慢性乙型肝炎核苷类似物抗病毒治疗应答的影响因素_West China Medical Journal

Authors：

 王文真 , 卢丽霞 ,  王丽春

四川大学华西医院生物治疗国家重点实验室感染性疾病研究室（成都，610041）;

Corresponding author：

王丽春, Email: mindywang0218@163.com

Keywords：

慢性乙型肝炎; 核苷类似物; 抗病毒治疗; 影响因素

DOI：

10.7507/1002-0179.20140236

Video：

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我国乙型肝炎病毒感染率高，慢性乙型肝炎的治疗目标是最大限度地长期抑制乙型肝炎病毒，延缓和减少疾病进展及肝脏失代偿、肝硬化、肝细胞癌等的发生，从而改善生活质量和延长存活时间。随着干扰素及核苷类似物两大类抗病毒治疗的进展，发现不同的患者在治疗疗效上有很大差异，研究认为，核苷类似物抗乙型肝炎病毒治疗的疗效主要受药物、病毒及宿主3个方面因素的影响。

Citation： 王文真, 卢丽霞, 王丽春. 慢性乙型肝炎核苷类似物抗病毒治疗应答的影响因素. West China Medical Journal, 2014, 29(4): 776-779. doi: 10.7507/1002-0179.20140236 Copy

1.	European Association for The Study of the Liver. EASL clinical practice guidelines:management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57(1):167-185.
2.	Lok AS, Mcmahon BJ. Chronic hepatitis B:update 2009[J]. Hepatology, 2009, 50(3):661-662.
3.	Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2012 update[J]. Hepatol Int, 2012, 6(3):531-561.
4.	中华医学会肝病学分会, 中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J]. 临床肝胆病杂志, 2011, 27(1):113-128.
5.	张贵琴, 王志敏, 郑爱萍. 核苷类抗乙型肝炎病毒药物研究进展[J]. 国际药学研究杂志, 2013, 40(1):8-13.
6.	Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States[J]. N Engl J Med, 1999, 341(17):1256-1263.
7.	Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy[J]. Hepatology, 2009, 49(Suppl 5):S174-S184.
8.	Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results:telbivudine Is superior to lamivudine in patients with chronic hepatitis B[J]. Gastroenterology, 2009, 136(2):486-495.
9.	Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J]. N Engl J Med, 2003, 348(9):808-816.
10.	Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[J]. N Engl J Med, 2003, 348(9):800-807.
11.	Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J]. Hepatology, 2008, 48(3):750-758.
12.	Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years[J]. Gastroenterology, 2006, 131(6):1743-1751.
13.	Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B[J]. Clin Gastroenterol Hepatol, 2007, 5(3):285-294.
14.	Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy[J]. Hepatology, 2009, 49(5):1503-1514.
15.	Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B[J]. N Engl J Med, 2006, 354(10):1011-1020.
16.	Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B[J]. N Engl J Med, 2006, 354(10):1001-1010.
17.	Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine[J]. Antimicrob Agents Chemother, 2004, 48(9):3498-3507.
18.	Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient[J]. J Hepatol, 2007, 46(3):531-538.
19.	Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes[J]. J Gen Virol, 1988, 69(Pt 10):2575-2583.
20.	Norder H, Couroucé AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes[J]. Virology, 1994, 198(2):489-503.
21.	Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype of hepatitis B virus:complete genome and phylogenetic relatedness[J]. J Gen Virol, 2000, 81(Pt 1):67-74.
22.	Cooksley WG. Do we need to determine viral genotype in treating chronic hepatitis B?[J]. J Viral Hepat, 2010, 17(9):601-610.
23.	Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C[J]. Gastroenterology, 2002, 122(7):1756-1762.
24.	Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B:a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline[J]. J Hepatol, 2005, 43(3):411-417.
25.	Hou J, Schilling R, Janssen HL, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance[J]. J Med Virol, 2007, 79(8):1055-1063.
26.	lloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology, 2006, 130(3):678-686.
27.	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[J]. Gastroenterology, 2008, 134(2):405-415.
28.	Chou YC, Yu MW, Wu CF, et al. Temporal relationship between hepatitis B virus enhancer Ⅱ/basal core promoter sequence variation and risk of hepatocellular carcinoma[J]. Gut, 2008, 57(1):91-97.
29.	Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection[J]. Antiviral Res, 2004, 64(1):1-15.
30.	Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy[J]. Gastroenterology, 2004, 126(7):1750-1758.
31.	李华东, 江建宁, 陆晖, 等. 慢性乙型肝炎患者肝细胞HBV cccDNA、tDNA及HBV表面标志物的相关性研究[J]. 中华实验和临床感染病杂志·电子版, 2012, 6(4):300-303.
32.	Kwon JH, Jang JW, Lee S, et al. Pretreatment HBeAg level and an early decrease in HBeAg level predict virologic response to entecavir treatment for HBeAg-positive chronic hepatitis B[J]. J Viral Hepat, 2012, 19(2):e41-e47.
33.	Zhang X, Lin SM, Ye F, et al. An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAg-positive patients[J]. J Viral Hepat, 2011, 18(7):e184-e190.
34.	符晓莉, 王磊, 刘峰. 乙肝病毒感染不同阶段血清HBsAg定量值及其与HBV DNA水平和年龄的相关性[J]. 山东大学学报·医学版, 2013, 51(5):94-98.
35.	Jin YJ, Shim JH, Chung YH, et al. HLA-DRB1*010101 allele is closely associated with poor virological response to lamivudine therapy in patients with chronic hepatitis B[J]. Digestion, 2011, 84(Suppl 1):35-42.
36.	Wu JF, Chen CH, Hsieh RP, et al. HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection:a long-term prospective sibling cohort study in Taiwan[J]. J Pediatr, 2006, 148(5):647-651.
37.	Wu JF, Wu TC, Chen CH, et al. Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion[J]. Gastroenterology, 2010, 138(1):165-172.
38.	Cheong JY, Cho SW, Oh B, et al. Association of interleukin-18 gene polymorphisms with hepatitis B virus clearance[J]. Dig Dis Sci, 2010, 55(4):1113-1119.
39.	Stoop JN, Woltman AM, Biesta PJ, et al. Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response[J]. Hepatology, 2007, 46(3):699-705.
40.	Wang S, Huang D, Sun S, et al. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa[J]. Virol J, 2011, 20(8):28.
41.	Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-inducible genes OAS associated with interferon-α treatment response in chronic HBV infection[J]. Antiviral Res, 2011, 89(3):232-237.
42.	Mizokami M. Discovery of critical host factor, IL-28B, associated with response to hepatitis C virus treatment[J]. J Gastroenterol Hepatol, 2012, 27(3):425-429.
43.	Thursz M, Yee L, Khakoo S. Understanding the host genetics of chronic hepatitis B and C[J]. Semin Liver Dis, 2011, 31(2):115-127.
44.	Fabris C, Falleti E, Cussigh A, et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis:role in the course of chronic viral hepatitis and the development of HCC[J]. J Hepatol, 2011, 54(4):716-722.
45.	Lampertico P, Viganö M, Cheroni C, et al. IL28B polymorphisms predict interferon-related HBsAg seroclearance in genotype D HBeAg-negative patients with chronic hepatitis B[J]. Hepatology, 2013, 57(3):890-896.

1. European Association for The Study of the Liver. EASL clinical practice guidelines:management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57(1):167-185.
2. Lok AS, Mcmahon BJ. Chronic hepatitis B:update 2009[J]. Hepatology, 2009, 50(3):661-662.
3. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2012 update[J]. Hepatol Int, 2012, 6(3):531-561.
4. 中华医学会肝病学分会, 中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J]. 临床肝胆病杂志, 2011, 27(1):113-128.
5. 张贵琴, 王志敏, 郑爱萍. 核苷类抗乙型肝炎病毒药物研究进展[J]. 国际药学研究杂志, 2013, 40(1):8-13.
6. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States[J]. N Engl J Med, 1999, 341(17):1256-1263.
7. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy[J]. Hepatology, 2009, 49(Suppl 5):S174-S184.
8. Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results:telbivudine Is superior to lamivudine in patients with chronic hepatitis B[J]. Gastroenterology, 2009, 136(2):486-495.
9. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J]. N Engl J Med, 2003, 348(9):808-816.
10. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[J]. N Engl J Med, 2003, 348(9):800-807.
11. Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J]. Hepatology, 2008, 48(3):750-758.
12. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years[J]. Gastroenterology, 2006, 131(6):1743-1751.
13. Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B[J]. Clin Gastroenterol Hepatol, 2007, 5(3):285-294.
14. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy[J]. Hepatology, 2009, 49(5):1503-1514.
15. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B[J]. N Engl J Med, 2006, 354(10):1011-1020.
16. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B[J]. N Engl J Med, 2006, 354(10):1001-1010.
17. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine[J]. Antimicrob Agents Chemother, 2004, 48(9):3498-3507.
18. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient[J]. J Hepatol, 2007, 46(3):531-538.
19. Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes[J]. J Gen Virol, 1988, 69(Pt 10):2575-2583.
20. Norder H, Couroucé AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes[J]. Virology, 1994, 198(2):489-503.
21. Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype of hepatitis B virus:complete genome and phylogenetic relatedness[J]. J Gen Virol, 2000, 81(Pt 1):67-74.
22. Cooksley WG. Do we need to determine viral genotype in treating chronic hepatitis B?[J]. J Viral Hepat, 2010, 17(9):601-610.
23. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C[J]. Gastroenterology, 2002, 122(7):1756-1762.
24. Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B:a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline[J]. J Hepatol, 2005, 43(3):411-417.
25. Hou J, Schilling R, Janssen HL, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance[J]. J Med Virol, 2007, 79(8):1055-1063.
26. lloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology, 2006, 130(3):678-686.
27. 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[J]. Gastroenterology, 2008, 134(2):405-415.
28. Chou YC, Yu MW, Wu CF, et al. Temporal relationship between hepatitis B virus enhancer Ⅱ/basal core promoter sequence variation and risk of hepatocellular carcinoma[J]. Gut, 2008, 57(1):91-97.
29. Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection[J]. Antiviral Res, 2004, 64(1):1-15.
30. Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy[J]. Gastroenterology, 2004, 126(7):1750-1758.
31. 李华东, 江建宁, 陆晖, 等. 慢性乙型肝炎患者肝细胞HBV cccDNA、tDNA及HBV表面标志物的相关性研究[J]. 中华实验和临床感染病杂志·电子版, 2012, 6(4):300-303.
32. Kwon JH, Jang JW, Lee S, et al. Pretreatment HBeAg level and an early decrease in HBeAg level predict virologic response to entecavir treatment for HBeAg-positive chronic hepatitis B[J]. J Viral Hepat, 2012, 19(2):e41-e47.
33. Zhang X, Lin SM, Ye F, et al. An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAg-positive patients[J]. J Viral Hepat, 2011, 18(7):e184-e190.
34. 符晓莉, 王磊, 刘峰. 乙肝病毒感染不同阶段血清HBsAg定量值及其与HBV DNA水平和年龄的相关性[J]. 山东大学学报·医学版, 2013, 51(5):94-98.
35. Jin YJ, Shim JH, Chung YH, et al. HLA-DRB1*010101 allele is closely associated with poor virological response to lamivudine therapy in patients with chronic hepatitis B[J]. Digestion, 2011, 84(Suppl 1):35-42.
36. Wu JF, Chen CH, Hsieh RP, et al. HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection:a long-term prospective sibling cohort study in Taiwan[J]. J Pediatr, 2006, 148(5):647-651.
37. Wu JF, Wu TC, Chen CH, et al. Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion[J]. Gastroenterology, 2010, 138(1):165-172.
38. Cheong JY, Cho SW, Oh B, et al. Association of interleukin-18 gene polymorphisms with hepatitis B virus clearance[J]. Dig Dis Sci, 2010, 55(4):1113-1119.
39. Stoop JN, Woltman AM, Biesta PJ, et al. Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response[J]. Hepatology, 2007, 46(3):699-705.
40. Wang S, Huang D, Sun S, et al. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa[J]. Virol J, 2011, 20(8):28.
41. Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-inducible genes OAS associated with interferon-α treatment response in chronic HBV infection[J]. Antiviral Res, 2011, 89(3):232-237.
42. Mizokami M. Discovery of critical host factor, IL-28B, associated with response to hepatitis C virus treatment[J]. J Gastroenterol Hepatol, 2012, 27(3):425-429.
43. Thursz M, Yee L, Khakoo S. Understanding the host genetics of chronic hepatitis B and C[J]. Semin Liver Dis, 2011, 31(2):115-127.
44. Fabris C, Falleti E, Cussigh A, et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis:role in the course of chronic viral hepatitis and the development of HCC[J]. J Hepatol, 2011, 54(4):716-722.
45. Lampertico P, Viganö M, Cheroni C, et al. IL28B polymorphisms predict interferon-related HBsAg seroclearance in genotype D HBeAg-negative patients with chronic hepatitis B[J]. Hepatology, 2013, 57(3):890-896.

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慢性乙型肝炎核苷类似物抗病毒治疗应答的影响因素

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