[AASLD 2012]医脉通 2012-11-16
肝移植后不应用乙肝免疫球蛋白（hepatitis B immune globulin，HBIG）而只应用口服抗病毒药物的远期预后尚不清楚。
来自中国香港大学医学院的一项研究——发表在美国肝病研究学会（AASLD）第63届年会摘要中，报告了大样本慢性乙肝（chronic hepatitis B，CHB）人群接受肝移植后单独应用口服抗病毒药物而未应用HBIG治疗的结果。研究结果表明，口服核苷（酸）类药物而不应用HBIG可以有效防止肝移植后移植肝乙肝复发。然而，新移植者应该将耐药的可能降至最小，以防止病毒学复发。
这项研究共纳入了363名2003年1月-2011年5月进行肝移植的CHB患者。患者均未接受过HBIG治疗。随诊期间规律监测病毒血清水平、病毒载量、肝生化指标。分析病毒学反弹患者的基因变异情况。
具体研究结果
363名患者中在进行肝移植时分别有174例（48%）例接受过拉米夫定（lamivudine，LAM）治疗、142例（39%）接受过恩替卡韦（entecavir，ETV）治疗，47 例（13%）接受过联合治疗（拉米夫定+阿德福韦酯）。移植指征为慢性失代偿（35%）、CHB急性发作（32.5%）、肝细胞癌（32.5%），其中221例（61%）为活体肝移植。中位随访时间为53个月。乙肝病毒DNA处于不可测水平的累积率分别为91.2%（6个月）、95.6%（12个月），三组间无明显差异（p=0.541）。病毒复发率（增加值>1 log）在1、3、5、8年时分别为5%、11%、14%、18%，三组间有明显差异。LAM、ETV、联合治疗组5年病毒复发率分别为20.2%、5%、11%（p=0.001）。LAM组36名患者出现病毒学复发，其中25名出现YMDD变异，应用加用药物治疗的方法。联合治疗组5名患者出现病毒学复发，其中4名出现YMDD变异。ETV组1名患者出现病毒学复制达到282 IU/mL，随后就转为了不可测水平，未出现基因变异。8年总生存率为83%，3组间无明显差异（p=0.98）。随访期间出现44例死亡，乙肝病毒复发相关死亡病例为0。LAM组中1例患者耐药后出现乙肝病毒复制引起纤维化淤胆性肝炎，需要再移植。随访期间，317例存活，其中307例HBV DNA水平不可测（97%）。其余10名患者HBV DNA水平中位值为53 IU/mL，且ALT水平正常。
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研究论文摘要
Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B——long term outcome
Background: The long term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) are not known. This study reports the results from a large population of chronic hepatitis B (CHB) liver transplant recipients treated with a HBIG-free regimen by using oral antiviral therapy alone
Methods: 363 consecutive CHB patients transplanted from Jan 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. Mutational analyses were performed for those with virological rebound.
Results: Of the 363 patients, 174 (48%), 142 (39%) and 47 (13%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM + adefovir) respectively at the time of liver transplant. The indications for transplant were chronic decompensation (35%), acute flare of CHB (32.5%), and hepatocellular carcinoma (32.5%), with 221 (61%) from living donors. The median follow-up length was 53 months. The cumulative rate of HBV DNA suppression to undetectable levels was 91.2% at 6 months and 95.6% at 12 months, with no significant difference between the three treatment groups (p=0.541). The virological relapse rates (defined as >1 log increase IU/mL) at 1, 3, 5, and 8 years were 5%, 11%, 14%, and 18% respectively, with significant differences between the treatment groups. The rebound rate at 5 years for LAM, ETV, and combination group was 20.2%, 5%, and 11% respectively (p=0.001). Thirty six patients had virological relapse in LAM group, of which 25 had YMDD mutation, and were treated with additional therapy. Five patients in the combination group had virological relapse, of which 4 had evidence of YMDD mutation. In the ETV group, one patient developed virological relapse of 282 IU/mL, which subsequently returned to undetectable levels, without evidence of mutation. Overall 8 year survival was 83%, with no difference between the 3 treatment groups (p=0.98). There were 44 deaths during the follow-up period, of which none were due to hepatitis B recurrence. One patient required re-transplantation due to fibrosing cholestatic hepatitis from hepatitis B recurrence in the LAM group due to resistance. At the time last follow-up, 317 were alive with 307 having undetectable HBV DNA (97%). The remaining 10 patients had a low median HBV DNA of 53 IU/mL with normal ALT levels.
Conclusion: Oral nucleoside/nucleotide analogs without HBIG are effective as in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, newer agents should be used to minimize drug resistance and to prevent virological rebound.