HBV DNA整合和克隆肝细胞扩展慢性乙型肝炎患者考虑免疫耐受

StephenW

HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant
William S. MasoncorrespondencePress enter key for correspondence informationemailPress enter key to Email the author
, Upkar S. Gill
, Samuel Litwin
, Yan Zhou
, Suraj Peri
, Oltin Pop
, Michelle L.W. Hong
, Sandhia Naik
, Alberto Quaglia
, Antonio Bertoletti
, Patrick T.F. Kennedy
Article has an altmetric score of 2
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.012


Background & Aims

Chronic infection with hepatitis B virus (HBV) progresses through different phases. The first, called the immune-tolerant phase, has been associated with a lack of disease activity. We examined HBV-DNA integration, clonal hepatocyte expansion, HBV antigen expression, and HBV-specific immune responses in patients in the immune-tolerant phase to assess whether this designation is appropriate or if there is evidence of disease activity.
Methods

We studied HBV-DNA integration, clonal hepatocyte expansion, and expression of hepatitis B surface antigen and core antigen in liver tissues from 26 patients with chronic HBV infection (ages, 14–39 y); 9 patients were positive for hepatitis B e antigen (HBeAg) in the immune-tolerant phase and were matched for age with 10 HBeAg-positive patients with active disease and 7 HBeAg-negative patients with active disease. Peripheral blood samples were collected and HBV-specific T cells were quantified for each group.
Results

Detection of HBV antigens differed among groups. However, unexpectedly high numbers of HBV-DNA integrations, randomly distributed among chromosomes, were detected in all groups. Clonal hepatocyte expansion in patients considered immune tolerant also was greater than expected, potentially in response to hepatocyte turnover mediated by HBV-specific T cells, which were detected in peripheral blood cells from patients in all phases of infection.
Conclusions

We measured HBV-specific T cells, HBV-DNA integration, and clonal hepatocyte expansion in different disease phases of young patients with chronic hepatitis B, with emphasis on the so-called immune-tolerant phase. A high level of HBV-DNA integration and clonal hepatocyte expansion in patients considered immune tolerant indicated that hepatocarcinogenesis could be underway—even in patients with early stage chronic HBV infection. Our findings do not support the concepts that this phase is devoid of markers of disease progression or that an immune response has not been initiated. We propose that this early phase be called a high-replication, low-inflammation stage. The timing of therapeutic interventions to minimize further genetic damage to the hepatocyte population should be reconsidered.
Keywords:
HBsAg, Antiviral Immunity, HBV Replication, Hepatocyte Proliferation

StephenW

HBV DNA整合和克隆肝细胞扩展慢性乙型肝炎患者考虑免疫耐受
William S. Masoncorrespondence按回车键输入通信信息
，Upkar S.Gill
，Samuel Litwin
，周洲
，Suraj Peri
，Oltin Pop
，Michelle L.W. Hong
，Sandhia Naik
，Alberto Quaglia
，Antonio Bertoletti
，Patrick T.F.肯尼迪
文章的得分为2
DOI：http://dx.doi.org/10.1053/j.gastro.2016.07.012


背景与目的

乙型肝炎病毒（HBV）的慢性感染通过不同阶段发展。第一种，称为免疫耐受期，与缺乏疾病活动相关。我们在免疫耐受期检查了HBV-DNA整合，克隆肝细胞扩增，HBV抗原表达和HBV特异性免疫应答，以评估这种指定是否适当或是否有疾病活动的证据。
方法

我们研究了HBV-DNA整合，克隆肝细胞扩增和乙肝表面抗原和核心抗原在26个慢性HBV感染患者（年龄，14-39岁）的肝组织中的表达; 9名患者在免疫耐受期中为乙型肝炎e抗原（HBeAg）阳性，并且与10名具有活动性疾病的HBeAg阳性患者和7名具有活动性疾病的HBeAg阴性患者匹配年龄。收集外周血样品，并对每组的HBV特异性T细胞进行定量。
结果

HBV抗原的检测在组之间不同。然而，在所有组中检测到意外的高数量的HBV-DNA整合，随机分布在染色体中。在认为免疫耐受的患者中的克隆肝细胞扩增也大于预期，可能响应于HBV特异性T细胞介导的肝细胞周转，其在来自感染的所有阶段的患者的外周血细胞中检测。
结论

我们测量HBV特异性T细胞，HBV-DNA整合和克隆肝细胞扩张在慢性乙型肝炎的年轻患者的不同疾病阶段，重点是所谓的免疫耐受阶段。在认为免疫耐受的患者中高水平的HBV-DNA整合和克隆肝细胞扩增表明肝癌发生可以进行 - 甚至在早期慢性HBV感染的患者中。我们的研究结果不支持这一阶段缺乏疾病进展的标志或免疫反应尚未启动的概念。我们建议这个早期阶段被称为高复制，低炎症阶段。应该重新考虑治疗干预以使对肝细胞群体的进一步遗传损伤最小化的时机。
关键词：
HBsAg，抗病毒免疫，HBV复制，肝细胞增殖

neilhbver

能否依据这类研究，在耐受期开始治疗？
既然现在强效核苷药物这么便宜，长期吃的话，耐药可能也不是问题

可与言者

国外确实有主动打破免疫耐受早期接受治疗的相关研究

StephenW

回复 neilhbver 的帖子

是的，应该治疗，但目前没有好的治疗.

Wai-Kay Seto和Man-Fung Yuen评论:

Wai-Kay Seto and Man-Fung Yuen are at the
Department of Medicine, University of Hong Kong, and
State Key Laboratory for Liver Research, University of
Hong Kong, Queen Mary Hospital,
102 Pokfulam Road, Hong Kong.
Correspondence to M.-F.Y.
[email protected]

On the basis of the results of this study2, the
immune tolerant phase of CHB is no longer
considered to be quiescent, as liver histology,
T-cell responses, viral integration and hepatocyte clonality all point to underlying disease activity (FIG. 1). In fact, the word “tolerance” is misleading, with the term “high- replicative low-inflammatory” (HRLI), suggested by the authors, being more appropriate2. Does this
imply earlier treatment is needed during this
HRLI phase? A double-blind randomized
study published in 2014 compared tenofovir
versus tenofovir plus emtricitabine in patients
positive for HBeAg with high viral load and
normal ALT levels. After a treatment duration
of 192 weeks, only 55% of those receiving
tenofovir and 76% of those receiving tenofovir plus emtricitabine achieved the primary study end point of undetectable serum HBV DNA levels (<69 IU/ml)9. In the context of the findings of Mason et al.2, serious doubt is cast
on the targeted primary end point defined by
undetectable serum HBV DNA. However, if
earlier treatment is advocated, commencement of antiviral therapy might need careful consideration in paediatric patients, in which
the safety profile of nucleoside analogues has
not been as well-established compared with
the adult population. Other barriers to  
earlier
treatment  commencement  include  drug  
incompliance and increased financial burden
to health-care systems.
Hence,  although  a  blanket  treatment  
recommendation for all patients positive for
HBeAg  with  high  viral  loads  and  normal  
serum ALT levels would be premature, treatment commencement might need consideration if there are other risk factors of disease
progression. Noninvasive methods of liver fibrosis assessment (for example, l
iver stiffness measurements) are now widely available,  meaning  invasive  liver  biopsies  can be avoided. Patients with serum ALT levels
outside the healthy ranges recommended by Prati et al.4 should be prioritized for fibrosis assessment, and those with substantial liver fibrosis should be considered for treatment.
In  addition,  as  first-degree  relatives  with  
CHB are at an increased risk of HBV-related
HCC10,  treatment  commencement  should  
be discussed with individuals with a positive family history for HCC. Although future
clinical studies are needed to evaluate if earlier
treatment brings about improved clinical outcomes, the message from Mason
et al.2 is clear:
in CHB patients considered immune tolerant, underlying danger lurks.

Wai-Kay Seto和Man-Fung Yuen正在
香港大学医学系
国立大学肝脏研究国家重点实验室
香港，玛丽医院，
香港薄扶林道102号。
对M.-F.Y.的对应
[email protected]

在本研究结果的基础上，
CHB的免疫耐受期不再存在
认为是静止的，作为肝脏组织学，
T细胞应答，病毒整合和肝细胞克隆能力都指向潜在的疾病活性（图1）。事实上，“耐受性”这个词是误导性的，作者建议的术语“高复制性低炎症”（HRLI）更适合2。做这个
这意味着需要更早的治疗
HRLI相位？双盲随机化
研究发表于2014年比较替诺福韦
与替诺福韦加恩曲他滨在患者
阳性HBeAg与高病毒载量和
正常ALT水平。治疗后持续时间
的192周，只有55％的接受
替诺福韦和接受替诺福韦加恩曲他滨的患者的76％达到了不可检测的血清HBV DNA水平（<69 IU / ml）的主要研究终点。在Mason等人2的发现的背景下，严重的怀疑
在定义的目标主端点上
不可检测的血清HBV DNA。但是，如果
提倡早期治疗，开始抗病毒治疗可能需要在儿科患者中仔细考虑，其中
核苷类似物的安全性
与之相比并没有被确立
成人人口。其他障碍
更早
治疗开始包括药物
不一致和增加的财政负担
到卫生保健系统。
因此，虽然进行了毯子处理
建议所有患者阳性
HBeAg具有高病毒载量和正常
血清ALT水平将是过早的，如果存在其他疾病的风险因素，则可能需要考虑治疗开始
进展。肝纤维化评估的非侵入性方法（例如，
iver刚度测量）现在广泛可用，意味着可以避免侵入性肝活检。患者血清ALT水平
在Prati等推荐的健康范围外4应优先进行纤维化评估，并且应考虑那些具有实质性肝纤维化的患者进行治疗。
此外，作为一级亲属
CHB的HBV相关风险增加
HCC10，治疗开始应该
与HCC阳性家族史的个体讨论。虽然未来
需要临床研究来评估是否更早
治疗带来改善的临床结果，来自梅森的消息
et al.2很清楚：
在CHB患者认为免疫耐受，潜在的危险潜伏