即使抗病毒，170个纤维化及肝硬化中，有60个得Ca！

newchinabok

也可用核苷类药，药效越强的降低发生率越明显。过去主要用拉米夫定加阿德福韦，我门诊每年约治疗肝硬化300人，约有10位患者发生肝癌；近3年中绝大多数用一线药，用恩替卡韦的已有4人肝癌，用替诺福韦的暂时还没有发生

newchinabok

肝硬化不抗病毒治疗每年有1%−4%的患者发生肝癌  转载骆抗先博客文章

zgct

英文原文

Risk of liver cancer from hepatitis B persists even after clearing the virus

Long-term infection with hepatitis B virus (HBV) can cause liver inflammation and increase the risk of liver cancer. Researchers from the US Centers for Disease Control and Prevention, however, found that resolving HBV infection was not associated with reduced rates of liver cancer.

A total of 238 patients who resolved HBV infection and 435 patients who did not were selected from among 1346 patients with chronic HBV infection followed for up to 31 years. The liver cancer risk, measured as a hazard ratio (HR), in patients after resolving HBV infection was similar compared with the risk in patients who did not resolve infection (HR: 0.7; 95% confidence interval: 0.2-2.4).

"Since the risk of liver cancer persists among adults with apparent cure of the infection, they might still need to be followed closely," said Dr. Prabhu Gounder, lead author of the Alimentary Pharmacology & Therapeutics article.

zgct

长期的感染乙型肝炎病毒（HBV）可导致肝脏炎症和增加肝脏癌症的风险。而来自美国疾病控制与预防中心（CDC）的研究人员发现，即使解决了乙型肝炎病毒感染的问题（病毒清除）而肝脏癌症的发生率未必会显著降低。

一项对1346名乙肝病毒感染的者为期31年的随访研究结果显示，其中有238名出现乙肝病毒清除，435名患者没有出现乙肝病毒清除。肝脏癌症的风险，以风险比（HR）来检测，乙肝病毒清除组患者跟未清除乙肝病毒组患者的风险比是相似的（HR：0.7；95%置信区间：0.2-2.4）。

“由于在乙肝病毒感染完全被治愈的成年人中仍然持续存在发生肝脏癌症的风险，因此，这些人群仍然非常有必要进行持续的监测，”发表在美国《营养药理学与治疗学》（Alimentary Pharmacology & Therapeutics）杂志上的该研究的主要作者 Prabhu Gounder 博士说道。

东霸天

回复 newchinabok 的帖子

楼主的话 把大家患者吓死了 那还研究新药干什么呢  都抗病毒呗  起码不能癌变

newchinabok

回复 东霸天 的帖子

骆老观察，应该可信，没人吓你，只有自己吓到自己，科学事实，可以掩盖吗？你掩盖，它还是在哪儿

newchinabok

医生要求每半年查甲胎，b超，潜台词说什么，大家不会不明白吧

StephenW

Original paper. Read for yourself.

http://onlinelibrary.wiley.com/doi/10.1111/apt.13621/full

Nested case–control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance

    P. P. Gounder1,*, L. R. Bulkow1, M. Snowball2, S. Negus2, P. R. Spradling3, B. C. Simons2 andB. J. McMahon1,2


原始论文。自己阅读自己。

巢式病例对照研究：乙肝表面抗原血清学清除后肝癌风险

    P.P。Gounder1，*，L.R。Bulkow1，M Snowball2，S Negus2，P.R。Spradling3，B。C。Simons2且B。 J. McMahon1,2

文章首次在线发表时间：2016年4月8日

DOI：10.1111 / apt.13621

2016年©约翰·威利父子有限公司

问题
封面图片的卷。 43第10期
消化系统药理学和治疗

早期的视图（记录的网上版本包括前一个问题出版）
文章中的76分altmetric


背景

解决慢性乙型肝炎病毒（HBV）感染后肝细胞癌（HCC）的风险是不清楚。
目标

为了比较阿拉斯加原住民（AN）患者之间的肝癌风险与无乙肝表面抗原（HBsAg）血清学清除。
方法

我们选择与（例病例），无（控制例）从1346队列慢性HBV感染患者AN在后面的HBsAg 1982年至2013年转阴者。我们试图在性别，HBV基因型和年龄匹配两个控制患者/病例患者。人 - 年的随访病例患者开始对HBsAg分辨率和控制患者的日期开始的日期等同于队列入境日期加上其对应的情况下，患者的HBsAg年期限。我们比较使用Cox比例风险模型肝癌的风险。
结果

238例病例（4-患有HCC）和435控制例（9肝癌）在年龄[P值（P）= 0.30]，性别（P = 0.53）和HBV基因型（P = 0.99）类似。病例患者有较长的人 - 年的随访中比控制病人（11.7对比10.1年; P = 0.04）。肝癌率/ 100 000人是病例（132）和控制患者之间的相似（178; P = 0.65）。调整后的风险比比较病例和控制患者是肝癌[0.7相似; 95％置信区间（CI）：0.2-2.4]，增加每1年增加年龄（1.1; CI：1.0-1.1; P <0.01），并且是更大的，如果最初的HBeAg阳性（3.5; CI： 1.1-11.0; P = 0.03）。
结论

乙型肝炎表面抗原血清清除未与降低肝癌风险相关联;肝癌风险评估是由宽95％置信区间的限制。乙肝表面抗原血清学清除之前满足HCC监测指征者转阴可以从后持续监督中受益。
Article first published online: 8 APR 2016

DOI: 10.1111/apt.13621

© 2016 John Wiley & Sons Ltd

Issue
Cover image for Vol. 43 Issue 10
Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)
Article has an altmetric score of 76


Background

Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear.
Aim

To compare HCC risk between Alaska Native (AN) patients with and without hepatitis B surface antigen (HBsAg) seroclearance.
Methods

We selected persons with (case-patients) and without (control-patients) HBsAg seroclearance from a cohort of 1346 chronically HBV-infected AN patients followed during 1982‒2013. We attempted to match two control-patients/case-patient on sex, HBV genotype, and age. Person-years of follow-up for case-patients began on the date of HBsAg resolution and for control-patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case-patient. We compared HCC risk using a Cox proportional hazards model.
Results

The 238 case-patients (4 with HCC) and 435 control-patients (9 with HCC) were similar in age [P-value (P) = 0.30], sex (P = 0.53) and HBV genotype (P = 0.99). Case-patients had longer person-years of follow-up than control-patients (11.7 vs. 10.1 years; P = 0.04). The HCC rate/100 000 persons was similar between case- (132) and control-patients (178; P = 0.65). The adjusted hazard ratio comparing case- and control-patients was similar for HCC [0.7; 95% confidence interval (CI): 0.2–2.4], increased for each 1-year increment for age (1.1; CI: 1.0–1.1; P < 0.01), and was greater if the initial HBeAg was positive (3.5; CI: 1.1–11.0; P = 0.03).
Conclusions

Hepatitis B surface antigen seroclearance was not associated with reduced HCC risk; the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.

StephenW

Conclusions

Previous studies evaluating the risk for HCC associated with HBsAg loss have included the time during which persons were seropositive for HBsAg in calculating the HCC rate.[3, 7, 9, 10] Our study is unique because we attempted to isolate the effect of HBsAg seroclearance on subsequent risk for developing HCC. The results indicate that HBsAg seroclearance was not associated with reduced risk for HCC. Although the small number of persons who developed HCC limits the strength of our conclusion, our case- and control-patients were sampled from one of the largest and longest followed population-based cohorts of persons with HBV infection in the world. As a result, this present study includes more persons with resolved HBsAg (including those who developed HCC) than similar previous studies that have evaluated the risk of HCC after resolving HBV infection.[3, 8, 9, 26] As it is unlikely a more precise estimate of HCC risk following HBsAg seroclearance can be obtained in the near future, it would be reasonable to offer HCC surveillance after HBsAg seroclearance for persons meeting AASLD practice guidelines criteria for surveillance prior to resolving HBV infection.[6]

Cirrhosis is an important risk factor for developing HCC among persons with chronic HBV infection. The presence of cirrhosis was not comprehensively known for our study participants who did not develop HCC in part because many patients lived in rural communities without ready access to liver biopsy capable facility. Therefore, we were unable to match case- and control-patients according to their cirrhosis status. For the subset of case- and control-patients with APRI and Fib4 available, we are reassured that there was no difference between the two groups in the proportion with advanced liver fibrosis as measured by these non-invasive makers. Furthermore, knowing the cirrhosis status only for case-patients who developed HCC still provides insights into the risk for HCC. Unlike previous studies where the majority of patients who developed HCC after resolving chronic HBV infection had cirrhosis at the time of HBsAg seroclearance,[3, 9, 26] only one of the four case-patients with HCC in our study had cirrhosis. However, the other three case-patients without cirrhosis would have met AASLD age/sex criteria for continuing HCC surveillance after HBsAg seroclearance.[6]

The reasons for why HBsAg seroclearance was not associated with reduced HCC rate are unknown but likely multifactorial. It is possible that factors early in the course of HBV infection, such as the HBV DNA level or degree of hepatic necroinflammation, might have had a greater influence on HCC risk.[10, 12, 27] We compared the distribution of HBV DNA level for the time periods before and after HBsAg seroclearance among case-patients and for the corresponding time periods among control-patients. The lack of difference in HCC rate between case- and control-patients corresponds with the similarity in HBV DNA levels among case-patients compared with control-patients before HBsAg clearance. These results support previous reports that the HBV DNA level before HBsAg seroclearance is an important predictor for developing HCC.[10, 12] It is likely for the reason that treatment with nucleos(t)ide analogues decreases both the risk for developing HCC and the risk of HCC recurrence after surgical resection.[28-31] One mechanism by which HBV infection causes HCC could be through the integration of HBV DNA into the host hepatocyte genome and as covalently closed circular (ccc) DNA in hepatocyte nuclei.[27, 32] The integrated viral DNA and cccDNA that result from HBV viremia persist after HBsAg seroclearance and might promote the development of HCC. Furthermore, a substantial proportion of case-patients in our study had a detectable HBV DNA level after HBsAg seroclearance. Thus, it is possible that ongoing low-level HBV DNA replication with continued integration into the host hepatocyte also contributes to the persistent HCC risk after HBsAg seroclearance.

In addition, the degree of HBV-associated hepatic inflammation, which can be assessed by measuring ALT levels, correlates with the risk for developing HCC.[27] The ALT level before HBsAg seroclearance was similar among case-patients compared with control-patients. The ALT level together with the HBV DNA level indicates that the majority of case- and control-patients were in the immune-inactive phase of HBV infection prior to HBsAg seroclearance. Results from this present study confirm previous evaluations in this cohort demonstrating that most patients with chronic HBV infection are HBeAg-negative and remain in the immune-inactive phase after HBeAg clearance.[33, 34] The lack of difference in the degree of hepatic inflammation between case- and control-patients prior to HBsAg could also partly account for the lack of association between HBsAg seroclearance and reduced HCC risk.

Our adjusted analysis indicates that the initial HBeAg status and increasing age at cohort entry were associated with HCC risk. The presence of HBeAg, indicating immune-active phase of disease, is associated with high HBV DNA levels and intermittent ALT elevations.[35] Therefore, HBeAg seropositivity could be associated with increased risk for HCC, because it is a surrogate marker for HBV DNA level and hepatic inflammation.[7, 36] Our adjusted analysis also confirmed results from previous studies indicating that increasing age in HBV-infected persons is a risk factor for HCC.[2, 37, 38] Although the exact date of HBV infection is unknown for patients in our study, it is likely that most patients acquired HBV infection in early childhood or at birth.[39] Thus, the age at cohort entry probably correlates with the duration of infection for most study patients. Since our control-patients were matched with case-patients on age and duration of follow-up, the results additionally suggest that increasing age might be a risk factor for HCC independent of duration of HBV infection.

This study has limitations. First, our HCC risk estimates had wide confidence intervals because few case- and control-patients developed HCC. Thus, we could have failed to detect a real reduction in HCC risk associated with HBsAg seroclearance because of insufficient statistical power. It is important to note, however, that both HBsAg seroclearance and development of HCC are rare events, and our study has more persons with HBsAg seroclearance and HCC than other similar studies.[3, 8-10, 26] Furthermore, it is important to note that the HCC incidence for a population cannot be calculated in a case–control study since the number of cases and controls are prespecified. The HCC rates we present allow for comparing the HCC risk between groups in this paper, but the absolute rates cannot be compared with the HCC incidence reported elsewhere. In addition, the presence of other HCC risk factors, such as HCV coinfection, family history of HCC, diabetes mellitus or fatty liver disease,[18-20] was not comprehensively known for our study participants not developing HCC. As a result, we could not adjust for several important HCC risk factors in our model comparing the HCC rate between case- and control-patients. We did demonstrate, however, that case- and control-patients were similar in terms of certain key risk factors, such proportion with HCV coinfection, HBV DNA level, hepatic inflammation as measured by ALT levels, and liver fibrosis as measured by APRI and Fib4. Finally, our results based on the AN population might not be generalisable to other populations. The risk for HCC varies by HBV genotype[11]; AN persons infected with genotypes C and F have a higher incidence of HCC compared with persons infected with other genotypes.[22] Differences in the prevalence of HBV genotypes between those found in AN persons compared with other geographical regions of the world could affect the incidence of HCC observed between persons with and without HBsAg seroclearance.

The goals of HBV treatment are to reduce the risk of developing cirrhosis, liver decompensation and HCC. Therapy for HBV infection is indicated for patients in the immune-active phase but not for patients in the immune-inactive phase of HBV infection.[40] Most patients in our study were in the immune-inactive phase of infection and did not receive HBV therapy. However, study patients were still at high risk for developing HCC and HBsAg seroclearance did not reduce the HCC risk. Given the effectiveness of nucleos(t)ide analogues in reducing HCC risk for persons with elevated HBV DNA levels,[30] further research to better understand the factors early in the course of infection that predict future risk for developing HCC risk could help to identify a subset of immune-inactive patients who might benefit from early treatment.

StephenW

结论

先前的研究评估与HBsAg消失相关肝癌的风险包括在此期间，人在计算HCC率分别为阳性的乙肝表面抗原的时间。[3，7，9，10]我们的研究是独一无二的，因为我们试图孤立HBsAg的影响在血清清除为开发后续肝癌的风险。结果表明，HBsAg的血清清除未与肝癌风险降低相关。虽然谁开发HCC的人的数量少限制了我们结论的实力，我们的病例和控制患者HBV感染在世界人的规模最大，时间最长的，随后基于人口的队列中的一个取样。其结果是，目前这个研究包括更多的人与解决乙肝表面抗原（包括那些谁开发HCC）比解决HBV感染后评估了肝癌的风险类似以往的研究[3，8，9，26]由于这是不可能的一在HBsAg血清学清除肝癌的风险更精确的估计可以在不久的将来取得的，可以合理地提供的HBsAg血清学清除为解决HBV感染满足AASLD实践指南标准，监控人员之前后HCC监测。[6]

肝硬化是慢性HBV感染者之间发生HCC的重要危险因素。肝硬化的存在并没有全面知道我们的研究参与者谁没有发展HCC，部分原因是许多患者生活在农村社区没有准备好进入肝活检能设施。因此，我们无法根据自己的肝硬化地位相匹配病例和控制病人。对于病例和控制患者的APRI和Fib4可用的子集，我们放心由这些非侵入性的制造商测量，有在有先进的肝纤维化的比例在两组之间没有差异。此外，只有知道肝硬化状态谁开发HCC仍然提供了深入了解肝癌的风险例病例。不像先前的研究，其中的大多数谁解决慢性HBV感染后发展HCC患者在HBsAg的血清清除的时间过肝硬化，[3,9，26]只有四个病例HCC患者之一的我们的研究有肝硬化。然而，其他三例病例无肝硬化会为乙肝表面抗原血清学清除后持续HCC监测满足AASLD年龄/性别标准。[6]

为什么乙肝表面抗原血清学清除不降低肝癌率相关的原因尚不清楚，但可能是多因素。这是可能的因素在HBV感染的过程中的早期，如乙肝病毒DNA水平或肝坏死性炎症的程度，可能有对肝癌风险较大的影响。[10，12，27]我们比较的HBV DNA水平的分布对于周期之前和病例患者的HBsAg血清清除后和控制患者的相应时间段的时间。缺乏病例和控制之间的患者肝癌率差异对应与HBsAg清除前控制组相比病例患者中的HBV DNA水平的相似性。这些结果支持以前的报告认为HBsAg的血清清除之前的HBV DNA水平是发展肝癌的重要预测指标。[10，12]这是可能的原因，与核苷（酸）类似物治疗降低既用于开发肝癌和风险手术切除后肝癌复发的风险。[28-31]一种机制，通过它HBV感染导致肝癌可以是通过整合的HBV DNA导入宿主肝细胞的基因组，并作为共价闭合环状（CCC）的DNA在肝细胞核。[27 32]集成的病毒DNA和cccDNA的，从HBV病毒血症导致的HBsAg血清清除后仍然存在，可以促进肝癌的​​发展。此外，个案的患者在我们的研究中有相当比例的HBsAg已经转阴后，可检测HBV DNA水平。因此，它有可能在持续整合到宿主的肝细胞持续低水平HBV DNA复制也有助于对HBsAg血清清除后的持久性肝癌的风险。

此外，HBV相关的肝的炎症的程度，这可通过测定ALT水平进行评估，相关联地发展肝癌的风险。[27]的HBsAg血清清除之前的ALT水平与对照-患者相比病例患者中相似。与HBV DNA水平的ALT水平，则说明大多数病例和控制患者均在之前对HBsAg血清学清除HBV感染的免疫无效阶段。从目前这个研究的结果证实了先前的评估在此队列表明大多数患者有慢性HBV感染HBeAg阴性，并保持在HBeAg清除后，免疫无效阶段[33，34]在肝脏炎症程度的缺乏差异病例和以前对HBsAg控制患者之间也可以部分解释缺乏乙肝表面抗原血清学清除和减少风险的肝癌之间的关联。

我们调整后的分析表明，在队列进入初始HBeAg状态和年龄的增加都与肝癌的风险。 e抗原的存在，表明疾病的免疫活性相，用高HBV DNA水平和间歇ALT升高相关联。[35]因此，HBeAg的血清阳性可以与肝癌风险增加相关，因为它是乙型肝炎病毒DNA的替代标记水平和肝脏炎症。[7，36]我们调整后的分析也证实了先前的研究表明，在HBV感染者年龄增加是肝癌的危险因素的结果。[2，37，38]虽然乙肝病毒感染的确切日期未知的患者在我们的研究中，它很可能是大多数患者在婴幼儿期或出生时获得的HBV感染。[39]因此，年龄队列的条目可能与感染的持续时间对大多数研究的患者相关。由于我们的控制患者与年龄和随访时间区分患者相匹配，结果还表明，随着年龄的增加可能是肝癌独立HBV感染的持续时间的一个危险因素。

这项研究有局限性。首先，我们的HCC风险估计有广泛的置信区间，因为一些病例和控制患者发展为肝癌。因此，我们可以没有检测乙肝表面抗原与转阴因为统计力量不足，相关肝癌风险真实的还原。然而要注意的是，这两种HBsAg的血清清除和HCC的发展是罕见的事件，和我们的研究中有更多的人用HBsAg血清清除和HCC比其他类似的研究是重要的。[3，8-10，26]此外，重要的是需要注意的是一个人群肝癌发病率不能在病例对照研究，因为案件的数量来计算和控制都是预先设定。我们目前的肝癌率允许在本文组之间的肝癌风险的比较，但绝对速率不能与别处报导的肝癌发病率进行比较。此外，其他肝癌的危险因素，如丙型肝炎病毒共感染，肝癌，糖尿病或脂肪肝疾病的家族史，[18-20]的存在下没有全面地知道我们研究的参与者不发展肝癌。其结果是，我们不能调整为在我们的模型比较病例和控制患者的肝癌率几个重要肝癌的危险因素。然而，我们却证明，该病例和控制患者在某些关键的风险因素，例如比例与HCV合并感染，HBV DNA水平，肝脏炎症方面类似由APRI和Fib4测量由ALT水平，与肝纤维化检测。最后，基于所述AN人口我们的结果可能不是普遍意义到其他人群。肝癌的风险由HBV基因型[11]而变化;感染基因型C和F AN人有肝癌的发生率较高与感染其它基因型者相比。[22]在那些AN人发现与世界其他地域可能影响发病率比之间HBV基因型的患病率差异肝癌的使用和不使用的HBsAg血清清除者之间观察到。

乙肝治疗的目标是减少发展为肝硬化，肝功能失代偿和HCC的风险。治疗HBV感染，适合治疗的免疫活性相，但不为患者在HBV感染的免疫惰性的相。[40]大多数患者在我们的研究是在感染的免疫无活性相和没有收到乙肝治疗。然而，研究患者仍处于高风险的发展HCC及HBsAg血清学清除并没有减少肝癌的风险。鉴于降低升高的HBV DNA水平的人肝癌风险核苷（酸）类似物的有效性，[30]进一步研究，以更好地了解在感染过程月初预测未来风险发展为HCC风险可能有助于确定的因素谁可能从早期治疗中获益免疫无活性的患者的子集。