拉米夫定预防肝移植术后乙型肝炎病毒再感染的研究

目的 探讨和评价拉米夫定预防原位肝移植术后乙型肝炎病毒（HBV）再感染的效果。方法 41例患者，术前诊断为肝炎后肝硬化（失代偿期）者22例，慢性重型肝炎并肝炎后肝硬化（失代偿期）者12例，慢性重型肝炎者7例，其中HBVDNA阳性16例。41例患者均采用背驮式原位肝移植，术前15例给予拉米夫定治疗，术后41例患者均服用拉米夫定。结果 10例患者术后出现HBV再感染，其中9例为YMDD变异毒株感染，术后1、2年的HBV再感染率分别为9．8％（4／41）、24．4％（10／41）。术前血清HBVDNA阴性者术后HBV再感染率（12．0％，3／25）明显低于HBVDNA阳性者（43．8％，7／16）。术前长期服用（超过6个月）拉米夫定者和未服用拉米夫定者术后HBV再感染率分别为66．7％、23．1％，均明显高于术前短期（未超过6个月）服用拉米夫定者（0，P〈0．05）。结论 术前服用拉米夫定可降低乙型肝炎患者肝移植后HBV再感染率，但服药时间不宜超过6个月；长期、单一的应用拉米夫定易导致病毒变异而出现耐药毒株感染。     

乙肝相关性终末期肝病肝移植后乙肝复发的防治

目的探讨乙肝相关性终末期肝病肝移植术后乙肝病毒再感染的防治。方法回顾性分析我院1999年10月到2007年10月肝移植109例乙肝相关性终末期肝病患者，移植后给予抗病毒预防乙型肝炎病毒再感染，拉米夫定治疗组50例、拉米夫定和乙肝免疫球蛋白（乙肝免疫球蛋白）联合治疗组59例，观察临床表现，血清HbsAg、血清HbeAg、血清HBVDNA及必要时肝穿刺免疫组织化学检测HbsAg等指标。结果109例接受了3个月一8年的抗病毒治疗随访。①拉米夫定治疗组50例，10例复发，复发率为20％，复发病例中2例分别于术后5个月、8个月死于乙肝复发爆发性肝炎；余8例给予阿德夫韦和乙肝免疫球蛋白后，肝功能好转，目前在随访中。②拉米夫定和乙肝免疫球蛋白联合治疗59例，2例复发，给予调整免疫抑制药后，肝功能好转。两组比较差异有统计学意义（χ^2=7．622，P〈0．05）。结论用拉米夫定和乙肝免疫球蛋白联合应用可以有效预防肝移植后乙型肝炎病毒的再感染。     

肝移植后单一拉米夫定干预下HBV再感染及其相关因素分析

目的　探讨在单一拉米夫定 (LMV)干预下乙型肝炎相关性肝病肝移植后HBV再感染的发生 ,并分析其发生的易感因素。方法　随访 1999～ 2 0 0 3年接受肝移植并采用单一LMV防治HBV再感染的 6 3例乙肝相关性肝病患者 ,术后定期进行乙肝标志物、肝功能及HBVDNA定量检测 ,调查HBV再感染发生率并采用Logistic回归分析方法就术前诊断、病毒学资料及抗病毒治疗等分析其可能的易感因素。结果　在不同时期共出现HBV再感染 17例 ;各时间段HBV再感染率分别是 :6个月内9.5 % (6 / 6 3,其中 5例术后HBV标志物一直未阴转 ) ,6个月～ 1年 13.2 % (7/ 5 3) ,1～ 2年 2 7.8% (10 /36 ) ,2～ 3年 4 1.2 % (7/ 17) ,3年以上 6 0 .0 % (3/ 5 ) ;患者术前HBVDNA阳性及长期服用LMV与术后再感染呈正相关 (P <0 .0 5 ) ,而术前诊断、性别、年龄及血清HBsAg和HBeAg状态与HBV再感染则未发现显著相关性。结论　单一LMV预防HBV再感染对大多数肝移植者仍有效 ,但随术后存活时间的延长HBV再感染率呈现上升 ;术前使HBVDNA阴转及建立针对LMV耐药性变异的监测对防治再感染是必要的。     

联合应用拉米呋定和乙肝免疫球蛋白预防肝移植术后乙肝复发的疗效观察

目的观察联合应用拉米呋定和小剂量乙肝免疫球蛋白预防肝移植术后乙肝复发的临床疗效。方法回顾性分析35例乙肝病毒（hepatitis B virus．HBV）相关终末期肝病患者行肝移植术后联合应用拉味夫定和小剂量乙肝免疫球蛋白的临床资料．观察此方案对预防肝移植术后乙肝病毒再感染的疗效。结果4例肝移植术后发生乙肝复发,复发率11％．其余31例病毒标志物均为阴性。结论联合应用拉米呋定和小剂量乙肝免疫球蛋白可以有效地预防乙肝病毒相关终末期肝病肝移植术后乙肝复发,小样本短期随访效果满意,有待于进一步大样本长期观察     

拉米夫定联合小剂量乙肝免疫球蛋白预防肝移植术后HBV再感染的临床分析

目的探讨拉米夫定联合小剂量乙肝免疫球蛋白预防肝移植术后HBV再感染的效果。方法回顾性分析76例HBV相关性肝病患者肝移植术后采用拉米夫定联合小剂量乙肝免疫球蛋白预防HBV再感染的临床资料,分析HBV再感染的危险因素。结果 76例患者术后HBs Ag转为阴性,HBV再感染9例,术后1年内HBV再感染率为9.2%(7/76),2年内再感染率11.8%(9/76)。结论拉米夫定与小剂量乙肝免疫球蛋白联合应用可有效地预防肝移植术后HBV的再感染,肝移植术前HBe Ag阳性及HBV-DNA阳性是HBV再感染的危险因素。     

肝移植术后乙型肝炎病毒再感染的预防与诊治

目的探讨肝移植术后HBV再感染的预防与诊治。方法回顾性分析1999年8月至2004年12月98例肝移植患者临床资料。其中40例术后采用拉米夫定（lamivudine，LAM）单用方案预防HBV再感染，58例采用LAM＋乙型肝炎免疫球蛋白（HBIg）联用方案。对HBV再感染者予以阿德福韦（adefovir，ADV）抗病毒治疗。结果17例肝移植患者出现HBV再感染，其中14例明确存在YMDD变异。术前血清HBVDNA阳性者术后2年HBV再感染率显著高于阴性者（P〈0．05），前者术后采用LAM＋HBIg联合预防者其HBV再感染率显著低于单用LAM预防者（P〈0．05），而后者术后LAM单用和LAM＋HBIg联用两组之间差异无统计学意义（P〉0．05）。15例HBV再感染者改用ADV治疗后，13例（86．7％）于治疗后1～3个月HBVDNA转阴。结论术前降低血清HBVDNA水平和术后LAM＋HBIg联合预防方案能有效降低肝移植术后HBV再感染率。对术前HBVDNA阴性者，术后可选用LAM单药预防方案。ADV能够有效地治疗肝移植术后HBV再感染，抑制HBV变异株的复制。     

乙肝病毒相关性肝病肝移植术后乙肝病毒再感染的防治

目的　探讨联合应用拉米呋啶、乙肝免疫球蛋白预防肝移植术后乙肝病毒再感染的疗效。方法　回顾性研究 6例乙肝病毒相关终末期肝病患者肝移植术后联合应用拉米呋啶、乙肝免疫球蛋白的临床资料 ,分析总结该方案对预防肝移植术后乙肝病毒再感染的疗效。结果　 1例于术后 3月内HBV DNA阳性 ,余 5例病毒检查阴性。结论　联合应用拉米呋啶、乙肝免疫球蛋白可有效预防乙肝病毒相关终末期肝病肝移植术后乙肝病毒再感染     

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。     

肌注型HBIg预防肝移植术后乙肝病毒再感染的疗效分析

目的评价小剂量肌肉注射剂型乙肝免疫球蛋白（HBIg）联合核苷类抗病毒药物预防肝移植术后乙肝病毒（HBV）再感染的疗效。方法对2003年9月至2004年12月在中山大学附属第三医院肝移植中心施行肝移植术且符合研究标准的130例病人进行前瞻性研究。采用肌肉注射剂型HBIg联合核苷类抗病毒药物预防术后乙肝病毒再感染，术后监测HBV再感染情况并同国内外研究进行比较。结果130例中128例术后血清HBsAg转为阴性并检测到HBsAb，平均随访12．2个月，HBV再感染率为6.3％（8／128）；对照组再感染率为3．1％，两组比较差异无显著性（P〉0．05）。结论肌注型HBIg联合核苷类抗病毒药物能有效预防肝移植术后HBV再感染。     

乙肝病毒相关性肝病肝移植术后乙肝病毒再感染的防治

目的 探讨联合应用拉米呋啶、乙肝免疫球蛋白预防肝移植术后乙肝病毒再感染的疗效。方法 回顾性研究6例乙肝病毒相关终末期肝病患者肝移植术后联合应用拉米呋啶、乙肝免疫球蛋白的临床资料，分析总结该方案对预防肝移植术后乙肝病毒再感染的疗效。结果 1例于术后3月内HBV-DNA阳性，余5例病毒检查阴性。结论 联合应用拉米呋啶、乙肝免疫球蛋白可有效预防乙肝病毒相关终末期肝病肝移植术后乙肝病毒再感染。     

Lamivudine for hepatitis B in liver transplantation: a single-center experience

BACKGROUND: Liver transplantation for hepatitis B virus (HBV) has been associated with a high rate of reinfection and graft failure. Lamivudine, a potent inhibitor of HBV replication, has been shown to prevent viral recurrence after transplantation. METHODS: The effectiveness of lamivudine monotherapy for the management of HBV recurrence after liver transplantation was assessed. Lamivudine was used in three patient groups: (1) patients started before transplantation and continued after transplantation (n = 13); (2) patients treated after transplantation (n = 15); and (3) patients with de novo hepatitis B after transplantation (n = 4). RESULTS: Median follow-up on lamivudine was 24 months. Active viral replication (HBV-DNA+) was seen in 17 (53%) of 32 at treatment initiation. All lost HBV-DNA at a mean of 2.4+/-1.6 months after lamivudine initiation. Twenty-six (81%) patients remain free of viral recurrence. Six (19%) patients have evidence of breakthrough infection with the YMDD mutant of HBV, two of whom progressed to graft failure. All four patients in group 1 who developed breakthrough had evidence of hepatitis B surface antigen expression in the explanted liver by immunohistochemistry despite being serum HBV-DNA negative before transplantation. No difference was observed among the three groups in DNA clearance or breakthrough rates. CONCLUSIONS: Lamivudine achieves viral DNA clearance in almost all patients. Expression of viral antigens in the liver seems to identify patients at risk of developing HBV-DNA recurrence. Disease-free survival of 81% at 22 months is similar to data with hepatitis B immunoglobulin therapy. Given the safe clinical profile and high efficacy in the prevention of disease recurrence, lamivudine will favorably change the outlook of liver transplantation for HBV.     

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。     

肝移植术后预防乙型肝炎病毒再感染的策略

目的探讨预防肝移植术后乙型肝炎病毒（HBV）再感染的综合策略.方法对术前存在HBV感染的130例肝移植患者进行前瞻性研究,采用肌肉注射剂型乙型肝炎免疫球蛋白（IMHBIg）联合口服拉米夫定（lamivudine）作为预防术后HBV再感染的治疗方案;术后监测HBV再感染的情况.结果在130例患者中,128例术后HBsAg转为阴性,检测血清HBsAb呈阳性.平均随访12.2个月,8例出现HBV再感染,再感染率为6.3%;术前HBeAg阳性者再感染率为14.3%,阴性者4.0%,两组间差异有统计学意义（P＜0.05）;术后第一天HBsAg阳性者再感染率为21.1%,阴性者3.7%,两组间差异有统计学意义（P＜0.05）.结论拉米夫定联合肌肉注射剂型的人乙型肝炎免疫球蛋白可有效预防肝移植术后HBV再感染;术前血清HBeAg阳性以及术后第一天HBsAg者是术后HBV复发的高危因素.     

Lamivudine After Hepatitis B Immune Globulin Is Effective in Preventing Hepatitis B Recurrence After Liver Transplantation

The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT. (Liver Transpl 2000;6:434-439.)     

Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence

Lamivudine combined with hepatitis B immune globulin (HBIg) is the standard of care for preventing the recurrence hepatitis B virus after liver transplant. To determine the risk of hepatitis B virus (HBV) recurrence after early withdrawal of HBIg in patients receiving lamivudine maintenance therapy, 20 patients receiving a course of HBIg and lamivudine after transplantation and long-term maintenance therapy with lamivudine and 9 patients receiving HBIg and lamivudine indefinitely were analyzed. The survival rate was 90% after a mean follow-up of 83 months. The HBV recurrence rate was 14% with a mean period of 91 months free from HBV recurrence. Both groups had similar HBV recurrence rates, 15% for the combination and 11% for lamivudine alone. Four patients, 3 of whom were noncompliant with therapy, experienced posttransplant HBV recurrence. Patients who adhere to long-term prophylaxis with lamivudine after early withdrawal of HBIg have a low risk of HBV recurrence, similar to those who receive combination prophylaxis.     

Prevention of and Treatment for Hepatitis B Virus Infection After Liver Transplantation in the Nucleoside Analogues Era

Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather ineffective in patients with pretransplant viremia. Moreover, long-term HBIG administration is very expensive and may be associated with emergence of escape HBV mutants. Lamivudine has been widely used in the management of HBV transplant patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of post-transplant HBV recurrence, but to try and minimize development of resistant HBV strains, it should start within the last 6 months of the anticipated transplantation timing. Preemptive post-transplant lamivudine monotherapy is associated with progressively increasing HBV recurrence rates, but combined therapy with lamivudine and HBIG at relatively low dosage is currently the most effective approach in this setting, even in HBV-DNA-positive patients, who also receive lamivudine in the pretransplant period. The most frequent therapy for post-transplant HBV recurrence is lamivudine, but the increasing resistance rates represent a rather challenging problem. Adefovir dipivoxil and entecavir are currently the most promising agents for lamivudine-resistant HBV strains. All these advances in anti-HBV therapy have made HBV liver disease an indication for liver transplantation irrespective of viral replication status, a complete turn around from 10 years ago.     

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。     

Combination Low-Dose Hepatitis B Immune Globulin and Lamivudine Therapy Provides Effective Prophylaxis Against Posttransplantation Hepatitis B

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post–liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost (∼US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)–positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.(Liver Transpl 2000;6:429-433.)     

Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: comparison with salvage treatment after hepatic dysfunction with HBV recurrence

BACKGROUND: Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication with recurrent hepatitis that has been regarded as a frequent and major risk factor for hepatic dysfunction and chronic liver disease in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary prophylactic use of lamivudine before transplantation may be more beneficial than a trial for the treatment of advanced hepatic dysfunction. METHODS: We conducted a double arm study to compare the efficacy of lamivudine between the preemptive (HBV DNA positive) or prophylactic (HBV DNA negative) trial for the maintenance of stable liver function (n=10) and the trial for the salvage of advanced hepatic dysfunction developed after renal transplantation (n=6) in hepatitis B viremia carrier renal transplant recipients. RESULTS: Hepatic dysfunction with recurrent HBV antigenemia developed in 11 of 36 (30.6%) hepatitis antigenemia patients with a mean duration of 8.4 months (range 5-19.4 months). In six patients treated with lamivudine after hepatic dysfunction from recurrent hepatitis B viremia, serum AST and ALT level normalized within 1 month and HBV-DNA disappeared in all cases. HBV-DNA, however, reappeared in three (50%) without any discontinuation of lamivudine. Liver biopsy revealed recurrent chronic active hepatitis with severe activity of fibrosis in four cases, cholestatic fibrosing hepatitis in one, and permanent cirrhotic change in one. In seven patients who had preemptive lamivudine treatment at 9, 6, 2, 2, 1, 0, 0 month before the transplantation, HBV-DNA had converted to negative with a mean follow up of 1.2 months (range 1-2 month) in all case. Three patients who had prophylactic trials with lamivudine have all remained HBV-DNA negative. The recurrence rate of HBV viremia in the preemptive or prophylactic lamivudine treated group is 10.0% (1/10), which is significantly lower than that (42.3%, 11/25) in the nonlamivudine-treated group. The re-recurrence rate of HBV viremia was significantly higher (3/6, 50.0%) in the reactive lamivudine treated group than in prophylactic or preemptive group (1/10, 10%). CONCLUSION: Although lamivudine treatment after hepatic dysfunction can be a sound conventional treatment modality, this preliminary study may suggest that preemptive or prophylactic trial of lamivudine before hepatic dysfunction might be a more effective strategy for prevention of permanent histological deterioration and recurrence of hepatitis B viremia.     

Use of combined treatment of hepatitis B immune globulin and lamivudine as prevention of hepatitis B virus recurrence in liver allograft

Antiviral prophylaxis with lamivudine appears to reduce hepatitis B virus (HBV) infection after liver transplantation, although recurrence of infection occurs in at least 20% of the patients because of the development of drug resistance. Treatment for HBV reinfection with lamivudine pretransplantation and posttransplantation together with hepatitis B immunoglobulin could abolish recurrence of HBV infections following liver transplantation. We report the experience at our center in which lamivudine has been used in combination with low doses of immunoglobulin. Lamivudine (100 mg/d) was administered to liver transplant candidates for at least 4 weeks before transplantation and was continued posttransplantation indefinitely. Immunoglobulin was administered intramuscularly (10,000 IU at time of liver transplantation; 1,000 IU for 1 week; 1,000 IU weekly the first month; and 1,000 IU monthly thereafter). Lamivudine and low-dose immunoglobulin administration prevents posttransplantation recurrence of hepatitis B with 100% efficiency; it is well tolerated and is less cost-effective than high-dose immunoglobulin regimens.