二醇化α-2a干擾素聯合恩替卡韋治愈慢性乙肝18例分析. 世界最新醫學信息文摘, 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. 尹熾標, 張復春, 冼建中, 等. 乙型肝炎病毒載量及ALT水平與干擾素應答關系的研究. 臨床肝膽病雜志, 2004, 20(2):97-98.
13. 陳新月, 于巖巖, 張文瑾, 等. 慢性乙型肝炎抗病毒治療療效及因素研究. 首都醫科大學學報, 2006, 27(2):166-170.
14. 張復春. 乙型和丙型肝炎病毒載量與干擾素療效關系的研究. 廣州:中山大學, 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. 恩替卡韋聯合長效干擾素治療乙肝的臨床研究. 中國衛生標準管理, 2015, 6(9):202-203.
22. 張志敏, 季寶玉, 李琳, 等. 恩替卡韋聯合a-2b干擾素治療慢性乙型肝炎的療效觀察. 蚌埠醫學院學報, 2014, 39(5):621-623.
23. 李瑞芝, 謝小花. 聚乙二醇干擾素聯合恩替卡韋治療慢性乙肝的療效觀察. 醫藥前沿, 2014, (31):147-148.
24. 曾文, 袁靜, 劉映霞, 等. 聚乙二醇干擾素alpha-2a聯合恩替卡韋治療高病毒載量HBeAg陽性慢性乙型肝樣的臨床研究. 中華實驗和臨床病毒學雜志, 2013, 27(2):115-118.
25. 阿衣枯力·托乎提. 聚乙二醇化α-2a干擾素聯合恩替卡韋治愈慢性乙肝18例分析. 世界最新醫學信息文摘, 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-na?ve Chronic Hepatitis B Patients: A Systematic Review

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