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Long-term outcome and hepatocellular carcinoma development in chronic hepatitis [复制链接]

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本帖最后由 风雨不动 于 2012-4-14 15:31 编辑

<http://onlinelibrary.wiley.com/doi/10.1111/j.1872-034X.2011.00785.x/abstract>

Long-term outcome and hepatocellular carcinoma development in chronic hepatitis
B or cirrhosis patients after nucleoside analog treatment with entecavir or
lamivudine

Haruhiko Kobashi1,*, Yasuhiro Miyake1, Fusao Ikeda1, Tetsuya Yasunaka1, Ken
Nishino2, Akio Moriya2, Jyunichi Kubota3, Shinichiro Nakamura1, Akinobu Takaki1,
Kazuhiro Nouso1, Gotaro Yamada2, Kazuhide Yamamoto1Article first published
online: 21 MAR 2011

DOI: 10.1111/j.1872-034X.2011.00785.x
© 2011 The Japan Society of Hepatology
Issue

Hepatology Research
Early View (Articles online in advance of print)

Abstract

Aim:  We conducted this prospective study to elucidate the long-term outcome
and incidence of hepatocellular carcinoma (HCC) development after nucleos(t)ide
analog (NA) treatment in patients with chronic hepatitis B (CHB) or cirrhosis.

Methods:  CHB or cirrhosis patients without past NA treatment or HCC were
started on entecavir (ETV) or lamivudine (LVD), and prospectively followed up
with monthly blood tests, and with abdominal imaging every 6 months in CHB and
every 3 months in cirrhosis patients.

Results:  A total of 256 subjects with CHB (n = 194) or cirrhosis (n = 62)
received ETV (n = 129) or LVD (n = 127) for 4.25 years (range: 0.41–10.0).
After NA treatment, serum HBV DNA, alanine aminotransferase and α-fetoprotein
(AFP) dropped significantly, along with significant increases in serum albumin
and prothrombin time. Drug-resistance developed in 60 cases in the LVD group and
in only one case in the ETV group. HCC developed in 35 patients, and the
incidence at years 1, 3, 5, 7 and 10 was significantly higher in patients with
cirrhosis (8.1%, 17.5%, 43.2%, 46.7% and 53.4%, respectively) than chronic
hepatitis (1.6%, 3.5%, 3.5%, 7.1% and 29.6%, respectively), with no difference
between ETV and LVD. After NA treatment, the sensitivity/specificity for HCC of
AFP and des-γ-carboxy prothrombin (DCP) was 45.7%/97.3% and 33.3%/96.2%,
respectively, with the specificity of AFP being higher than at baseline (64.4%),
at the cut-off of 10 ng/mL.

Conclusion:  NA exerted a long-term efficacy and improved hepatic reservation
in CHB and cirrhosis. After NA treatment, AFP dropped to lower than 10 ng/mL
with marked elevation of specificity, leading to an earlier detection of HCC.



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发表于 2011-3-22 23:17 |只看该作者
长期的结果,肝癌,慢性肝炎的发展
后恩替卡韦或模拟核苷治疗B或肝硬化患者
拉米夫定

晴彦Kobashi1,*,中曾根Miyake1,房雄Ikeda1,哲也Yasunaka1,肯
Nishino2,昭雄Moriya2,Jyunichi Kubota3,真一郎Nakamura1,昭信Takaki1,
弘Nouso1,Gotaro Yamada2,和秀Yamamoto1Article首次出版
在线:2011年3月21日

分类号:10.1111/j.1872-034X.2011.00785.x
© 2011香港日本文化协会的杂志
发行

肝脏病学研究
厄尔利维尤(第预先在网上打印)

摘要

目的:我们进行这项前瞻性研究,以阐明远期疗效
和肝癌的发生率(HCC)的发展,经过核苷(酸)的IDE
模拟(NA)的治疗慢性乙型肝炎(CHB)或肝硬化患者。

方法:没有过去不适用治疗慢性乙肝或肝硬化或肝癌患者
开始替卡韦(教育电视)或拉米夫定(LVD)的,和前瞻性随访
每月血液测试,并与腹部影像CHB和每6个月
肝硬化患者每3个月。

结果:256例慢性乙型肝炎科目组(n = 194)或肝硬化(62例)的总
接受教育电视组(n = 129)或LVD组(n = 127)为4.25年(范围:0.41-10.0)。
北美治疗后,血清HBV DNA,丙氨酸氨基转移酶和α-胎儿蛋白
(法新社)大幅下降以及血清中显着增加,白蛋白
和凝血酶原时间。耐药性发展的LVD组和60例
只在一个案件中的教育电视组。在35例肝癌发展,以及
在1年,3,5,7和10的患者发病率显着高于
肝硬化(8.1%,17.5%,43.2%,46.7%和53.4%)明显高于慢性
肝炎(1.6%,3.5%,3.5%,7.1%和29.6%,分别),无差异
教育电视和LVD之间。治疗后不适用,其灵敏度/肝癌的特异性
法新社和des -γ-羧基凝血酶原(DCP)的为45.7%/ 97.3%和33.3%/ 96.2%,
分别与被比基准(64.4%)高出法新社特异性,
在禁了10毫微克/毫升。

结论:不适用产生了长期疗效和改善肝预订
慢性乙型肝炎和肝硬化。治疗后不适用,法新社下降到低于10毫微克/毫升
与显着升高的特殊性,导致肝癌的早期检测。

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发表于 2011-3-23 09:44 |只看该作者
回复 StephenW 的帖子

我看完这个数据之后,和直观感觉差的比较远。感觉肝癌在慢性肝炎人群中的发生率应该没有这么高。
因为,从以往的文章看,一般的结论是病毒载量是指示肝癌发生率的直接因素。

但是,在该文章中,使用enti的人中,持续治疗之后,DNA的转阴率没有给。从以往的直观感觉应该很高。
但是,还是有那么高的致癌率。我非常困惑这个结果。。。

你怎么看?


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发表于 2011-3-23 10:27 |只看该作者
本帖最后由 StephenW 于 2011-3-23 10:27 编辑
kennyu 发表于 2011-3-23 09:44
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我看完这个数据之后,和直观感觉差的比较远。感觉肝癌在慢性肝炎人群中的发生率应该 ...

是的,必须阅读整篇文章.

"感觉肝癌在慢性肝炎人群中的发生率应该没有这么高。" - 肝硬化(62例), 慢性乙型肝炎(n = 194). 样本包含许多肝硬化cirrhosis病人, 年龄分布(age distribution unknown)不知.
在35例肝癌发展, 肝硬化病人(8.1%,17.5%,43.2%,46.7%和53.4%)明显高于慢性
肝炎病人(1.6%,3.5%,3.5%,7.1%和29.6%).

"从以往的文章看,一般的结论是病毒载量是指示肝癌发生率的直接因素。" - 是的.(我会发帖子)

你怎么看?(只是我个人的意见)
1.
慢性肝炎人群中,肝硬化是肝癌最大的风险因素. (治疗可以预防,制止,逆转纤维化)
2.
肝癌许多风险因素: 年龄, 基因(your genes), 肝炎.

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5
发表于 2011-3-23 10:44 |只看该作者
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我提问的还有一层意思是,既然NT的耐压只有一例,
那就意味着多数病人的病毒得到了持续压缩,DNA应该相对处于一个非常低的载量,肝癌的发生率能达到1.6%,感觉实在是有些高。

我记得看过一个数据,DNA 《 10^5时,肝癌发生率在0.4%?左右。

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发表于 2011-3-23 12:08 |只看该作者
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<http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2011.06695.x/abstract>

Natural history of chronic hepatitis B REVEALed

Chien-Jen Chen1,2,*, Hwai-I Yang3Article first published online: 21 MAR 2011

DOI: 10.1111/j.1440-1746.2011.06695.x
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell
Publishing Asia Pty Ltd Issue

Journal of Gastroenterology and Hepatology
Volume 26, Issue 4, pages 628–638, April 2011

The REVEAL-HBV Study was supported by grants from the Academia Sinica, National
Health Research Institutes, and Bristol-Myers Squibb Co., USA

Abstract
Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural
history of chronic hepatitis B is important for the management of the disease. A
community-based prospective cohort study was carried out to evaluate the risk
predictors of progression of chronic hepatitis B in Taiwan. A total of 23 820
participants were enrolled in 1991–1992 from seven townships in Taiwan. Their
serum samples were collected at study entry and tested for hepatitis B surface
antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus
(anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A
subcohort of 3653 male and female participants who were seropositive for HBsAg
and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load
Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV)
study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC)
were ascertained through follow-up examination and data linkage with profiles of
the National Cancer Registry, National Health Insurance Database and Death
Certification System. The incidence of both HCC and cirrhosis were significantly
associated with serum HBV DNA levels in a dose-response relationship from < 300 (undetectable) to ≥ 1 000 000 copies/mL.
The biological gradients remained
significant (P < 0.001) after adjustment for age, sex, habits of cigarette
smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort
entry. A significant association with risk of cirrhosis and HCC was also
observed for HBV genotype, precore G1896A mutant and basal core promoter
A1762T/G1764A double mutant. Nomograms have been developed for the long-term
risk prediction of cirrhosis and HCC for patients with chronic hepatitis B.
Inactive carriers of HBV have an increased HCC incidence and liver-related
mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry
is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg.
These findings may inform the effective and efficient management of chronic
hepatitis B.

自然史揭示慢性乙型肝炎

陈建仁Chen1,2,*,怀余Yang3Article首次在网上公布:2011年3月21日

分类号:10.1111/j.1440-1746.2011.06695.x
© 2011年胃肠病学和肝病基金会和Blackwell
亚洲私人有限公司出版发行

胃肠病学和肝病
第26卷第4期,页628-638,2011年4月

在揭示乙肝病毒研究由中研院赠款,国家
卫生研究院和Bristol - Myers Squibb公司公司,美国

摘要
慢性乙肝是一个世界性的公共卫生挑战。自然知识
慢性乙型肝炎历史是疾病的管理十分重要。一
以社区为基础的前瞻性队列研究进行了评估风险
预测对慢性乙型肝炎在台湾的进展。总共有23 820
与会者从1991-1992年就读于台湾七个乡镇。他们
血清样品采集和测试,在研究开始对乙型肝炎表面
抗丙型肝炎病毒抗原(HBsAg)和e抗原(HBeAg)阳性,抗体
(抗- HCV),谷丙转氨酶(ALT),α-甲胎蛋白(AFP)。一
对男性和女性参加者3653 subcohort谁属乙肝表面抗原阳性
和抗- HCV阴性被列入病毒载​​量风险评估
高程及相关肝病/癌症乙肝病毒(揭示乙肝病毒)
研究。新开发的肝硬化和肝细胞癌(HCC)的案件
确定了通过后续检查和数据连接的配置文件
美国国家癌症登记处,全民健康保险资料库及死亡
认证制度。这两个肝癌和肝硬化的发生率显着
相关的剂量反应关系,从<300例血清乙肝病毒DNA水平
(不到)到≥1 000 000拷贝/毫升。在维持生物梯度
显着(P“0.001)后的年龄,性别,生活习惯调整卷烟
吸烟和饮酒,e抗原血清状态,血清ALT水平在队列
项。一个与肝硬化和肝癌的风险也显着相关
乙型肝炎病毒基因型观察,前C区G1896A突变体和基本核心启动子
A1762T/G1764A双突变。列线图已经制定了长期
风险预测患者的慢性乙型肝炎,肝硬化和肝癌
乙肝病毒携带者不活动有增加肝癌的发生率和肝脏相关
死亡率高于乙肝表面抗原,阴性对照。血清HBV DNA水平的研究项目
是一种对HBeAg,HBV DNA及乙肝表面抗原自发血清廓清主要指标。
这些发现可通知慢性有效和高效的管理
B型肝炎

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发表于 2011-3-23 17:50 |只看该作者
本帖最后由 kennyu 于 2011-3-23 17:52 编辑

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http://www1.easl.eu/easl2011/program/Posters/Abstract182.htm

Poster Presentations    Session Title: Category 07b: Viral Hepatitis B & D: Clinical (except therapy)
Presentation Date:  31 MAR, 2011
GENERATION OF THE PREDICTION MODELS FOR THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B AND EXTERNAL VALIDATION BY INDEPENDENT COHORTS

M. Kurosaki1*, M.-F. Yuen2, W.-K. Seto2, T. Kumada3, K. Tanaka1, Y. Suzuki1, Y. Hoshioka1, N. Tamaki1, T. Kato1, Y. Yasui1, T. Hosokawa1, K. Ueda1, K. Tsuchiya1, T. Kuzuya1, H. Nakanishi1, J. Itakura1, Y. Takahashi1, Y. Asahina1, N. Izumi1
1Musashino Red Cross Hospital, Tokyo, Japan, 2University of Hong Kong, Hong Kong, Hong Kong S.A.R., 3Ogaki Municipal Hospital, Gifu, Japan. *[email protected]


Aims: Data mining analysis was used to generate predictive models for the development of HCC and to evaluate the efficacy of nucleos(t)ide analog (NUC) therapy to reduce HCC in patients at high risk.
Methods: A cohort of 588 chronic hepatitis B patients was screened for HCC (average period 7.5 years). Data mining analysis (IBM-SPSS Modeler 13) was used to identify risk factors for HCC and to generate predictive models. Independent cohort in Hong Kong (cohort-H, n=525) and in Ogaki, Japan (cohort-O, n=576) was used for external validations. Sensitivity to identify patients at risk for HCC was compared between models and the guideline criteria for antiviral treatment. Data from 151 patients on long-term NUC therapy was applied on these models to evaluate the efficacy of NUC to prevent HCC.
Results: The 5 year prevalence of HCC in untreated cohort was 5.3%. Age (≥40), platelet (< 150 x 109/L), HBV DNA (>5.8 log copies/ml), and mutations in core promoter 1762/1764 were identified as risk factors and were used to build prediction model of HCC (model-1). The 5 year prevalence of HCC in patients having 0, 1, 2, 3, and 4 risk factors was 0%, 0-3.4%, 3.2-4.3%, 17.6% and 30%, respectively. In the model without incorporating core promoter mutations (model-2), the 5 year prevalence of HCC in patients having 0, 1, 2, and 3 risk factors was 0%, 1.1-1.8%, 5.0-9.1%, and 28.1%, respectively. The external validations confirmed the reproducibility of these models (cohort-H: r2=0.87-0.95, cohort-O: r2=0.93). Sensitivity for identifying HCC development was as follows: AASLD guideline 19%, EASL guideline 67%, model-1 83%, and model-2 98%. In patients with high risk of HCC, long-term NUC therapy reduced the 5 year incidence of HCC by 11-23% (p < 0.05).
Conclusions: Prediction models that include age, platelet counts, HBV DNA, and core promoter mutations had high reproducibility and sensitivity to identify patients with risk for the development of HCC. These models may be used to extract patients at risk for HCC out of those excluded from therapy by treatment guidelines. The NUC therapy significantly reduced the incidence of HCC among patients with high risk for HCC.

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发表于 2011-3-23 17:51 |只看该作者
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这个结果还是比较给力的。因为,预测的准确性还是比较高的。
感觉比使用现有的治疗指南更保险一些。

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才高八斗

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发表于 2011-3-23 18:01 |只看该作者
kennyu 发表于 2011-3-23 17:51
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这个结果还是比较给力的。因为,预测的准确性还是比较高的。

Thanks. The Taiwan study is very influential on the treatment of HBV - everybody wants hbvdna to be 0.
My only comment on your paper is that it is a 5-year span study. The longer and older, of course, the more chances of getting HCC.
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