在肝移植中的安全使用肝移植乙肝表面抗原阳性献血者

StephenW

Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation
Songfeng Yu†,Jun Yu†,Wei Zhang,Longyu Cheng,Yufu Ye, Lei Geng,Zhiyong Yu,
Sheng Yan,Lihua Wu,Weilin Wang,Shusen Zheng
l
†These authors contributed equally to this work.
Received: January 7, 2014; Received in revised form: May 1, 2014; Accepted: May 5, 2014; Published Online: May 10, 2014
See Focus, pages 717–719
DOI: http://dx.doi.org/10.1016/j.jhep.2014.05.003

   
Background & Aims

Liver grafts from hepatitis B surface antigen (HBsAg) positive donors could have potential to increase the donor pool. However, knowledge is extremely limited in this setting because currently available data are mostly from case reports. We aimed to assess the outcomes and experiences of liver transplantation from HBsAg positive donors in a single centre study.
Methods

From January 2010 to February 2013, 42 adult patients underwent liver transplantation from HBsAg positive donors and 327 patients from HBsAg negative ones. The outcomes including complications and survival of two groups were compared and antiviral therapy retrospectively reviewed.
Results

HBsAg positive liver grafts were more likely to be allocated to patients with hepatitis B (HBV)-related diseases. Post-transplant evaluation showed similar graft function regaining pace and no differences in complications such as primary non-function, acute rejection and biliary complications. Patient and graft survivals were comparable to that of HBsAg negative grafts. Furthermore, HBsAg persisted after transplant in all patients that received positive grafts. The donor HBV serum status determined the one of the recipient after transplantation. No HBV flare-ups were observed under antiviral therapy of oral nucleotide analogues, regardless of using hepatitis B immunoglobulin combination.
Conclusions

Utilization of HBsAg positive liver grafts seems not to increase postoperative morbidity and mortality. Therefore it is a safe way to expand the donor pool when no suitable donor is available. Our experience also suggests that hepatitis B immunoglobulin should be abandoned in recipients of HBsAg positive liver grafts, in whom HBV prophylaxis could be the only oral antiviral therapy.
Abbreviations:
LTx (liver transplantation), HBV (hepatitis B virus), HBsAg (hepatitis B surface antigen), HBIG (hepatitis B immunoglobulin), NAs (nucleotide analogues), HBcAb (hepatitis B core antibody), MELD (model for end stage liver disease), HBeAg (hepatitis B e antigen), HBsAb (hepatitis B surface antibody), ALT (alanine transaminase), AST (aspartate aminotransferase), TB (total bilirubin), DB (direct bilirubin), PT (prothrombin time)
Keywords:
Liver transplantation, HBsAg positive donor, Marginal graft, Antiviral therapy

StephenW

在肝移植中的安全使用肝移植乙肝表面抗原阳性献血者
松风宇†，君宇†，魏张龙宇成，渝富烨，雷庚，智勇宇，
盛押嗯，梨花湖，蔚林王，郑树森
升
†同等贡献这项工作。
收稿日期：2014年1月7日;收到修改稿：2014年5月1日;接受日期：2014年5月5日;发表时间：2014年5月10日
请参阅对焦，页717-719
DOI：http://dx.doi.org/10.1016/j.jhep.2014.05.003

   
背景与目的

乙肝表面抗原（HBsAg）阳性献血者肝移植可能有潜在的增加了供体库。但是，知识是极其有限的此设置，因为目前可用的数据大多来自病例报告。我们的目的是评估在一个单中心的研究成果和肝移植的经验，从HBsAg阳性献血者。
方法

从2010年1月至2013年2月，42成人患者经历了从HBsAg阳性献血者肝移植和327例患者HBsAg阴性的。成果包括并发症和两组生存率比较和抗病毒治疗的回顾性分析。
结果

HBsAg阳性肝移植更可能被分配到患者的乙肝病毒（HBV）相关的疾病。移植后的评价表现出类似的移植肾功能恢复的速度和并发症无显着差异，如原发性无功能，急性排斥反应，胆道并发症。患者和移植物存活率均媲美的HBsAg阴性移植。此外，乙肝表面抗原移植手术后坚持收到积极的移植所有患者。供体HBV血清状态测定移植后的收件人之一。没有乙肝病毒的突发被下口服核苷类似物抗病毒治疗观察，无论使用乙肝免疫球蛋白结合。
结论

对HBsAg阳性肝移植的利用率似乎不增加术后并发症发生率和死亡率。因此，它是一种安全的方式来扩大捐助池时，没有合适的供体是可用的。我们的经验还表明，乙肝免疫球蛋白应在乙肝表面抗原阳性的肝移植受者被抛弃，在其中乙肝预防可能是唯一的口服抗病毒药物治疗。
缩写：
LTX（肝移植），HBV（乙肝病毒），乙肝表面抗原（乙肝表面抗原），乙肝免疫球蛋白（乙肝免疫球蛋白）和NAS（核苷酸类似物），HBcAb阳性（乙肝核心抗体），MELD（型号为终末期肝病），e抗原（乙肝e抗原），抗 -  HBs（乙肝表面抗体），ALT（谷丙转氨酶），AST（谷草转氨酶），肺结核（总胆红素），DB（直接胆红素），PT（凝血酶原时间）
关键词：
肝移植，乙肝表面抗原阳性的供体，移植边际，抗病毒治疗

StephenW

Persistent hepatitis B virus (HBV) infection has been and still is a leading cause for end-stage liver disease in endemic regions in Asia and Africa. In contrast, in the Western hemisphere, the rates of HBV infection in liver transplant candidates is lower and declining as reflected in a recent UNOS analysis, reporting a 5.3% rate of HBV infection as the cause for liver failure and HBV associated hepatocellular carcinoma among 48,654 liver transplant candidates in the US [1]. The ongoing worldwide organ shortage for liver transplantation (LTx) has been a driving force for exploring new means to expand the pool of potential organ donors. Depending on the age of acquisition, acute HBV infection resolves spontaneously in up to ∼90% of infected adults with an intact immune system. Consequently, the pool of potential liver donors includes a fraction of either anti-HBs+/anti-HBc+ or HBsAg−/anti-HBs−/anti-HBc+ individuals with normal liver functions who have such recovered from HBV infection. The size of this pool is driven by the particular prevalence of HBV infection in designated regions worldwide ranging between 1.8% and 6% in the US (between 1994 and 2006) as compared for example to 63% (2003) in Taiwan [[2], [3]]. A retrospective survey among 35,620 cadaveric adult transplant recipients in the US (1994–2006) identified up to 8.5% anti-HBc+ donors. Understandably, the safety of using livers from such potential donors has initially been challenged due to the presence of occult HBV infection in some of the grafts, manifested by residual hepatic intra-nuclear cccHBV-DNA even in anti-HBc+/anti-HBs+ individuals, which can serve as a template for post transplantation HBV reactivation in immune suppressed recipients. More than two decades have passed since the first reports on transmission of occult HBV infection from HBsAg−/anti-HBc+ or anti-HBc+/anti-HBs+ liver transplant donors to HBV naïve recipients [[4], [5], [6], [7]]. It soon became clear that the risk of HBV reactivation or de novo infection in recipients of such previously infected grafts may reach 75–80% in HBV naïve recipients, declining to 15–20% in anti-HBc+ or anti-HBs+ patients and to 0–5% in anti-HBs+/anti-HBc+ individuals. Meanwhile the development of potent nucleot(s)ide analogues as well as hepatitis B immune globulin (HBIG) provide excellent means to protect HBV naïve or even anti-HBc+ liver graft recipients against either de novo or reactivation of HBV infection. Consequently there is by now almost worldwide consensus that anti-HBc+ as well as anti-HBc+/anti-HBs+ grafts can be transplanted to matched patients with overt, occult or past HBV infection (and under certain circumstances in emergency conditions and with some precautions even to HBV naïve recipients). Recipients of such organs were reported to have an overall similar post transplant survival (with some exceptions [8]) as compared to anti-HBc−/HBsAg− naïve donors [[2], [9], [10], [11], [12], [13], [14]]. The current approach to the utilization of such grafts is reflected in the results of a 2007 international survey suggesting that most transplant centres will accept anti-HBc+ grafts even for HBV naïve recipients [15]. It took almost a decade to evaluate the advantages, the short term and intermediate safety and the limitations of using liver transplant grafts with occult HBV infection for patients with liver failure. Although data on long-term follow-up and safety in recipients of anti-HBc+ grafts are still unavailable, there is already a consensus as quoted from a recent editorial in the Journal of Hepatology by Cholangitas et al.:

“Liver grafts from anti-HBc positive donors can be safely used, preferentially in HBsAg-positive or anti-HBc/anti-HBs positive recipients. HBsAg-negative recipients should receive prophylaxis with lamivudine, while both anti-HBc and anti-HBs positive recipients may need no prophylaxis at all” [14]. A similar view is expressed in the title of an editorial by M. Prieto “Antibody to hepatitis B core antigen-positive grafts: Not perfect but no longer marginal” [12].

Attention is now shifting to explore further means for expansion of the donor pool through utilization of HBsAg+ grafts from donors with overt HBV infection but with preserved liver function and without significant fibrosis for HBsAg+ recipients.

The first case report on the utilization of HBsAg+ grafts appeared in 1994 [16] followed by more case reports between 2005 and 2007 [[16], [17], [18], [19], [20]]. Single centre reports on small series of patients receiving HBsAg+ grafts in 6–10 patients [[21], [22], [23]] followed by a larger study in 92 liver transplant recipients [24], paved the road for exploring this avenue of salvage further. A recent retrospective analysis of the US national data base (N = 78) confirmed that transplantation of HBsAg+ grafts, mainly in recipients with a history of HBV infection, did not reduce graft and patients survival post transplantation, provided recipients were protected with anti-viral therapy [25]. In the study using US national registry data, the 5 year HBsAg+ patient survival was 71% compared to 71% in the control group with a graft survival of 66% and 64% for recipients of HBsAg+ grafts and matched controls, respectively. Yet, the worldwide experience using HBsAg+ liver grafts is limited. In the present issue of the Journal of Hepatology, Yu and co-workers report their experience in a cohort of 42 adult Chinese patients who underwent liver-transplantation with an HBsAg+ graft [26].

In this study, the investigators have retrospectively compared the short-term follow-up as well as the clinical, laboratory and serologic postoperative course and outcome of 42 orthotopic liver transplant recipients from HBsAg+ donors to 327 LTx recipients from HBsAg− donors. Among the HBsAg+ positive graft recipients, 38 patients survived more than 1 month and the maximal follow-up period was about 3 years. The overall mean follow-up for the recipients of an HBV positive graft was 13.9 ± 11.2 months as compared to 19 ± 11.8 months for the control group (p ⩽ 0.01). Among the 327 patients in the control group, 25.7% had apparently some HBV marker (details not mentioned) as a result of past exposure to HBV while 4/42 LTx patients who received an HBsAg+ graft were apparently HBV naïve.

The main results of the study include: (1) The immediate rates of postoperative morbidity and mortality as reflected by follow-up of primary graft non-function, acute rejection, biliary complications and liver function tests were similar in both study groups. (2) Since HBsAg positivity persists in recipients of HBV infected grafts, anti-viral treatment with a nucleos(t)ide analogue should be continued for an indefinite period post operatively but there is no rational in the administration of HBIG in such patients. (3) Immune suppressive treatment of HBsAg+ patients receiving an HBsAg+ graft did not result in overt HBV reactivation. (4) All in all, transplantation of HBsAg+ grafts from HBV infected patients with preserved liver functions and presumably no significant liver disease to HBsAg+ recipients is a legitimate means to provide rescue for LTx candidates when no HBV naïve or anti-HBc+/HBsAg− donors are available.
Comments

The results of this study confirm previous retrospective observations regarding the utility of using HBsAg+ grafts in situations where no other options such as an HBV naïve cadaveric or living related donor are available. Thus, these results provide further justification for expanding the donor pool, especially in countries endemic for HBV such as China where the current prevalence of HBsAg is around 7% [27], not to speak of a rather high anti-HBc+ rate. Furthermore, as also reported previously, transplantation of HBsAg+ grafts may likewise be considered under special circumstances when other options are unavailable even for HBV negative recipients (with adequate anti-viral protection) as well as for anti-HBc+ and or anti-HBs+ patients with liver failure. The paper by Yu and coworkers is well written although the study design and results have some limitations as acknowledged by the authors. These include among others the retrospective and partially controlled design of the study; the relatively short-term follow-up, which does not enable a firm conclusion regarding the long-term safety and assessment of HBV associated complications. Interestingly, most organ recipients from HBeAg+ donors maintained an HBeAg+ status post transplantation, regardless of their original HBeAg or anti-HBe status prior to transplantation. This observation justifies a more in depth analysis including quantitative serum, intrahepatic and cccHBV-DNA measurements, genotyping and comparative sequencing of HBV-DNA with phylogenetic analysis in donors and recipients alike. In this context it is worthwhile to cite a previous report from Hong-Kong [28] and an accompanying editorial [29] describing a so called competition between two occult hepatitis B virus infections, which originated from an anti-HBc+ donor whose liver was transplanted to a patient with occult HBV who has previously been infected with HBV as well and treated with lamivudine. Therefore, further studies should include long-term monitoring of these parameters, which should lead to better understanding of the molecular pathophysiology in such patients, including the impact of genotype on the natural history of the graft. Finally, there are other, albeit experimental means for providing protection against HBV to graft recipients which remain to be explored, including adoptive transfer of immunity from anti-HBs positive donors to recipients [30] or immunization with a PreS/S vaccine [[31], [32]].

In conclusion, the results of this chinese study by Yu and co-workers confirm and complement a number of previous observations from Europe and the US regarding the utility and short-term safety of LTx using HBsAg+ donors for HBsAg+ recipients. At present, data from a prospectively adequately controlled trial are unavailable. The logistics of conducting such a study in the future are complex and it is doubtful that results will be available in the near future. Meanwhile, and until then, it is the opinion of this viewer that the already obtained evidence justifies the use of HBsAg+ donors for patient persistently infected with HBV and liver failure when no other donor is available. However, in the absence of data regarding the safety of using grafts from HBsAg(+) donors with delta virus co-infection, or vise versa transplanting HBsAg(+) grafts to delta virus infected recipients, caution is advised regarding approval of transplantation in such a situation. Not less important, further long-term follow-up is required for those HBsAg+ LTx recipients who have already received a graft from an HBsAg+ donor.

StephenW

持久性乙型肝炎病毒（HBV）感染一直并且仍然是治疗终末期肝病在亚洲和非洲流行地区的主要原因。相反，在西半球，HBV感染的肝移植候选者的比率较低，下降反映在最近的UNOS的分析，报告HBV感染的5.3％的税率作为其中48654原因为肝功能衰竭和HBV相关的肝癌肝移植候选者在美国[1]。正在进行的全球器官短缺的肝移植（LTX）一直探索新的途径，扩大潜在的器官捐献者的池中的驱动力。根据采集的年龄，急性HBV感染会自行消退感染的成年人高达约90％，具有完整的免疫系统。因此，潜在的肝脏捐赠者的池包括两种抗HBs+/抗HBc+或HBsAg-/抗HBs-/抗HBc+个体与正常肝功能谁从HBV感染这种回收的一小部分。此池的大小是由HBV感染的特定患病在台湾从动中指定的区域，在美国（1994年和2006年之间）之间的1.8％和6％全世界范围相比，例如到63％（2003年）[[2] ，[3]。其中35,620成人尸体移植受者进行回顾性调查，在美国（1994-2006年）确定的高达8.5％，抗HBc+供体。可以理解的是，利用肝脏的这种潜在的捐助者的安全性已初步被由于隐匿性HBV感染中的一些移植物的存在，即使在​​抗HBc+/抗HBs+个人挑战，残余肝脏内的核cccHBV-DNA的体现，它可作为免疫抑制受者移植后HBV再激活的模板。因为从HBsAg-/抗HBc+或抗HBc对隐匿性HBV感染传播的第一次报告超过二十年过去了+/抗HBs+肝移植供体乙肝病毒天真收件人[[4]，[5]，[6] [7]。它很快变得清晰，乙肝病毒再激活或从头感染等先前感染的移植受者的风险可能在HBV的天真收件人达到75-80％，在抗HBc+或抗HBs阳性患者和0下降至15-20％ -5％的抗HBs+/抗HBc+个人。同时强效nucleot（S）类似物的开发，以及乙肝免疫球蛋白（HBIG），提供优异的手段来保护乙肝病毒天真，甚至抗HBc+肝移植对任何从头或HBV感染的再激活收件人。因此存在由现在几乎全世界的共识，即抗HBc+以及抗HBc+/抗HBs+移植物可被移植到匹配的患者明显的，隐匿或过去的HBV感染（和下在紧急情况下，用一些预防措施甚至某些情况下乙肝病毒天真收件人）。这样的器官接受者据报道，有一个整体的类似移植后存活（有一些例外[8]）相比，抗HBc-/ HBsAg-幼稚捐助[[2]，[9]，[10]，[11] ，[12]，[13]，[14]。目前的做法，以这种移植的利用体现在2007年的国际调查表明，大部分移植中心接受抗HBc+移植甚至是乙肝病毒天真收件人[15]的结果。花了将近十年的时间来评估的优势，短期和中期的安全性和使用肝移植移植与隐匿性HBV感染的肝衰竭患者的局限性。虽然长期随访和安全的抗HBc+移植受者的数据​​仍然无法使用，已经有从最近的一篇社论中肝胆病杂志引述Cholangitas等人的共识：

从抗HBc阳性献血者“肝移植可以安全使用，优先在HBsAg阳性，或抗-HBc阳性/抗HBs阳性的受者。 HBsAg阴性受者应接受预防性使用拉米夫定，同时兼具抗HBc和抗-HBs阳收件人可能不需要预防可言“[14]。类似的观点体现在社论中由M.普列托的标题是“抗体乙肝核心抗原阳性的移植物：不完美的，但不再边缘”[12]。

现在将注意力转移到探讨进一步措施，通过利用从捐赠者有明显HBV感染乙肝表面抗原+扩展移植供体池但保留肝功能不显著纤维化的乙肝表面抗原+收件人。

对乙肝表面抗原+移植的利用率首例报告出现在1994年[16]其次是更多的病例报告2005年至2007年[[16]，[17]，[18]，[19]，[20]]。在6-10病患小编收到的HBsAg+移植患者单中心报告[[21]，[22]，[23]]，然后在92肝移植受者[24]更大规模的研究，奠定了探索这条大道的路进一步打捞。美国国家数据库的最近的回顾性分析（N =78）证实，乙肝表面抗原+移植移植，主要是受者HBV感染的病史，并没有减少移植物和患者的生存期后移植，提供了受者的保护与抗病毒治疗[25]。在使用美国国家登记数据的研究，5年的HBsAg+的患者存活率为71％，比71％，对照组有66％的移植物存活率和64％的乙肝表面抗原+移植和匹配的对照组，分别收件人。然而，使用的HBsAg+肝移植全世界的经验是有限的。在肝脏，宇和同事的杂志目前的问题报告他们的经验，在42个中国成年患者谁接受肝移植的乙肝表面抗原+移植[26]的队列。

在这项研究中，研究者回顾性比较短期的随访以及临床，实验室和术后血清学课程，并从42乙肝表面抗原原位肝移植+供体，从HBsAg-捐赠327 LTX收件人的结果。其中乙肝表面抗原阳性+移植受者，38例存活超过1个月，最大随访时间为3年左右。整体平均随访为HBV阳性移植的受者为13.9±11.2个月相比，19±11.8个月，对照组（P⩽0.01）。其中327例，对照组中，25.7％的人显然有些乙肝病毒标志物（未提及的细节），由于过去接触到乙肝病毒的结果，而谁收到的HBsAg+移植4/42 LTX患者乙肝病毒显然天真。

该研究的主要结果包括：（1）术后发病率和死亡率所反映后续原发性移植物无功能，急性排斥反应，胆道并发症和肝功能试验的直接率分别在两个研究组中相似。 （2）由于乙肝表面抗原阳性持续存在乙肝病毒感染的移植受者，抗病毒治疗与核苷（酸）类似物IDE应继续无限期后操作但在乙肝免疫球蛋白对此类患者的管理不理性的。 （3）免疫抑制治疗的HBsAg+接收患者的HBsAg+植骨没有造成明显的乙肝病毒再激活。 （4）所有的一切，移植来自乙肝病毒感染患者的HBsAg+移植与保留肝功能，想必没有显著肝病乙肝表面抗原+收件人是一个合法的手段，为抢救LTX候选人时，没有乙肝初治或抗HBc+/ HBsAg-捐助是可用的。
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这项研究的结果证实了先前关于使用的HBsAg+移植的情况下，有没有其他的选择，如乙肝病毒天真尸体或活体捐赠者的效用追溯意见。因此，这些结果提供了进一步的理由扩大捐助池，尤其是在流行的HBV国家，如中国，乙肝表面抗原目前患病率在7％左右[27]，更不要说具有相当高的抗HBc+速度。此外，也如以前报道，乙型肝炎病毒表面抗原+移植物移植同样可以在特殊情况下考虑时，其它选项不可用，即使为HBV阴性收件人（具有足够的抗病毒的保护），以及用于抗HBc+和或抗HBs+患者肝功能衰竭。由宇和同事的论文写得很好，虽然这项研究的设计和结果有一定的局限性所承认的作者。等等这些包括研究的回顾和部分控制设计;相对短期的随访，不能够对乙肝并发症的长期安全性和评估肯定的结论。有趣的是，HBeAg阳性献血者大多数器官接受者保持了HBeAg阳性状态移植后，无论其原始的HBeAg或抗HBe状态之前移植。这一观察结果证明了较为深入的分析，包括定量血清，肝内和cccHBV-DNA的测定，基因分型和HBV-DNA与在捐助者和受者的一致好评系统发育分析比较测序。在这方面，值得引用来自香港，香港以前的报告[28]以及随后的社论[29]描述两个隐匿性乙肝病毒感染之间存在所谓的竞争，这是源于一种抗HBc+供体的肝移植与谁曾感染过乙肝病毒，以及与拉米夫定治疗隐匿性乙肝患者。因此，进一步的研究应该包括长期监测这些参数，这将导致更好地理解这样的患者，包括基因型对移植物的自然史的影响的分子病理生理学的。最后，还有一些其他的，尽管实验装置，用于提供保护对抗HBV接枝收件人其中有待探讨，包括免疫，从抗HBs阳性供体过继转移到受者[30]或免疫用前S/ S的疫苗[[31 〕，〔32〕。

总之，这个中国研究的俞结果和同事确认，并补充有关LTX使用的HBsAg+捐助者的HBsAg+收件人的效用和短期安全了许多以前的意见，来自欧洲和美国。目前，从充分的前瞻性对照研究的数据不可用。进行这项研究，在未来的物流是复杂的，这是值得怀疑的结果将在不久的将来。与此同时，在那之前，正是这种浏览器，已经获得的证据证明使用的HBsAg+供体的患者持续感染乙肝病毒和肝功能衰竭时，没有其他捐助可用的意见。然而，在没有关于使用移植自HBsAg的安全数据（+），捐助者与增量病毒合并感染，或反之亦然移植的HBsAg（+），嫁接到三角洲病毒感染的接受者，应该特别注意对移植的有关批准的情况。不那么重要，更长期的随访，需要为那些谁已经接受了移植物的乙肝表面抗原+捐助的HBsAg+ LTX收件人。