血浆置换对恩替卡韦治疗慢性乙型肝炎患者肝去补偿和急性

StephenW

Original Article

Hepatology International

May 2016, Volume 10, Issue 3, pp 462-469

First online: 19 October 2015
The effect of plasma exchange on entecavir-treated chronic hepatitis B patients with hepatic de-compensation and acute-on-chronic liver failure

    Wan Yue-Meng , Li-Hong Yang, Jin-Hui Yang , Ying Xu , Jing Yang, Gui-Bo Song


Abstract
Background and aims

Various studies showed that entecavir (ETV) failed to improve the short-term survival in chronic hepatitis B (CHB) patients with severe acute exacerbation (SAE) and hepatic de-compensation or acute-on-chronic liver failure (ACLF). One study concluded that plasma exchange (PE) significantly decreased the short-term mortality of CHB patients with ACLF who were treated with lamivudine (LAM). Our study was designed to examine the effect of PE on CHB patients with ACLF who were treated with ETV.
Methods

From August 2010 to January 2015, 38 (PE group) and 120 (control group) consecutive CHB-naïve patients with hepatic de-compensation and ACLF treated with PE plus ETV and ETV, respectively, were recruited. The primary endpoint was liver-related mortality at week 12. Biochemical and virological responses were also studied.
Results

At baseline, the PE group had higher serum alanine aminotransferase (ALT) levels and model for end-stage liver disease (MELD) scores, and had lower albumin levels than the control group. The cumulative survival rate at week 4 and week 12 in the PE group and control group were, respectively, 37 and 18 %, and 29 and 14 % (p < 0.001, by log rank test). While the bilirubin levels in the PE group were more quickly lowered by PE therapy (p < 0.001), the decrease of ALT levels and virological response were similar in the two groups (p > 0.05). Univariate analysis showed that the control group had a higher liver-related mortality (p = 0.038) at week 12 than the PE group. Multivariate analysis showed that hepatic encephalopathy, ascites, PE treatment, and MELD scores were independent factors for liver-related mortality at week 12.
Conclusions

PE significantly improved the short-term survival of CHB patients with hepatic de-compensation and ACLF who were treated with ETV. Hepatic encephalopathy, ascites, PE treatment, and MELD scores were independent factors for liver-related mortality at week 12.
Keywords
Chronic hepatitis B Hepatic de-compensation Acute-on-chronic liver failure Entevavir Plasma exchange

Wan Yue-Meng and Ying Xu contributed equally to this work.
Hepatology International Hepatology International Look
Inside

    Asian Pacific Association for the Study of the Liver

    Co-published with:
    Asian Pacific Association for the Study of the Liver

StephenW

原始文章

国际肝病

2016年5月，第10卷，第3期，第462-469

首先在线：2015年10月19日
血浆置换对恩替卡韦治疗慢性乙型肝炎患者肝去补偿和急性发作慢性肝功能衰竭的影响

    玩月猛，李宏阳，金汇洋，徐莹，景阳，桂宋波


抽象
背景和目的

各种研究表明，恩替卡韦（ETV）未能改善慢性乙型肝炎（CHB）患者严重急性发作（SAE）和肝去补偿或急性发作，慢性肝功能衰竭（ACLF）的短期生存。一项研究得出的结论是血浆置换（PE）显著下跌CHB患者ACLF谁用拉米夫定（LAM）治疗的短期死亡率。我们的研究旨在探讨PE对慢性乙型肝炎患者的ACLF谁是恩替卡韦治疗的效果。
方法

从2010年8月至2015年1月，38（PE组）和120（对照组）连续CHB初治患者与PE加ETV教育电视和肝治疗去补偿和ACLF，分别被招募。主要终点是在周肝脏相关的死亡率12.生化和病毒学反应进行了研究。
结果

基线时，PE组终末期肝病（MELD）得分较高的血清丙氨酸氨基转移酶（ALT）水平和模型，并有白蛋白水平比对照组低。在PE组和对照组在第4周和第12周的累积存活率分别为37和18％，29％和14％（P <0.001，通过对数秩检验）。而PE组中的胆红素水平通过PE疗法（对更快速地降低<0.001），ALT水平的降低和病毒学应答分别在两个组（第类似> 0.05）。单变量分析表明，与对照组有12周更高的肝相关的死亡率（p值= 0.038）比PE组。多因素分析表明，肝性脑病，腹水，PE治疗和MELD评分均于12周肝脏相关死亡率的独立危险因素。
结论

PE显著改善慢性乙型肝炎患者肝去补偿和ACLF谁是恩替卡韦治疗的短期生存。肝性脑病，腹水，PE治疗和MELD评分均于12周肝脏相关死亡率的独立危险因素。
关键词
慢性乙型肝炎肝脱补偿急性发作，慢性肝衰竭Entevavir血浆置换

玩月猛和徐莹同样促成了这一工作。
肝病肝病国际看国际
内

    亚太协会肝病研究学会

    共出版了：
    亚太协会肝病研究学会

StephenW

Editorial

Hepatology International

May 2016, Volume 10, Issue 3, pp 387-389

First online: 04 February 2016
Plasma exchange for acute on chronic liver failure: is there a light at the end of the tunnel?

    Rakhi Maiwall , Richard Moreau

10.1007/s12072-016-9703-z

Copyright information

In the last decade there has been renewed interest in artificial liver support systems (ALSs), which have emerged as a potential tool for management of patients with acute and acute-on-chronic liver failure (ACLF) [1, 2]. Traditionally, management of these patients has been based on hemodynamic, neuroprotective and renal support systems with liver transplantation (LT) as the only definitive treatment option [1]. However, LT remains a limited resource, and therefore there is an unmet need for alternative therapies for this disease. Use of ALSs was shown to be associated with a reduction in mortality in controlled and uncontrolled series compared to traditional treatment options in these patients [2]. However, the mechanisms by which ALSs improve outcome of ACLF are poorly understood. The first stage of ACLF is characterized by a systemic inflammatory response syndrome (SIRS), which may be excessive and cause tissue damage. The SIRS stage further progresses to one of compensatory antiinflammatory response syndrome (CARS) or a state of immunoparalysis. This stage is characterized by an impaired ability to clear bacterial pathogens, development of second or nosocomial infections, opportunistic infections and death [1–4]. Defects in the clearance of antibody-coated bacteria and the complement system, a decrease in HLA-DR expression on monocytes and defects in neutrophil function, i.e., impairment of the phagocytic capacity, chemotaxis and an increase in the resting oxidative burst are seen in this phase [4]. Therefore, it may be important to restore an appropriate inflammatory response of the host in the initial phase of SIRS and prevent progression to CARS. Plasma exchange (PE), by causing elimination of a wide array of accumulated toxins in patients with liver failure, can facilitate recovery of the failing liver by providing an environment conducive to liver regeneration and can be used as an effective therapy for bridging the failing liver to LT [2, 5]. During this procedure, the patient’s plasma is removed an exchanged with fresh frozen plasma. Treatment with PE in addition to correction of coagulopathy can potentiate removal of toxic metabolites as well as the poorly identified mediators of multiorgan failure. In a recent prospective, multicenter, randomized controlled trial of 182 patients with acute liver failure, treatment with high-volume PE was shown to modulate the inflammatory cytokine storm, dampen the antiinflammatory responses and ameliorate multiorgan failure, which was associated with improved transplant-free survival [5]. However, there have been no randomized controlled trials of PE for ACLF.

In a retrospective study Wan Yue Meng and colleagues investigated the efficacy of PE in patients with acute-on-chronic liver failure and acute decompensation of cirrhosis treated with entecavir (ETV) [6]. Patients who were extremely sick with unstable hemodynamics and disseminated intravascular coagulation were excluded from the study. Patients were enrolled into two groups, i.e., the PE group (n = 38) and control group (n = 120). All enrolled patients were treated with entecavir 0.5 mg daily along with the standard of care. Patients in the PE group received 2–5 sessions of PE therapy. PE therapy was performed twice every week until the patient’s condition was stable. Patients in the PE group were sicker with higher MELD scores and lower albumin levels compared to the control group. The proportion of patients with other complications such as hepatic encephalopathy, variceal bleed and renal dysfunction was not different between the two groups at baseline. The baseline virological parameters, such as the presence of HBeAg as well as HBV DNA, were also not significantly different between the two groups. At 3-month follow-up it was noted that patients in the PE group had lower mortality compared to the control group. The cumulative survival rate at 1 and 3 months in the PE and control group was 37, 18, 29 and 14 %, respectively (log rank p = 0.001, HR 1.98, 95 % CI 1.29–3.03). On multivariate analysis, treatment with PE therapy was associated with improved survival at 3 months. Further, this benefit in survival was not associated with improved virological response as no significant difference was noted in the mean HBV DNA in patients treated with PE compared to the control group, 3.69 ± 0.26 and 3.81 ± 0.19 log10 copies/ml and 3.42 ± 0.12 and 3.54 ± 0.21 log10 copies/ml at week 2 and 4, respectively. Moreover, the number of patients with HBeAg-positive disease achieving HBeAg seroconversion was also not significantly different between the two groups.

Even though the study has the limitation of a retrospective and monocentric design, it nevertheless provides useful information on additional therapeutic approaches that could be beneficial in improving liver functions in patients with HBV-related ACLF (HBV-ACLF). Furthermore, despite the fact that patients in the PE group were sicker than those in the control group, a significantly better survival at both 1 and 3 months was seen in the PE group compared to the control group. All patients were treated with entecavir and conventional treatment for the associated complications.

Published data from controlled and uncontrolled series has demonstrated a survival benefit with treatment with nucleos(t)ide analogs in patients with HBV-ACLF related to potent viral suppression [7]. Therefore, according to the current recommendations, all patients with HBV-ACLF should be immediately considered for antiviral therapy to reduce the severity of liver failure and the risk of viral recurrence post-LT [7]. However, unfortunately, only limited benefit has been reported for antivirals alone in HBV-ACLF, necessitating the exploration of alternative therapeutic options for these patients [8]. Other options that have been evaluated in clinical trials include detoxification strategies with artificial liver support systems (ALSs) and therapies to potentiate liver regeneration [8]. None of the currently available ALS devices, i.e., the molecular adsorbent recirculating system (MARS), single-pass albumin dialysis (SPAD) and Prometheus, were associated with a survival benefit in randomized controlled trials done in patients with ACLF [9]. However, data from uncontrolled series have suggested a beneficial role of plasma exchange in these patients because of the clearance of ammonia [10], inflammatory cytokines [11], markers of oxidative stress, i.e., advanced oxidation protein products [12], and amelioration of dysregulated immune systems [13, 14]. In a Chinese study of patients with hepatitis B-related ACLF, it was seen that a decrease in the MELD score after treatment with artificial liver support pre-transplantation led to improved survival post-transplantation, which was comparable to that of patients who underwent emergency liver transplantation [15]. In another study, 62 patients with HBV ACLF who received PE treatment were compared with 131 patients treated with standard of care. The 30-day survival rate of the patients who received PE was significantly higher compared to controls (41.9 versus 25.2 %; p < 0.05). Interestingly, this benefit was limited only to patients with less severe disease with MELD scores in the range of 20–30 and was not seen for patients with MELD scores >30 [16]. Further, a combination of PE treatment with continuous hemodialfiltration [17], plasma bilirubin adsorption [18] or MARS [19] has been shown to be more effective than PE alone. The reason for the lack of a consistent survival benefit with PE and other ALS systems remains the functional incompetence, as these provide only the detoxification function of the entire armamentarium of liver functions. Therefore, therapies that incorporate synthetic functions by means of living hepatocytes in the ‘bioartficial liver’ or could potentiate hepatic regeneration look more realistic [2]. In patients with HBV-ACLF, randomized controlled trials have shown an improvement in survival by use of mesenchymal stem cells and granulocyte colony-stimulating factor (G-CSF) [20, 21]. A strategy of combining PE with G-CSF has also been proposed; this needs to be studied in larger randomized controlled clinical trials [22].

In summary, even though liver transplant remains the primary treatment modality for patients with HBV ACLF, ALSs including PE can be considered as an effective form of bridging therapy in combination with antiviral therapy in patients with a MELD scores <30 and without multiorgan failure. PE in these patients not only provided transient improvement in biochemical and clinical parameters and help in supporting the failing liver until LT, but could also potentially rescue patients to spontaneous regeneration. In patients with more severe liver failure with a MELD score >30, the benefit of PE remained questionable. It would also be interesting to explore the strategy of combining PE with G-CSF or stem cell therapy in patients with HBV-ACLF. However, considering the limited available evidence, larger prospective randomized controlled trials are needed before recommendations can be made for routine incorporation of PE into standard clinical practice.

StephenW

社论

国际肝病

2016年5月，第10卷，第3期，第387-389

首先在线：2016年02月04日
对慢性肝衰竭的急性血浆置换：有没有在隧道尽头的亮光？

    拉祈彩Maiwall，理查德·莫罗

10.1007 / s12072-016-9703-Z

版权信息

在过去的十年中一直存在在人工肝支持系统（的ALS），其已经成为用于患者管理的潜在工具的急性和急性上慢性肝衰竭（ACLF）新的兴趣并[1,2]。传统上，这些病人的管理已经基于血液动力学，肝移植（LT）作为唯一的决定性的治疗选择的神经保护和肾支持系统[1]。然而，LT仍然有限的资源，并且因此存在用于这种疾病替代疗法未满足的需要。的ALS的使用被证明是与死亡率在受控和不受控制系列的减少相比，在这些患者中[2]传统的治疗方案相关联。然而，通过其中的ALS提高ACLF的结果的机制知之甚少。 ACLF的第一阶段的特征是全身性炎症反应综合征（SIRS），其可以是过度的，并导致组织损伤。的SIRS阶段进一步前进到补偿性抗炎症反应综合症（CARS）的一种或免疫麻痹的状态。这一阶段的特征是用来清除细菌病原体，第二或医院内感染，机会性感染和死亡[1-4]发展的能力受损。在抗体包被的细菌的清除率和补体系统，在对嗜中性粒细胞功能，即单核细胞和缺陷HLA-DR的表达的减少缺陷，吞噬能力，​​趋化性并增加在静止氧化猝发减值被视为在本相[4]。因此，它可能以恢复在SIRS的初始阶段的主机的一个适当的炎症反应和防止发展为CARS是重要的。血浆置换（PE），由患者引起消除丰富的积累的毒素的肝衰竭，可以通​​过对肝再生提供一种有利于环境促进失败肝脏的恢复，并且可以作为一种有效的疗法用于桥接发生故障的肝到LT [2,5]。在此过程中，患者的血浆除去新鲜冷冻血浆的交换。与除了凝血的校正PE治疗可以使可能去除有毒的代谢物，以及所识别的较差多脏器衰竭的介质。在最近的一项前瞻性，多中心，随机对照的182例急性肝功能衰竭，具有高容量的PE治疗试验结果表明，以调节炎症细胞因子风暴，挫伤抗炎反应和改善多器官衰竭，其具有改进的移植 - 自由关联存活[5]。然而，一直是ACLF PE的随机对照试验。

在回顾性研究玩月猛和他的同事研究了PE的疗效急性上，慢性肝功能衰竭和恩替卡韦（ETV）治疗肝硬化失代偿急[6]。谁是恶心至极不稳定血流动力学和弥散性血管内凝血患者被排除在研究。例患者分为两组，即PE组​​（n = 38）和对照组（n = 120）。所有入选患者均采用恩替卡韦每天0.5毫克的护理标准一起处理。在PE组患者接受治疗的PE 2-5会话。每星期，直到患者的病情稳定进行两次的PE治疗。相比于对照组的PE组中患者具有较高MELD分数​​和低白蛋白水平病情加重。患者的其他并发症，如肝性脑病，静脉曲张出血和肾功能不全的比例为不基线两组之间不同。基线病毒学参数，如e抗原的存在以及HBV DNA，也没有两组间显著不同。在3个月的随访有人指出，患者PE组较对照组降低死亡率。在PE和对照组1和3个月累积生存率为37，18，29和14％，分别为（日志等级P = 0.001，HR 1.98，95％CI 1.29-3.03）。多变量分析显示，与PE疗法治疗与改善生存3个月有关。另外，在生存这种好处不具有改善的病毒学反应，因为没有显著差异，在用PE相比于对照组治疗的患者中的平均的HBV DNA指出相关联，3.69±0.26和3.81±0.19 log10拷贝/ ml和3.42±0.12和3.54±0.21 log10拷贝/毫升分别在第2周和4。此外，例HBeAg阳性患者达到HBeAg血清学转换的数量也丝毫不两组间显著不同。

尽管该研究具有追溯和单中心设计的限制，但它提供了有关可能有助于提高患者的HBV相关ACLF（HBV-ACLF）肝脏功能有益的附加治疗方法的有用信息。此外，尽管事实上患者PE组中比对照组中，一个显著更好的生存在两个1和3个月时看到的PE组中相比于对照组病情加重。所有患者均采用恩替卡韦和常规治疗的相关并发症治疗。

从受控和不受控制的一系列公布的数据表明患者HBV-ACLF相关的强效抑制病毒[7]生存益处与治疗核苷（酸）类似物。因此，根据当前的建议，与HBV-ACLF所有患者应立即考虑抗病毒治疗，以减少肝衰竭的严重性和病毒复发后LT的风险[7]。然而，不幸的是，只有有限的益处已被报道用于在HBV-ACLF单独抗病毒药，因此需要替代的治疗方法对这些患者的勘探[8]。已在临床试验中被评估其他选项包括人工肝支持系统的排毒策略（个ALS）和治疗能增强肝脏的再生[8]。目前可用的ALS设备没有限制，即，分子吸附再循环系统（MARS），单通白蛋白透析（SPAD）和普罗米修斯，用生存受益于患者完成与ACLF [9]的随机对照试验有关。然而，从不受控制的一系列数据也表明血浆置换，在这些患者由于氨[10]，炎性细胞因子[11]，氧化应激，也就是说，高级氧化蛋白产物[12]，以及改善的标志物的清除有益的作用的失调免疫系统[13，14]。在乙肝患者相关ACLF中国​​的研究，它被认为人工肝支持预移植治疗后的MELD评分的减少导致改善生存移植后，这是媲美的谁接受急诊病人肝移植[15]。在另一项研究中，62例HBV ACLF谁收到PE进行治疗与护理标准治疗的131例患者进行比较。谁收到PE患者30天的生存率比较高显著对照（41.9与25.2％，P <0.05）。有趣的是，这样做的好处是只限于患者不太严重的疾病，在20-30的范围内MELD评分，并没有看到患者的MELD评分> 30 [16]。此外，利用连续hemodialfiltration [17]，血浆胆红素吸附[18]或MARS已经显示[19]为比单独的PE更有效的PE治疗的组合。究其原因，缺乏与PE和其他ALS系统一致的生存获益仍然是功能无能，因为这些只提供肝功能，整个医疗设备的解毒功能。因此，通过在“bioartficial肝脏”活肝细胞的手段掺入合成的功能，或者可以使可能的肝再生疗法看起来更逼真[2]。患者的HBV-ACLF，随机对照试验通过使用间充质干细胞和粒细胞集落刺激因子（G-CSF）[20，21]示出在生存的改善。 PE与G-CSF相结合的策略也被提出;这需要在更大的随机对照临床试验[22]待研究。

总之，尽管肝脏移植仍然是主要的治疗方式对患者的HBV ACLF，ALS的包括PE可以被认为是患者的抗病毒治疗的组合桥接治疗与MELD评分<30和没有多器官衰竭的有效形式。 PE在这些患者不仅提供瞬态改善生化和临床参数以及支持失败的肝脏，直到LT帮助，但也有可能抢救患者自然发生。在患者与MELD评分> 30更严重的肝功能衰竭，PE的好处仍然值得怀疑。这也将是有趣的探索与PE G-CSF相结合的策略，或干的患者HBV-ACLF细胞疗法。但是，考虑到有限的现有证据，需要较大的前瞻性随机对照试验之前的建议可以为聚乙烯的常规掺入标准临床实践进行。