核苷和核苷酸类药物治疗慢性乙型肝炎的长期性

doi:10.3969/j.issn.1672-5069.2015.01.032

摘要/Abstract

摘要： 核苷和核苷酸类药物（NAs）已成功用于慢性乙型肝炎（CHB）治疗。目前一致认为,乙型肝炎病毒（HBV）复制是肝损伤和疾病进展的关键因素,因此CHB治疗的主要目的是最大限度地持续抑制HBV复制。现已证明,应用NAs长期治疗CHB可明显改善肝脏组织学、逆转肝纤维化或肝硬化,以及减少肝细胞癌的发生。本文对CHB长期治疗的必要性、临床获益及管理进行了综述。

关键词: 肝炎, 乙型, 慢性, 核苷和核苷酸类药物, 长期治疗, 管理

Abstract: Nucleos（t）ide analogs（NAs） have been successfully used for treatment of chronic hepatitis B. Hepatitis B virus（HBV） replication is now recognized as the key driverof liver injury and disease progression, so the primaryaim of treatment forchronic HBV infection is to maximize sustained suppression of HBV replication to undetectablelevels. The long-term treatment has also beenshown to achieve substantial histological improvement and regression of liver fibrosis orcirrhosis,and reduction of hepatocellular carcinoma. This paper has reviewed the necessity, clinical benefits, and the management of long-term treatment for chronic hepatitis B.

Key words: Hepatitis B, chronic, Nucleoside and nucleotide analogs, Long-term treatment, Management

参加慢性乙型肝炎长期治疗讨论会专家. 核苷和核苷酸类药物治疗慢性乙型肝炎的长期性[J]. 实用肝脏病杂志, 2015, 18(1): 113-119.

参考文献

[1] 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. Gastroenterology,2004,126（7）:1750-1758.
[2] Busca A,Kumar A. Innate immune responses in hepatitis B virus （HBV） infection. Virol J,2014,11:22.
[3] Glebe D. Recent advances in hepatitis B virus research:a German point of view. World J Gastroenterol,2007,13（1）:8-13.
[4] Chan C,Abu-Raddad E,Golor G,et al. Clinical phamacokinetics of alamifovir and its metabolites.Antimicrob Agents Chemother, 2005,49（5）:1813-1822.
[5] Bertoletti A,Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections:towards restoration of immune control of viral infection. Gut,2012,61（12）:1754-1764.
[6] Marcellin P,Asselah T. Long-term therapy for chronic hepatitis B:hepatitis B virus DNA suppression leading to cirrhosis reversal. J Gastroenterol Hepatol,2013,28（6）:912-923.
[7] 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）. 中国病毒病杂志,2011,1（1）:9-23.
[8] European Association for the Study of the Liver. EASL clinical practice guidelines:management of chronic hepatitis B virus infection. J Hepatol,2012,57（1）:167-185.
[9] Liaw YF,Kao JH,Piratvisuth T,et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2012 update. Hepatol Int,2012,6 （3）:531-561.
[10] Lok AS,McMahon BJ. Chronic hepatitis B:update 2009. Hepatology,2009,50（3）:661-662.
[11] Locarnini S. Molecular virology of hepatitis B virus. Semin Liver Dis,2004,24 Suppl 1:3-10.
[12] Levrero M,Pollicino T,Petersen J,et al. Control of cccDNA function in hepatitis B virus infection. J Hepatol,2009,51（3）:581-592.
[13] Wei Y,Neuveut C,Tiollais P,et al. Molecular biology of the hepatitis B virus and role of the X gene. Pathol Biol （Paris）, 2010,58（4）:267-272.
[14] Abu-Amara M,Feld JJ. Does antiviral therapy for chronic hepatitis B reduce the risk of hepatocellular carcinoma Semin Liver Dis,2013,33（2）:157-166.
[15] Wursthorn K,Lutgehetmann M,Dandri M,et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology,2006,44（3）:675-684.
[16] Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection. Antiviral Res,2004,64（1）:1-15.
[17] Balsano C,Alisi A. Viral hepatitis B:established and emerging therapies. Curr Med Chem,2008,15（9）:930-939.
[18] Fung J,Lai CL,Seto WK,et al. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother,2011,66（12）:2715-2725.
[19] Kamiya N. The mechanisms of action of antivials against hepatitis B virus infection. J Antimicrob Chemother,2003,51（5）:1085-1089.
[20] Gish R,Jia JD,Locarnini S,et al. Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis,2012,12（4）:341-353.
[21] Reijnders JG,Janssen HL. Relapse of chronic hepatitis B after discontinuation of nucleos（t）ide analogs:is the glass half full or half empty Hepatology,2013,58（6）:1885-1887.
[22] Chang TT,Liaw YF,Wu SS,et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology,2010,52（3）:886-893.
[23] Marinos G,Naoumov NV,Williams R. Impact of complete inhibition of viral replication on the cellular immune response in chronic hepatitis B virus infection. Hepatology,1996,24（5）:991-995.
[24] Boni C,Bertolatti A,Penna A,et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest,1998,102（5）:968-975.
[25] Boni C,Penna A,Ogg GS,et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B:new perspectives for immune therapy. Hepatology,2001,33（4）:963-971.
[26] Evans A,Riva A,Cooksley H,et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B:impact of hepatitis B e-antigen seroconversion. Hepatology,2008,48（3）:759-769.
[27] Zhang JY,Song CH,Shi F,et al. Decreased ratio of Treg cells to Th17 cells correlates with HBV DNA suppression in chronic hepatitis B patients undergoing entecavir treatment. PLoS One,2010,5（11）:e13869.
[28] Yeh CT,Hsu CW,Chen YC,et al.你Withdrawal of lamivudine in HBeAgpositivechronic hepatitis B patients afterachieving effective maintained virologicalsuppression. J Clin Virol,2009,45（2）:114-118.
[29] Liaw YF,Leung N,Kao JH,et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2008 update. Hepatol Int,2008,2（3）:263-283.
[30] Lee HW,Lee HJ,Hwang JS,et al. Lamivudinemaintenance beyond one yearafter HBeAg seroconversion is a majorfactor for sustained virologic response inHBeAg-positive chronic hepatitis B. Hepatology,2010,51（2）:415-421.
[31] Lok AS,McMahon BJ. Chronic hepatitis B:update of recommendations. Hepatology,2004,39（3）:857-861.
[32] Liang Y,Jiang J,Su M,et al. Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy. Aliment Pharmacol Ther,2011,34（3）:344-352.
[33] Pan XF,Zhang K,Yang XA,et al. Relapse rate and associated-factor of recurrence after stopping NUCs therapy with different prolonged consolidation therapy in HBeAg positive CHB patients. PLoS One,2013,8（7）:e68568.
[34] LiawYF,Leung N,Guan R,et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2005 update . Liver Int,2005,25（3）:472-489.
[35] Jiang JN,Huang ZL,He LX,et al. Residual amount of HBV DNA in serum is related to relapse in chronic hepatitis B patients after cessation of nucleos（t）ide analogs. J Clin Gastroenterol,2014. [Epub ahead of print]
[36] Jeng WJ,Sheen IS,Chen YC,et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology,2013,58（6）:1888-1896.
[37] Seto WK,Hui AJ,Wong WS,et al. Treatment cessation of entecavir in Asian patientswith hepatitis B e antigen negative chronic hepatitis B:a multicentre prospective study. Gut,2014. [Epub ahead of print]
[38] Song BC,Suh DJ,Lee HC,et al. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology,2000,32（4 Pt 1）:803-806.
[39] Reijnders JG,Perquin MJ,Zhang NP,et al. Nucleos（t）ide analogues only induce temporary hepatitis B e antigenseroconversion in most patients with chronic hepatitis B. Gastroenterology,2010,139（2）:491-498.
[40] Fung SK,Wong F,Hussain M,et al. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat,2004,11（5）:432-438.
[41] Chan HL,Wang H,Niu J,et al. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B:a double-blind,placebo-controlled trial. Antivir Ther,2007,12（3）:345-353.
[42] Hadziyannis SJ,Sevastianos V,Rapti I,et al. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology,2012,143（3）:629-636.
[43] Liu F,Wang L,Li XY,et al. Poor durability of lamivudine effectiveness despite stringent cessation criteria:a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients. J Gastroenterol Hepatol,2011,26（3）:456-460.
[44] Dienstag JL,Goldin RD,Heathcote EJ,et al. Histological outcome during long-term lamivudine therapy. Gastroenterology,2003,124（1）:105-117.
[45] Xu B,Lin LY,Xu GG,et al. Long-term lamivudine treatment achieves regression ofadvanced liver fibrosis/cirrhosis in patients with chronic hepatitis B. JGastroenter Hepatol,2014. [Epub ahead of print]
[46] 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. Gastroenterology,2006,131（6）:1743-1751.
[47] 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. Hepatology,2008,48（3）:750-758.
[48] Liaw YF. Reversal of cirrhosis:an achievable goal of hepatitis B antiviral therapy. J Hepatol,2013,59（4）:880-881.
[49] Schiff ER,Lee SS,Chao YC,et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol,2011,9（3）:274-276
[50] Liaw YF,Raptopoulou-Gigi M,Cheinquer H,et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompesation:a randomized,open-label study. Hepatology,2011,54（1）:91-100.
[51] Liaw YF,Sheen IS,Lee CM,et al. Tenofovir disoproxil fumarate （TDF）,emtricitabine/TDF,and entecavir in patients with decompesated chronic hepatitis B liver disease. Hepatology,2011,53（1）:62-72.
[52] Yuen MF,Seto WK,Chow DH,et al. Long-term lamivudinetherapy reduces the risk of long-term complicationsof chronic hepatitis B infection even in patients without advanced disease. Antivir Ther,2007,12（8）:1295-1303.
[53] Liaw YF,Sung JJ,Chow WC,et al. TheCALM Study Group.Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med,2004,351（15）:1521-1531.
[54] Matsumoto A,Tanaka E,Rokuhara A,et al. The Inuyama Hepatitis Study Group. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B:a multicenter retrospective study of 2795 patients. Hepatol Res,2005,32（3）:173-184.
[55] Di Marco V,Marzano A,Lampertico P,et al. Italian Association for the Study of the Liver（AISF） Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology,2004,40（4）:883-891.
[56] Sung JJ,Tsoi KK,Wong VW,et al. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther,2008,28（9）:1067-1077.
[57] Papatheodoridis GV,Lampertico P,Manolakopoulos S,et al. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos（t）ide therapy:a systematic review. J Hepatol,2010,53（2）:348-356.
[58] Eun JR,Lee HJ,Kim TN,et al. Risk assessment for thedevelopment of hepatocellular carcinoma:according toon-treatment viral response during long-term lamivudinetherapy in hepatitis B virus-related liver disease. J Hepatol,2010,53（1）:118-125.
[59] Su TH,Hu TH,Lin CC,et al. Reduction of hepatocellular carcinoma in hepatitis B related cirrhosis patients with long-term entecavir therapy-an interim report of C-TEAM study. Hepatology,2013,58Suppl 1:301A.
[60] Wu CY,Lin JT,Ho HJ,et al. Association of nucleos（t）ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B-a nationwide cohort study. Gastroenterology,2014,147（1）:143-151.
[61] Kumada T,Toyoda H,Tada T,et al. Effect of nucleos（t）ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients:a propensity score analysis. J Hepatology,2013,58（3）:427-433.
[62] Papatheodoridis GV,Manolakopoulos S,Touloumi G,et al. Virological suppression does not prevent the developmentof hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral（s） starting with lamivudine monotherapy:results of the nationwide HEPNET. Greece cohort study . Gut,2011,60（8）:1109-1116.
[63] Fattovich G,Bortolotti F,Donato F. Natural history of chronic hepatitis B:special emphasis on disease progression and prognostic factors. J Hepatology,2008,48（2）:335-352.
[64] Papatheodoridis G,Manolakopoulos S,Touloumi G,et al. Hepatocellularcarcinoma （HCC） risk in HBeAg-negative chronic hepatitis B （CHBe-） with or without cirrhosis treated with entecavir: results of the nationwide HepNet Greece Cohort Study. J Hepatol,2013, 58Suppl 1:S312.
[65] Lampertico P,Soffredini R,Yurdaydin C,et al. Four years of tenofovir monotherapy for NUC naive field practice European patients suppress HBV replication in most patients with a favourable renal safety profile but do not prevent HCC in patients with or without cirrhosis. Hepatology,2013,58Suppl 1:653A.
[66] Papatheodoridis GV,Dalekos GN,Yurdaydin C,et al. Risk and risk factors of hepatocellular carcinoma（HCC） in Caucasian chronic hepatitis B（CHB） patients with or without cirrhosis treated with entecavir（ETV） or tenofovir（TDF）. Hepatology,2013,58Suppl 1:302A.
[67] Cho JY,Paik YH,Sohn W,et al. Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease . Gut,2014.
[68] Lampertico P,Soffredini R,Vigano M,et al. 5-year entecavir treatment in NUC-naive,field-practice patients with chronic hepatitis B showed excellent viral suppression and safety profile but no prevention of HCC in cirrhosis. J Hepatol,2013,58Suppl 1:S306.
[69] Hosaka T,Suzuki F,Kobayashi M,et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology,2013,58（1）:98-107.
[70] Wong GL,Chan HL,Chan HY,et al. Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment. Gastroenterology,2013,144（5）:933-944.
[71] Kim WR,BergT,Loomb R,et al. Long-term tenofovir disoproxil fumarate therapy and the risk of hepatocellular carcinoma. J Hepatol,2013,58Suppl 1:S19.
[72] Hilleret MN,Larrat S,Stanke-Labesque F,et al. Does adherence to hepatitis B antiviral treatment correlate with virological response and risk of breakthrough J Hepatol,2011,55（6）:1468-1469.
[73] Berg T,Marcellin P,Zoulim F,et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic hepatitis B virus infection. Gastroenterology,2010,139（4）:1207-1217.
[74] World Health Organization. Adherence to long-term therapies: evidence for action[EB/OL]. [2014-08-12]. http://www.who.int/chp/knowledge/publications/adherencefull_report.pdf.
[75] Chotiyaputta W,Peterson C,Ditah FA,et al. Persistence and adherence to nucleos（t）ide analogue treatment for chronic hepatitis B. J Hepatol,2011,54（1）:12-18.
[76] Lee M,Keeffe EB. Study of adherence comes to the treatment of chronic hepatitis B. J Hepatol,2011,54（1）:6-8.
[77] Giang L,Sellinger CP,Lee AU. Evaluation of adherence to oral antiviral hepatitis B treatment using structured questionnaires . World J Hepatol,2012,4（2）:43-49.
[78] 孙秘书,王贵强,张伟,等. 拉米夫定经治慢性乙型肝炎患者治疗现状调查分析. 中国预防医学杂志,2012,13（1）:18-22.
[79] 叶丽华, 胡兆琴, 李正莲. 慢性乙型肝炎患者诊断治疗依从性行为调查. 实用肝脏病杂志,2013,16（2）:155-156.
[80] An P,Bian L,Yin B,et al. Risk factors of gene-resistantmutations in different nucleosides. Hepato-Gastroenterology,2012,59 （113）:228-230.
[81] Zeng MD,Mao YM,Yao GB,et al. Five years of treatment with adefovir dipivoxil in Chinese patients withHBeAg-positive chronic hepatitis B . Liv Int,2012,32（1）:137-146.
[82] Sun J,Xie Q,Tan DM,et al. The 104-week efficacy and safety of telbivudine-based optimization strategy in chronichepatitis B patients:a randomized,controlled study. Hepatology,2014,59（4）:1283-1292.
[83] 参加乙型肝炎耐药讨论会专家. 核苷和核苷酸类药物治疗慢性乙型肝炎的耐药及其管理. 中国病毒病杂志,2013,3（1）:1-11.
[84] Pipili C, Cholongitas E,Papatheodoridis G. Review article: nucleos（t）ide analogues in patients with chronichepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther,2014,39（1）:35-46.
[85] Jung YK,Yeon JE,Choi JH,et al. Fanconi’ssyndrome associated with prolonged adefovir dipivoxil therapy in a hepatitis B virus patient. Gut Liver,2010,4（3）:389-393.
[86] Verhelst D, Monge M,Meynard JL,et al. Fanconi syndrome and renalfailure induced by tenofovir:a first case report. Am J Kidney Dis,2002,40（6）:1331-1333.
[87] Gaspar G,Monereo A,García-Reyne A,et al. Fanconi syndrome and acute renal failure in a patient treated with tenofovir: a call for caution. AIDS,2004,18（2）:351-352.
[88] Pol1 S,Lampertico P. First-line treatment of chronic hepatitis B with entecavir ortenofovir in real-life settings:from clinical trials to clinicalpractice. J Viral Hepat,2012,19（6）:377-386.
[89] Liaw YF,Gane E,Leung N,et al. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology,2009,136（2）:486-495.
[90] Lai CL,Gane E, Liaw YF,et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med,2007,357（25）:2576-2588.
[91] 任江波,王宇,李红艺, 等. 替比夫定治疗慢性乙型肝炎期间肌酸激酶升高的观察与分析. 中华肝脏病杂志,2012,20（9）:641-643.
[92] Chan HL,Wong VW,Tse AM,et al.Serum hepatitis B surfaceantigen quantitation can reflect hepatitis Bvirus in the liver and predict treatment response. Clin GastroenterolHepatol,2007,5（12）:1462-1468.
[93] Ning Q,Han M,Sun Y,et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B:a randomised open-label trial （OSST trial）. J Hepatol,2014.
[94] Xie Q,Zhou HJ,Bai XF,et al. A Randomized,open-label clinical study of combined peginterferon alfa-2a（40KD） and entecavir treatment for HBeAg-positive chronic hepatitis B. Clin Infect Dis,2014.