拉米呋啶、乙肝免疫球蛋白防治肝移植术后HBV再感染的功效比较及临床应用进展

在2006年4月召开的第41届欧洲肝病研究学会年会上,专家们普遍认为肝移植术后乙肝复发预防的关键是联合应用抗病毒药物和乙型肝炎免人疫球蛋白(hepatitis B immunoglobulin,HBIg):但也存在联合应用拉米呋啶(lamivudine,lami)和HBIg与单用lami在预防乙肝复发效果上没有     

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。     

拉米夫定联合乙肝免疫球蛋白防治肝移植术后乙肝复发的多中心临床研究

目的研究拉米夫定联合乙肝免疫球蛋白防治肝移植术后乙肝复发的效果。方法自2004年5月～2005年10月,采用随机、阳性药物平行对照、多中心临床研究的方法,在9家医院对230例病人进行了研究。结果在有效病例,在同等剂量给药的条件下,HBIG对靶抗原HBsAg的中和量及术后7天内HBsAg阴转率的变化趋势充分体现了HBIG的量效、时效性及给药途径不同存在的量效、时效区别。在联合使用拉米夫定时,HBIG剂量若定为无肝期至术后HBV标志物转阴前HBsAb效价维持在300IU/L,HBV标志物转阴后效价维持在100IU/L似乎更科学,间隔4周给药可维持体内相对稳定的药物浓度。观察到的不良事件与HBIG无关,无效病例可能与乙肝病毒变异有关。结论拉米夫定联合乙肝免疫球蛋白防治肝移植术后乙肝复发的方案是安全、有效的。     

乙肝免疫球蛋白(HBIG)预防肝移植后HBV复发

随着移植技术的改进和围手术期处理方法的提高，肝移植在过去的20年间得到了迅速的发展，现已成为治疗各种急慢性终末期肝病的有效办法。在众多肝移植适应证中争论较大的是HBV感染后的晚期肝病病人，原因主要是移植术后HBV再感染，致使移植肝存活时间短。在这类病人中，如果肝移植后不加任何防治措施，移植后     

小剂量乙肝免疫球蛋白(HBIG)联合拉米夫定(LAM)防治肝移植术后乙肝复发的应用研究

肝移植术后乙肝再感染与复发导致移植肝失功严重地影响了病人的预后。因此，防治乙肝复发已成为临床急需解决的重要课题。研究报告乙肝免疫球蛋白联合拉米夫定在防治乙肝复发方面具有较大优势。现将我院采用该治疗方案防治乙肝复发的临床效果进行总结分析。     

拉米呋定与乙肝疫苗预防HBcAb阳性供肝儿童肝移植术后新发乙肝病毒感染效果的对照研究

目的 比较拉米呋定与乙肝疫苗方案预防乙型肝炎核心抗体(hepatitis B core antibody,HBcAb)阳性供肝儿童肝移植术后新发乙型肝炎病毒(hepatitis B virus,HBV)感染效果.方法 对天津市第一中心医院自2013年5月—2019年6月251例接受HBcAb阳性供肝儿童肝移植的资料进行...     

肝移植术后乙肝复发的预防和治疗

目的 探讨乙肝相关疾病患者肝移植术后乙型肝炎病毒(HBV)再感染的防治。方法 复习有关文献并进行综述。结果 与HBV有关的急、慢性肝病是肝移植的主要适应证，但未作预防者移植后HBV再感染率可达80％～100％，对移植肝的存活和患者的生存有重大的影响。如何防治肝移植后乙型肝炎的复发，成为急需解决的问题。经过一系列的摸索，目前已有许多用于防治HBV再感染的药物，包括抗乙肝免疫球蛋白、干扰素、核苷类似物等，其各自有不同的应用特点，在单独及联合用药方面也有了新的研究进展。结论 肝移植是治疗乙肝相关疾病的有效方法，围手术期的积极药物治疗，对提高乙肝相关疾病患者肝移植的成功率至关重要。     

182例肝移植病人术后19个月乙肝复发的临床随访观察

目的 肝移植病人术后乙肝复发的临床随访观察.方法 复诊与随访表调查.结果 拉米呋啶和HBIG联用的情况下,8个分中心的182例肝移植病人术后19个月随访期的乙肝复发率为0.55%.若将术后1周内230个研究病例中血清HBsAg未阴转的9个病例(3.91%)视为乙肝复发病例,术后19个月试验与对照组复发率分别为6.89%(6/87),4.21(4/95).采用循证医学方法,分析世界范围内单用HBIG、拉米呋啶及拉米呋啶和HBIG联用3种方法,认为均有不同程度防治肝移植病人术后乙肝复发的效果.结论 该次临床随访时间与多数的历史文献对照观察时间点形成重叠,临床研究与随访的乙肝复发率与既往文献结果吻合,拉米呋啶和HBIG联用是较优的防治策略.     

替诺福韦单一用药预防肝移植术后乙肝复发的疗效分析

目的 探讨乙型肝炎病毒(hepatitis B virus,HBV)相关肝移植(liver transplantation,LT)后停用乙肝免疫球蛋白(hepatitis B immunoglobulin,HBIG)单用替诺福韦(tenofovir disoproxil fumarate,TDF)预防HBV复发的有效性...     

重建主动免疫预防肝移植术后乙肝复发的临床应用前景

乙肝相关肝病目前仍是肝移植的主要指征。在现有的小剂量乙肝免疫球蛋白（hepatitis B immune globulin,HBIG）联合拉米夫丁（lamivudine,LAM）预防方案的保护下,乙肝相关肝病肝移植术后5年乙肝病毒再感染/乙肝复发的总体发生率已能控制于5%以下。基于HBIG＋LAM的良好效果,近10年来临床已将其作为肝移植术后预防乙肝复发的＂金标准＂。但是,该方案也存在某些缺陷或不足。     

Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis

There is a controversy over whether the different outcomes of prophylaxis of hepatitis B virus (HBV) recurrence are attributable to different treatments. A systematic review and a meta-analysis were conducted to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in HBV infected liver recipients. A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes. Six articles (551 patients) fulfilled the inclusion criteria. Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence [ P  < 0.0001; RR = 0.38; 95% CI (0.25, 0.58)], YMDD mutant [ P  = 0.002; RR = 0.40; 95% CI (0.23, 0.72)] and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation [ P  < 0.00001; RR = 0.31; 95% CI (0.21, 0.45)]. No significant differences were observed in patient survival [ P  = 0.59; RR = 1.02; 95% CI (0.95, 1.09)], graft survival [ P  = 0.56; RR = 1.02; 95% CI (0.95, 1.09)] and diseases leading to death between the two groups [HBV recurrence leading to death: P  = 0.05; RR = 0.47; 95% CI (0.22, 1.02); hepatocellular carcinoma recurrence leading to death: P  = 0.13; RR = 0.34; 95% CI (0.09, 1.36)]. In conclusion, combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly. Well-designed large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.     

Prevention of hepatitis B virus recurrence after liver transplantation

Abstract:  Liver transplantation for hepatitis B virus (HBV)-related liver disease has changed from a contraindication to outcomes comparable with non-HBV-related liver transplantations during the last two decades. Mainly the implementation of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the use of nucleoside analogs such as lamivudine and adefovir account for this dramatic change. The standard of care in most centers today consists of lamivudine treatment in replicating hepatitis B pre-orthotopic liver transplantation (OLT) and a combination regimen of lamivudine and HBIG post-OLT. With adefovir, a potent antiviral drug became available in recent years that allows for the treatment of patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD)-mutant HBV. In the transplantation setting, first studies indicate that a triple prophylactic therapy consisting of lamivudine, adefovir, and HBIG will become the standard of care for YMDD-mutant-related hepatitis B. With new drugs emerging for the treatment of chronic HBV, there is optimism for new options also in the transplant setting.     

Outcome of lamivudine resistant hepatitis B virus mutant post-liver transplantation on lamivudine monoprophylaxis

BACKGROUND: We aimed to investigate the clinical outcome of patients who develop lamivudine resistant hepatitis B virus mutants (YMDD mutants) after liver transplantation. METHODS: Patients who received liver transplantation for hepatitis B-related liver diseases from 1999 to 2002 were studied. All patients received lamivudine monotherapy before and after liver transplantation. HBsAg and HBV DNA were regularly monitored, and YMDD mutation was detected by direct sequencing. RESULTS: Twenty patients were followed up for median 94 wk (range: 15-177 wk) post-liver transplantation. Six patients developed YMDD mutants, and the cumulative probability of developing YMDD mutations post-liver transplantation was 21% in 1 yr and 34% in 2 yr. One patient developed YMDD mutants before liver transplantation and died of hepatitis reactivation and liver failure 15 wk post-transplantation. The other five patients developed YMDD mutants 32-72 wk after liver transplantation. Two of them developed severe hepatitis which responded promptly to adefovir dipivoxil. The remaining three patients with YMDD mutants had minimal to mild hepatitis. The cumulative survival for patients with YMDD mutants was 83% and 28% at 1 and 2 yr, respectively. Only one patient who did not develop YMDD mutants died at week 119 due to chronic rejection. The post-transplant survival for patients with YMDD mutants was significantly poorer than those without YMDD mutants (log rank test p = 0.083). CONCLUSIONS: The emergence of YMDD mutants after liver transplantation on lamivudine monoprophylaxis had wide range of clinical presentations and was associated with increased mortality.     

Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation

Yuefeng M, Weili F, Wengxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation.
Clin Transplant 2011: 25: 517–522. © 2010 John Wiley & Sons A/S. Abstract: Background: The aim of this study is to examine the efficacy of long‐term prophylaxis with lamivudine (LAM) after a course of post‐operative hepatitis B immunoglobulin (HBIG) in patients who underwent liver transplantation (LT) for hepatitis B virus (HBV)‐related disease. Result: The medical records of HBV‐infected patients who underwent a LT in our institution between July 2001 and May 2005 were reviewed. There were 15 liver transplant recipients who were administered HBIG for <18 months and used LAM as a maintenance prophylaxis regime enrolled in this study. At enrollment, all patients were hepatitis B surface antigen (HBsAg) positive and three patients were HBeAg positive. There were 13 patients who were HBV DNA positive with a mean viral load of 5.4 log copies/mL, and among them, 12 recipients were on antiviral therapy with LAM (100 mg/d orally) for 12–168 d, resulting in HBV DNA negative levels in nine patients prior to their transplant. HBV recurrence post‐LT was noted in two patients who had very high‐HBV DNA levels pre‐LT. Both of these patients showed LAM‐resistant mutation at the time of recurrence. The 11 patients who were HBV DNA negative before LT (low‐risk patients) had no HBV recurrence during a follow‐up at a median of 58 months post‐LT. This included five patients who had intermittent low‐level HBV DNA post‐LT (HBsAg negative), of whom two had YMDD mutation and these two were given adefovir in addition to LAM. Conclusion: Our retrospective study demonstrated excellent long‐term outcomes in the low‐risk patients treated with LAM after a short course of HBIG.     

Network meta-analysis on prophylactic regimens against recurrent hepatitis B virus infection after liver transplantation

Background

Previous meta-analyses of non-randomized studies suggested that the hepatitis B immunoglobulin (HBIG) and lamivudine (LAM) combination therapy was significantly better than HBIG or LAM alone in preventing hepatitis B virus (HBV) recurrence after transplantation. However, substantial evidences supporting the superiority of combination therapy are still insufficient. Therefore, we sought to conduct a multiple-treatment comparison to integrate current data which was based on randomized controlled trials (RCTs).

Methods

We searched electronic databases of PubMed, Embase and the Cochrane Library for eligible literatures. Pair-wise meta-analyses were to synthesize studies comparing the same pair of treatments. Appropriate networks for overall and 1-year recurrence rates were established. Bayesian algorithm was used in multiple-treatment comparisons to compare relative effects of all included regimens.

Results

Four RCTs on prophylaxis against HBV recurrence after liver transplantation, involving 162 participants, were included. HBIG mono-therapy, LAM mono-therapy and HBIG plus LAM showed no statistically difference in risk ratios (RRs) in terms of overall HBV recurrence rate in network meta-analysis. Nevertheless, HBIG mono-therapy had potential advantage compared with combination of HBIG and LAM in 1-year HBV recurrence rate [RR 0.00, 95% confidence interval (CI): 0.00 to 0.91] while the rest comparisons revealed no significance. The cumulative probabilities of treatments associated with the highest recurrence were (overall HBV recurrence rate, 1-year HBV recurrence rate): HBIG (18%, 1%), LAM (32%, 42%) and HBIG plus LAM (50%, 57%).

Conclusions

This network meta-analysis based on data from RCTs showed no significant differences among HBIG mono-therapy, LAM mono-therapy, combination of HBIG and LAM in overall HBV recurrence rate after liver transplantation. Further well designed and large-scale RCTs are warranted to clarify these issues.     

Lamivudine monoprophylaxis for liver transplant recipients with non-replicating hepatitis B virus infection

Background: The aim of this study was to evaluate the efficacy of lamivudine (LAM) monoprophylaxis for patients with non-replicating hepatitis B virus (HBV) infection at orthotopic liver transplantation (OLT). METHODS: Among 128 liver recipients with HBV infection between 1994 and 2004 transplanted at our institution, 60 had non-replicating HBV infection at the time of OLT. Of those, 26 patients received LAM prophylaxis (monoprophylaxis group) and 34 patients received LAM and hepatitis B immunoglobulin (HBIG) prophylaxis (combination group) after OLT. RESULTS: Median follow-up after OLT was 67 and 54 months, for monoprophylaxis and combination groups respectively. One and five yr patient/graft survival were 96/85% and 96/80% in monoprophylaxis group, and 85/79% and 67/55% in combination group. HBV DNA was re-detected or increased >10(5) IU/mL in four patients (15%) at 20-29 month in monoprophylaxis group and six (18%) at 4-35 months in combination group. Recurrent hepatitis was seen in two patients (8%) at 27 and 45 months and monoprophylaxis group and three (9%) at 21-35 months in combination group. The rate of recurrence was not statistically different between two groups. CONCLUSION: LAM monoprophylaxis seemed to be effective for OLT recipients with HBV infection who had non-replicating HBV at transplantation. HBIG administration may play a less valuable role in preventing HBV recurrence in this group of patients.     

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。     

Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine.

BACKGROUND: In end-stage renal disease patients with hepatitis B surface antigen (HBsAg), the risk of hepatic dysfunction after immunosuppression represents a large barrier in renal transplantation. Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. We retrospectively investigated the outcome of HBsAg-positive renal transplantation recipients after lamivudine had become available. METHODS: From July 1994 to August 2000, seventeen HBsAg-positive patients (M:F=15:2) received renal allografts (13:4=living:cadaveric donors). Liver function tests at the time of transplantation were normal in all patients. Pre-transplant liver biopsies performed in 15 patients demonstrated minimal inflammatory histology, except in three patients showing pathological and clinical signs of active hepatitis. Lamivudine was started pre-operatively in these three subjects. Another seven patients were treated with lamivudine for post-operative hepatic dysfunction. The remaining seven patients did not develop hepatic dysfunction after transplantation. RESULTS: Lamivudine was initially effective in decreasing serum HBV DNA titres, and in normalizing hepatic enzymes. Lamivudine was well tolerated without significant side effects for 35.5+/-8.9 months after initiation of treatment. HBV DNA became negative in nine patients but remained positive in one patient. Among the nine patients with initial negative conversion of HBV DNA, two developed transient positive conversion of HBV DNA and two demonstrated persistent positive conversion. Among the patients with normal liver histology in the pre-transplant period, 41.6% (5/12) developed liver pathology progression after immunosuppression. All 17 patients had functioning grafts, except for one patient who developed relapsed IgA nephropathy. CONCLUSIONS: Our data showed relatively favourable outcomes in hepatitis B-positive renal transplant recipients receiving lamivudine treatment, even though two patients developed lamivudine resistance.     

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。