乙肝表面抗原定量监测自然史和治疗结果的作用

StephenW

http://onlinelibrary.wiley.com/doi/10.1111/liv.12075/full
The role of HBsAg quantification for monitoring natural history and treatment outcome
    Michelle Martinot-Peignoux1,*,
    Martine Lapalus1,
    Tarik Asselah1,2,
    Patrick Marcellin1,2
    1    INSERM, U-773, CRB3, Université Paris-Diderot, Hôpital Beaujon, Clichy, France
    2    Service d'Hépatologie, Hôpital Beaujon, Clichy, France

Since its discovery by Blumberg in 1965, the hepatitis B virus antigen (HBsAg) is used as the fingerprint of hepatitis B infection. The HBsAg level is a reflection of the transcriptional activity of cccDNA. It is an important marker that not only indicates active hepatitis B infection but can also predict clinical and treatment outcomes. Assays for HBsAg quantification are fully automated and have high output. HBsAg titres are higher in HBe antigen (HBeAg)(+) than in HBeAg(−) patients and are negatively correlated with liver fibrosis in HBeAg(+) patients. In HBeAg(−) chronic hepatitis B, an HBsAg level <1000 IU/ml and an HBV DNA titre <2000 IU/ml accurately identify inactive carriers. During PEG-IFN treatment, HBsAg quantification is used to identify patients who will not benefit from therapy as early as week 12 on therapy, so that treatment may be stopped or switched- ‘week 12 stopping rule’. With nucleos(t)ide analogues (NA), the role of HBsAg quantification must be clarified. Several studies show that baseline and on-treatment HBsAg levels might identify patients that can be treated with no subsequent risk of reactivation. In clinical practice, HBsAg quantification is a simple and reproducible tool that can be used in association with HBV DNA to classify patients during the natural history of HBV and to monitor therapy.
Conclusions

Recent studies on serum HBsAg monitoring show that HBsAg levels change during the natural course of chronic hepatitis B and during ongoing therapy. These results can be used to determine the best management strategy for patients. During the natural history of HBV, HBsAg quantification can be used to differentiate between inactive carriers (no need for treatment) and HBeAg (−) chronic hepatitis B patients, who are likely to reactivate (closer monitoring) and who can benefit from therapy. During PEG-IFN therapy, early HBsAg monitoring could be used to develop a response-guided algorithm: to stop or switch therapy at week 12 in poor responders, to continue standard 48-week treatment in most patients with a favourable response and to extend therapy for intermediate on-treatment responders to improve the chances of response. The role of HBsAg monitoring during NA therapy must be clarified. The development of stopping rules should be determined in these life-long therapies. Several studies suggest that baseline and on-treatment HBsAg levels might help identify patients who can stop therapy with no risk of reactivation.

StephenW

乙肝表面抗原定量监测自然史和治疗结果的作用
    米歇尔马丁诺德的Peignoux1 *，
    马丁Lapalus1，
    塔里克Asselah1，2，
    了帕特里克Marcellin1，2
    1 INSERM，U-773，CRB3，巴黎狄德罗大学，医院的Beaujon，克利希，法国
    2服务D'Hépatologie，医院的Beaujon，克利希，法国

布隆伯格在1965年发现以来，B型肝炎病毒抗原（HBsAg）作为B型肝炎病毒感染的指纹。 HBsAg水平的转录活性的cccDNA的反映。这是一个重要的标志，不仅表明活动性乙肝感染，而且还可以预测临床表现和治疗效果。乙肝表面抗原定量检测是完全自动化的，具有高输出。乙肝表面抗原滴度较高，在HBeAg（ - ）患者和HBe抗原（HBeAg）阳性（+），在HBeAg（+）患者的肝纤维化呈负相关。对于HBeAg（ - ）慢性乙型肝炎，HBsAg水平<1000 IU / ml和HBV DNA滴度<2000 IU / ml的准确识别非活动性携带者。在PEG-IFN治疗过程中，乙肝表面抗原定量是用来识别谁也不会从治疗中受益，早治疗12周的患者，这样的处理可能会停止或切换“1​​2周停止规则”。随着核苷（酸）类似物（NA），乙肝表面抗原定量的作用，必须加以澄清。一些研究表明，基线和治疗HBsAg水平可能确定患者没有后续风险的激活是可以治疗的。在临床实践中，乙肝表面抗原定量是一个简单的和可再生的工具，可用于HBV DNA与HBV的自然历史过程中病人分类，并监测治疗。
结论

最近的研究血清HBsAg监测显示，在慢性乙肝的自然病程治疗过程中乙型肝炎表面抗原水平的变化。这些结果可以用来确定患者的最佳管理策略。在HBV的自然史，乙肝表面抗原定量可用于区分非活动性携带者（无需治疗）和HBeAg（ - ）慢性乙肝患者，谁都有可能激活（更密切的监测），以及谁可以从治疗中获益。在PEG-IFN治疗过程中，早期的乙肝表面抗原监测可用于开发的响应制导算法：停止或切换治疗12周时，反应差，继续标准的48周的治疗，大多数患者反应良好，并延长治疗为中间对治疗的反应，以提高反应的机会。乙肝表面抗原监测期间NA治疗的作用必须予以澄清。停止规则的发展应确定在这些终身治疗。一些研究表明，基线和治疗HBsAg水平可能有助于识别病人谁可以停止治疗，无风险的激活。

StephenW

The hepatitis B virus (HBV) is a small DNA virus. Upon entry into the cell, HBV sheds its protein coat and the partially double-strand genome is transported into the nucleus of the hepatocyte where it is transformed into a fully double-strand covalently closed circular DNA (cccDNA). The cccDNA resides in the nucleus of infected hepatocytes, where it acts as a template for transcription of the viral gene and recycles in the nucleus to renew the cccDNA pool [1, 2]. Viral proteins of clinical importance include the envelope protein (HBsAg) whose synthesis during the HBV viral life cycle is complex. HBsAg production exceeds that required for virion assembly, and excess surface envelope proteins are covalently linked and secreted as empty non-infectious filamentous or spherical sub-viral particles [3]. These empty particles may co-exist with anti-HBs as part of circulating immune complexes [4]. Serum HBsAg is a result of the combination of these proteins (complete virion, filamentous or spherical sub-viral particles). HBsAg quantification measures all three forms of systemic HBsAg.
B型肝炎病毒（HBV）是一种小DNA病毒。一旦进入细胞，HBV脱其蛋白质外壳和部分双链基因组被输送到肝细胞的细胞核，在那里它被转换成一个完全双链共价闭合环状DNA（cccDNA）。的共价闭合环状DNA驻留在受感染的肝细胞的细胞核，它作为病毒基因的转录的模板和回收的核更新的cccDNA的池[1，2]。重要的临床意义的蛋白质包括病毒的包膜蛋白（HBsAg）的合成过程中的HBV病毒的生命周期是复杂的。 HBsAg的产量超过所需的病毒粒子组装，和过量的表面的包膜蛋白共价连接，并为空的非感染性的丝状或球形的亚病毒颗粒分泌[3]。这些空粒子可能共存的抗-HBs的循环免疫复合物的一部分，[4]。血清HBsAg是这些蛋白质的组合的结果，（完整的病毒颗粒，丝状或球形的亚病毒颗粒）。乙肝表面抗原定量测量全身所有三种形式的乙肝表面抗原。

Several studies have shown the relationship between intrahepatic markers of HBV infection (cccDNA and integrated HVB DNA) and serum HBsAg [3, 5-7]. Differences in HBsAg levels during the different phases of the disease reflect the distribution of cccDNA during the respective infection phases. HBsAg levels are higher in HbeAg-positive (+) than in HBeAg-negative (−) patients [6-8].
一些研究表明，肝内标记的HBV感染（cccDNA和集成HVB DNA）和血清HBsAg [3，5-7]之间的关系。疾病的过程中的不同阶段中的HBsAg水平差异反映cccDNA的各自的感染阶段期间的分布。
HBeAg阳性（+）乙肝表面抗原水平较高比较HBeAg阴性（ - ）患者[6-8]。

Clinical applications

HBsAg seroconversion (loss of HBsAg and development of anti-HBs) is rarely observed during the natural course of chronic HBV infection. The annual incidence is 1–2% world-wide [1]. It is the ultimate goal of therapy. Recently, quantitative serum HBsAg assays have been developed [9, 10], and the importance of HBsAg quantification has been recognized as an important marker to monitor the natural history in chronic hepatitis and predict treatment outcome [11-13]. HBsAg levels decrease more in patients receiving interferon (IFN), an immune modulator, than in those receiving nucleos(t)ides analogues (NA), potent inhibitors of HBV DNA replication [14].
临床应用

乙肝表面抗原血清学转换（损失HBsAg和生产抗-HBs）在慢性HBV感染的自然病程是很少看到。每年的发生率是1-2％，全球范围内[1]。这是治疗的最终目标。近日，血清HBsAg定量分析[9，10]，和重要性的一个重要标志，已被确认为乙肝表面抗原定量监测慢性肝炎的自然史和预测治疗结果[11〜13]。 患者接受干扰素（IFN），免疫调节剂，HBsAg水平的下降更多相比在接受核苷（T）的IDE类似物（NA），强效抑制HBV DNA复制[14]。

StephenW

Natural history
HBeAg positive chronic hepatitis B

In the initial 2–3 decades of life, HBV infection is characterized by an immune tolerance phase in which patients usually have positive HBeAg, very high HBV DNA, normal ALT levels and minimal histological damage [14]. This is followed by an immune-clearance phase, which may lead to HBeAg seroconversion. Based on the results of cross-sectional studies, serum HBsAg levels were generally higher in patients in the immune tolerance phase than in the immune-clearance phase [3, 6-8, 13] (Fig. 1).

Figure 1. Serum HBsAg levels during natural history of hepatitis B virus infection. Median values with 95% CI. Adapted from Nguyen et al. [6]. Serum HBsAg levels are higher in HBeAg-postive (immune-tolerant and immune-clearance) than in HBeAg-negative chronic hepatitis B.
image

自然史
HBeAg阳性慢性乙型肝炎

在最初的2-3几十年的生活中，的特点是HBV感染的免疫耐受期患者通常在HBeAg阳性，HBV DNA非常高，ALT水平正常和最少的组织损伤[14]。其次是免疫清除期，这可能会导致HBeAg血清学转换。基于截面的研究的结果，在患者中的免疫耐受阶段血清HBsAg水平普遍较高比[3，6-8，13]（图1）中的免疫清除期。

图1。 B型肝炎病毒感染的自然历史过程中的血清HBsAg水平。 95％CI的中间值。改编自Nguyen等人。 [6]。比HBeAg阴性慢性乙型肝炎血清HBsAg水平较高的HBeAg阳性（免疫宽容和免疫清除）
图像
HBeAg negative chronic hepatitis B

Later in life, most of the HBV-infected population progresses to the immune active phase, loses HBeAg and seroconverts to anti-HBe (with various degrees of activity and fibrosis). Then, most of this HBeAg (−) chronic hepatitis B (CHB) population enters the inactive or low replicative phase, (characterized by wide fluctuations in serum HBV DNA levels and transaminases [15]. The clinical spectrum of HBeAg (−) CHB ranges from ‘inactive carrier’ status to aggressive HBeAg (−) CHB that is generally differentiated from ‘inactive carriers’ by serial serum ALT and HBV DNA level determinations [16, 17]. However, in 45–65% of cases, ALT activity can fluctuate with long periods of normal ALT levels, resulting in misclassification (Fig. 2). Inactive carriers have no or mild histological lesions in the liver with an excellent prognosis for survival and a low incidence of cirrhosis and HCC, while patients with HBeAg (−) CHB with fluctuating activity have a more severe disease progression with frequent cirrhosis [17-19]. Differentiating the latter from inactive carriers is highly important as these patients could benefit from therapy. According to NIH and EASL guidelines [20, 21], the differentiation between inactive and active phases of HBeAg (−) CHB is based on an HBV DNA cut-off of 2000 IU/ml. This cut-off has led to several controversial studies [17, 22-25].

Figure 2. Kinetics of HBsAg, HBV DNA and ALT follow-up during the natural history of a chronic hepatitis B-negative patient. This patient with ‘an inactive carrier’ pattern at inclusion shows several reactivation episodes, ALT >2N and dramatically increase in serum HBV DNA during the follow-up, while HBsAg level remained steady and above 3.3 log IU/ml.
image

HBeAg阴性慢性乙型肝炎

以后在生活中，大部分的HBV感染人群进行的免疫活性相，失去HBeAg阳性和抗-HBe seroconverts有不同程度的活动和纤维化。然后，最本的HBeAg（ - ）慢性乙型肝炎（CHB）的人口进入非活动或低复制期（血清HBV DNA水平和转氨酶[15]。临床频谱的HBeAg（ - ）CHB范围内大幅波动，特点从“非活动载体的地位积极的HBeAg（ - ）CHB，一般是区别于”非活动性携带者“系列血清ALT和HBV DNA水平测定[16，17]。然而，在45-65％的情况下，谷丙转氨酶活性可以波动与长时间的ALT水平正常，造成分类错误（图2）。非活动性携带者，无或轻度的肝组织学病变，预后良好生存和肝硬化和肝癌的发生率较低，而患者的HBeAg（ - ）CHB的起伏活动与经常性肝硬化[17〜19]。鉴别，后者从非活动性携带者是非常重要的，因为这些患者从治疗中获益。据美国国立卫生研究院和EASL指南[20，21]，有更严重的疾病进展根据HBV DNA，截止2000 IU / ml的分化之间的无效和有​​效阶段的HBeAg（ - ）CHB。截止，导致几个有争议的研究[17，22〜25]。

图2。在自然史的慢性乙肝阴性患者的HBsAg，HBV DNA和ALT后续动力学。这名患者显示了几个“非活性载体”的模式，包容激活发作，ALT> 2N并显着提高血清中HBV DNA，而在后续HBsAg水平保持稳定，3.3日志IU /毫升以上。
图像
Based on longitudinal studies, HBsAg levels are higher in patients with active HBeAg (−) CHB than in ‘inactive carriers’ [22-26].
基于纵向研究，活动性的HBeAg（ - ）乙肝表面抗原的水平较高比在患者在“非活动性携带者[22〜26]。
A longitudinal Asian study in 68 HBeAg (−) CHB patients predominantly infected with genotype C reported that the patients with inactive disease tend to have lower HBsAg levels than those with active disease; 2.24 ± 1.61 log10 IU/ml vs. 2.98 ± 0.88 log10 IU/ml respectively (P = 0.054). No cut-off value can confidentially differentiate ‘inactive carriers’ [22]. During long-term follow-up (median 10 years), the authors report that HBsAg <1000 IU/ml predicts seroclearance (91% specificity: 75% sensitivity) [23]. A study performed by Brunetto et al. [24] in Italian genotype D patients reported that HBsAg levels are higher in patients with HBeAg (−) CHB than in ‘inactive carriers’ and that a single point quantification of HBV DNA <2000 IU/ml and HBsAg <1000 IU/ml identifies inactive carriers with a positive predictive value (PPV) of 88%. However, this observation must be validated across all HBV genotypes. Similar results were reported in a recent study from France [25] in 165 patients with HBeAg (−) CHB (genotypes A–E). HBsAg levels in this study were lower in the 76 ‘inactive carriers’ than in the 89 patients with an HBeAg (−) CHB; 3.25 ± 0.96 log10 IU/ml vs. 3.67 ± 0.70 log10 IU/ml respectively (P < 0.001). The combination of a single measurement of HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml identifies ‘inactive carriers’ with a PPV of 86%. More recently, the authors reported that the combination of a single measurement of HBsAg >1000 IU/ml and HBV DNA >200 IU/ml identifies patients with a ‘high risk of reactivation’ with a negative predictive value (NPV) of 96%, and sensitivity 92% [26]. The authors conclude that combination of HBsAg and HBV DNA levels at a single time point may accurately indentify HBeAg (−) CHB patients, during remission with a high probability of reactivation and who are good candidates for treatment.
亚洲的纵向研究68的HBeAg（ - ）CHB患者主要感染C基因型活跃的疾病，患者往往有较低的HBsAg水平较活动性疾病; 2.24±1.61 LOG10 IU / ml比2.98±0.88 log10的国际单位/毫升（P = 0.054）。没有cut-off值可以保密区分“非活动性携带者”[22]。在长期（平均10年），作者报告说，乙型肝炎表面抗原（HBsAg）<1000 IU / ml的预测转阴（91％特异性：敏感性为75％）[23]。由布鲁涅托等人进行的一项研究。 [24]在意大利D基因型患者HBsAg水平较高的HBeAg（ - ）CHB患者比在“非活动性携带者，HBV DNA <2000 IU / ml和乙型肝炎表面抗原（HBsAg）<1000 IU / ml的识别，单点定量的非活动性携带者，阳性预测值（PPV）为88％。然而，这种观察必须在所有HBV基因型的验证。来自法国最近的一项研究报告了类似的结果[25]在165例HBeAg阳性（ - ）CHB（基因型A-E）。在这项研究中HBsAg水平低76'非活动性携带者“的89例患者的e抗原（ - ）CHB; 3.25±0.96 LOG10 IU / ml比3.67±0.70 log10的国际单位/毫升（P <0.001）。组合的单次测量的乙型肝炎表面抗原（HBsAg）<1000 IU / ml和HBV DNA <2000 IU / ml的识别与PPV为86％的“非活动性携带者”。最近，作者报告说，乙肝表面抗原相结合的单次测量> 1000 IU / ml和HBV DNA> 200 IU / ml的患者识别，激活了一个“高风险”的阴性预测值（NPV）为96％，敏感性92％[26]。作者的结论是在一个单一的时间点相结合的HBsAg和HBV DNA水平，可准确恒等式e抗原（ - ）CHB患者，缓解激活的几率非常高，是很好的候选人治疗。
HBsAg and liver histology

Seto et al. [27] found an association between higher HBsAg (≥25 000 IU/ml) serum levels and mild fibrosis (stage F ≤ 1) in a cohort of 140 Asian HBeAg (+) CHB patients (no indication of HBV genotype) with ALT ≤ 2 times the upper limit of normal. Similar results are reported in a cohort of 406 chronic hepatitis B patients with genotypes A–E [28]. A negative correlation was found between the level of HBsAg and the stage of fibrosis, so that patients with no or mild fibrosis (F 0–1 Metavir score) could be distinguished from those with moderate or severe fibrosis (≥ F2), in HBeAg (+) patients, with a high NPV (91%). Furthermore, the authors describe a specific serum HBsAg cut-off (3.85 log10 IU/ml) to identify moderate to severe fibrosis (≥ F2) in HBeAg (+) CHB patients infected with HBV genotypes B or C. This association was not observed in HBeAg (−) patients [28]. There was no association between HBsAg titre and histological grade found in either study.
乙肝表面抗原和肝组织学

濑户等。 [27]发现之间的关联较高的乙肝表面抗原（≥25 000 IU / ml）的血清水平和轻度纤维化（第二阶段F≤1）在一组140亚洲e抗原（+）慢性乙型肝炎患者的HBV基因型（无指示），ALT≤正常上限的2倍。类似的结果在一组报道的406例慢性乙型肝炎患者的基因型A-E [28]。发现HBsAg和纤维化分期之间的水平呈负相关，因此，患者无或轻度肝纤维化（F 0-1 METAVIR评分）可区别于那些中度或重度肝纤维化（≥F2），在HBeAg（ +）患者中，与一个高NPV（91％）。此外，作者描述了一个特定的血清HBsAg（3.85 log10的国际单位/毫升），以确定截止中度至重度纤维化（≥F2），在HBeAg（+）慢性乙型肝炎患者感染HBV基因型B或C。该协会并没有观察到e抗原（ - ）患者[28]。没有任何一项研究中发现乙肝表面抗原滴度和组织学分级之间的关系。

咬牙硬挺

感谢分享

StephenW

HBsAg level and therapyHBsAg水平和治疗
Interferon therapy干扰素治疗


Only a small proportion of patients (3–7%) experience HBsAg loss during 48 weeks of interferon-based (IFN) therapy [21]. The efficacy of pegylated-IFN (PEG-IFN) has been confirmed in two large pivotal studies [29, 30]. The HBeAg seroconversion rate was observed in 32% in HBeAg-positive patients [29] and an HBV DNA <400 IU/ml in 19% in HBeAg-negative patients [30]. In the early 1990's, HBsAg quantification was already considered to be a promising, simple and inexpensive method to monitor viral replication in chronic hepatitis B patients who were receiving IFN treatment [31]. More recently, the availability of well-standardized commercial assays has renewed interest in the quantitative serum HBsAg as a biomarker for treatment response in chronic hepatitis B [9, 10].
只有一小部分（3-7％）的患者在48周的干扰素为基础的经验HBsAg消失（IFN）治疗[21]。聚乙二醇化干扰素（PEG-IFN）的疗效已被证实在两大关键的研究[29，30]。在HBeAg阳性患者的HBeAg血清学转换率在32％[29]和HBV DNA <400 IU / ml的HBeAg阴性患者中，19％[30]。在20世纪90年代初，乙肝表面抗原定量已经被认为是一种很有前途的，简单和廉价的方法来监测病毒复制的慢性乙肝患者接受干扰素治疗[31]。最近，提供标准化的商业分析的新的兴趣作为慢性肝炎的治疗反应的生物标志物的定量血清HBsAg B [9，10]。

HBeAg-positive patientsHBeAg阳性患者

Current data [32-37] indicate that on-treatment HBsAg quantification could help identify either patients with a high probability of sustained virological response (SVR) or non-responders. In a study by Chan et al. [32], SVR rates were 62 and 11% in patients with HBsAg ≤300 IU/ml and in those with HBsAg >300 IU/ml at 24 weeks of therapy respectively. The authors also showed that patients with a combined response of HBsAg ≤300 IU/ml and a decrease of ≥1 log10 IU/ml at 24 weeks had higher SVR rates than those without the combined response (75% vs. 15%), with a PPV and NPV of 75 and 85% respectively. Tangkijvanich et al. [33] report that baseline HBsAg levels were lower in patients with HBeAg seroconversion at the end of therapy than in non-responders. In the NEPTUNE study [35, 37] the highest HBeAg seroconversion rates were observed in patients with HBsAg levels ≤ 1500 IU/ml at 12 or 24 weeks of therapy with a PPV of 57 or 54% and a NPV of 72 or 76% respectively. These results confirm those of the phase III PEG-IFN alpha 2a treatment registration trial on [34]. Sonneveld et al. [36] showed that patients who received a combination of PEG-IFN plus lamivudine had a more pronounced on-treatment decrease in HBsAg patients than those who received PEG-IFN alone, although the former relapsed. The absence of decline at week 12 had a NPV of 97% for SVR and no chance of HBsAg loss. The phase III registration trial [34] by Lau et al. reported a lower NPV (82%) than the study by Sonneveld et al. The discrepancies between the two studies [34, 36] might be owing to the different populations studied. Indeed, in the study by Sonneveld et al., most of the patients had genotypes A and D, whereas the Lau study included genotypes B and C Asian patients. It is interesting to note that certain studies have reported a more significant decrease in HBsAg and more frequent HBsAg in patients with HBV genotype A who receive PEG-IFN [38-40].
目前的数据[32-37]表明，可能有助于发现治疗乙肝表面抗原定量无论是患者的持续病毒学应答（SVR）或无应答的概率很高。 Chan等人的研究。 [32]，SVR率分别为62和11％的患​​者与HBsAg≤300 IU / ml时，与HBsAg> 300 IU /毫升在24周的治疗。作者还表明，患者与乙肝表面抗原≤300 IU / ml和减少≥1 log10的国际单位/毫升在24周的综合反应（75％对15％），有较高的SVR率比那些没有一个综合反应一个PPV和NPV为75和85％。 tangkijvanich等。 [33]报告的基线HBsAg水平在治疗结束时的HBeAg血清学转换的患者比无应答者。 NEPTUNE研究[35，37]，观察患者的HBeAg血清学转换率最高的HBsAg水平≤1500 IU /毫升在12或57或54％的PPV和NPV为72或24周的治疗76％ 。这些结果证实第三阶段的PEG-IFNα-2a治疗登记试验[34]。 sonneveld等。 [36]的研究表明，相结合的PEG-IFN联合拉米夫定的患者有较明显的减少乙肝表面抗原的患者比那些谁收到PEG-IFN单独处理，虽然前者复发。下降的情况下在第12周的SVR为97％的HBsAg转阴并没有机会的净现值。 III期注册临床试验[34]刘等人。低级NPV（82％）比由Sonneveld等的研究报道。两者之间的研究[34，36]的差异可能是由于不同人群的研究。事实上，由Sonneveld等人在研究中，大多数患者基因型A和D，而刘的研究，包括B，C基因型亚洲​​患者。有趣的是，某些研究报告的一个显着减少患者的HBsAg和更频繁的乙肝表面抗原，乙肝病毒基因型阿谁接受PEG-IFN [38〜40]。

StephenW

HBeAg-negative patientsHBeAg阴性患者

The response rate to PEG-IFN is low (<20%) in HBeAg (−) patients [41-44]. These patients are difficult to monitor. Indeed, most of them achieve undetectable serum HBV DNA at the end of therapy, but relapse after treatment is stopped [30, 43, 44]. Therefore, predictive factors of on-treatment response may help define more appropriate treatment strategies in certain patients. The most recent evidence suggests that HBsAg quantification is a worthwhile marker for monitoring PEG-IFN therapy [45-47] (Fig. 3).
PEG-IFN的反应率较低（<20％）的HBeAg（ - ）患者[41〜44]。这些患者难以监测。事实上，他们中的大部分实现在治疗结束时的血清HBV DNA检测不到，但停止治疗后复发[30，43，44]。因此，对治疗反应的预测因素可以帮助确定更合适的治疗策略，在某些患者。最近的证据表明，乙肝表面抗原定量监测PEG-IFN治疗是一个值得标记[45〜47]（图3）。
Figure 3. Changes in serum HBV DNA (A) and HBsAg (B), during PEG-IFN therapy. Illustration of HBV DNA and HBsAg kinetics in sustained responder (solid line) and relapser (dash line) during peginterferon therapy. Adapted from Moucari et al. [45]. Serum HBV DNA was undetectable at the end of therapy (A) in both patients with sustained virological response and with relapse. During therapy, HBsAg decreased (B) only in patients who developed sustained virological response.
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图3。血清中HBV DNA（A）和HBsAg（B），PEG-IFN治疗过程中的变化。插图HBV DNA和HBsAg动力学在持续应答器（实线）和聚乙二醇干扰素治疗过程中relapser（虚线）。改编自Moucari等。 [45]。血清HBV DNA检测不到，在这两个持续的病毒学应答和复发的患者在治疗结束时（A）。在治疗过程中，乙肝表面抗原下降（B）只在谁开发的持续病毒学应答的患者。
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Rijckborst et al. [43] reported that the combination of HBsAg and a decrease in HBVDNA is the best predictor of an SVR in patients receiving PEG-IFN. A lack of decrease in HBsAg and a serum HBVDNA decline of less than 2 log10 IU/ml have a NPV of 100% for SVR. Another [45] study has shown that a serum HBsAg decrease of ≥ 0.5 log IU/ml at week 12 had a high PPV of SVR (PPV 89%) and a lack of decrease of ≥1 log10 IU/ml at week 24 had a high NPV of non-SVR (NPV 92%).
rijckborst等。 [43]报道，乙肝表面抗原和HBVDNA下降的组合是最好的预测SVR的患者接受PEG-IFN。减少乙肝表面抗原和血清HBV DNA下降小于2个log10 IU / ml的缺乏SVR的净现值为100％。另一人[45]的研究表明，血清HBsAg下降≥0.5日志IU /毫升12周时有很高的SVR（PPV PPV的89％）和缺乏减少≥1 log10的国际单位/毫升在24周了非SVR高NPV（净现值92％）。
Studies have investigated end- and post-treatment HBsAg titres to predict SVR and loss of HBsAg during post-treatment follow-up. In a cohort of 127 HBeAg-negative genotype D patients who received 48 weeks of PEG-IFN treatment, Brunetto et al. [46] showed that an on-treatment ≥1 log10 IU/ml HBsAg decrease and an HBsAg level <10 IU/ml at the end of therapy were highly predictive for a SVR at the 24-week post-treatment follow-up and for HBsAg loss at the 3-year post-treatment follow-up. In this study, at the 3-year post-treatment follow-up, an HBsAg loss was observed in 52% of the patients with an HBsAg <10 IU/ml at week 48 of treatment, compared with only 2% of the patients with an HBsAg>10 IU/ml at week 48. The authors did not find any association between serum HBV DNA response (<400 IU/ml) at the end of therapy and HBsAg loss. A French retrospective study [48] also reported that most of the patients who lost HBsAg during post-treatment follow-up had a ≥1 log10 IU/ml decrease in HBsAg levels at the end of 48 weeks of IFN treatment followed by a steady decrease until seroclearance.
有研究调查结束和治疗后乙肝表面抗原滴度的乙肝表面抗原在治疗后的后续预测SVR和损失。在队列的127例HBeAg阴性D基因型患者接受48周的PEG-IFN治疗，布鲁涅托等。 [46]的研究表明，对治疗≥1 log10的国际单位/毫升乙肝表面抗原减少和HBsAg水平<10 IU / ml的治疗结束时高度的SVR在24周的治疗后，后续的预测HBsAg消失在3年的治疗后随访。在这项研究中，在3年后治疗随访观察，HBsAg消失，52％的患者与乙肝表面抗原<10 IU / ml的，只有2％的患者在48周的治疗， > 10 IU /毫升在48周的乙肝表面抗原。作者没有发现任何协会之间血清HBV DNA响应（<400 IU / ml）的治疗结束时HBsAg消失。一位法国的回顾性研究[48]也报道，谁失去了乙肝表面抗原在治疗后的患者随访≥1 log10的国际单位/毫升下降HBsAg水平在IFN治疗结束48周持续下降直至转阴。

StephenW

Week 12 stopping rule第12周停止规则

Most studies report that the absence of a decrease in HBsAg or a HBV DNA decline of < 2 log10 after 12–24 weeks of a 48-week course of PEG-IFN is associated with a NPV of 84–100% for SVR [49] (Table 1). Rijckborst et al. [50] confirmed these results in patients in the PARC study [51] and performed external validation in the phase III registration study [28] and the PegBeLiver study [51], both of which included patients with HBV genotypes A–D. There was a NPV ≥95% for SVR in both validation studies in the absence of a decrease in HBsAg or a decline in HBV DNA <2 log10 IU/ml at week 12 of treatment. The authors propose a response-guided therapy algorithm based on HBsAg kinetics at week 12 of treatment. Early identification of non-responders would allow discontinuation of therapy and/or changing the treatment strategy (Table 1).
大多数研究报告，在HBsAg或HBV DNA下降<2 log10的12-24周的PEG-IFN 48周的课程后减少的情况下与84-100％，NPV为SVR [49] （表1）。 rijckborst等。 [50]证实了这些结果的患者在PARC的研究[51]，并进行外部验证的III期注册研究的PegBeLiver研究[28]和[51]，两个，其中包括患者的HBV基因型A-D。有一个NPV≥95％，SVR在这两个验证的情况下减少HBsAg或HBV DNA下降<2 log10的国际单位/毫升在12周的治疗研究。本文提出了响应引导治疗治疗12周时乙肝表面抗原动力学算法。无应答的早期识别，可以停止治疗和/或改变治疗策略（表1）。

StephenW

Nucleos(t)ides analogues核苷（酸）的IDE类似物The treatment paradigm for HBV has shifted in the past decade from a finite duration of treatment with IFN to long-term HBV suppression with nucleos(t)ides analogues (NA). Indeed, the newer agents such as tenofovir or entecavir are more effective in suppressing HBV and are less likely to be associated with drug resistance than original NA. In addition, they are orally administered and have excellent safety profile. However, they must probably be taken indefinitely because withdrawal is generally associated with viral reactivation, and HBsAg seroconversion is rarely reported. Although HBVDNA becomes rapidly undetectable, studies have clearly shown that the decline in HBsAg titres is significantly lower with NA therapy than with IFN-based treatment [57, 58] (Fig. 4). Several studies have reported that baseline HBsAg levels and on-treatment HBsAg quantification are good predictive markers of the end of treatment response and SVR [57-66]. Zoutendijk et al. [67] investigated HBsAg kinetics in patients who were successfully treated with long-term entecavir (ETV) or tenofovir (TDF). The authors used linear mixed regression analysis of individual HBsAg declines to estimate the duration of therapy required to achieve an HBsAg decline of 1 log10 UI/ml from baseline and HBsAg clearance. They showed that the median durations of therapy to achieve a 1 log10 IU/ml decrease were as follows: 6.6 [1.7–18] years and 8 [0.5–15] years in HBeAg (+) and HBeAg (−) patients respectively. Median durations for HBsAg clearance were as follows: 36 [10–93] years and 39 [1.3–90] years in HBeAg (+) and HBeAg (−) patients respectively. These results show the importance of determining HBsAg cut-offs to discontinue NA therapy with lowest risk of reactivation.
对HBV的治疗模式已转向在过去的十年，从一个有限的时间与IFN治疗HBV抑制长期的核苷（酸）的IDE类似物（NA）。事实上，新的更有效地抑制HBV药物如替诺福韦或恩替卡韦是不太可能与耐药性比原来的NA。此外，口服给药和具有优异的安全更新。然而，他们可能会无限期，因为的提取通常与病毒的再活化，乙肝表面抗原血清学转换是鲜有报道。虽然HBVDNA很快变得无法检测，研究清楚地表明，在HBsAg滴度下降显着降低NA治疗比干扰素为基础的治疗[57，58]（图4）。一些研究报告的基线HBsAg水平和对治疗的乙肝表面抗原定量良好的预测标志物的治疗反应和SVR [57-66]。 zoutendijk等。 [67]研究的乙型肝炎表面抗原（HBsAg）动力学的患者成功治疗与长期恩替卡韦（ETV）和替诺福韦（TDF）。作者用混合线性回归分析，个人乙肝表面抗原下降，估计持续时间的治疗需要实现从基线下降1 log10的UI /毫升的乙肝表面抗原HBsAg清除。他们指出，治疗持续时间的中位数分别实现一个1 log10的国际单位/毫升减少如下：6.6 [1.7-18]年[0.5-15]年在HBeAg（+）和HBeAg（ - ）患者。 HBsAg清除的持续时间中位数如​​下：36 [10-93]和39 [1.3-90]年在HBeAg（+）和HBeAg（ - ）患者。这些结果表明，重要性，决定停止NA治疗的乙肝表面抗原切的平衡，激活与风险最低的。

Figure 4. Changes in HBsAg levels in HBeAg-positive and HBeAg-negative patients during PEG-IFN or Entecavir therapy. Mean changes compared with baseline for HBsAg titres in patients receiving either peginterferon or entecavir therapy. Adapted from Reijinders et al. [58]. The kinetics shows sharper decrease in patients receiving peginteferon therapy than in patients receiving entecavir therapy independently from AgHBe status. Similar results are reported in HBeAg-negative chronic hepatitis B patients receiving either interferon or lamivudine [57].




图4。在PEG-IFN或恩替卡韦治疗HBeAg阳性和HBeAg阴性患者HBsAg水平的变化。在接受聚乙二醇干扰素或恩替卡韦治疗的患者的HBsAg滴度与基线相比的平均变化。改编自Reijinders等。 [58]。的动力学显示更清晰的下降在的患者接受peginteferon治疗患者接受恩替卡韦治疗独立从AgHBe状态。类似的研究结果发表在HBeAg阴性慢性乙型肝炎患者接受干扰素或拉米夫定[57]。
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In the two pivotal studies of TDF [68, 69], study 102 (HBeAg −) and study 103 (HBeAg +) patients, the authors confirm that HBsAg kinetics is deeper in HBeAg (+) patients than in HBeAg (−) and in patients receiving TDF monotherapy. The only patients with HBsAg loss were HBeAg (+) patients with a ≥2 log10 IU/ml HBsAg decrease from baseline at 24 weeks of therapy, a higher baseline HBsAg level and genotypes A or D. In a cohort of 162 HBeAg (+) patients with HBV DNA <60 IU/ml after 3 years of telbuvidine therapy, Wursthorn et al. [62] showed that 25% of patients with ≥1 log10 IU/ml HBsAg decrease after 1 year of therapy had an HBsAg loss compared with 1.4% of patients with <1log10 IU/ml HBsAg decrease. The study by Reijnders et al. [58] in HBeAg (+) or (−) patients, who received 48 weeks of either PEG-IFN or ETV, an HBsAg decline was only observed in HBeAg (+) patients after 48 weeks of either PEG-IFN or ETV therapy. In HBeAg (−) patients, no decline in HBsAg levels was observed in patients receiving ETV. Recent studies including treatment-naive patients receiving NA report that low baseline HBsAg levels and an early decline in HBsAg (24-week therapy) are good predictors of SVR [63-66]. Furthermore, studies suggest that an HBsAg cut-off ≤2–3 log10 IU/ml could be used for treatment discontinuation [70-73]. In the study by Liang et al. [70], 121 consecutive patients were prospectively recruited after treatment was stopped (lamivudine, adefovir, entecavir). The authors report that higher HBsAg levels at the end of treatment were associated with higher risk of relapse. End of the treatment, HBsAg levels ≤ 3 log10 IU/ml and ≤ 2 log10 IU/ml were associated with a 31 and 9% relapse respectively. Similar results are reported by Cai et al. [73] in patients receiving 2 years of telbuvidine therapy. An HBsAg level ≤2 IU/ml at the end of treatment cessation had a PPV and NPV for the prediction of SVR of 100 and 93% respectively.

Recently, it has been proposed that in HBe negative-patients the combination of HBsAg level < 1000 IU/ml and HBV DNA < 2000 IU/ml can be considered as a probable criteria to define the minimal risk for hepato-cellular carcinoma (74).
在这两个关键的研究TDF [68，69]，研究102（HBeAg的 - ），研究103（例HBeAg +）患者，确定乙肝表面抗原动力学是在HBeAg（+）患者在HBeAg（ - ）和深患者接受TDF单药治疗。唯一的HBsAg转阴的患者为HBeAg（+）患者与A≥2 log10的国际单位/毫升乙肝表面抗原减少从基线到24周的治疗，有较高的基线HBsAg水平和基因型A或D在队列的162的HBeAg（+）患者HBV DNA <60 IU / ml后，3年telbuvidine治疗，Wursthorn等。 [62]的研究表明，25％≥1 log10的国际单位/毫升乙肝表面抗原减少1年的治疗后，患者的HBsAg消失<1log10 IU / ml的乙肝表面抗原减少患者则为1.4％。的研究由Reijnders等。 [58]在HBeAg（+）或（ - ）患者，接受48周的PEG-IFN或ETV，在HBeAg（+）或PEG-IFN或ETV治疗48周后患者的HBsAg的下降仅见于。对于HBeAg（ - ）患者，HBsAg水平没有下降，观察患者接受ETV。最近的研究，包括治疗过的患者接受NA报告说，低基线HBsAg水平下降，乙肝表面抗原和早期（24周的治疗）的SVR有很好的预测[63-66]。此外，研究表明，乙肝表面抗原截止≤2-3 log10的国际单位/毫升可用于终止治疗[70-73]。 Liang等人在研究中。 [70]，前瞻性纳入121例患者经治疗后停止（拉米夫定，阿德福韦，恩替卡韦）。作者报告说，较高的HBsAg水平在治疗结束与较高的复发风险。治疗结束时，HBsAg水平≤3 LOG10 IU / ml和≤2 log10的国际单位/毫升，分别为31和9％的复发有关。 Cai等人报告的相似的结果。 [73]在患者接受2年的telbuvidine治疗。 HBsAg水平≤2 IU / ml的治疗结束时停止了PPV和NPV的预测SVR分别为100和93％。

最近，已经提出，HBe抗体阴性患者的HBsAg的水平的组合<1000 IU / ml和HBV DNA <2000 IU / ml的可视为一个可能的标准来定义的风险最小为肝细胞癌（74） 。

MP4

HBe抗体阴性患者的HBsAg的水平的组合<1000 IU / ml和HBV DNA <2000 IU / ml的可视为一个可能的标准来定义的风险最小为肝细胞癌（74） 。