核苷（酸）类似物为基础的化学预防肝癌：：有效的，然而

StephenW

Nucleos(t)ide Analogs-Based Chemoprevention of Liver Cancer in Hepatitis B Patients: Effective, Yet in Search of Optimization

    Pietro Lampertico
    ,
    Massimo Colombo

published online 20 September 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor


Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir (ETV) treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58:98–107.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer occurring in a mitogenic and mutagenic environment. The HBV-infected liver undergoes rounds of necrosis and regeneration caused by the humoral and cell-mediated immune attack to persistently infected hepatocytes (Nat Rev Cancer 2006;6:674–687). Owing to the key role of HBV replication in liver carcinogenesis, pharmacologic suppression of HBV has repeatedly been attempted to prevent liver cancer. Indeed, development of cirrhosis is the most important predictor of HCC and long-term administration of nucleot(s)ide (NUC) analogs has been shown to attenuate progression of cirrhosis, reverse cirrhosis, and prevent decompensation in cirrhotics (Hepatology 2009;50:661–662; Hepatol Int 2012;6:531–561; J Hepatol 2012;57:167–185). On the contrary, it is still debated whether HCC can be prevented after long-term pharmacologic suppression of HBV. This is because antiviral therapy may not prevent integration of sequences of HBV DNA, which could lead to establishment of liver cell clones committed to carcinogenesis and this phenomena will not be impacted by antiviral therapy. Another disputed point of HCC chemoprevention is the partial efficacy of lamivudine or adefovir therapy as a consequence of the high rates of treatment related drug resistance. This has fueled hopes that high genetic barrier NUC analogs might minimize HBV-related HCC because these agents suppress HBV replication while being well tolerated and safe. Although potent third-generation agents, such as ETV and tenofovir, inactivate some of the virus-related risk factors for HCC, it is unclear whether chemoprevention of HCC with these agents may be overcome by co-factors, such as specific patient-related factors and exposure to alcohol, tobacco and aflatoxin.

The case-control study conducted by Hosaka et al in Japan analyzed patients’ response to ETV after patient stratification for cancer risk variables. The investigators compared the incidence of HCC in 316 patients with chronic hepatitis B who received ETV for 5 years with 316 untreated controls in the last 4 decades in a single hospital center. They used a propensity score matching model to mitigate confoundings due to pretreatment predictors of HCC. The study found that the 5-year risk of liver cancer was higher in untreated than in treated cirrhotics (39% vs 7%; P < .001), whereas it was unaffected in the larger group of noncirrhotic patients with chronic hepatitis B (2.5% vs 3.6%; P = .440). After patient stratification with HCC risk scores for untreated HBV-infected Asians, ETV was found to have stronger chemopreventive effects than first-generation lamivudine in high-risk patients, but not low-risk patients. These observations provided useful insights for optimizing NUC therapy in Japanese patients with chronic hepatitis B.

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Comment

The long debated question about whether HCC risk in HBV-infected patients is attenuated once HBV becomes permanently suppressed by NUC seems to have been partially answered by the case-control study of Hosaka et al in Japan. Indeed, a 5-year treatment period with ETV resulted in full suppression of HBV in virtually all clinically compensated cirrhotics. Also, a 5.5-fold reduction in HCC compared with historical controls of untreated cirrhotics was observed after controlling for a number of pretreatment predictors of tumor risk. This remarkable outcome of NUC therapy is somehow tarnished by the lack of efficacy of ETV chemoprevention in noncirrhotic HBV patients who maintained virologic response to treatment. This chasm between cirrhotics and noncirrhotics might be accounted for by multiple factors, including overrepresentation of the HCC risk in the historical control groups who did not have access to therapeutic algorithms of HBV, did not have accurate virologic assays, and had poorly standardized programs of surveillance. Moreover, assessment of HCC chemoprevention by ETV could have been biased by the lack of universal histologic or clinical proof of cirrhosis in patients analyzed by a propensity score matching. Mismatching of patients for pretreatment predictors of liver cancer and censoring liver cancer end points during the first year of study might have further affected the interpretation of the study outcomes as well. Also, the 10% mean yearly rate of HCC observed in untreated cirrhotics is puzzling because it exceeds previous reports in cirrhotics in Asia. Uncertainties in the interpretation of the study outcomes might reflect the limited time frame of the study as 5 years of HBV suppression might not be sufficient to overcome the multistep and complex carcinogenic process caused, promoted, and expanded by the interplay of host and virus related factors over several decades of HBV infection. Although all these black holes of NUC chemoprevention of HBV-related HCC could more appropriately be solved by a randomized, controlled study, this is probably unfeasible for both practical and ethical reasons, mainly as a consequence of the recognized clinical benefits of NUCs to slow development of fibrosis and portal hypertension. Nevertheless, the lesson learned by the study by Hosaka et al is clear. First, because HCC cannot fully be prevented by successful NUC therapy in HBV patients, surveillance for HCC is mandatory in all treated patients. Second, the lack of chemoprevention in noncirrhotic patients with chronic hepatitis B challenges the practice of starting anti HBV therapy in young patients with mild chronic hepatitis B with the sole aim of reducing cancer risk.

StephenW

乙型肝炎病毒（HBV）相关的肝细胞癌（HCC ）是炎症相关的癌症发生在有丝分裂和诱变环境的原型。 HBV感染的肝坏死和再生引起的体液和细胞介导的免疫攻击，持续感染的肝细胞（ 2006年纳特牧师癌症; 6:674-687 ）经历了两轮。由于肝癌发生，药物抑制HBV乙肝病毒复制的关键作用已多次试图阻止肝癌。事实上，发展为肝硬化是肝癌的最重要的预测和长期管理nucleot （次） IDE （NUC ）类似物，已被证明衰减反向肝硬化，肝硬化的进展，并防止肝硬化失代偿（ 2009年肝病; 50 ： 661-662诠释肝脏病杂志2012 ; 6:531-561 ;肝2012 ， 57:167-185 ） 。相反，它仍然是辩论是否可以预防肝癌药物长期抑制HBV后。这是因为抗病毒治疗，可能无法防止整合的HBV DNA序列，这可能导致发生，这样的现象，将不会影响抗病毒治疗的肝细胞克隆的建立。肝癌化学预防的另一个争议点是局部疗效的拉米夫定或阿德福韦疗法的治疗相关的耐药率居高不下的后果。这起到了推波助澜的高基因屏障的NUC类似物可能减少HBV相关HCC ，因为这些药物​​抑制乙肝病毒复制，同时被很好的耐受性和安全的希望。虽然强大的第三代药物，如ETV和替诺福韦，灭活某些病毒相关的肝癌的危险因素，目前还不清楚是否可以克服这些药物化学预防肝癌的共同因素，如具体的患者的相关因素和暴露于酒精，烟草和黄曲霉素。

由保坂等人在日本进行病例对照研究，分析患者的反应ETV病人分层后癌症风险变数。研究者比较了肝癌的发病率在316例慢性乙型肝炎谁收到ETV为5年，在过去的四十年在一个单一的中心医院的316名未经治疗的对照。他们使用了一种倾向得分匹配模型，以减轻confoundings由于预处理的预测肝癌。研究发现，肝癌的5年风险比治疗肝硬化在未经处理的高（39 ％比7 ％ ，P <0.001 ） ，而不受大组肝硬化的患者，慢性乙型肝炎（2.5 ％对3.6 ％ ， P = .440 ） 。未经治疗的HBV感染亚洲人与肝癌风险评分患者分层后， ETV发现比第一代拉米夫定在高风险的患者，但不低危患者有较强的预防作用。这些意见提供了有益的见解，优化NUC在日本患者治疗慢性乙型肝炎


评论

在HBV感染的患者是肝癌的风险是否衰减，一旦成为永久抑制HBV国统会的长期争议的问题似乎已经部分回答了保坂等人在日本的病例对照研究。事实上， 5年恩替卡韦治疗期间完全抑制HBV几乎所有临床补偿的肝硬化患者。此外， 5.5倍相比减少肝癌的治疗肝硬化与历史对照观察在一些预处理预测肿瘤的风险控制。这个了不起的结果莫名其妙地玷污NUC治疗缺乏疗效的的ETV化学预防肝硬化的乙肝患者维持治疗的病毒学应答。这种肝硬化和noncirrhotics之间的鸿沟可能占由多个因素，包括谁没有进入乙肝治疗算法的历史对照组的肝癌风险的比例过高，没有准确的病毒学检测，标准化不佳监测方案。此外，评估ETV肝癌的化学预防可能已经偏向缺乏普遍的组织学或临床证明，肝硬化患者倾向得分匹配分析。预处理预测肝癌及审查肝癌终点不匹配的患者在第一年的学习过程中，有可能进一步影响的研究成果，以及解释。此外， 10％的平均年增长率在治疗肝硬化肝癌观察是令人费解的，因为它超出了以前在亚洲肝硬化报告。在解释这项研究成果的不确定性可能会反映在有限的时间5年的抑制乙肝病毒的研究框架，可能不足以克服由主机和病毒相关因素的相互作用引起的多步和复杂的致癌过程，促进和扩大过去几十年的乙肝病毒感染。 NUC化学预防HBV相关HCC虽然所有这些黑洞可以更恰当地解决了一项随机，对照研究，这可能是不可行的实际和道德上的原因，主要因公认的临床益处NUCs发展缓慢纤维化和门脉高压症。然而，由保坂等人的研究中吸取的教训是显而易见的。首先，由于肝癌不能完全被阻止成功NUC治疗的乙肝患者，肝癌监测是强制性的，所有治疗的患者。其次，缺乏化学预防肝硬化的慢性乙型肝炎患者的挑战开始抗乙肝治疗的年轻患者与轻度慢性乙型肝炎与降低癌症风险的唯一目的的做法。

疯一点好

看不太懂，对预防肝癌的文章我是最关切的，恐癌恐出抑郁啦，，不知道斯蒂芬能否用几句哈说明一下呢？

StephenW

回复 疯一点好 的帖子

这是两个意大利科学家在评论一个日本科学家

的研究:"长期恩替卡韦（ETV）治疗可降低肝癌的发病"

研究发现，
1.在肝硬化患者:肝癌的5年风险 未经治疗 高于 治疗的患者;
2. 不过恩替治疗不影响非肝硬化患者的肝癌风险

评论讨论
肝硬化和非肝硬化患者之间的差异的种种原因.

NUC化学预防HBV相关肝癌虽然可以从一项随机，对照研究更恰当地解决了这些黑洞，对照研究，实际和道德上的原因这可能是不可行的. 主要是因公认的NUCs对发展缓慢纤维化和门脉高压症临床益处。然而，由保坂等人的研究中吸取的教训是显而易见的。
首先，由于肝癌不能完全被NUC治疗被阻止成功，所有治疗的患者肝癌监测是强制性的。
其次，缺乏化学预防非肝硬化的患者肝癌, 挑战 开始抗治疗 年轻患者与轻度慢性,
唯一目的为降低癌症风险的做法。

疯一点好

肝硬化患者和非肝硬化患者的肝癌发生比例本身有明显差异，肝硬化患者明显高于非硬化患者，但非硬化患者的也存在病毒导致肝细胞发生癌变。抗病毒药物控制乙肝病毒对肝脏的损坏是肯定的，但对肝细胞的突变作用是不明显的。