风险慢性乙肝病毒感染的病程和治疗核苷（酸）类似物的保

StephenW

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analoguesIrene Rapti and  Stephanos Hadziyannis

Irene Rapti, Stephanos Hadziyannis, Liver Unit and its Molecular Biology Laboratory, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 15669 Athens, Greece
Irene Rapti, Athens Medical Center, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 15669 Athens, Greece
Author contributions: Both authors contributed to this manuscript.

Correspondence to: Stephanos Hadziyannis, Emeritus Professor of Medicine and Hepatology, Liver Unit and its Molecular Biology Laboratory, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 4 Dirrachiou Str., 15669 Athens, Greece. rg.tenhtrof.hta@sinnayizdah

Telephone: +30-21-06516807 Fax: +30-21-06543299

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Abstract

Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.

Keywords: Chronic hepatitis B, Cirrhosis, Hepatocellular carcinoma, Hepatitis B virus, Treatment, Interferon, Lamivudine, Adefovir, Entecavir, Tenofovir, Virological remission, Nucleos(t)ide analogues

Core tip: Hepatocellular carcinoma (HCC) represents a major health problem worldwide. It develops on the grounds of chronic liver disease, with chronic hepatitis B virus infection (CHB) being responsible for more than 50% of HCC worldwide. Currently, the vast majority of patients with CHB are being treated with nucleos(t)ide analogues, which have changed the natural history of the disease, reducing at a considerable extent its long-term consequences. However, although the risk of HCC has also been reduced, it has not been eliminated even after HBsAg loss or seroconversion. Therefore, constant surveillance, according to guidelines should never be omitted, unless new more potent treatment options are identified.

StephenW

风险慢性乙肝病毒感染的病程和治疗核苷（酸）类似物的保护作用肝癌
艾琳拉布蒂和斯蒂法诺斯[461 Hadziyann​​is
艾琳拉布蒂，斯蒂法诺斯[461 Hadziyann​​is，肝股及其分子生物学实验室，国家和雅典Kapodistrian大学，雅典Evgenidion医院，15669雅典，希腊
艾琳拉布蒂，雅典医学中心，国家和雅典Kapodistrian大学，雅典Evgenidion医院，15669雅典，希腊
作者的贡献：两位作者促成了这一手稿。

通讯作者：斯蒂法诺斯[461 Hadziyann​​is，医药学和肝病，肝单位的名誉教授和分子生物学实验室，国家和雅典Kapodistrian大学，雅典Evgenidion医院，4 Dirrachiou海峡，15669雅典，希腊。 rg.tenhtrof.hta@sinnayizdah

电话：+ 30-21-06516807传真：+ 30-21-06543299
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抽象

肝细胞癌（HCC）是一个主要的健康问题全世界，占死亡的主要原因之一。慢性乙型肝炎病毒（HBV）感染（CHB）是这种肿瘤的最主要的致病因素，占病例在世界上50％以上的发展。一级预防肝癌是可以通过接种乙肝疫苗的HBV感染授予的保护。不过，根据世界卫生组织乙型肝炎实况204（2014年7月更新）全球存在的> 2.4亿人感染慢性乙肝病毒谁是在危险中为肝癌发展的大型游泳池。这些人代表了目标人群的二级预防和HCC的两个肝硬化。因为在慢性乙型肝炎持续HBV复制与潜在的肝脏疾病肝硬化的发展以及患有HCC的发展相连，在慢性乙型肝炎有效的抗病毒治疗也已在HCC的二级预防方面进行评价。目前，大多数患者积极CHB受到长期治疗的第一线核苷（酸）类似物恩替卡韦和替诺福韦。这些化合物是高的抗病毒效力，并具​​有高阻挡对HBV电阻相比拉米夫定，阿德福韦酯，甚至夫定。许多研究已经表明，在抗病毒治疗，特别是那些在病毒学缓解患者，开发较少肝癌比未处理的。然而，对于肝癌的发展的风险不能被消除。因此，监视肝癌的发展慢性乙型肝炎必须终生或直到在未来的时候，新的治疗方法将能够从肝脏彻底根除乙肝病毒尤其是在CHB感染的早期阶段。在此背景下，本次审查的目的是概述其中慢性乙肝患者肝癌发展的危险性的大小，在感染的各个阶段以及有关病毒，宿主和环境因素所评价的，世界文学。此外，抗病毒治疗慢性乙型肝炎的与核苷/潮类似物，已改变的疾病的自然历史，并已减少，但不能消除HCC的风险的好处还审查。
关键词：慢性乙型肝炎，肝硬化，肝癌，乙肝病毒，治疗，干扰素，拉米夫定，阿德福韦，恩替卡韦，替诺福韦，病毒学缓解，核苷（酸）类似物

核心提示：肝细胞癌（HCC）代表世界各地的主要健康问题。它开发的慢性肝病负责全球超过50％的肝癌为由，慢性乙肝病毒感染（CHB）。目前，慢性乙型肝炎患者绝大多数是正在接受核苷（酸）类似物，它已经改变了疾病的自然史，在相当程度上降低了其长期后果。然而，虽然HCC的风险也被降低，它并没有被即使HBsAg消失或血清转换消除。因此，持续不断的监视，根据准则不应该被忽略，除非有新的更有效的治疗方案确定。

StephenW

The topic of the risk for development of HCC in chronic hepatitis B patients and its possible reduction by antiviral treatment has been widely covered in the last AASLD meeting of 2014 in Boston with several oral presentations and posters[79-88]. From an overall analysis of these studies it can be deduced that antiviral therapy is associated with reduction of the risk for development of HCC. However, the risk still remains high, particularly in males of older age and in patients with cirrhosis. Therefore continuous surveillance is imperative in all CHB patients regardless of the outcome of anti-HBV therapy even if HBsAg has been cleared and anti-HBs have developed. Irrespective of virological remission induced by antiviral treatment, CHB patients and especially those with the highest risk - men > 50 and cirrhotics - should continue to be surveilled, according to the existing recommendations[45]. Moreover, CHB patients whether with or without cirrhosis, who experience HBsAg loss with or without seroconversion to anti-HBs, continue to remain at risk for HCC and therefore, their surveillance should also be continued[89,90].

Moreover, loss of HBsAg at the age ≥ 50 years was found to be an independent predictor of development of HCC.
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CONCLUSION

In view of the above pooled data from studies of more than ten years, it is reasonable to conclude that treatment of chronic hepatitis B with oral antiviral agents, especially the first line ones ETV and TDF, definitely prolongs survival and changes the natural history of the disease, with significant reduction of the incidence of cirrhosis, decompensation of cirrhosis, and end-stage liver disease leading to death or liver transplantation[52,53,69,91,92]. Yet, the potential benefits of antiviral treatment in the reduction of the risk for development of HCC have not been very impressive. A reduction but not elimination in its incidence has been documented even in patients who achieved loss of HBsAg. This has an impact also in the waiting lists of liver transplantation. Thus, in the United States patients enlisted for transplantation for complications of CHB, a 42% relative reduction of end-stage liver disease and a concomitant 72% relative increase of HCC are recorded. To a significant extent, these changes have been secondary to antiviral treatment[93]. Furthermore, in Europe the percentage of HBV cirrhotics transplanted for consequences of viral hepatitis has been reduced from 24% to 16% of the total[92].

The self-contradictory finding that antiviral treatment in CHB can prevent clinical decompensation while it does not seem to affect considerably the development of HCC, is due on the one hand to the prolongation of survival without clinical consequences of hepatic decompensation, and on the other hand to the ongoing extended exposure of the patients to the harmful effects of integrated HBV sequences.

Hopefully, in the years to come, new anti-HBV therapies may manage to timely and completely eradicate HBV from the host genome and therefore may also manage to eliminate the risk for development of HCC in CHB[94].

StephenW

在慢性乙肝患者肝癌的发展和其可能通过降低抗病毒治疗的风险的话题已被广泛覆盖在2014年在波士顿的最后一次会议AASLD与几个口头报告和海报[79-88]。从这些研究的整体分析，可以推断，抗病毒治疗与减少对HCC的发展的风险相关联。然而，风险仍然很高，尤其是在年龄较大的男性和肝硬化患者。因此连续监控是必须在所有慢性乙肝患者无论即使乙肝表面抗原已被清除和抗-HBs已经开发出抗乙肝病毒治疗的结果。无论病毒学缓解诱导抗病毒治疗，慢性乙肝患者，特别是那些具有最高风险 - 男性> 50和肝硬化 - 应继续监控的，根据现有的建议[45]。此外，慢性乙型肝炎患者不论是否有肝硬化，谁的经验HBsAg转阴或血清转换不以抗HBs，继续保持在危险中为肝癌，因此，他们的监视也应继续[89,90]。

此外，HBsAg消失在年龄≥50年被发现是HCC的发展的独立预测因子。

结论

鉴于上述汇集从十余年的研究数据，这是合理的结论是治疗慢性乙型肝炎的口服抗病毒药物，特别是第一线的人ETV和TDF，绝对延长生存期，并改变的自然史病，与显著减少肝硬化的发生率，肝硬化失代偿，和终末期肝病导致死亡或肝移植[52,53,69,91,92]。然而，在肝癌的发展的风险降低抗病毒治疗的潜在好处没有得到非常可观。的减少而不是消除其发病率已经证明，即使在谁取得HBsAg消失的患者。这都有影响也在肝移植等候名单。因此，在美国患者征募对移植CHB的并发症，42％的相对减少终末期肝病和HCC的伴随72％的相对增加被记录。到一个显著程度，这些变化是次要的抗病毒治疗[93]。此外，在欧洲的HBV肝硬化的移植病毒性肝炎的后果的百分比已减少从24％到总[92]的16％。

自相矛盾的发现，在慢性乙型肝炎抗病毒治疗可预防的临床失代偿而它似乎并没有显着影响肝癌的发展，是因为，一方面，以生存的延长无肝功能失代偿的临床后果，并在另一方面到的病人的持续长期暴露在集成的HBV序列的有害影响。

我们希望，在未来的岁月里，新的抗乙肝病毒治疗可能设法及时，彻底铲除从宿主基因组中乙肝病毒，因此也可以管理，以消除CHB [94]对肝癌的发展风险。

MP4

50岁

yelanglms

年龄大于50岁，即使没有肝硬化，也可能得肝癌？

StephenW

回复 yelanglms 的帖子

HBsAg消失在年龄大于50岁, 也可能得肝癌。

hchu

反过来说，如果50岁前消除S，即可大大解除风险？

StephenW

hchu 发表于 2015-6-24 09:24
反过来说，如果50岁前消除S，即可大大解除风险？

问得好. 对我来说，是一个合理的结论.

zgct

好