肝移植术后HBV再感染的治疗

Management of hepatic HBV reinfection after liver transplantation

目的分析肝移植术后乙型肝炎病毒(HBV)再感染患者的抗病毒治疗与乙肝病毒基因变异情况。方法317例HBV相关终末期肝病患者肝移植术后15例单独使用LAM,302例使用小刺量乙肝免疫球蛋白(hepatitis B immune globulin,HBIG)和拉米夫定(lamivudine,LAM)(或adefovir dipivoxil,ADV)联合预防HBV再感染,同时检测HBV血清标志物、血清HBV DNA、YMDD区变异、及肝活检组织乙型肝炎标记物。结果术后LAM组有4例术前HBV DNA阳性患者术后HBV再感染,LAM+HBIG联合用药组16例HBV再感染,两组术后HBV再感染差异有统计学意义(26．7％vs．5．30％,P<0．01)。317例患者术后12例发生YMDD变异,发生率为3．79％,再感染病例60％(12／20)。经加用ADV治疗后5例HBV DNA转阴性,4名患者HBV DNA滴度下降,肝功能显著改善,3例发生纤维淤胆性肝炎,2例死亡,1例经再次肝移植治愈。结论小剂量HBIG+LAM可以有效地预防肝移植术后HBV再感染;在小剂量HBIG+LAM用药基础上HBV再感染可能产生YMDD(tyrosine,methionine,aspartate,aspartate)变异;ADV可作为LAM耐药后用药,对于发生突破性感染的患者应采取以ADV为主的综合治疗。

Objective To study the effect of antivirus therapy of HBV reinfection and YMDD mutation after liver transplantation. Methods Fifteen of 317 patients with HBV-related end-stage liver diseases received lamivudine （LAM） monothereapy, others received combination low-dose hepatitis B immune globulin （HB1G） and LAM （ or adefovir dipivoxil, ADV ） therapy, as prophylaxis against HBV reinfection after OLT. Hepatitis serum markers, HBsAg, HBeAg, HBcAb-IgM, and HBcAg were detected every 2 weeks by immunohistochemistry. Serum HBV DNA was examined by PCR every 2 weeks. HBsAg and HBcAg in the liver specimens were examined by immunohistochemistry. YMDD mutation was detected by PCR in those patients with recurrence of positive HBV DNA posttransplantation. Results In LAM monotherapy group, 4 developed HBV reinfection out of 15 patients with pretreatment positve HBV DNA. Sixteen of 302 patients with combination HBIG and LAM therapy suffered from posttransplant HBV reinfection, the difference between the two groups was significant （26.7% vs. 5.30%, P 〈 0.01 ）. The positive rates of YMDD mutation were 3.79% （12/317）. Treated with ADV, 5 of 12 liver transplant recipients with YMDD mutation became HBV DNA negative, and HBV DNA titer decreased in the other 4 patients with liver function improved, and 2 died of fibrosing cholestatic hepatitis（FCH） , and one underwent liver retransplantation. Conclnsion Our preliminary data suggest that this combination prophylaxis with low dose HBIG and LAM is effective; liver transplant recipients with recurrent HBV infection on combination low dose HBIG and LAM treatment are associated with YMDD mutations. ADV effective for liver transplant recipients with LAM-resistant HBV reinfection.