肝移植术后乙型肝炎复发的预防和治疗

目的探讨拉米夫定联合低剂量乙型肝炎（乙肝）免疫球蛋白（HBIG）预防肝移植术后乙肝复发的效果及乙肝复发后的治疗。方法对2000年12月至2003年5月因乙肝相关性终末期肝病和（或）合并肝细胞癌于我院接受肝移植手术并经随访的11例患者进行回顾性分析。所有患者均接受拉米夫定联合低剂量HBIG预防乙肝复发方案。观察术后近期乙肝转阴情况、术后较远期乙肝复发情况以及乙肝复发后的治疗情况。结果（1）所有患者HBsAg、HBeAg、HBV-DNA均于术后1-4d转为阴性,术后1周所有患者对HBIG均有反应,HBsAb滴度水平逐渐上升;（2）所有患者于观察期内生存情况均良好,对患者HBsAb滴度水平定期进行监测结果示大部分患者HBsAb滴度水平与预期治疗水平基本符合;（3）1例患者于术后25个月乙肝复发,通过改用阿德弗韦并加大HBIG用量,基本得到控制。结论拉米夫定联合低剂量HBIG预防肝移植后乙肝复发疗效确切,而且可显著降低治疗费用。     

乙型肝炎疫苗在预防肝移植术后乙型肝炎再感染中的应用

肝移植术后乙型肝炎（乙肝）再感染是影响肝移植预后的主要因素之一。乙肝免疫球蛋白（HBIG）及拉米夫定的应用已使乙肝相关性肝病成为肝移植的适应证。但是，HBIG及拉米夫定用于预防肝移植后乙肝复发存在不少缺点。同时非乙肝相关性肝病的受者也可以通过输血、供肝及其他途径感染乙肝。因此，寻找更经济、有效、安全可靠、更具潜力的预防策略，减少或停用HBIG及拉米夫定，成为学者们的研究目标，而乙肝疫苗即是研究热点之一。因此，笔者对就近年来乙肝疫苗用于预防肝移植术后乙肝再感染的研究作一简要综述。     

肝移植术后乙型肝炎复发的回顾性分析

目的:回顾性分析肝移植术后乙型肝炎(乙肝)复发的发病及防治情况.方法:对我院1994年5月～2003年3月因乙肝相关性终末期肝病接受肝移植手术病人进行回顾性分析,调查其术前、术后乙肝相关检查及复发情况.结果:在351例病人中,围手术期(术后30 d以内)因感染、多脏器功能衰竭等各种原因而死亡的病人59例.生存>30 d的292例病人中有19例出现乙肝复发,乙肝复发率为6.51%(19/292),其中未使用任何预防措施的7例病人中,复发率为71.43%(5/7);单用拉米夫定的15例病人中,复发率为13.33%(2/15),拉米夫定联合低剂量乙肝免疫球蛋白(HBIG)的270例病人中,复发率为4.44%(12/270).3组病人复发率比较具有统计学差异(P<0.001).乙肝复发时间在0.3～66.6个月(中位值为6.1个月);复发后采取加用或改用阿德福韦(Adefovir)或恩替卡韦(Enticavir)等措施,疾病得到控制.结论:核苷类似物联合低剂量HBIG的应用能有效预防肝移植术后乙肝复发,及时发现及治疗可改善乙肝复发病人预后.定期监测术后长期生存病人的乙肝标记物及HBV-DNA十分重要.     

原位肝移植术后乙型肝炎病毒再感染的预防(附68例报告)

目的探讨原位肝移植术后乙型肝炎病毒(HBV)再感染的预防。方法68例病人分别为慢性乙型重型肝炎、终末期肝硬化和肝硬化合并肝癌病人,移植前后给予抗病毒药物预防HBV再感染,拉米夫定2例,拉米夫定加乙型肝炎免疫球蛋白(HBIG)63例,阿德夫韦加HBIG3例;观察预防性治疗后的临床表现、血清HBV、HBVDNA及肝活检免疫组织化学法检测等指标。结果应用拉米夫定的2例病人,有1例发生再感染,其血清HBsAg、抗Hbe、抗HBc和HBVDNA均呈阳性,肝活检免疫组织化学检测有HBsAg表达。用拉米夫定加HBIG预防的63例中,有2例再感染,血清均呈HBsAg、抗HBe和抗HBc阳性,肝活检免疫组织化学法检测有HBsAg表达,其中1例血清HBVDNA阳性。用阿德夫韦加HBIG预防的3例中,血清学和肝活检免疫组织化学法检测均无HBsAg表达。结论原位肝移植术是治疗HBV感染相关的终末期肝病的有效手段,拉米夫定加HBIG或阿德夫韦加HBIG联合应用可以有效地预防HBV的再感染。     

肝移植术后预防乙型肝炎复发单中心治疗方案的变迁

目的比较单中心不同年代预防肝移植术后乙型肝炎(乙肝)复发治疗方案的临床效果,总结、优化治疗方案。方法选择天津市第一中心医院器官移植中心1994年5月至2012年12月因乙肝相关良性肝病接受首次肝移植术的984例成年患者,剔除围手术期(术后30天内)死亡者62例。依据患者术后预防乙肝复发治疗方案分为未治疗组、泛昔洛韦组、拉米夫定组和核苷(酸)类似物+乙肝免疫球蛋白(HBIG)组。结果 922例患者中共有27例肝移植术后出现乙肝复发,其中3例肝移植术后未接受任何预防乙肝复发治疗的患者,均出现了乙肝复发,手术日期为1994~1999年间;术后接受泛昔洛韦治疗组患者2例,均出现乙肝复发,手术日期为1998至1999年间;单一应用拉米夫定组患者共15例,其中6例出现乙肝复发(40.0%),手术日期为1998至2001年间;1999年起接受核苷(酸)类似物+HBIG联合治疗组患者乙肝复发率为1.8%(16/902);四组患者间累积乙肝复发率差异有显著的统计学意义(χ2=48.99,P=0.000),累积存活率的差异也有显著的统计学意义(χ2=62.694,P=0.000)。结论伴随核苷(酸)类似物及HBIG的成功研制上市,我中心肝移植术后预防乙肝复发的治疗方案逐步得到优化完善,核苷(酸)类似物+HBIG联合治疗方案可有效预防肝移植术后乙肝复发,并已推广应用至全国,为肝移植术治疗乙肝相关终末期肝病提供有力保障。     

恩替卡韦联合乙肝免疫球蛋白预防肝移植术后乙肝复发

肝移植是乙肝相关终末期肝病的最主要适应证,而肝移植术后乙肝复发则是影响肝移植受者长期生存的主要原因之一.文献报道,拉米夫定联合乙型肝炎免疫球蛋白(hepatitis B immuno globulin,HBIG)预防移植术后乙肝复发,其1年复发率为2.1%～13.5%,2年复发率为4.5%～15.2%[1-2].目前,用恩替卡韦联合HBIG预防肝移植后乙肝复发的文献报道较少.本文对我中心2007年1月至2009年4月采用恩替卡韦联合HBIG以及拉米夫定联合HBIG预防肝移植术后乙肝复发的104例临床资料进行了回顾性分析.     

拉米夫定联合小剂量乙型肝炎免疫球蛋白预防肝移植术后乙型肝炎病毒复发

目的:初步探讨拉米夫定联合小剂量乙型肝炎免疫球蛋白预防肝移植术后乙型肝炎病毒(HBV)复发的疗效。方法:35例HBV相关疾病病人接受肝移植后使用拉米夫定联合小剂量乙型肝炎免疫球蛋白(HBIg)预防HBV复发,同时监测乙型肝炎血清标志物、血清HBV鄄DNA、YMDD区变异及肝活检组织乙型肝炎标记物免疫组化。结果:本组病例平均获随访557d,结果5例(14.3%)出现了HBV复发:复发病例中2例HBV鄄DNA阳性,无YMDD变异。病人术前HBeAg状态与肝移植术后HBV复发间无明显相关(P>0.05),而术前HBV鄄DNA阳性的病人术后HBV复发率显著增加(P<0.05)。结论:拉米夫啶联合小剂量HBIg预防肝移植术后HBV复发的近期疗效较为肯定。术前HBV鄄DNA状态是影响术后HBV复发的重要因素。     

重型乙型肝炎肝移植术后乙型肝炎病毒再感染的防治

目的探讨重型乙型肝炎肝移植术后乙型肝炎病毒(HBV)再感染的防治。方法回顾性分析了73例重型乙型肝炎患者,移植前后给予抗病毒药物预防乙型肝炎病毒再感染,拉米夫定 乙肝免疫球蛋白(HBIG)71例,阿德夫韦 拉米夫定 乙肝免疫球蛋白2例,观察临床表现、血清HBSAg、血清HBeAg、血清HBV DNA及肝活检免疫组织化学检测等指标。结果应用拉米夫定 HBIG预防的71例中,有2例再感染,血清HBSAg为阳性,肝活检免疫组织化学检测有HBSAg表达,其中1例血清HBV DNA阳性,另1例经治疗后HBSAg又转阴。用阿德夫韦 拉米夫定 HBIG预防的2例中,血清学和肝活检免疫组织化学检测均无HBSAg表达。结论拉米夫定 HBIG或拉米夫定 阿德夫韦 HBIG联合应用以及合理的使用免疫抑制剂可以有效预防重型乙型肝炎患者移植术后乙型肝炎病毒的再感染。     

乙型肝炎患者肝移植术后乙型肝炎复发的预防

目的 探索乙型肝炎DNA阳性的终末期肝病患者肝移植前快速转阴及肝移植术后复发的防治。方法 4例乙型肝炎两对半小三阳、HBV-DNA(-)的患者术前开始联合口服拉米夫定(1amivudine)及泛昔洛韦．术后3个月内治疗同前，3个月后仅口服拉米夫定维持至今；2例乙型肝炎两对半大三阳、HBV-DNA( )的患者,术前除口服拉米夫定及泛昔洛韦外，同时肌注乙肝免疫球蛋白共14d，肝移植术中无肝期快速静脉滴注15000u静脉用乙肝免疫球蛋白，术后3个月内联合口服拉米夫定及泛昔洛韦，术后3个月内治疗同前，3个月后仅口服拉米夫定维持至今。结果 1例患者术后第19天死于肺部霉菌感染,1例患者第49天死于肝动脉及门静脉栓塞；4例患者长期存活，生存时间最长的患者已接近3年，术后全部患者均未发现有乙型肝炎复发。结论 拉米夫定、乙肝免疫球蛋白及泛昔洛韦联合使用可使乙型肝炎DNA阳性的终末期肝病患者在肝移植前快速转阴，并能预防乙肝复发。     

替比夫定与HBIG联用预防肝移植术后乙型病毒性肝炎复发的疗效

目的 评价替比夫定与乙型肝炎人免疫球蛋白(HBIG)预防肝移植术后乙型病毒性肝炎(乙肝)复发的疗效和安全性.方法 26例乙肝相关终末期肝病患者,其中HBV 脱氧核糖核酸(DNA)阳性者12例,乙型肝炎表面抗原(HBsAg)阳性20例,乙型肝炎e抗原(HBeAg)阳性7例.无YMDD变异阳性病例.患者均联合应用替比夫定和...     

血液透析患者乙型肝炎和丙型肝炎病毒感染的血清学调查

目的 :了解血透患者乙型肝炎和丙型肝炎病毒感染的情况。方法 :用第二代酶联免疫法 (ELISA)及聚合酶链反应法 ,(PCR)分别检测丙型肝炎抗体 (抗 -HCV)和HCVRNA ,以ELISA法检测乙型肝炎病毒标志物 (HB VM )。结果 :抗 -HCV阳性率为 4 5 .1% ,HCVRNA阳性率为 6 4 % ,总阳性率为 6 7.6 % ;HBVM阳性率为 5 5 .6 %。结论 :乙型和丙型肝炎病毒在血透患者中感染率较高。筛查献血员及血制品对预防丙型及乙型肝炎传播十分重要。     

Environmental Transmission of Hepatitis B and Hepatitis C Viruses Within the Hemodialysis Unit

Abstract: The hepatitis B virus (HBV) can be transmitted in the dialysis setting through blood transfusions and environmental surfaces. Transfusion related hepatitis C virus (HCV) infection is very well known, but only recently the environmental transmission of this virus was postulated. In order to study the prevalence, mechanisms of transmission, and the ALT patterns of HBV and HCV infections in hemodialysis and CAPD patients before the implementation of HBV vaccination and HCV screening in the blood bank, we conducted a study from January 1987 to January 1990. Sera from 185 hemodialysis and 124 CAPD patients were stored in this period and later analyzed for HBsAg, anti-HBc, anti-HBs, and anti-HCV (second generation ELISA). The prevalence of any HBV marker was 55.7% (103/185) for hemodialysis patients and 31.5% (39/124) for CAPD patients (hemodialysis vs. CAPD, p < 0.001). The prevalence of positive anti-HCV was 35.1% (65/185) for hemodialysis and 33.9% (42/124) for CAPD patients (not significant). There was a significant association between HBV markers positivity and anti-HCV positivity. The multivariate analysis of risk factors revealed an association of the positivity of each virus with the duration of renal replacement therapy (RRT), number of previous blood transfusions, and past history of hemodialysis treatment. Thus, besides the transfusion-related transmission, hemodialysis environmental transmission may also occur for both viruses. The findings of a high prevalence of both viruses and evidence for environmental transmission in the dialysis setting are of major importance for the planning of future preventive measures.     

乙型肝炎病毒X蛋白抑制足细胞增殖

目的 通过构建复制缺陷型腺病毒载体将乙型肝炎病毒（HBV）X基因（即HBx基因）导入足细胞株,探讨HBx蛋白对足细胞增殖的影响及其分子机制。 方法 采用pAdxsi系统构建携带HBx基因的复制缺陷型腺病毒载体。以瑞氏-吉姆萨染色观察细胞形态。以MTT检测和羧基荧光素二乙酸盐琥珀酰亚胺酯（CFDA-SE）荧光染料示踪细胞增殖的方法,对细胞增殖进行定量评估。采用流式细胞仪检测细胞周期分布。采用cyclin/DNA双参数流式细胞术和Western印迹检测细胞周期调控蛋白的表达。 结果 PCR和基因测序鉴定证实,Ad.HBx构建成功。Western印迹显示,足细胞感染Ad.HBx（感染复数MOI =100）后第3、5天均可表达相对分子质量为17 000的HBx蛋白,表明HBx可在足细胞株稳定表达。细胞形态学观察显示腺病毒感染后第5天Ad.HBx组细胞呈现明显的有丝分裂障碍特征,双核、多核和多形核细胞比例明显增加。MTT检测结果显示空白组和Ad组足细胞的生长曲线基本吻合,而Ad.HBx组细胞的生长曲线自第4天起较前两组偏低,至第5天时该差异具有统计学意义（P < 0.01）;同时,CFDA-SE细胞增殖示踪实验也证实,于腺病毒感染后第3天Ad.HBx组细胞的增殖速度已明显低于空白组和Ad组（增殖指数11.2比15.4、13.3）,且随时间推移进一步减慢（增殖指数32.5 比 61.6、54.0）,表明HBx可显著抑制足细胞增殖。细胞周期分析和细胞周期调控蛋白检测的结果显示,HBx可诱导足细胞周期G2/M阻滞,同时伴有cyclin B1、p21的表达上调及cyclin A的下调。 结论 乙肝病毒基因编码的HBx蛋白可使cyclin B1降解受阻,同时下调cyclin A和上调细胞周期负调蛋白p21的表达,导致细胞周期阻滞于G2/M期,从而抑制足细胞增殖。这可能是乙型肝炎病毒相关性肾炎患者肾小球足细胞缺失,肾脏病变慢性进展的重要机制之一。     

拉米夫定治疗肾移植术后乙型病毒性肝炎的临床观察

目的 :观察拉米夫定 (lamivudine)对肾移植术后乙型病毒性肝炎肝损害的保护作用。方法 :患有慢性乙型病毒性肝炎的肾移植受者为 4 6例 ,术后 12例出现HBV -DAN( )、转氨酶升高 ,在一般护肝治疗的同时给予拉米夫定 10 0mg/d以抑制病毒的复制。治疗中观察乙肝病毒指标及肝功能、血生化、血常规等变化。结果 :经过治疗后患者的病情改善转氨酶下降 ,并有 2例 (16 .7% )发生病毒血清转换率。治疗过程中无 1例发生肝功能衰竭。对移植肾功能无影响。结论 :应用拉米夫定可显著降低肾移植受者乙肝肝损害的发生 ,对肾移植后的乙肝有一定的治疗作用 ,而未发现对移植肾功能的损害。拉米夫定可用于有效治疗肾移植术后乙肝     

Comparison of Surgical Outcomes for Hepatocellular Carcinoma in Patients With Hepatitis B Versus Hepatitis C: A Western Experience

Background: We reviewed our experience in patients with hepatocellular carcinoma (HCC) and chronic hepatitis to determine if differences exist in preoperative status and postoperative survival between those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.Methods: We reviewed the records of 240 consecutive patients with HCC who underwent hepatic resection or liver transplantation at Mount Sinai Hospital between February 1990 and February 1998. Patients who tested negative for hepatitis B antigen and hepatitis C antibody (74 patients) as well as those who tested positive for both (2 patients) were excluded. Age as well as preoperative platelet count, prothrombin time (PT), albumin, and total bilirubin were measured in all patients. The presence of encephalopathy or ascites also was noted. Explanted livers and resection specimens were examined for size, number, and differentiation of tumors as well as the presence of vascular invasion and cirrhosis in the surrounding parenchyma.Results: One hundred twenty-one patients with HCC tested positive for HCV, and 43 tested positive for HBV. A significantly higher proportion of patients with HCV required transplant for the treatment of their HCC when compared to those with HBV. In the resection group, patients with HCV were significantly older that those with HBV. They also had significantly lower mean preoperative platelet counts and albumin levels and higher mean PT and total bilirubin levels. Resected patients with HCV had significantly less-differentiated tumors and a higher incidence of vascular invasion and cirrhosis when compared to those with HBV. There was no statistical difference in the multicentricity and size of tumors between the two groups. The 5-year disease-free survival was significantly higher for HBV patients treated with resection when compared to those with HCV (49% vs. 7%, P 5 .0480). Patients with HCC and HCV had significantly longer 5-year disease-free survival with transplant when compared to resection (48% vs. 7%, P 5 .0001).Transplanted patients with HBV and HCC had preoperative status, pathological findings, and survival similar to those of patients with HCV.Conclusions: Based on preoperative liver function and tumor location, a much higher proportion of HCC patients with HBV were candidates for resection. Significant differences in preoperative status, tumor characteristics and disease-free survival exist between HCC patients with chronic HBV and HCV infection who have not yet reached end-stage liver disease. Serious consideration should be given to transplanting resectable HCC with concomitant HCV, especially in cases with small tumors.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Prospective Study on Lamivudine-Resistant Hepatitis B in Renal Allograft Recipients

The natural history of lamivudine-resistant hepatitis B virus (HBV) infection in renal transplant recipients (RTx) is unclear, despite its increasing incidence. Twenty-nine HBsAg-positive RTx with rising HBV DNA received lamivudine therapy. The course of lamivudine-resistant HBV infection was studied prospectively. During 68.7 +/- 12.5 months of follow-up, 14 (48.3%) patients developed lamivudine resistance, at 10-35 months (mean 16.9 +/- 7.0). All showed mutant sequences at codons 552 and 528 of the YMDD motif, while 13 patients demonstrated wild-type sequence at codon 555. Lamivudine resistance was unrelated to patient demographics, HBeAg status/sero-conversion, or genotype. Following resistance, HBV DNA and alanine aminotransferase showed an initial increase followed by spontaneous gradual reduction. The subsequent peak HBV DNA was lower (1.26 +/- 1.09 x 10(9) vs. 6.26 +/- 12.23 x 10(9) copies/mL, p = 0.011), while that of alanine aminotransferase was higher (196 +/- 117 vs. 77 +/- 47 imicro/l, p = 0.005), compared with pretreatment levels. Post-resistance hepatitic flare occurred in 11 (78.6%) patients. This was transient in four (36.4%), but became chronic in six (54.5%) patients. Decompensation was noted in one patient during this flare, but all survived. We conclude that drug resistance is prevalent in lamivudine-treated RTx. Despite a lower ensuing peak viremia compared with baseline, hepatitic flare is common. While most patients have spontaneous resolution, a minority may develop potentially fatal decompensation during the preceding exacerbation.     

Posttransplantation Hepatitis B Prophylaxis with Combination Oral Nucleoside and Nucleotide Analog Therapy

Liver transplant recipients are at risk of developing recurrent hepatitis B after liver transplantation for hepatitis B virus (HBV)‐related liver disease. We evaluated the efficacy of a new hepatitis B prophylaxis regimen involving conversion from at least 12 months of HBIg with lamivudine to combination therapy with an oral nucleoside and nucleotide analog. Between June 2008 and May 2010, a total of 61 liver transplant recipients were converted to a combination of a nucleoside and nucleotide analog. The mean (±standard deviation) follow‐up time after conversion was 15.0 (±6.1) months. Recurrent HBV occurred in two (3.3%) patients at 3.1 and 16.6 months after HBIg cessation. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person‐years. The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. HBIg cessation a minimum of 12 months after liver transplantation with subsequent combination therapy with a nucleoside and nucleotide analog provides effective prophylaxis against recurrent HBV infection. The clinical implications of HBsAg detection without clinical, biochemical or molecular manifestations of recurrent hepatitis B require further study.