1、乙肝肝硬化抗病毒治疗的现乙肝肝硬化抗病毒治疗的现状和思考河南会状和思考河南会 代偿性乙型肝炎肝硬化是HBV感染相关疾病中的特殊人群，但其抗病毒治疗指征、药物选择、疗程、治疗终点、停药指征等均和慢性乙型肝炎普通人群一致，并无特殊，只是抗病毒治疗的指征更宽，停药指征应更严。这里不做讨论，而重点讨论失代偿乙肝肝硬化的抗病毒治疗的有关问题。核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”
2、基本共识：指征、目标、策略Yao FY,et al.Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation:a comparative study using amatched,untreated cohort.HEPATOLOGY 2001;34:411-4162001：美国加州Yao等用拉米夫定治疗23例HBV相关终末期肝病
3、患者，并与55例患者历史对照。拉米夫定治疗患者肝移植需求减少（35%比74%），随访1-44个月无患者死亡。In a study from the University of California San Francisco,Yao and coworkers compared a cohort of 23 patients with HBV-related end-stage liver disease referred for liver transplantation and who were treated with lamivudine,to a group of 55 histor
4、ical controls.The lamivudine-treated patients had markedly improved survival,beginning 6 months after starting lamivudine with a decreased need for liver transplantation(35%versus 74%:P 0.04).Excluding patients who underwent liver transplant,none of the lamivudine-treated patients died(follow-up for
5、 1-44 months)compared to six historical controls(within 3-12 months)(P 0.009).早期探索：药物、疗效、安全Yao FY,et al.Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation:a comparative study using amatche
6、d,untreated cohort.HEPATOLOGY 2001;34:411-416早期探索：药物、疗效、安全2001：Perrillo等用拉米夫定治疗等待肝移植的77例失代偿肝硬化患者，病毒等各项指标好转，且4年生存率70%，明显高于 2项先期报道的约60%和30%。Perrillo and colleagues from multiple liver transplant centers throughout North America treated 77 liver transplant candidates with end-stage chronic hepatitis B
7、with lamivudine(100 mg daily).No control group was used,but results were compared to outcomes in two previously published studies of decompensated cirrhosis due to hepatitis B.HBV DNA levels decreased on lamivudine therapy,but levels were not reported.Alanine aminotransferase(ALT)values decreased an
8、d became normal in more than half of patients with elevations before treatment.Average serum bilirubin,albumin,and prothrombin times improved with treatment.The 4-year survival rate among amivudine-treated patients was 70%,which was higher than historical cohorts(60%and 30%).Lamivudine was well tole
9、rated.Antiviral esistance developed in a proportion of patients,and appearance of resistance was generally followed by reversal of the virological and clinical benefit.Perrillo,et al.A multi-center United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation f
10、or chronic hepatitis B.HEPATOLOGY 2001;33:424-432早期探索：药物、疗效、安全2003：Schiff等报道阿德福韦酯治疗等待肝移植的肝硬化患者128例，48周时HBV DNA下降4.1log、ALT复常率76%、Child-Pugh稳定或改善90%以上、1年存活率84%。肝移植率43%，36%等待移植，21%不需移植，5%死亡。In a third study,Schiff and colleagues from multiple clinical centers in North America,Europe,and Asia treated 1
11、28 patients with HBV-related cirrhosis awaiting liver transplantation with adefovir(10mg daily).Therapy was associated with significant declines in HBV DNA levels(median decline of 4.1 log10 by week 48)and serum aminotransferase levels(normal ALT in 76%by week 48).The Child-Pugh score stabilized or
12、improved in more than 90%of patients and the 1-year survival rate was 84%.A total of 43%of patients underwent liver transplantation,36%were still on the waiting list,21%had been removed from the waiting list,and 5%of patients died without undergoing liver transplantation.Schiff ER,et al.Adefovir dip
13、ivoxil therapy for lamivudine-resistant hepatitis B in pre-and post-liver transplantation patients.HEPATOLOGY 2003;38:1419-1427.早期探索：药物、疗效、安全核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略2007：Schiff等报道,等待肝移植患者226例和肝移植后患者241例在拉米夫定耐药后改阿德福韦酯治疗39-99周，等待肝移植者48周和96周时HBV DNA1,000
14、者为59%和65%。生化和肝功指标同时改善。因不良事件中断治疗者4%，48周、94周、144周耐药发生率0、2%和2%。Wait-listed(n=226)or postliver transplantation(n=241)chronic hepatitis B(CHB)patients with lamivudine-resistant hepatitis B virus(HBV)were treated with adefovir dipivoxil for a median of 39 and 99 weeks,respectively.Among wait-listed patien
15、ts,serum HBV DNA levels became undetectable(1,000 copies/mL)in 59%and 65%at weeks 48 and 96,respectively.After 48 weeks alanine aminotransferase(ALT),albumin,bilirubin,and prothrombin time normalized in 77%,76%,60%,and 84%of wait-listed patients,respectively.Among posttransplantation patients,serum
16、HBV DNA levels became undetectable in 40%and 65%at week 48 and 96,respectively.After 48 weeks,ALT,albumin,bilirubin,and prothrombin time normalized in 51%,81%,76%,and 56%of posttransplantation patients,respectively.Among wait-listed patients who underwent on-study liver transplantation,protection fr
17、om graft reinfection over a median of 35 weeks was similar among patients who did(n=34)or did not(n=23)receive hepatitis B immunoglobulin(HBIg).Hepatitis B surface antigen was detected on the first measurement only in 6%and 9%of patients who did or did not receive HBIg,respectively.Serum HBV DNA was
18、 detected on consecutive visits in 6%and 0%of patients who did or did not receive HBIg,respectively.Treatment-related adverse events led to discontinuation of adefovir dipivoxil in 4%of patients Cumulative probabilities of resistance were 0%,2%,and 2%at weeks 48,96,and 144,respectively.In conclusion
19、,adefovir dipivox is effective and safe in wait-listed or posttransplantation CHB patients with lamivudine-resistant HBV and prevents graft reinfection with or without HBIg.Eugene Schiff,et al.Adefovir Dipivoxil for Wait-Listed and PostLiver Transplantation Patients With Lamivudine-Resistant Hepatit
20、is B:Final Long-Term Results.Liver Transpl 13:349-360,2007当前热点：更优治疗方案选择Eugene Schiff,et al.Adefovir Dipivoxil for Wait-Listed and PostLiver Transplantation Patients With Lamivudine-Resistant Hepatitis B:Final Long-Term Results.Liver Transpl 13:349-360,2007当前热点：更优治疗方案选择 In a study of 79 HBeAg positiv
21、e,treatment-naive patients who completed 104 weeks of a randomized controlled study of lamivudine and placebo versus lamivudine and adefovir,the combination was associated with lower rate of virological breakthrough(19%versus 44%),less antiviral resistant mutations(15%versus 43%),and a higher rate o
22、f ALT normalization(45%versus 34%)than lamivudine alone.The combination did not result in a higher rate ofHBeAg seroconversion than monotherapy(13%versus 20%).Combination therapy does not appear to increase the rate of decline of HBV DNA or result in a more rapid clinical improvement,even in decompe
23、nsated patients.Thus,the major reason for using combination nucleoside analog therapy is to prevent antiviral resistance to one or both of the agents.Sung JJ,et al.Lamivudine compared with lamivudine and adefovir dipivoxil for thetreatment of HBeAg-positive chronic hepatitis B.J Hepatol 2008;48:728-
24、735.2008：Sung等用拉米夫定或拉米夫定联合阿德福韦酯治疗79例HBeAg阳性患者104周，联合组病毒突破率更低（19%比44%），耐药率更低（15%比43%）；HBeAg血清转化率无显著差异（13%比20%），HBV DNA抑制程度和临床改善无差异。联合治疗的理由是预防耐药。当前热点：更优治疗方案选择 2010：韩国Shim等用恩替卡韦治疗失代偿性肝硬化70例，对其中治疗1年时有病毒学应答的55例患者与144例代偿性肝病有病毒学应答者进行比较。治疗1年时免于肝移植者87.1%，Child-Pugh下降至A级者66%（36/55)、Child-Pugh下降2.0分以上者49%(27/5
25、5)。HBV DNA阴转率、生化指标和HBeAg消失率与对照组无差别。Cox回归分析提示，HBeAg阳性患者的应答比阴性患者较低。提示恩替卡韦治疗代偿性与失代偿性肝硬化患者同样有效，安全。J H Shim,et al.Efficacy of entecavir in treatment-nave patients with hepatitis B virus-related decompensated cirrhosis.J Hepatology 2010,52:176182当前热点：更优治疗方案选择Yun-Fan Liaw,et al.EFFICACY AND SAFETY OF ENTEC
26、AVIR VERSUS ADEFOVIR IN CHRONIC HEPATITIS B PATIENTS WITH EVIDENCE OF HEPATIC DECOMPENSATION.HEPATOLOGY,2009,50(SUPPL):505A,poster 422Rates of adverse events,serious adverse events,and discontinuations due to adverse events were comparable between the treatment groups.Death rates through Week 24 for
27、 both ETV and ADV were 12%.当前热点：更优治疗方案选择当前热点：更优治疗方案选择本文报道恩替卡韦治疗16例肝硬化和慢性乙型肝炎患者，其中5例发生乳酸酸中毒。这些患者均有肝功能严重受损，终末期肝病模型评分（Model for End-Stage Liver Disease MELD score）20。乳酸酸中毒(乳酸盐26-200 mg/dL,pH 7.02-7.40,剩余碱-5 mmol/L到-18 mmol/L)发生于恩替卡韦治疗后4-240天。有1例患者的乳酸酸中毒是致命的，另4例在终止恩替卡韦治疗后缓解。其余11例慢性乙型肝炎和肝硬化患者MELD评分均低于18，
28、患者的乳酸盐血清浓度均未升高。MELD 评分及其单个指标胆红素、国际标准化比率和肌酐与乳酸酸中毒的发生相关(P 20).Lactic acidosis(lactate 26-200 mg/dL,pH 7.02-7.40,base excess 5 mmol/L to 18 mmol/L)occurred between 4 and 240 days after treatment initiation with entecavir.Lactic acidosis was lethal in one patient but resolved in the other cases after te
29、rmination/interruption of entecavir treatment.No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18.TheMELD score correlated with the development of lactic acidosi
30、s(P 0.005)as well as its single parameters bilirubin,international normalized ratio,and creatinine.In contrast,Child-Pugh Score did not correlate with the development of lactic acidosis.Our data indicate that entecavir should be applied cautiously in patients with impaired liver function.Christian M
31、.Lange,et al.Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with Entecavir in Patients with Impaired Liver Function.HEPATOLOGY 2009;50:2001-20062009：Liaw等使用替诺福韦、替诺福韦/恩曲赛他平（另2组治疗24周时如HBV DNA400拷贝者也入该组）、恩替卡韦治疗失代偿肝硬化患者45、45、22例。治疗168周设计中的48周初步安全性评估，不能耐受者为6.7%、4.4%、9.1%；肾功指标异常8.9%、6.7%、4
32、.5%；病死率4%、4%、9%，6例肝移植。48周时，维持在原治疗组中患者32例、40例、16例，HBV DNA7和肝硬化或门静脉高压)按基线Child-Pugh评分和ALT水平分层 49例患者继续治疗到4年(数据将在Q3/2010公布)目前可用的是199例随机患者数据 最后数据分析在Q2/2010 统计学分析统计学分析:疗效结果基于ITT人群.漏失数据视为失败(治疗失败,死亡或AE)目前的结果是基于2009年9月完成的初步分析 最终分析将对临床应答(HBV DNA 4 log copies/ml&ALT复常&Child-Pugh 评分稳定或改善)作非劣效性分析 EJ Gane,et al:T
33、REATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)基线人口统计学特征基线人口统计学特征 所有人群所有人群(ITT*)ITT 人群人群替比夫定替比夫定拉米夫定拉米夫定N=114*N=114*平均年龄平均年龄(SD)49.6(10.88)51.9(9.98)男性男性87(76.3)81(71.1)人种人种 亚洲亚洲 n(%)74(64.9)74(6
34、4.9)高加索人高加索人10(8.8)17(14.9)基线基线 HBeAg 状态状态 阴性阴性 n(%)63(55.3%)68(59.6%)基线基线 HBV DNA (Log10 copies/ml)均值均值(SD)7.6(1.91)7.6(1.92)基线基线Child-Pugh评分评分 均值均值(SD)8.1(1.58)8.5(1.76)基线基线 MELD 评分评分 均值均值(SD)14.8(3.7)15.9(4.73)基因型基因型 B/C n(%)74(64.9%)73(64.1%)D n(%)33(28.9%)29(25.4%)*ITT 人群:患者接受至少一次药物治疗和一次基线后的复查
35、EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)初步结果：初步结果：患者分布患者分布(随机人群随机人群*)随机人群随机人群*替比夫定替比夫定N=100*拉米夫定拉米夫定N=99*药物暴露中位数时间(周)104100完成 104周 n/N(%)56/100(56%)47/99(47%)早期终止治疗原因(停药)死亡1
36、2(12)16(16)病毒学突破12(12)16(16)患者,研究者或发起方要求8(8)6(6)依从性差/失访5(4)3(3)不良事件4(4)4(4)肝移植3(3)3(3)治疗失败3(3)4(4)肌酐清除率 30 或透析0(0.0)1(0.9)*随机人群:至少参加基线访视的患者 EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENT
37、ATIONS)治疗治疗104周替比夫定与拉米夫定疗效比较周替比夫定与拉米夫定疗效比较 300copies/mL 4 log10copies/mLp=0.615p=0.6866p=0.7291p=0.4753EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)104周两组患者稳定肝功能作用相似且无肾功能改变*Patie
38、nts who discontinued pre-maturely last on-treatment result is reported.ITT 人群人群替比夫定替比夫定n=98拉米夫定拉米夫定n=97p-值值LS Mean Change SEChild-Pugh评分评分0.40.3-0.60.30.6166MELD 评分评分-0.20.7-1.00.70.3125GFR(Cockroft Gault)0.33.62-4.13.350.2230GFR(MDRD)3.33.26-4.33.070.0223EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV
39、-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)104周替比夫定组与拉米夫定组病死率比较存活率:24周96%替比夫定 91%拉米夫定(p=ns)104周83%替比夫定75%拉米夫定(p=ns)104968472604836241200.00.10.20.30.41.0Week拉米夫定替比夫定0.90.80.70.60.5病死率%EJ Gane,et al:TREATMENT OF DECOMPENS
40、ATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)因SAE/AEs 终止研究药物治疗，两治疗组无差异安全性人群安全性人群*替比夫定替比夫定N=99拉米夫定拉米夫定N=99P-值值死亡死亡 n15(13%)22(19%)0.2198SAEs(包括死亡包括死亡)54(55%)60(61%)0.338 药物相关药物相关2 1(0.9%)0 非药物相关非药物相关253(55%)60(59%)0
41、.3149AE 导致研究终止导致研究终止 4(4%)4(4%)1AE 导致研究药物终止导致研究药物终止 9(9%)10(10%)0.8093 SAEs 与重症肝病严重程度相关 无药物相关性死亡病例2 无横纹肌溶解或乳酸性酸中毒病例报告1 安全性人群:任何接受1剂研究药物的患者 2 研究者判断EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL P
42、RESENTATIONS)替比夫定替比夫定拉米夫定拉米夫定安全性人群安全性人群*N=99*N=99*任何任何 AEs患者患者 n(%)94(94.9)95(96.0)腹水腹水43(43.4)37(37.4)周围性水肿周围性水肿28(28.3)17(17.2)腹胀腹胀22(22.2)12(12.1)发热发热17(17.2)16(16.2)咳嗽咳嗽16(16.2)7(7.1)肝性脑病肝性脑病15(15.2)20(20.2)疲劳疲劳14(14.1)14(14.1)黄疸黄疸14(14.1)10(10.1)凹陷性水肿凹陷性水肿14(14.1)12(12.1)上呼吸道感染上呼吸道感染14(14.1)11(
43、11.1)消化不良消化不良13(13.1)12(12.1)104104周期间两组患者不良事件发生率相似周期间两组患者不良事件发生率相似*安全性人群:任何接受1剂研究药物的患者EJ Gane,et al:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE.J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS)核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状早期探索：药物、疗效、安全当前热点：更优治疗
44、方案选择初步印象：“五不够”基本共识：指征、目标、策略初步印象循证级别不够高；研究人数不够多；治疗时间不够长；设计分组不够严；结论得出不够硬。核苷（酸）类似物治疗失代偿性乙型肝炎肝硬化的现状早期探索：药物、疗效、安全当前热点：更优治疗方案选择初步印象：“五不够”基本共识：指征、目标、策略AASLD指南（指南（2009）推荐意见）推荐意见慢性乙型肝炎的抗病毒治疗慢性乙型肝炎的抗病毒治疗推荐意见推荐意见24.24.失代偿性肝硬化应选快速抑制病毒、耐药失代偿性肝硬化应选快速抑制病毒、耐药风险低的核苷（酸）类似物立即治疗（风险低的核苷（酸）类似物立即治疗（-1-1）。）。1.1.初始治疗时可选拉米夫定
45、或替比夫定联合阿德福韦初始治疗时可选拉米夫定或替比夫定联合阿德福韦酯或替诺福韦酯，以减少耐药风险（酯或替诺福韦酯，以减少耐药风险（-2-2）。）。2.2.也可选恩替卡韦或替诺福韦酯治疗，但尚缺乏治疗也可选恩替卡韦或替诺福韦酯治疗，但尚缺乏治疗失代偿性肝硬化的安全和有效的临床资料（失代偿性肝硬化的安全和有效的临床资料（）。）。3.3.失代偿性肝硬化治疗应与肝脏移植中心协同进行失代偿性肝硬化治疗应与肝脏移植中心协同进行（）。）。4.4.不应选普通或聚乙二醇干扰素不应选普通或聚乙二醇干扰素治疗（治疗（-3-3）。）。LOK AND MCMAHON.HEPATOLOGY,Vol.50,No.3,200
46、9;LOK AND MCMAHON.www.aasld.org AASLD指南（指南（2009）推荐意见）推荐意见慢性乙型肝炎的抗病毒治疗慢性乙型肝炎的抗病毒治疗推荐意见推荐意见32.32.核苷（酸）类似物的疗程。核苷（酸）类似物的疗程。1.HBeAg1.HBeAg阳性者治疗到阳性者治疗到HBeAgHBeAg血清转换，继续治疗至少血清转换，继续治疗至少6 6个月（个月（）。停药后密切监测（）。停药后密切监测（）。）。2.HBeAg2.HBeAg阴性患者，应持续治疗直至阴性患者，应持续治疗直至HBsAgHBsAg清除（清除（）。）。3.3.代偿性肝硬化患者应长期治疗。代偿性肝硬化患者应长期治疗。
47、HBeAgHBeAg阳性患者治阳性患者治疗到疗到HBeAgHBeAg血清转换，并在巩固治疗至少血清转换，并在巩固治疗至少6 6个月后个月后或者或者HBeAgHBeAg阴性患者治疗到阴性患者治疗到HBsAgHBsAg清除（清除（-3-3）。）。停药后必须密切监测是否复发和肝炎发作。停药后必须密切监测是否复发和肝炎发作。4.4.失代偿性肝硬化和肝移植后复发者，应终生治疗。失代偿性肝硬化和肝移植后复发者，应终生治疗。LOK AND MCMAHON.HEPATOLOGY,Vol.50,No.3,2009;LOK AND MCMAHON.www.aasld.org 建议4.11.2：失代偿性肝硬化应当在
48、肝病专科治疗，抗病毒治疗同时可根据患者具体情况考虑肝移植。只要能检出HBV DNA的患者，都应立即抗病毒治疗，应当选用强效和低耐药的核苷（酸）类似物，如恩替卡韦或替诺福韦治疗，但关于这些药物的安全性尚需进一步研究（B1）。4.11.2.Patients with decompensated cirrhosis should be treated in specialized liver units,as the application of antiviral therapy is complex,and these patients may be candidates for liver t
49、ransplantation.End-stage liver disease should be treated as a matter of urgency.Treatment is indicated even if HBVDNA level is low in order to prevent recurrent reactivation.Potent NUCs with good resistance profiles(entecavir or tenofovir)should be used.However,there are little data for the safety o
50、f these agents in decompensated cirrhosis.(B1)European Association for the Study of the Liver.EASL Clinical Practice Guidelines:Management of chronic hepatitis B.J Hepatology，2009，50:227-242Yun-Fan Liaw,et al.Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2008 update He
