恩替卡韦长期治疗可减少 肝癌

StephenW

Long-Term Entecavir Treatment Reduces Hepatocellular Carcinoma Incidence in Patients With Hepatitis B Virus Infection

Tetsuya Hosaka,1 Fumitaka Suzuki,1 Masahiro Kobayashi,1 Yuya Seko,1 Yusuke Kawamura,1 Hitomi Sezaki,1
Norio Akuta,1 Yoshiyuki Suzuki,1 Satoshi Saitoh,1 Yasuji Arase,1 Kenji Ikeda,1 Mariko Kobayashi,2 and
Hiromitsu Kumada1


Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma
(HCC). Antiviral agents are thought to reduce HCC development, but agents such as lamivudine (LAM) have a high rate of drug resistance. We compared the incidence of HCC in
472 entecavir (ETV)-treated patients and 1,143 nontreated HBV patients (control group).
Propensity score matching eliminated the baseline differences, resulting in a sample size of
316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV
group. The cumulative HCC incidence rates at 5 years were 3.7% and 13.7% for the ETV
and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis,
adjusted for a number of known HCC risk factors, showed that patients in the ETV group
were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95%
confidence interval: 0.15-0.91; P 5 0.030). Both cohorts were applied in three previously
reported risk scales and risk scores were generated based on age, gender, cirrhosis status,
levels of alanine aminotransferase, hepatitis B e antigen, baseline HBV DNA, albumin,
and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored
higher on respective risk scales. In sub analyses, we compared treatment effect between
nucleos(t)ide analogs, which included matched LAM-treated patients without rescue therapy
(n 5 182). We found HCC suppression effect greater in ETV-treated (P < 0.001) than
nonrescued LAM-treated (P 5 0.019) cirrhosis patients when they were compared with
the control group.

Conclusion: Long-term ETV treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk
of HCC. (HEPATOLOGY 2013;58:98-107)

StephenW

慢性B型肝炎病毒（HBV）感染导致肝硬化和肝癌
（HCC）。抗病毒药物被认为可以降低肝癌的发展，如拉米夫定，但代理
（LAM）具有较高的耐药率。我们比较了肝癌的发病率
472恩替卡韦（ETV）治疗的患者和1,143名未治疗的乙肝患者（对照组）。
倾向得分匹配消除了基线的差异，导致样本大小
每316例队列。的药物的突变性为0.8％（4/472）中的ETV
组。累计肝癌5年发病率分别为3.7％和13.7％的ETV
和对照组（P <0.001）。 Cox比例风险回归分析，
调整了一些已知的肝癌危险因素，结果显示，患者在ETV组
不太可能发展成肝癌比对照组（危险比：0.37; 95％
置信区间：0.15-0.91，P = 0.030）。两个同伙被应用在三个以前
风险尺度和风险评分的基础上产生的年龄，性别，肝硬化状态，
谷丙转氨酶，乙肝e抗原，基线HBV DNA，血清白蛋白水平，
和胆红素。在高风险的患者，谁拿下最大的肝癌发生风险降低
均在各自的风险尺度。在撒哈拉分析，我们比较之间的治疗效果
核苷（酸）类似物，其中包括匹配LAM治疗的患者没有抢救治疗
（5 182）。我们发现肝癌的抑制效果较大ETV治疗（P <0.001）
nonrescued林治疗（P = 0.019），肝硬化患者时，他们进行了比较
对照组。
结论：长期ETV治疗可能会降低发病率
在HBV感染的患者肝癌。在风险较高的患者治疗效果
肝癌。 （肝病2013; 58:98-107）

StephenW

Does Hepatitis B Treatment Reduce the Incidence of
Hepatocellular Carcinoma? Editorial - pdfs attached
See article below
Hepatology July 2013

MORRIS SHERMAN, M.B., B.CH., PH.D., F.R.C.P.(C)
Department of Medicine
Division of Gastroenterology University of Toronto
Toronto, ON, Canada

"The study showed that treatment with entecavir did in fact reduce the incidence of HCC and did so to a greater extent than lamivudine did…….This means that patients at higher risk for HCC, i.e., those with cirrhosis, those who were older, and who had more active disease obtained greater benefit from treatment than younger patients and those without cirrhosis.
These results are consistent with the discussion above describing that it is easier to demonstrate the effect of antiviral suppression in cirrhosis (and other patients at higher risk). The study also suggests that the effect of antiviral therapy is mediated by viral suppression. This is implicit in the finding that entecavir had a greater effect than lamivudine. This report is the first study that demonstrates a reduction in HCC incidence with one of the newer, more potent antiviral agents…...Given that we will never have an additional randomized controlled data for outcomes of HBV treatment, is the Hosaka study11 the last word on the subject? Do we still need a similar study using tenofovir? It seems clear that the effect of antiviral therapy is related to a reduction in viral load, and that anything that reduces viral replication will have a beneficial effect. Furthermore, the stronger the antiviral effect, the greater the improvement in outcomes. If we accept this, then it is probably not necessary to undertake a similar study with tenofovir (although I am sure someone will do such a study). Do we need a study comparing the effects of entecavir and tenofovir on HCC incidence? Again, probably not! Such a study would need a very long follow-up and a very large sample size, and even then the difference, at best, will be small…...Thus, we can summarize the evidence from this current study and from others as follows: Suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC. Suppression of viral replication in noncirrhosis also reduces the risk of HCC, but since the risk of HCC is not as high as in cirrhosis patients, the magnitude of the risk reduction is less. It is not yet clear whether treatment of non cirrhosis, if instituted early enough, can eliminate the risk of HCC altogether. Given the difficulty of performing such a study, we may never get that answer. However, that should not stop us from providing treatment for those with active disease.
”
It has been difficult to prove that hepatitis B virus (HBV) treatment reduces the incidence of hepatocellular carcinoma (HCC). Most previous studies have been retrospective without adequate controls. In this issue of HEPATOLOGY Hosaka et al. present data on a large cohort, propensity matched for HCC risk with historical controls, demonstrating that HCC incidence is reduced with entecavir therapy.

The advent of potent oral antivirals for the treatment of chronic HBV has had a major impact on our ability to treat this disease. Entecavir and tenofovir are both highly effective, very well tolerated, and there is very little to no resistance. The fall in viral load on treatment is dramatic. The effect on inflammation as measured by alanine aminotransferase (ALT) or on biopsy is equally impressive. Yet the effect of these agents on long-term outcomes such as the development of cirrhosis and HCC remains in question. Hepatologists and others have embraced the use of potent antivirals as effective methods to reduce the incidence of these outcomes, but the evidence supporting this action has been remarkably difficult to come by. In part this is because it takes many years for these outcomes, HCC in particular, to present themselves, much longer than pharmaceutical companies are prepared to wait for licensing, and longer than the duration of most investigator-initiated follow-up studies. The other reason is that it is no longer possible to undertake a randomized controlled trial with an untreated control group, so strong is the belief that these agents are effective. It is considered unethical to leave patients untreated for the duration required to assess changes in incidence of cirrhosis and HCC.

There has been a single randomized controlled trial using oral agents in which patients with HBV cirrhosis were treated with lamivudine or nothing.1 This study showed that there was a reduction in ‘‘outcomes’’ in the treated group. However, it was not clear that there was a reduction in the incidence of HCC. Once those who developed HCC early after recruitment, and who presumably had undiagnosed HCC prior to enrollment, were excluded, the improvement in HCC incidence was no longer significant. A number of studies have attempted to address this question, the results of which were summarized in a review earlier this year. Lai and Yuen2 found that the results from interferon studies are inconsistent, but the vast majority of studies of oral antiviral agents demonstrated a decrease in HCC incidence. Only one study was randomized (referred to above).1 The agents used included only lamivudine and adefovir. The studies included more than 2,000 subjects, cirrhosis and noncirrhosis patients, and demonstrate a reduction in HCC incidence in both groups. A prior meta-analysis3 and a systematic review4 came to the same conclusion. Nonetheless, with the one exception these were all retrospective data, with all the caveats that come with such studies. Implicit in the discussion of these studies is that even in the absence of additional randomized controlled data the evidence is sufficiently strong to support that antiviral therapy does reduce HCC incidence.

In addition to these analyses there is a considerable amount of indirect evidence that adequate suppression of viral replication, however achieved, leads to improved outcomes. Entecavir has been shown to reverse fibrosis and even cirrhosis.5 We also know that the risk of HCC is related to the viral load,6 so that presumably reduction of viral load with therapy will reduce the incidence of HCC. Virological response to entecavir has been shown to be associated with better outcomes than in those who did not achieve a sufficient response (and therefore, presumably better outcomes than those who have not been treated).7 However, this would not be considered high-level evidence, and would not convince skeptics.

Despite the fact that most of those who treat HBV have accepted that suppression of viral replication is a useful surrogate marker of improved outcomes, there
are those who have reservations about this. At the recent American Association for the Study of Liver Diseases (AASLD) meeting in Boston in 2012 a Cochrane-type systematic review and meta-analysis was presented as a poster.8 This study came to the conclusion that the evidence showed only a minor reduction in HCC incidence in cirrhosis patients and no effect in noncirrhosis patients. This analysis included 27 trials and more than 7,000 patients. Another abstract showed that the natural history of HBV in Olmstead County, Minnesota, was similar before and after the introduction of hepatitis B antivirals,9 again suggesting that HBV treatment had not effect. However, the uptake of appropriate treatment was not mentioned.

In addition to the difficulty in performing a randomized controlled trial there are other obstacles to proving that HBV treatment reduces HCC incidence. In theory, one should not expect a major reduction in HCC incidence in cirrhosis patients. Cancer development is a drawn-out process that does not initiate in the months prior to the diagnosis of even small lesions. Rather, the oncogenic process starts years earlier. A cirrhotic liver probably contains many clones of cells carrying genetic abnormalities that predispose to cancer. There is even data suggesting that the whole liver, or a great part of it, may be one abnormal clone that carries the predisposition to cancer.10 Thus, stopping the process at a late stage, such as in cirrhosis, should not be expected to have a major impact on HCC incidence. Of course, since the period of followup required to document these outcomes is relatively short, this effect will be more easily demonstrated than in noncirrhosis patients, in whom it may take many years to document the difference in outcomes. This, then, is one of the other major obstacles to proving the effect of antiviral therapy in noncirrhosis patients, the time required to see the development of HCC. If one institutes treatment early enough to reduce the incidence, e.g., in 30-year-olds or 40-year-olds, the study would have to follow the cohort for 10? years to be certain of an effect or no effect.

In this issue of HEPATOLOGY Hosaka et al.11 describe a study in which they document that treatment of chronic HBV with entecavir reduces the incidence of HCC. This is a retrospective analysis of a sufficientlymlarge number of subjects and of historical controls with an adequate length of follow-up. Controls had to be obtained from an era before HBV treatment was available. However, the controls were propensity matched to the treated subjects. In propensity matching subjects are matched according to the likelihood that they might develop the outcome of interest rather than simply matching on demographic factors. The authors took advantage of the fact that the HCC risk in HBV has been quantitated in at least three different studies in different populations. These studies developed scores that can be used to determine the likelihood that an individual might develop HCC. The authors looked at propensity matching for all three scores, and their results were consistent whatever score was used. In the absence of randomization this is the next best method of ensuring that the experimental and control groups are similar.

The study showed that treatment with entecavir did in fact reduce the incidence of HCC and did so to a greater extent than lamivudine did. Furthermore, the magnitude of the risk reduction increased as risk scores increased. This means that patients at higher risk for HCC, i.e., those with cirrhosis, those who were older, and who had more active disease obtained greater benefit from treatment than younger patients and those without cirrhosis. These results are consistent with the discussion above describing that it is easier to demonstrate the effect of antiviral suppression in cirrhosis (and other patients at higher risk). The study also suggests that the effect of antiviral therapy is mediated by viral suppression. This is implicit in the finding that entecavir had a greater effect than lamivudine. This report is the first study that demonstrates a reduction in HCC incidence with one of the newer, more potent antiviral agents.

Given that we will never have an additional randomized controlled data for outcomes of HBV treatment, is the Hosaka study11 the last word on the subject? Do we still need a similar study using tenofovir? It seems clear that the effect of antiviral therapy is related to a reduction in viral load, and that anything that reduces viral replication will have a beneficial effect. Furthermore, the stronger the antiviral effect, the greater the improvement in outcomes. If we accept this, then it is probably not necessary to undertake a similar study with tenofovir (although I am sure someone will do such a study). Do we need a study comparing the effects of entecavir and tenofovir on HCC incidence? Again, probably not! Such a study would need a very long follow-up and a very large sample size, and even then the difference, at best, will be small.

Thus, we can summarize the evidence from this current study and from others as follows: Suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC. Suppression of viral replication in noncirrhosis also reduces the risk of HCC, but since the risk of HCC is not as high as in cirrhosis patients, the magnitude of the risk reduction is less. It is not yet clear whether treatment of non cirrhosis, if instituted early enough, can eliminate the risk of HCC altogether. Given the difficulty of performing such a study, we may never get that answer. However, that should not stop us from providing treatment for those with active disease.

StephenW

乙肝治疗发病率降低
肝癌？社论 -  PDF文件附
请参阅以下文章
肝病七月2013

MORRIS SHERMAN，M.B.，B.CH.，博士，F.R.C.P.（C）
医学系
胃肠科多伦多大学
多伦多，ON，加拿大

“这项研究表明，治疗恩替卡韦并在事实上减少肝癌的发病率，这样做是为了在更大程度上优于拉米夫定一样......这意味着，患者的风险较高，即肝癌，肝硬化，那些谁是老年人，谁更积极的疾病获得更大的效益比年轻患者的治疗，无肝硬化者。
这些结果与上面的讨论中描述，这是更容易证明在肝硬化的抗病毒抑制效果（以及其他在更高的风险患者）一致。研究还表明，抑制病毒介导的抗病毒治疗的效果。这是隐含在发现，恩替卡韦比拉米夫定有较大的影响。该报告是第一个更新，更强大的抗病毒制剂研究，显示肝癌的发病率减少......我们将永远不会有一个额外的随机对照数据乙肝治疗的结果，是最后保坂研究11字的主题？我们还需要使用替诺福韦一项类似的研究？抗病毒治疗的效果似乎很清楚，减少病毒载量相关，并且，减少病毒复制，任何将产生有利的影响。此外，更强的抗病毒效果，更大的改善结果。如果我们接受这一点，那么它很可能没有必要进行了类似的研究，替诺福韦（虽然我肯定会有人做这样的研究）。我们需要的一项研究，对肝癌的发病率比较恩替卡韦和替诺福韦的影响？再次，可能不是！这样的研究需要一个很长的跟进和一个非常大的样本大小，即使在当时的差异，在最好的情况下，将小......因此，我们可以总结从目前的研究证据，并从别人如下：乙肝肝硬化患者抑制病毒复制减少，但不排除肝癌的风险。抑制病毒复制无肝硬变，肝癌的风险也降低，但因为肝硬化患者肝癌的风险不高，风险减少的幅度较少。目前尚不清楚是否非肝硬化的治疗，如果提起早期，足量，可以消除共发生HCC的风险。鉴于执行这种研究的难度，我们可能永远不会得到这个问题的答案。然而，这不应该阻止我们提供治疗疾病活动。
“
一直难以证明，乙肝病毒（HBV）治疗肝细胞癌（HCC）的发生率降低。追溯以往的研究大多已经没有足够的控制。在这个肝病保坂等问题。目前的数据在一个大的队列中，倾向匹配肝癌风险与历史对照，证明恩替卡韦治疗，肝癌的发病率降低。

的问世，有效的口服抗病毒药物用于治疗慢性乙肝已经产生了重大影响，对我们的能力来治疗这种疾病。恩替卡韦和替诺福韦都是非常有效的，耐受性很好，很少有到无阻力。治疗的病毒载量的下降是显着的。谷丙转氨酶（ALT）或活检作为衡量炎症的影响是同样令人印象深刻。然而，这些药物的效果对长期的结果，如肝硬化和肝癌的发展仍然是一个问题。肝病和其他人已经接受了使用强效抗病毒药物，有效的方法，以减少发病的这些成果，但取得了显着的证据支持这一行动很难得的。这部分是因为它需要许多年，对这些成果，特别是肝癌，展示自己，远长于制药公司正在准备等待许可，比大多数研究者发起的后续研究持续时间更长。另外一个原因是，它是不再可能与未经处理的对照组进行随机对照试验，如此强烈的信念，这些药物是有效的。它被认为是不道德的离开未经治疗的患者肝硬化和肝癌的发病率的变化进行评估所需的时间。

已经有一个单一的随机对照试验组使用口服药物治疗乙肝肝硬化患者拉米夫定或nothing.1的这项研究表明，有一个减少''成果“。然而，这是不明确的，有一个降低肝癌的发病率。一旦这些开发肝癌早期招聘后，谁可能有未确诊的肝癌入学前，被排除在外，肝癌的发病率是改善不再显着。许多研究都试图解决这个问题，其结果在评论中总结了今年早些时候。黎Yuen2发现，干扰素研究的结果是不一致的，但绝大多数的口服抗病毒药物的研究表明减少肝癌的发病率。只有一个研究是随机（上文提到的）.1所用药物包括拉米夫定和阿德福韦。这些研究包括2000多名受试者，肝硬化和无肝硬变患者，并证明在这两个群体的减少肝癌的发病率。在事情​​之前的荟萃分析3和系统化review4的来到了同样的结论。不过，一个例外，这些都是回顾性的数据，所有的注意事项，来与这些研究。隐在讨论这些研究的证据，即使没有额外的随机对照数据是强大到足以支持抗病毒治疗，降低肝癌的发病率。

除了这些分析中，有相当数量的间接证据有足够的抑制病毒复制，但实现的，导致改进的结果。恩替卡韦已被证明能逆转纤维化甚至cirrhosis.5我们也知道，HCC的风险有关的病毒载量，6，这样可能减少病毒载量与治疗肝癌的发病率会降低。病毒学应答恩替卡韦已经被证明是更好的结果比那些谁没有达到足够的响应（因此，想必比那些没有得到治疗的更好的结果）.7但是，这会不会被认为是高层次证据，并不会说服持怀疑态度的。

尽管事实上，大多数接受治疗HBV，抑制病毒的复制是一个非常有用的替代标记改进的成果，
是那些人对此有所保留。在最近的美国肝病研究协会（AASLD）会议2012年在波士顿作为poster.8的Cochrane系统回顾和荟萃分析研究得出的结论的证据显示，只有轻微减少肝硬化患者的肝癌发病率无肝硬变患者并没有什么作用。这种分析包括27项临床研究和超过7,000名患者。另一个抽象表明HBV的自然史奥姆斯特德县，明尼苏达州，类似的乙肝抗病毒药物前和出台后，再次表明乙肝治疗有没有效果。但是，适当的治疗的摄取没有提及。

除了在执行一项随机对照试验的难度有其他障碍，证明乙肝病毒治疗肝癌的发病率降低。从理论上讲，人们不应该指望在肝硬化患者的肝癌发病率大幅度减少。癌症的发展是一个漫长的过程，不会启动前的几个月甚至是小病灶的诊断。相反，致癌过程年前开始。肝硬化的肝脏可能包含许多携带易患癌症的遗传异常的细胞克隆。甚至有数据表明，整个肝，它的很大一部分，可能是一个异常克隆携带易感性因此cancer.10，在后期阶段停止的过程，如肝硬化，不能指望对肝癌发病率有重要影响。当然，由于需要记录这些成果后续期间相对较短，这样效果会更容易表现出比无肝硬变患者，在其中，它可能需要许多年才能结果的差异文件。那么，这是其他的主要障碍之一是要证明在无肝硬变患者的抗病毒治疗的效果，所需的时间看肝癌的发展。如果一个机构治疗早期，足量，以减少发病率，例如，在30岁的人或40岁的人，这项研究将有跟随队列为10？年是一定的效果或没有效果。

肝病保坂等[11]在这个问题上，描述了一项研究，他们的文件与恩替卡韦治疗慢性乙型肝炎的降低肝癌的发病率。这是一个sufficientlymlarge的题材和后续足够长度的历史对照的回顾性分析。控制必须从时代获得乙肝治疗前。然而，对照组治疗的受试者匹配的倾向。倾向匹配的主题匹配的可能性，他们可能发展利益的结果，而不是简单的人口因素匹配。作者利用了已在不同人群中，至少在三个不同的研究定量HBV肝癌风险的事实。这些研究开发了可以使用的分数来确定的可能性，一个人可能会发展HCC。看着匹配所有三个分数的倾向，他们的结果是一致的，使用任何得分。在随机化的情况下，这是下一个最好的方法，确保实验组和对照组类似。

研究表明，恩替卡韦治疗并降低肝癌的发病率其实，这样做是为了在更大程度上优于拉米夫定。此外，风险降低的幅度增加风险分数增加。这意味着的风险较高，即肝癌，肝硬化的病人，那些谁是年龄大了，谁更积极的疾病从治疗获得更大的利益比年轻患者无肝硬化者。这些结果与上面的讨论中描述，这是更容易证明在肝硬化的抗病毒抑制效果（以及其他在更高的风险患者）一致。研究还表明，抑制病毒介导的抗病毒治疗的效果。这是隐含在发现，恩替卡韦比拉米夫定有较大的影响。该报告是第一个更新，更强大的抗病毒制剂研究，显示肝癌的发病率减少。

鉴于我们将永远不会有一个额外的随机对照数据乙肝治疗的结果，是保坂研究11关于这个问题的最后一句话？我们还需要使用替诺福韦一项类似的研究？抗病毒治疗的效果似乎很清楚，减少病毒载量相关，并且，减少病毒复制，任何将产生有利的影响。此外，更强的抗病毒效果，更大的改善结果。如果我们接受这一点，那么它很可能没有必要进行了类似的研究，替诺福韦（虽然我肯定会有人做这样的研究）。我们需要的一项研究，对肝癌的发病率比较恩替卡韦和替诺福韦的影响？再次，可能不是！这样的研究将需要一个很长的跟进和一个非常大的样本大小，即使在当时的差异，在最好的情况下，将小。

因此，我们可以总结从目前的研究，并从别人的证据如下：在乙肝肝硬化患者病毒复制的抑制肝癌的风险降低，但并不能消除。抑制病毒复制无肝硬变，肝癌的风险也降低，但因为肝硬化患者肝癌的风险不高，风险减少的幅度较少。目前尚不清楚是否非肝硬化的治疗，如果提起早期，足量，可以消除共发生HCC的风险。鉴于执行这种研究的难度，我们可能永远不会得到这个问题的答案。然而，这不应该阻止我们提供治疗疾病活动。