低剂量乙肝免疫球蛋白与拉米夫定长期联用预防肝移植后HBV复发

Low-dose intra-muscular hepatitis B immunoglobulin combined with lamivudine for long-term prophylaxis of hepatitis B recurrence after liver transplantation

目的:评价长期低剂量HBIgim联用LAM预防急慢性HBV相关性终末期肝病OLT后HBV复发的效能.方法:肝移植患者173例,根据OLT后接受的抗病毒预案分成3组,LAM组(n=2)、HBIg+LAM组(n=168)和阿德福韦组(ADF,n=3).所有OLT受者术前至少接受1-2wkLAM治疗.施药剂量,LAM100mg/d,阿德福韦10mg/d.术中和术后1wk内,HBIg每日静脉给予(HBVDNA>108copies/L,总量10000U;否则总量5000U);此后imHBIg400U/次,并根据血中HBsAb滴度调整im间隔时间.1mo内维持HBsAb滴度>300U/L;3mo内HBsAb滴度>200U/L;超过3moHBsAb滴度>100U/L.定期检测肝功能、血清HBV标志物,必要时穿刺肝组织免疫组化检查.平均随访20.8±14mo.统计3种预案HBV复发的例数并分析原因;与国外同期研究结果比较.结果:4例HBV复发.LAM组1例HBV复发,术后1wkHBsAg(+),术后2moHBV(+),伴ALT升高,诊断LAM药物耐受;术后8mo死于多器官功能衰竭.HBIg+LAM组3例HBV复发,分别出现在12d,12mo和1.5mo;3例患者术前HBV-DNA>108copies/L.第1例术后血中HBeAg和HBVDNA持续(+),血中HBsAb滴度远低于有效预防浓度,诊断HBIg治疗失败,术后11mo死于爆发性肝炎.第2例成为乙肝携带者,术后15mo死于肿瘤复发.第3例HBV复发后改用HBIg+阿德福韦治疗,术后5.5moHBsAg(-),目前肝功能正常.第2和第3例可能存在HBV逃逸突变.阿德福韦组受者随访期间无HBV复发.HBIg+LAM预案,HBV相关性终末期肝病OLT后HBV复发率为1.8%(3/168);所有患者imHBIg耐受性好.OLT后HBV复发率与国外肝移植部比较,两者无统计学意义(χ2=0.28037),预防费用3000-4000＄/a.结论:长期低剂量HBIgim联用LAM可以有效预防HBV相关性终末期肝病OLT后的HBV复发,费用相对低.阿德福韦治疗HBV-YMDD变异株有效,可能是预防HBV复发的更有效因子.

AIM： To evaluate the efficacy of long-term, lowdose intra-muscular hepatitis B immunoglobulin （HBIg） combined with lamivudine （LAM） in patients who received orthotopic liver transplants （OLT） and have been followed up for acute or chronic HBV-related end-stage liver disease. METHODS： The liver transplantation recipients （n = 173） who have been followed up and received antiviral prophylaxis post-OLT were divided into 3 sub-groups according to their post-OLT antiviral therapy, which were group A （LAM monotherapy, n = 2）, group B （HBIg and LAM therapy, n = 168） and group C （HBIg and ADF therapy n =3）. All the patients received LAM treatment for 1 or 2 wk ahead of OLT. Either LAM （100 mg） or ADF （adefovir dipivoxil, 10 mg） was administered orally every day. HBIg were administered intravenously during the first post-operative week （total 5000 or 10 000 U according to HBV copies/L pre-operative） and intramuscularly thereafter （400 U per time, the interval can be adjusted according to HBsAb titer in the blood） to maintain an HBsAb titer 〉 300 U/L within 1 too, 〉 200 U/L between 2-3 mo and 〉 100 U/L beyond 3 mo after operation. Mean follow-up period was 20.8 ± 14 mo. The periodical investigation for the liver function, the serological HBV and the analyses of liver tissues by immunohistochemistry were performed. The recurrent HB and the death suffered from it were recorded and analyzed in this research. The recurrence rates of HBV infection between UCLA and our institute were statistically analyzed. RESULTS： Four patients experienced HBV recurrence overall. One patient in group A experienced HBV recurrence （1 week after OLT） and positive HBV DNA （2 months after OLT） associated with an increase in serum alanine aminotransferase. The treatment resistance of LAM was defined and the recipient died of the multiple organ failure 8 months after OLT. Recurrent HBV appeared in 3 patients, whose HBV DNA levels in the pre-OLT blood were more than 108 copies/L, in group B （12 d, 12 mo and 1.5 mo after OLT respectively）. The pre- and postoperative HBeAg and HBV DNA were always positive in the first case whose blood HBsAb titer was far lower than programming effective one. The treatment resistance of HBIg was de- fined and the patient died of fulminant hepatitis 11 mo after OLT. The second case became an HBsAg carrier after HBV recurrence and was dead due to tumor recurrence 15 mo after OLT. The third case was fine with the treatment of HBIg combined with ADF and was negative for HBsAg after 5.5 mo. The HBV mutation might exist in both of the second and third case. None of group C had HBV recurrence. The HBV recurrence rate under the prophylaxis of HBIg combined with LAM was 1.8% （3/168）. Intra-muscular HBIg was tolerated well in all the cases. The study showed no difference between UCLA and our institute （X^2 = 0.280 37）, and the expenditure was 3000-4000 US dollars per year. CONCLUSION： The low-dose intra-muscular HBIg combined with LAM is efficacious in the long-term prophylaxis of hepatitis B recurrence after OLT. The total expenditure of prophylaxis is lower. ADF shows efficacy against the HBV- YMDD lamivudine-resistant mutation and may be a more efficacious agent for the prophylaxis of HBV recurrence after OLT.