乙肝病毒DNA水平升高的E抗原阴性患者:临床预后

StephenW

PLoS One. 2015 Dec 22;10(12):e0144777. doi: 10.1371/journal.pone.0144777. eCollection 2015.
Prediction of Clinical Outcomes in Hepatitis B E Antigen Negative Chronic Hepatitis B Patients with Elevated Hepatitis B Virus DNA Levels.Ahn JM1,2, Sinn DH1, Gwak GY1, Paik YH1, Choi MS1, Lee JH1, Koh KC1, Paik SW1.
Author information

• 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
• 2Department of Medicine, Korea University School of Medicine, Seoul, Korea.
  

AbstractOBJECTIVES: We investigated whether long-term clinical outcomes such as disease progression or inactive hepatitis B virus (HBV) carrier state can be predicted by baseline factors in hepatitis B e antigen (HBeAg)-negative HBV infected patients with an elevated viral load.
METHODS: A retrospective cohort of 527 HBeAg-negative chronic HBV infected patients with an elevated viral load (HBV DNA ≥ 2,000 IU/ml) was assessed for disease progression defined by the development of hepatocellular carcinoma (HCC) or cirrhotic complication, as well as becoming an inactive carrier.
RESULTS: During a median 3.6 years of follow-up, disease progression was detected in 46 patients (40 with HCC, 6 with cirrhotic complication), and 31 of 309 non-cirrhotic patients became inactive carriers. Older age, male gender, cirrhosis, high HBV DNA levels at baseline, and short antiviral therapy duration were independent risk factors for HCC. Low HBV DNA and quantitative hepatitis B surface antigen (qHBsAg) levels were independent predictors for becoming inactive carriers in patients without cirrhosis. In non-cirrhotic patients with both low qHBsAg and HBV DNA levels, the 5-year cumulative incidence of an inactive carrier was 39.8%, while that of disease progression was 1.6%.
CONCLUSION: HBeAg negative patients without cirrhosis can be closely monitored for becoming an inactive carrier when both HBV DNA and qHBsAg levels are low, as the risk of disease progression is low while incidence of an inactive carrier is high.

StephenW

公共科学图书馆之一。 2015年12月22日; 10（12）：e0144777。 DOI：10.1371 / journal.pone.0144777。 eCollection 2015年。
在肝炎临床预后预测BE抗原阴性慢性乙型肝炎患者升高的乙肝病毒DNA水平。
安JM1,2，新芬DH1，郭氏GY1，白YH1，崔MS1，李JH1，苏梅KC1，白SW1。
作者信息

    医学教研室，三星医疗中心，韩国成均馆大学医学院，首尔，韩国。
    教研室医学，高丽大学医学院，韩国首尔。

抽象
目的：

我们调查是否长期的临床结果，如疾病进展或不活动的乙肝病毒（HBV）携带者可以通过在乙肝e抗原（HBeAg）阴性乙肝病毒感染者与被举起的病毒载量的基线因素进行预测。
方法：

527 HBeAg阴性慢性乙肝病毒感染者有较高的病毒载量的回顾性队列（HBV DNA≥2000 IU / ml）的评估由肝细胞癌（HCC）或肝硬化的并发症，发展定义的疾病进展，以及成为不活动的载体。
结果：

在中位数3.6年的随访，病情恶化46例（40肝癌，6肝硬化并发症）检测，以及31 309非肝硬化患者成为非活动性携带者。高龄，男性，肝硬化，高HBV DNA水平在基线和短期抗病毒治疗时间的独立危险因素为肝癌。低HBV DNA和定量乙肝表面抗原（qHBsAg）水平独立预测变为非活动载波的患者没有肝硬化。在非肝硬化患者兼有低qHBsAg和HBV DNA水平，非活动载体的5年累积发生率为39.8％，而疾病进展为1.6％。
结论：

HBeAg阴性患者没有肝硬化可以成为当两个HBV DNA和qHBsAg水平较低，作为疾病进展的危险性是低的，而一个非活性载体的发病率是很高的非活性载体进行密切监测。

StephenW

Patients and Methods
Study design, setting, and participants

We screened consecutive HBsAg positive patients from the database of Samsung Medical Center, Seoul, Korea between January 2008 and December 2011. We included 1,199 patients who met the following inclusion criteria: 1) age ≥ 18 years; 2) chronic HBV infection, defined by the presence of HBsAg in serum for ≥ 6 months or by clinical history; 3) HBeAg negative; 4) HBV DNA ≥ 2,000 IU/ml; 5) qHBsAg measured at the same day as HBV DNA and 6) no history of cirrhotic complication, such as variceal hemorrhage, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, or hepatic encephalopathy. These patients were further evaluated and excluded from the study if any of the following exclusion criteria were met: 1) history of HCC or other chronic liver disease (n = 389); 2) history or current use of antiviral therapy (AVT) [either nucleos(t)ide analogues (NUC) or interferon] (n = 117); 3) HCC detected within 6 months from baseline or follow-up duration ≤ 6 months (n = 166). Finally, 527 treatment-naïve HBeAg negative CHB patients were analyzed. The study was reviewed and approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2014-07-032-001). Because the study is based on the retrospective analysis of existing administrative and clinical data, the requirement of obtaining informed patient consent was waived by the Institutional Review Board of Samsung Medical Center. Patient records/information was anonymized and de-identified prior to analysis.

Discussion

In our study, several baseline factors were independently associated with development of HCC, which were older age, male gender, high HBV DNA levels, and presence of cirrhosis. Furthermore AVT duration during follow up was significantly associated with reduced risk of HCC development. Our findings are in line with several previous studies that reported risk factors for HCC in chronic HBV infected patients [3, 5]. Guidelines for management of hepatitis B recommend prompt antiviral therapy for cirrhotic patients with an elevated viral load [2, 3]. Our data also support that cirrhotic patients should receive prompt antiviral therapy, as the risk of disease progression was substantial (21.7% at 5-years) and as the risk of HCC was reduced by increasing AVT duration. In contrast, the 5-year cumulative incidence of disease progression was low for patients without cirrhosis (2.4% at 5-years). The rate was even lower (1.4% at 5-years) for young patients (age < 50 years), while quite a large proportion of patients without cirrhosis (8.3% at 3-years and 13.1% at 5-years) became inactive carriers. Thus close monitoring is an attractive option, as currently available AVT just controls viral replication without eradication so it should be received life-long until the HBsAg disappears [5].

We found that HBV DNA and qHBsAg levels help select those who may benefit from close monitoring over prompt therapy. qHBsAg and HBV DNA levels were significant factors associated with inactive carriers. Our results were consistent with those of previous cross-sectional studies showing that the qHBsAg level is lower in inactive carrier state than in immune tolerance or immune clearance phase [11, 12], those of previous retrospective cohort studies that showed low qHBsAg levels can predict maintenance of inactive carrier states [6, 13], or those of a prospective cohort study showing that qHBsAg levels help to identify inactive carrier state from active CHB phase in genotype D HBeAg negative patients [14]. The 5-year cumulative incidence of an inactive carrier was 42.2% for non-cirrhotic patients aged ≥ 50 years with both low HBV DNA and low qHBsAg levels, and it was 39.5% for < 50 years. In contrast, the cumulative incidence of an inactive carrier was 0% at 5-years in either non-cirrhotic patients aged ≥ 50 years or those aged < 50 years when both HBV DNA and qHBsAg levels were high. Those with high HBV DNA and low qHBsAg levels or those with low HBV DNA and high qHBsAg levels were in between. These data show that HBsAg and HBV DNA levels are useful to identify patients who will become inactive carriers among those with HBeAg negative CHB and an elevated viral load, and can help select patients who may benefit from close monitoring over prompt AVT. We further assessed the risk of disease progression in non-cirrhotic patients stratified by HBV DNA levels, qHBsAg levels and age. Notably, there was no case of cirrhotic complication in non-cirrhotic patients, and all the cases were HCC. In this analysis, we could note that the risk of disease progression was generally low in non-cirrhotic patients with low qHBsAg plus low HBV DNA levels, especially when they were young (age < 50 years). This suggested that young patients with low HBV DNA (< 20,000 IU/ml) plus low qHBsAg levels (< 2500 IU/ml) may be monitored over prompt AVT.

In this study, qHBsAg levels were not related with development of HCC. Consistent with our results, another study reported that qHBsAg levels are not associated with development of HCC in patients with an elevated viral load [15]; in that study, qHBsAg levels did not predict HCC in HBeAg negative patients with HBV DNA ≥ 2,000 IU/mL (p = 0.247) [15]. In contrast, a study from Japan reported that the qHBsAg level is a significant predictor for the development of HCC in patients treated with NUC [16], suggesting qHBsAg levels may have value in prediction of HCC in patients receiving AVT. However, the data from Japan are limited by a small sample size (167 patients and nine with HCC). In our study, about 50% of patients started AVT during follow-up at a different time point for each patient, so our data were also limited in answering this clinical question. Whether qHBsAg levels may have a role predicting development of HCC in NUC treated patients is still an open question, which warrants further study.

Our study has several limitations. This was a retrospective study with inherent limitations. HBV genotype can influence incidence of HCC as well as qHBsAg loss [1, 3, 17], which we did not investigate in this study, as almost all Korean patients are infected with HBV genotype C [18]. Thus application to other HBV genotype remains to be determined. In addition, presence of pre S/S mutant, one of risk factors for HCC, affects serum qHBsAg levels [19], which we did not investigate. Fibrosis stage of the liver was also missing and cirrhosis was defined clinically by thrombocytopenia, varices, or radiologic findings. In this study, patients were treatment naïve patients, but subsequently started AVT during follow-up. AVT is a well-known factor associated with development of HCC, and yet AVT was initiated at variable time point during follow-up. We used time-dependent variables (AVT duration) instead of use of AVT (yes vs. no) to minimize potential bias. However, AVT may act as a potential bias in this study, as time to start AVT was different from person to person. Finally, the rate of clinical event was relatively low (e.g., patients with cirrhosis complications = 6) and the follow-up period was not long enough. Therefore, our data need to be interpreted in the context of these limitations.

Despite these limitations, this study was a large scale study with clinical implications. Some HBeAg negative patients with an elevated viral load showed controlled HBV replication (persistent decrease of serum HBV DNA < 2,000 IU/ml combined with normal ALT levels in the absence of AVT). These results show that not all HBeAg negative patients with elevated HBV DNA levels are in HBeAg-negative CHB state requiring prompt AVT. Cirrhotic patients should receive prompt AVT, as the risk of disease progression is substantial. However, for some of patients without cirrhosis, close monitoring can be considered, as the risk of disease progression is low while incidence of an inactive carrier can be high. Our data indicate that qHBsAg and HBV DNA levels are helpful for selecting those who may benefit from monitoring among patients without cirrhosis.

In summary, our study found that older age, male gender, high HBV DNA level, cirrhosis and short AVT duration were independently associated with development of HCC in HBeAg negative patients with elevated viral loads, while low HBV DNA and qHBsAg levels were significant predictors for becoming inactive carriers in non-cirrhotic patients. Thus our study suggested that HBeAg negative patients without cirrhosis can be closely monitored when both HBV DNA and qHBsAg levels are low, as the risk of disease progression is low while incidence of an inactive carrier is high.

StephenW

患者与方法
研究设计，设置，和参与者

我们连续筛查HBsAg阳性患者的三星医疗中心，首尔，韩国数据库2008年1月和2011年12月间，我们包括谁符合以下两个标准的1199例患者：1）年龄≥18岁; 2）慢性HBV感染，由乙肝表面抗原的血清中的存在为≥6个月或由临床病史所定义; 3）HBeAg阴性; 4）HBV DNA≥2000国际单位/毫升; 5）qHBsAg在同一天的HBV DNA测定和肝硬化的并发症，如静脉曲张出血，腹水，自发性细菌性腹膜炎，肝肾综合征，或肝性脑病的6）没有历史。这些患者被进一步评价并排除在研究之外，如果以下任何排除标准得到满足：肝癌或其他慢性肝病（N = 389）的1）病史; 2）历史或当前使用的抗病毒治疗（AVT的）无论是核苷（酸）类似物（NUC）或干扰素（N = 117）; 3）肝癌6个月的基准或随访时间≤6个月（N = 166）中检测到。最后，527初治HBeAg阴性慢性乙型肝炎患者进行了分析。这项研究是审查和批准由三星医疗中心机构审查委员会（IRB号2014-07-032-001）。由于该研究是基于对现有的行政和临床数据的回顾性分析，得到患者的知情同意的要求被放弃了由三星医疗中心的机构审查委员会。病历/信息是匿名和去鉴定之前分析。

讨论

在我们的研究中，有几个基本因素独立与肝癌，这是老年，男性，高HBV DNA水平和肝硬化的存在发展有关。此外随访时AVT持续时间显著与肝癌发展的风险降低。我们的研究结果都符合，在慢性HBV感染者报告了危险因素的肝癌几个以前的研究[3,5]。指南乙型肝炎管理建议及时进行抗病毒治疗的肝硬化患者升高的病毒载量[2，3]。我们的数据也支持了肝硬化患者应及时接受抗病毒治疗，因为病情恶化的风险是相当大（21.7％在5年），为肝癌的风险降低了增加AVT持续时间。与此相反，疾病进展的5年累积发生率很低的患者无肝硬化（在5年为2.4％）。率更低（在5年1.4％）的年轻患者（年龄<50岁），而相当大比例的患者无肝硬化（3年，5年8.3％和13.1％）成为非活动性携带者。因此，密切监测是一个有吸引力的选择，因为目前市面上AVT只是控制病毒复制，而不铲除所以应该终生接受，直到乙肝表面抗原消失[5]。

我们发现，HBV DNA和qHBsAg水平有助于选择那些谁可能会密切监测了及时治疗中获益。 qHBsAg和HBV DNA水平与非活动性携带者相关显著的因素。我们的结果与显示先前的横断面研究一致认为qHBsAg水平较低的非活动携带状态比在免疫耐受和免疫清除期[11，12]，这些以往的回顾性队列研究，即表现为低qHBsAg水平可以预测维护非活动载体状态[6,13]，或者这些前瞻性队列研究显示，qHBsAg水平有助于识别非活动性携带状态从活动CHB阶段D型HBeAg阴性患者[14]。非活动载体，5年累计发生率为对于年龄≥50年了低HBV DNA和低qHBsAg水平非肝硬化患者42.2％，这是对<50岁39.5％。与此相反，非活性载体的累积发生率是0％，在5年中任一老年非肝硬化患者≥50年那些年龄<50岁的时候都HBV DNA和qHBsAg水平高。那些具有较高的HBV DNA和低qHBsAg水平或那些低HBV DNA和高qHBsAg水平之间。这些数据表明，HBsAg和HBV DNA水平是有用的，以确定病人谁就会成为在那些有HBeAg阴性CHB和升高病毒载量无活性的载体，并能帮助患者选择谁可能从密切监测过提示AVT受益。我们进一步评估疾病进展的非肝硬化患者由HBV DNA水平，qHBsAg水平和年龄分层的风险。值得注意的是，出现了非肝硬化患者肝硬化并发症的任何情况下，所有病例均为HCC。在这种分析中，我们可以注意到，疾病进展的风险普遍较低的非肝硬化患者低qHBsAg加低HBV DNA水平，尤其是当他们年轻（年龄<50岁）。这表明，年轻患者低HBV DNA（<20000国际单位/毫升）加低qHBsAg水平（<2500国际单位/毫升）可以在提示AVT监视。

在这项研究中，qHBsAg水平不相关与肝癌的发展。符合我们的结果，另一项研究报告说，qHBsAg水平不与肝癌的发展相关联的患者升高的病毒载量[15];在这项研究中，qHBsAg水平没有HBeAg阴性患者的HBV DNA≥2000国际单位/毫升（P = 0.247）[15]预测肝癌。与此相反，来自日本的一项研究报告说，qHBsAg水平与NUC治疗的患者肝癌的发展显著的预测[16]，这表明qHBsAg水平可能在接受AVT患者肝癌的预测值。但是，从日本的数据是由一个小样本（167例和九个患有HCC）的限制。在我们的研究中，约50％的患者开始AVT随访期间，在每个病人不同的时间点，所以我们的数据也被限制在回答这一临床问题。无论qHBsAg水平可能有肝癌的作用，预测发展NUC治疗的患者仍然是一个悬而未决的问题，这需要进一步的研究。

我们的研究也有一些局限性。这是一项回顾性研究固有的局限性。 HBV基因型可影响肝癌的发生率以及qHBsAg损失[1，3，17]，这是我们在本次研究没有调查，因为几乎所有的韩国患者感染HBV C基因型[18]。因此，适用于其他HBV基因型仍有待确定。此外，前期的S / S突变的存在，危险因素，肝癌之一，影响血清qHBsAg水平[19]，这是我们没有调查。肝纤维化阶段，也缺少和肝硬化是由血小板减少临床上定义，静脉曲张，或影像学表现。在这项研究中，患者初​​次接受治疗的患者，但随后在后续启动AVT。 AVT是与肝癌发展相关联的公知的因素，然而AVT进行随访期间发起的以可变的时间点。我们使用时间相关的变量（AVT持续时间），而不是使用AVT（是相对于没有），以尽量减少潜在的偏见。然而，AVT可以作为在本研究的潜在偏差，随着时间开始AVT是从人到人不同。最后，临床事件的速率相对较低（例如，肝硬化患者的并发症= 6）和随访期是不够长。因此，我们的数据需要在这些限制的范围内来解释。

尽管有这些限制，这项研究是有临床意义的大型研究。部分HBeAg阴性患者升高的病毒载量控制，表现为乙肝病毒复制（血清HBV DNA持续下降<2000 IU / ml的结合在没有AVT的ALT水平正常）。这些结果表明，并非所有的HBeAg阴性患者升高的HBV DNA水平在HBeAg阴性CHB状态需要迅速AVT。肝硬化患者应接受提示AVT，疾病进展的风险是巨大的。然而，对于一些患者无肝硬化，严密监测，可以认为，作为疾病进展的危险性是低的，而一个非活性载体的发生率可能很高。我们的数据表明，qHBsAg和HBV DNA水平是选择那些谁可能从监测受益的患者中没有肝硬化很有帮助。

总之，我们的研究发现，老年，男性，高HBV DNA水平，肝硬化和短AVT持续时间独立与HBeAg阴性患者升高的病毒载量HCC发生，发展有关，而低HBV DNA和qHBsAg水平显著预测因子成为非活动性携带者非肝硬化患者。因此，我们的研究表明，HBeAg阴性患者没有肝硬化随时监测时既HBV DNA和qHBsAg水平较低，作为疾病进展的危险性是低的，而一个非活性载体的发病率是很高的。

StephenW

全文:
http://journals.plos.org/plosone ... ournal.pone.0144777

咬牙硬挺

感谢分享

默然10

也就是让DNA 和HBsAG保存稳定比较低很好是吧，
不过现在有另外一种声音，核苷治疗后虽然这些数值保持了但是HCC风险是上升了，我个人来说是不相信的。
这个我觉得医院的肝病科医生最能回答，中国每天排队肝病门诊那么长，一份长期统计病例数据就可以看出来。

StephenW

回复 默然10 的帖子

如果DNA < 20,000 iu/ml, HBsAg < 2,500 iu/ml, HBeAg-ve可以观察，年龄<50岁, 没有必要立即治疗.
核苷治疗能降低HCC风险, 不能消除HCC风险.