肝移植后乙型肝炎复发的研究现状

肝移植是治疗乙型肝炎相关性终末期肝病的有效方法,而术后乙型肝炎复发和再感染是导致移植物功能丧失、影响长期预后的重要因素。近年来,许多新的防治策略明显地降低了该类患者术后乙型肝炎的复发率。本文从肝移植后乙型肝炎复发的感染来源和进程、诊断和防治等方面进行讨论。     

肝移植术后乙型肝炎复发的研究进展

由于乙型肝炎病毒感染难以根除,肝移植术后乙型肝炎仍有较高的复发率,并成为内外科医师的一大困扰。如何防止乙型肝炎复发,如何鉴别诊断,如何早期诊断,有效防治乙型肝炎复发是临床工作难点,也是目前研究的热点。本文就移植后乙型肝炎复发的一系列临床问题作一综述。     

肝移植术后乙型肝炎复发的防治现状

1 肝移植术后乙肝复发的预防 降低肝移植术后乙肝复发率的关键在于有效的预防,目前主要有以下几种预防方法：     

肝移植术后乙型肝炎复发的预防和治疗

原位肝移植是治疗急慢性肝衰竭的最有效手段。在我国，接受肝移植的大多数患者患有ＨＢＶ相关性疾病（如急性重型肝炎、乙型肝炎肝硬化终末期）。如果不采取有效的预防措施，这些患者在接受肝移植后８０％以上均会发生ＨＢＶ的再感染，并且在平均２年左右即可形成肝硬化。尤其是一旦发生由于病毒在肝细胞内大量复制所致的纤维淤胆性肝炎（ｆｉｂｒｏｓｉｎｇｃｈｏｌｅｓｔａｔｉｃ ｈｅｐａｔｉｔｉｓ），可于数月内死于肝衰竭。这些患者肝移植术后的１年和５年存活率分别为７２％和５１％，均低于因其它疾病（如胆汁郁积性疾病）而接受肝…     

肝移植术后乙型肝炎复发患者的预后分析

目的 分析肝移植术后乙型肝炎复发患者的预后及其相关资料.方法 回顾性分析天津市第一中心医院器官移植中心1998年12月至2009年11月因乙型肝炎相关终末期肝病行肝移植术,且术后接受小剂量乙型肝炎免疫球蛋白联合核苷(酸)类似物预防乙型肝炎复发的1506例患者资料.对其中出现复发病例的资料及其预后进行分析.所有患者术后均行HBV相关血液学检测,检测HBV DNA水平、肝功能,HBV血液学标志物阳性时行肝脏病理学活组织检查,随访至2010年11月.生存分析及复发率采用Kaplan-Meier生存分析,复发率及生存率的比较采用log-rank test检验.结果 共有38例肝移植术后病例确诊为乙型肝炎复发,中位随访时间为45.1个月,非肝癌肝移植患者乙型肝炎中位复发时间为31.8个月(0.3 ～ 72.8个月),肝癌肝移植患者乙型肝炎中位复发时间为13.7个月(0.3 ～ 66.6个月);8例患者检测出HBV耐药基因变异;18例病例接受恩替卡韦或阿德福韦酯挽救治疗,病毒复制转为阴性,肝功能恢复正常;其中22例病例由于肝癌复发、肝功能衰竭及其他原因死亡,16例病例生存.结论 HBV耐药基因变异及肝癌复发是肝移植术后乙型肝炎复发的重要原因,良性肝病肝移植患者乙型肝炎复发后接受阿德福韦酯或恩替卡韦挽救治疗可获得较好预后,而肝癌肝移植术后乙型肝炎复发患者预后较差.     

肝细胞癌患者肝移植术后复发的危险因素及预后分析

目的探讨肝细胞癌(HCC)患者肝移植术后肿瘤复发和死亡的危险因素,了解患者生存情况。方法选取2005年1月-2019年2月于解放军总医院第五医学中心行肝移植的391例HCC患者。根据肝移植术后HCC是否复发分为HCC复发组(n=78)和无复发组(n=313)。计量资料两组间比较采用t检验或Mann-Whitney U检验;计数资料两组间比较采用χ2检验。利用单因素和多因素Cox比例风险回归模型分析肝移植术后患者HCC复发和死亡的危险因素。应用Kaplan-Meier法分析生存情况,并通过受试者工作特征曲线(ROC曲线)分析肝移植术后肿瘤死亡相关危险因素的预测价值。结果 391例HCC肝移植患者的中位随访时间2年,其中78例(19.95%)患者出现HCC复发。肝移植术后患者肿瘤复发和死亡的独立危险因素包括术前AFP水平 200 ng/ml[风险比(HR)=2.52,95%可信区间(95%CI):1.58～4.03,P 0.001; HR=2.99,95%CI:1.59～5.62,P 0.001]、肿瘤直径总和(HR=1.20,95%CI:1.12～1.28,P 0.001; HR=1.10,95%CI:1.02～1.17,P=0.002)、血管侵犯(HR=1.15,95%CI:1.04～1.26,P=0.016; HR=1.10,95%CI:1.03～1.18,P=0.004)。HCC肝移植患者术后1、5和10年总生存率分别为94.8%、84.2%和83.5%; 1、5和10年无瘤生存率分别为84.0%、75.1%和75.1%。AFP、大血管侵犯、BMI与肿瘤直径总和联合因素对于HCC复发患者死亡有一定的预测价值(ROC曲线下面积为0.789,95%CI:0.719～0.858)。结论肝移植术前肿瘤生物学特征是肝移植术后肿瘤复发的关键因素。     

乙型肝炎相关性肝病肝移植术后乙型肝炎复发的预防

肝移植是目前治疗急慢性终末期肝病最有效的方法.近10年来,肝移植技术和器官保存方法的改进以及手术后免疫抑制治疗的进展,肝移植术后长期生存成为可能.我国是肝炎大国,尤以乙型肝炎居多,与乙型肝炎相关的肝炎后肝硬化以及肝癌患者成为我国肝移植患者的主体.     

肝移植术后乙型肝炎复发的处理——13例分析

目的总结和探讨乙型肝炎相关终末期肝病肝移植术后乙型肝炎复发的处理方法。方法回顾性分析我院13例肝移植术后患者发生乙型肝炎再感染或复发后的处理措施及疗效。结果13例患者分别采取拉米夫定改为阿德福韦、恩替卡韦或加大乙型肝炎免疫球蛋白用量的方法,其中5例HBsAg经治疗后转阴,5例HBsAg明显下降,总有效率76.9%。结论肝移植术后HBIG、恩替卡韦、阿德福韦能不同程度控制肝移植术后乙型肝炎复发。     

乙型肝炎与肝移植

乙型肝炎相关的末期肝病变乃至于接受肝脏移植手术的治疗与愈后是一个重要的课题 ,乙型肝炎病毒 (ＨＢＶ )与肝脏移植手术后面临的问题 ,可分为 3个重点 :第一、肝脏移植手术后如何预防乙型肝炎的复发 ;第二、非乙型肝炎相关肝病在肝脏移植手术后如何预防新生性 (ｄｅｎｏｖｏ)     

乙型肝炎相关性肝移植后乙型肝炎复发的临床特点分析

目的 总结和探讨乙型肝炎相关性终末期肝病患者在肝移植术后乙型肝炎复发的临床特点.方法 回顾性分析2005年4月至2010年4月期间的253例乙型肝炎相关性肝移植患者的术后随访资料.结果 253例肝移植患者中乙型肝炎复发16例,复发率6.32%(16/253),中位复发时间为术后13个月,术后1、3、5年的累积复发率分别...     

肝移植后乙型肝炎复发的临床表现与预后

目的 研究肝移植后乙型肝炎复发的临床特点、治疗和预后.方法 回顾性分析25例因终末期乙肝肝病行肝移植的患者术后乙型肝炎复发的临床类型、乙肝病毒指标的变化、对抗病毒再治疗的反应以及预后.结果 肝移植后乙型肝炎复发的高峰时间是在第1年;YMDD变异在拉米夫定失效患者中占61%;本组病例肝移植后乙型肝炎复发呈现3种临床类型:①纤维淤胆型肝炎,占8%(2/25),病情凶险,病死率高.②亚急性重型肝炎,占12%(3/25),恢复期后表现为肝硬化.③慢性肝炎,占80%(20/25),其中包括活动型和轻型.病情呈活动型者占48%(12/25),其中病情进展较快者可在4-5年内进展为肝硬化.预后与肝病活动程度关系密切,需要与排异反应及药物中毒相鉴别.病情呈轻型占32%(8/25),表现为一过性肝功能异常,预后较好.25例乙型肝炎复发患者.死亡2例,死亡原因均为纤维淤胆型肝炎.结论 肝移植后乙型肝炎复发的临床表现类型与抗病毒治疗是否及时有效密切相关.应用核苷类似物联合乙肝免疫球蛋白治疗,能有效地预防及治疗肝移植术后乙型肝炎复发.早期发现乙型肝炎复发并及时调整治疗,能显著改善患者的预后.     

乙肝病毒相关肝病肝脏移植术后乙肝复发的预防和治疗

在我国施行肝移植的患者中,绝大多数是乙肝病毒相关性终末性肝病患者,术前病毒复制程度、个体免疫状态和病毒类型与移植术后易感复发密切相关。联合应用乙肝免疫球蛋白与核苷类似物可用于肝脏移植术后抗病毒治疗,近年来报道乙肝疫苗也可有效预防移植术后乙肝复发。本文重点介绍肝脏移植术后乙肝复发的机制及影响因素,探讨预防乙肝复发的各种方案的优劣。     

Management of hepatitis B virus infection after liver transplantation

Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.     

Current prophylactic strategies against hepatitis B virus recurrence after liver transplantation

Prophylactic strategies against hepatitis B virus （HBV） recurrence after liver transplantation （LT） are essential for patients with HBV-related disease. Before LT, lamivudine （LAM） was proposed to be down-graded from first- to second-line therapy. In contrast, adefovir dipivoxil （ADV） has been approved not only as first-line therapy but also as rescue therapy for patients with LAM resistance. Furthermore, combination of ADV and LAM may result in lower risk of ADV resistance than ADV monotherapy. Other new drugs such as entecavir, telbivudine and tenofovir, are probably candidates for the treatment of hepatitis-B-surface-antigen-positive patients awaiting LT. After LT, low-dose intramuscular hepatitis B immunoglobulin （HBIG）, in combination with LAM, has been regarded as the most cost-effective regimen for the prevention of post-transplant HBV recurrence in recipients without pretransplant LAM resistance and rapidly accepted in many transplant centers. With the introduction of new antiviral drugs, new hepatitis B vaccine and its new adjuvants, post-transplant HBIG-free therapeutic regimens with new oral antiviral drug combinations or active HBV vaccination combined with adjuvants will be promising, particularly in those patients with low risk of HBV recurrence.     

Recent advances in prevention of hepatitis B recurrence after liver transplantation

Liver transplantation is the only effective treatment for hepatitis B virus(HBV)-related end-stage liver disease.However,without antiviral prophylaxis,the recurrence rate of hepatitis B is as high as 80%-100%,which leads to a 50% mortality rate in the first 2 years after liver transplantation.Combination therapy of hepatitis B immunoglobulin(HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%.The strategy of HBIG combined with lamivudine has been the standard treatment in many centers.However,the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the longterm efficacy of this strategy for the prevention of HBV reinfection.Recently,new nucleos(t)ide analogues,such as entecavir and tenofovir,have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection.These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation.Various therapies that are composed of entecavir,tenofovir,and lamivudine plus adefovir,with or without HBIG have been adopted in several liver transplant centers.This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.     

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation

BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS: Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS: Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS: Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.     

肝移植术后原发性肝癌复发与乙型肝炎病毒再感染的关系

目的 探讨肝移植术后原发性肝癌复发与HBV再感染的关系.方法 对2004年1月-2008年12月在中山大学附属第三医院因乙型肝炎相关性终末期肝病行肝移植手术并长期随访的340例患者回顾性分析.患者被列入肝移植等待名单后给予核苷(酸)类似物抗病毒治疗,术中和术后均给予核苷(酸)类似物联合低剂量乙型肝炎免疫球蛋白进行预防.术后定期随访并监测患者HBV再感染的发生率及生存率,用多因素COX回归分析筛选出影响术后HBV再感染的危险因素.计量资料用t检验、计数资料用x2检验进行统计学处理.用Kaplan-Meier方法进行生存率分析,对HBV再感染危险因素用COX多因素回归分析,对HBV再感染与原发性肝癌复发的时间进行Spearman线性相关分析.结果 340例患者术后发生HBV再感染33例,术后1、3、5年再感染率分别为7%、10%、13%.HBV再感染的时间为1～21个月,中位数为5个月.原发病为原发性肝癌(风险比为2.98;95%可信区间为1.08～8.25,P＜0.05)、术前HBV DNA载量＞5log10拷贝/ml(风险比为3.99;95%可信区间为1.85～8.62,P＜0.01)是发生HBV再感染的危险因素.原发性肝癌复发者HBV再感染发生率高于未复发者,分别为27.9%和8.7%(风险比为4.58; 95%可信区间为1.88～11.12;P＜0.01).12例患者肝移植术后发生HBV再感染和原发性肝癌复发,两者的复发时间具有相关性(r=0.583,P＜0.05).结论肝移植术后原发性肝癌复发是HBV再感染的危险因素.

Abstract：

Objective To investigate the relationship between hepatocellular carcinoma (HCC)recurrence and hepatitis B virus (HBV) recurrence. Method The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. Result 33 patients suffered from HBV recurrence post transplantation.The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P＜0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P＜0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR =- 4.58;95% CI 1.88-11.12; P＜0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r= 0.583, P＜0.05). Conclusion Post transplantation HCC recurrence is a risk factor for HBV recurrence.     

A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation

BACKGROUND/AIMS: To compare the efficacy in preventing hepatitis B virus (HBV) recurrence of lamivudine vs. lamivudine plus hepatitis B immune globulin (HBIg) after a short course of HBIg and lamivudine in liver transplanted chronic hepatitis B patients.METHODS: Forty-six patients with HBV cirrhosis received lamivudine before liver transplantation and were then randomized to receive lamivudine plus HBIg for 1 month followed by lamivudine or both drugs for 17 months.RESULTS: Thirty-two patients were transplanted and 29 were randomized to receive combination therapy (15 cases) or lamivudine monotherapy (14 cases). HBV DNA was undetectable in all cases (17 induced by lamivudine therapy) at the time of liver transplantation. After 18 months of follow-up, all patients survived without HBV recurrence: hepatitis Bs antigen and HBV DNA were negative; however, HBV DNA was detected by polymerase chain reaction in four cases (three with HBIg plus lamivudine and one with lamivudine). Alanine aminotransferase levels were normal except in six cases (one HCV and two HDV coinfections). There were no drug-related adverse events.CONCLUSIONS: Lamivudine monotherapy after a short course of lamivudine and HBIg is equally as efficacious in preventing HBV recurrence as HBIg plus lamivudine during the first 18 months after liver transplantation. This strategy is more economic and convenient to administer than long-term HBIg plus lamivudine.