乙肝肝硬化抗病毒治療的現(xiàn)狀和思考河南會(huì)

1、失代償性乙型肝炎肝硬化抗病毒治療的現(xiàn)狀與思考,上海長(zhǎng)海醫(yī)院感染科萬(wàn)謨彬2010.9.25 鄭州,代償性乙型肝炎肝硬化是HBV感染相關(guān)疾病中的特殊人群，但其抗病毒治療指征、藥物選擇、療程、治療終點(diǎn)、停藥指征等均和慢性乙型肝炎普通人群一致，并無(wú)特殊，只是抗病毒治療的指征更寬，停藥指征應(yīng)更嚴(yán)。這里不做討論，而重點(diǎn)討論失代償乙肝肝硬化的抗病毒治療的有關(guān)問(wèn)題。,核苷（酸）類(lèi)似物治療失代償性乙型肝炎肝硬化的現(xiàn)狀,早期探索：藥物、療效、安全

2、當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識(shí)：指征、目標(biāo)、策略,核苷（酸）類(lèi)似物治療失代償性乙型肝炎肝硬化的現(xiàn)狀,早期探索：藥物、療效、安全當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識(shí)：指征、目標(biāo)、策略,Yao FY, et al. Lamivudine treatment is bene?cial in patients with severely decompensated cirrhosis and

3、 actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using amatched, untreated cohort. HEPATOLOGY 2001;34:411-416,2001：美國(guó)加州Yao等用拉米夫定治療23例HBV相關(guān)終末期肝病患者，并與55例患者歷史對(duì)照。拉米夫定治療患者肝移植需求減少

4、（35%比74%），隨訪(fǎng)1-44個(gè)月無(wú)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

5、 were treated with lamivudine, to a group of 55 historical controls. The lamivudine-treated patients had markedly improved survival, beginning 6 months after starting lamivudine with a decreased need for liver transplant

6、ation (35% versus 74%: P ＜0.04). Excluding patients who underwent liver transplant, none of the lamivudine-treated patients died (follow-up for 1-44 months) compared to six historical controls (within 3-12 months) (P ＜ 0

7、.009).,早期探索：藥物、療效、安全,Yao FY, et al. Lamivudine treatment is bene?cial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study u

8、sing amatched, untreated cohort. HEPATOLOGY 2001;34:411-416,早期探索：藥物、療效、安全,2001：Perrillo等用拉米夫定治療等待肝移植的77例失代償肝硬化患者，病毒等各項(xiàng)指標(biāo)好轉(zhuǎn)，且4年生存率70%，明顯高于 2項(xiàng)先期報(bào)道的約60%和30%。,Perrillo and colleagues from multiple liver transplant centers th

9、roughout North America treated 77 liver transplant candidates with end-stage chronic hepatitis B with lamivudine (100 mg daily). No control group was used, but results were compared to outcomes in two previously publishe

10、d 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 and became normal in more than half o

11、f 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 histo

12、rical cohorts (~60% and 30%). Lamivudine was well tolerated. Antiviral esistance developed in a proportion of patients, and appearance of resistance was generally followed by reversal of the virological and clinical bene

13、?t.,Perrillo , et al. A multi-center United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. HEPATOLOGY 2001;33:424-432,早期探索：藥物、療效、安全,2003：Schiff等報(bào)道阿德

14、福韋酯治療等待肝移植的肝硬化患者128例，48周時(shí)HBV DNA下降4.1log、ALT復(fù)常率76%、Child-Pugh穩(wěn)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 tre

15、ated 128 patients with HBV-related cirrhosis awaiting liver transplantation with adefovir (10mg daily). Therapy was associated with signi?cant declines in HBV DNA levels (median decline of 4.1 log10 by week 48) and serum

16、 aminotransferase levels (normal ALT in 76% by week 48). The Child-Pugh score stabilized or improved in more than 90% of patients and the 1-year survival rate was 84%. A total of 43% of patients underwent liver transplan

17、tation, 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 dipivoxil therapy for lamivudine-resist

18、ant hepatitis B in pre-and post-liver transplantation patients. HEPATOLOGY 2003;38:1419-1427.,早期探索：藥物、療效、安全,核苷（酸）類(lèi)似物治療失代償性乙型肝炎肝硬化的現(xiàn)狀,早期探索：藥物、療效、安全當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識(shí)：指征、目標(biāo)、策略,2007：Schiff等報(bào)道,等待肝移植患者226例和肝移植后患者

19、241例在拉米夫定耐藥后改阿德福韋酯治療39-99周，等待肝移植者48周和96周時(shí)HBV DNA<1,000者為59%和65%。生化和肝功指標(biāo)同時(shí)改善。因不良事件中斷治療者4%，48周、94周、144周耐藥發(fā)生率0、2%和2%。,Wait-listed (n= 226) or post–liver transplantation (n= 241) chronic hepatitis B (CHB) patients with la

20、mivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (<1,000 copies/mL) in

21、 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 pos

22、ttransplantation patients, serum 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 po

23、sttransplantation patients, respectively. Among wait-listed patients who underwent on-study liver transplantation, protection from graft reinfection over a median of 35 weeks was similar among patients who did (n= 34) or

24、 did not (n= 23)receive hepatitis B immunoglobulin (HBIg). Hepatitis B surface antigen was detected on the ?rst measurement only in 6% and 9% of patients who did or did not receive HBIg, respectively. Serum HBV DNA was d

25、etected 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 probabiliti

26、es of resistance were 0%, 2%, and 2% at weeks 48, 96, and 144, respectively. In conclusion, adefovir dipivox is effective and safe in wait-listed or posttransplantation CHB patients with lamivudine-resistant HBV and prev

27、ents graft reinfection with or without HBIg.,Eugene Schiff,et al. Adefovir Dipivoxil for Wait-Listed and Post–Liver Transplantation Patients With Lamivudine-Resistant Hepatitis B: Final Long-Term Results. Liver Transpl 1

28、3:349-360, 2007,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,,,Eugene Schiff,et al. Adefovir Dipivoxil for Wait-Listed and Post–Liver Transplantation Patients With Lamivudine-Resistant Hepatitis B: Final Long-Term Results. Liver Transpl 13:349-360, 20

29、07,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,,In a study of 79 HBeAg positive, treatment-naive patients who completed 104 weeks of a randomized controlled study of lamivudine and placebo versus lamivudine and adefovir, the combination was associate

30、d with lower rate of virological breakthrough (19% versus 44%), less antiviral resistant mutations (15% versus 43%), and a higher rate of ALT normalization (45% versus 34%) than lamivudine alone. The combination did not

31、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 dec

32、ompensated 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 adefovi

33、r dipivoxil for thetreatment of HBeAg-positive chronic hepatitis B. J Hepatol 2008;48:728-735.,2008：Sung等用拉米夫定或拉米夫定聯(lián)合阿德福韋酯治療79例HBeAg陽(yáng)性患者104周，聯(lián)合組病毒突破率更低（19%比44%），耐藥率更低（15%比43%）；HBeAg血清轉(zhuǎn)化率無(wú)顯著差異（13%比20%），HBV DNA抑制程度和臨床改善無(wú)差

34、異。聯(lián)合治療的理由是預(yù)防耐藥。,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,2010：韓國(guó)Shim等用恩替卡韋治療失代償性肝硬化70例，對(duì)其中治療1年時(shí)有病毒學(xué)應(yīng)答的55例患者與144例代償性肝病有病毒學(xué)應(yīng)答者進(jìn)行比較。治療1年時(shí)免于肝移植者87.1%，Child-Pugh下降至A級(jí)者66%（36/55)、 Child-Pugh下降2.0分以上者49%(27/55)。HBV DNA陰轉(zhuǎn)率、生化指標(biāo)和HBeAg消失率與對(duì)照組無(wú)差別。Cox回歸分析提示，H

35、BeAg陽(yáng)性患者的應(yīng)答比陰性患者較低。提示恩替卡韋治療代償性與失代償性肝硬化患者同樣有效，安全。,J H Shim, et al. Ef?cacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatology 2010, 52:176–182,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,

36、Yun -Fan Liaw, et al. EFFICACY AND SAFETY OF ENTECAVIR VERSUS ADEFOVIR IN CHRONIC HEPATITIS B PATIENTS WITH EVIDENCE OF HEPATIC DECOMPENSATION. HEPATOLOGY, 2009,50(SUPPL):505A,poster 422,Rates of adverse events, serious

37、 adverse events, and discontinuations due to adverse events were comparable between the treatment groups. Death rates through Week 24 for both ETV and ADV were 12%.,,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,本文報(bào)道恩替卡韋治療16例肝硬化和慢性乙型肝炎患者，

38、其中5例發(fā)生乳酸酸中毒。這些患者均有肝功能?chē)?yán)重受損，終末期肝病模型評(píng)分（Model for End-Stage Liver Disease [MELD] score）≥ 20。乳酸酸中毒(乳酸鹽26-200 mg/dL, pH 7.02-7.40, 剩余堿-5 mmol/L到-18 mmol/L) 發(fā)生于恩替卡韋治療后4-240天。有1例患者的乳酸酸中毒是致命的，另4例在終止恩替卡韋治療后緩解。其余11例慢性乙型肝炎和肝硬化患者M(jìn)ELD

39、評(píng)分均低于18，患者的乳酸鹽血清濃度均未升高。MELD 評(píng)分及其單個(gè)指標(biāo)膽紅素、國(guó)際標(biāo)準(zhǔn)化比率和肌酐與乳酸酸中毒的發(fā)生相關(guān)(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 wit

40、h entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with

41、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 acidosis (P < 0.005) as well as its single para

42、meters 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

43、patients with impaired liver function.,Christian M. Lange, et al. Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with Entecavir in Patients with Impaired Liver Function. HEPATOLOGY 2009;50:2001-2006,2009：

44、Liaw等使用替諾福韋、替諾福韋/恩曲賽他平（另2組治療24周時(shí)如HBV DNA≥400拷貝者也入該組）、恩替卡韋治療失代償肝硬化患者45、45、22例。治療168周設(shè)計(jì)中的48周初步安全性評(píng)估，不能耐受者為6.7%、4.4%、9.1%；腎功指標(biāo)異常8.9%、6.7%、4.5%；病死率4%、4%、9%，6例肝移植。48周時(shí)，維持在原治療組中患者32例、40例、16例，HBV DNA<400拷貝者71%、88%、73%；HBeAg消

45、失/轉(zhuǎn)換者21%/21%、27%/13%、0/0。各治療組均有效和安全，聯(lián)合治療更優(yōu)。,Yun-Fan Liaw, et al. INTERIM RESULTS OF A DOUBLE-BLIND, RANDOMIZED PHASE 2 STUDY OF THE SAFETY OF TENOFOVIR DISOPROXIL FUMARATE, EMTRICITABINE PLUS TENOFOVIR DISOPROXIL FUMARAT

46、E, AND ENTECAVIR IN THE TREATMENT OF CHRONIC HEPATITIS B SUBJECTS WITH DECOMPENSATED LIVER DISEASE. HEPATOLOGY. 2009,50(SUPPL):409A,poster 222,當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,替比夫定對(duì)照拉米夫定治療失代償性慢性乙型肝炎肝硬化隨機(jī)雙盲試驗(yàn),當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇,EJ Gane, et al

47、:TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS: FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),研究設(shè)計(jì),目的:評(píng)估替比夫定對(duì)照拉米夫定治療失代償性乙型肝炎肝硬化患者的臨床和病毒學(xué)療效,,,,,,雙盲治療,Days -35

48、 to -4,52 周 104 周,共隨訪(fǎng)4個(gè)月,拉米夫定 100 mg + 安慰劑,替比夫定600 mg + 安慰劑,篩選,n = 116,n = 116,,,,,,,EJ Gane, et al :TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS: FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVU

49、DINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),患者人群和統(tǒng)計(jì)學(xué)方法,患者人群: 232 例失代償性CHB患者 (Child-Pugh評(píng)分 >7和肝硬化或門(mén)靜脈高壓) 按基線(xiàn)Child-Pugh評(píng)分和ALT水平分層49例患者繼續(xù)治療到4年 (數(shù)據(jù)將在Q3/2010公布)目前可用的是199例隨機(jī)患者數(shù)據(jù)最后數(shù)據(jù)分析在Q2/2010 統(tǒng)計(jì)學(xué)分析:

50、 療效結(jié)果基于ITT人群. 漏失數(shù)據(jù)視為失敗 (治療失敗, 死亡或AE)目前的結(jié)果是基于2009年9月完成的初步分析 最終分析將對(duì)臨床應(yīng)答 (HBV DNA <4 log copies/ml & ALT復(fù)常&Child-Pugh 評(píng)分穩(wěn)定或改善)作非劣效性分析,,EJ Gane, et al :TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS: FROM 2-

51、YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),基線(xiàn)人口統(tǒng)計(jì)學(xué)特征 所有人群 (ITT*),,* ITT 人群: 患者接受至少一次藥物治療和一次基線(xiàn)后的復(fù)查,EJ Gane, et al :TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:

52、 FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),初步結(jié)果：患者分布(隨機(jī)人群*),* 隨機(jī)人群: 至少參加基線(xiàn)訪(fǎng)視的患者,EJ Gane, et al :TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS: FROM 2-YE

53、ARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),治療104周替比夫定與拉米夫定療效比較,,<300copies/mL,<4 log10copies/mL,p=0.615,p=0.6866,p=0.7291,p=0.4753,EJ Gane, et al :TREATMENT OF

54、DECOMPENSATED HBV-CIRRHOSIS:RESULTS: FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),104周兩組患者穩(wěn)定肝功能作用相似且無(wú)腎功能改變*,*Patients who discontinued pre-maturely last on-tr

55、eatment result is reported.,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),104周替比夫定組與拉米夫定組病死率比較

56、,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),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

57、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,104,96,84,72,60,48,36,24,12,0,0.0,0.1,0.2,0.3,0.4,1.0,Week,拉米夫定,替比夫定,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0.9,0.8,0.7,0.6,0.5,,病死率 %,EJ Gane, et al :TREATMENT OF DECOMPENSATED HBV-CIRRHOSIS:RESULTS:

58、 FROM 2-YEARS RANDOMIZED TRIAL WITH TELBIVUDINE OR LAMiVUDINE. J HEPATOLOGY 2010,52:S4(ORAL PRESENTATIONS),因SAE /AEs 終止研究藥物治療，兩治療組無(wú)差異,SAEs 與重癥肝病嚴(yán)重程度相關(guān)無(wú)藥物相關(guān)性死亡病例2無(wú)橫紋肌溶解或乳酸性酸中毒病例報(bào)告,,1 安全性人群: 任何接受1劑研究藥物的患者 2 研究者判斷,EJ Gan

59、e, 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周期間兩組患者不良事件發(fā)生率相似,*安全性人群: 任何接受1劑研究藥物的患者,EJ Gane, et

60、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）類(lèi)似物治療失代償性乙型肝炎肝硬化的現(xiàn)狀,早期探索：藥物、療效、安全當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇初步印象：“

61、五不夠”基本共識(shí)：指征、目標(biāo)、策略,初步印象,循證級(jí)別不夠高；研究人數(shù)不夠多；治療時(shí)間不夠長(zhǎng)；設(shè)計(jì)分組不夠嚴(yán)；結(jié)論得出不夠硬。,核苷（酸）類(lèi)似物治療失代償性乙型肝炎肝硬化的現(xiàn)狀,早期探索：藥物、療效、安全當(dāng)前熱點(diǎn)：更優(yōu)治療方案選擇初步印象：“五不夠”基本共識(shí)：指征、目標(biāo)、策略,AASLD指南（2009）推薦意見(jiàn),慢性乙型肝炎的抗病毒治療推薦意見(jiàn)24.失代償性肝硬化應(yīng)選快速抑制病毒、耐藥風(fēng)險(xiǎn)低的核苷（酸）類(lèi)似物立即治療

62、（Ⅱ-1）。1.初始治療時(shí)可選拉米夫定或替比夫定聯(lián)合阿德福韋酯或替諾福韋酯，以減少耐藥風(fēng)險(xiǎn)（Ⅱ-2）。2.也可選恩替卡韋或替諾福韋酯治療，但尚缺乏治療失代償性肝硬化的安全和有效的臨床資料（Ⅲ）。3. 失代償性肝硬化治療應(yīng)與肝臟移植中心協(xié)同進(jìn)行（Ⅲ）。4.不應(yīng)選普通或聚乙二醇干擾素α治療（Ⅱ-3）。,LOK AND MCMAHON. HEPATOLOGY, Vol. 50, No.3, 2009; LOK AND MCMAHON

63、. www.aasld.org,AASLD指南（2009）推薦意見(jiàn),慢性乙型肝炎的抗病毒治療推薦意見(jiàn)32.核苷（酸）類(lèi)似物的療程。1.HBeAg陽(yáng)性者治療到HBeAg血清轉(zhuǎn)換，繼續(xù)治療至少6個(gè)月（Ⅰ）。停藥后密切監(jiān)測(cè)（Ⅰ）。2.HBeAg陰性患者，應(yīng)持續(xù)治療直至HBsAg清除（Ⅰ）。3.代償性肝硬化患者應(yīng)長(zhǎng)期治療。HBeAg陽(yáng)性患者治療到HBeAg血清轉(zhuǎn)換，并在鞏固治療至少6個(gè)月后或者HBeAg陰性患者治療到HBsAg清除（Ⅱ-

64、3）。停藥后必須密切監(jiān)測(cè)是否復(fù)發(fā)和肝炎發(fā)作。4.失代償性肝硬化和肝移植后復(fù)發(fā)者，應(yīng)終生治療。,LOK AND MCMAHON. HEPATOLOGY, Vol. 50, No.3, 2009; LOK AND MCMAHON. www.aasld.org,建議4.11.2：失代償性肝硬化應(yīng)當(dāng)在肝病專(zhuān)科治療，抗病毒治療同時(shí)可根據(jù)患者具體情況考慮肝移植。只要能檢出HBV DNA的患者，都應(yīng)立即抗病毒治療，應(yīng)當(dāng)選用強(qiáng)效和低耐藥的核苷（酸）

65、類(lèi)似物，如恩替卡韋或替諾福韋治療，但關(guān)于這些藥物的安全性尚需進(jìn)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 candidate

66、s for liver transplantation. 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 resista

67、nce pro?les (entecavir or tenofovir) should be used. However, there are little data for the safety of these agents in decompensated cirrhosis. (B1),European Association for the Study of the Liver. EASL Clinical Practice

68、Guidelines: Management of chronic hepatitis B. J Hepatology，2009，50:227-242,Yun-Fan Liaw ,et al. Asian-Paci?c consensus statement on the management of chronic hepatitis B: a 2008 update Hepatol Int (2008) 2:263–283,,Asi