乙型肝炎表面抗原动力学通知策略停止抗病毒治疗有多好？

StephenW

J Hepatol. 2017 Mar 15. pii: S0168-8278(17)30136-8. doi: 10.1016/j.jhep.2017.03.002. [Epub ahead of print]
How Good Is Hepatitis B Surface Antigen Kinetics Informing Strategy to Stop Antiviral Therapy?
Brunetto M1, Cornberg M2, Chan HL3.
Author information

1
    Department of Clinical and Experimental Medicine, University of Pisa - Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses - University Hospital of Pisa, Italy. Electronic address: [email protected].
2
    Department of Gastroenterology, Hepatology and Endocrinology. Hannover Medical School; German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address: [email protected].
3
    Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Electronic address: [email protected].
Reply
We agree with W-J Jeng and Y-F Liaw on the pivotal
role of spontaneous hepatitis B surface
antigen (HBsAg) serum clearance in the clinical his
tory of a hepatitis B virus (HBV) carrier [1] as it
is, the hallmark of the control of HBV replication
and transition from inactive to occult infection
[2]. However, the reported annual rates of HBsAg clearance are highly variable (0.31 to 3.2 x 100 persons/years) because of the heterogeneity of the
studied populations [3–6]: mode of infection, age
and ethnicity are major factors influencing the HBs
Ag loss [5–8]. Furthermore, viral features as
HBV genotype could play a role as suggested by the
lower yearly HBsAg decline in genotype D
infected carriers (0.287 and 0.35 log10 IU/ml during 38 months and 9 years median follow-ups, respectively) as compared to genotype B/C infected
carriers (0.53 and 0.751 log10 IU/ml during the 5  and 3 years prior serum HBsAg loss, respectively) [9–12]. Finally, different HBsAg kinetics
were described according to residual viral replication: a progressive decline till HBsAg clearance
was seen in carriers with undetectable HBV DNA at variance with a sharp HBsAg drop about 2 years prior HBsAg clearance in carriers with detectable viremia [8]. Thus, the identification of a
universal threshold predictive of short term HBsAg
clearance would require the studies of a large
cohort of patients infected with different genotype
s where all the relevant variables are analyzed:
demographic features (age, sex and ethnicity), viral profile (history of HBeAg positivity,
HBeAg/anti-HBe seroconversion time, viral load), overall follow-up duration and yearly HBsAg
clearance rate. Accordingly, the scoring system developed on the HBeAg negative REVEAL cohort
shows that only the combination of several variable
s (age, BMI, HBsAg and HBV DNA serum
levels) can predict with adequate accuracy the probability of HBsAg clearance in the single carrier
[8].  On the other hand, acceptable positive predictive value and diagnostic accuracy are achievable
only at very low HBsAg levels, as 100 IU/ml proposed by several studies in Asia where genotype B
and C HBV are predominant [7,8,13-14]. In fact, when a higher HBsAg threshold (such as 200 IU/ml) is used, HBsAg kinetics have to be added to
improve the diagnostic performance [11-12].
This implies the need to monitor HBsAg levels over
time.  Thus, the use of the latter approach
would not modify the current clinical practice since serum HBsAg monitoring would be required
anyway to predict and finally to show HBsAg clearance.  
W-J Jeng and Y-F Liaw commented also on the issue of HBsAg quantification in the context of
nucleos(t)ide analogue (NA) therapy.  They discussed their data that HBsAg decline during NA
therapy is stronger in patients with higher baseline alanine aminotransferase (ALT; >5x ULN) and
higher alfa-fetoprotein (AFP) levels. AFP reflects
cell turnover and may be another surrogate for
immune responses [15]. The data are in line with our discussion that the immune response but not
the mode of action of the NA is important for HBsAg
decline [16]. However, the value of baseline
parameter (ALT, AFP or IP-10) and on-treatment HBsAg level for the decision when to stop NA
treatment is still limited in our view. There are different stop NA approaches in different regions.
The APASL guideline suggests stopping NA therapy in
HBeAg negative patients after treatment for
at least 2 years with undetectable HBV DNA documented on three separate occasions, 6 months
apart [17]. This is in contrast to the EASL and AASLD guidelines that give a strong
recommendation treating all HBeAg negative patients
until HBsAg loss [2,18]. Demands for a cut-off identifying patients who should maintain on treatment or may stop earlier may be different in
different regions. As we have discussed in our review, HBsAg levels <100 IU/mL may be a good
predictor for maintained HBV DNA suppression after
stopping NA therapy [16]. Higher cut-offs of <150 IU/ml [19] or <200 IU/ml [20] have been discussed by other investigators. Other factors such
as age [19], previous therapies, kinetics of ALT levels or duration of consolidation therapy could
influence the risk of relapse after stopping NA treatment [21]. In our view, the current evidence
does not support a strong recommendation for stopping NA therapy at a certain cut-off at this stage.
To prevent clinical relapse, we suggested the lower
HBsAg cut-off of <100 IU/ml and a
consolidation therapy for at least 3 years in our review [16]. However, another strategy to stop NA
treatment may be to induce flares and increase HBsAg rates. Hadziyannis et al., have stopped
adefovir and observed ALT flares in 76% and subsequently 39% of patients lost HBsAg in the
long-term follow-up [22]. Höner zu Siederdissen et al. showed 20% HBsAg loss after stopping
long-term NA therapy in a small cohort of HBeAg negative patients. Interestingly, not HBsAg
levels at stop of therapy but the peak level of HBV
DNA and peak ALT during the relapse were the
best predictors for later HBsAg decline. The study
also showed that IP-10, IL-12, TNF and IL-10
were significantly induced after stopping NA therapy [23]. As discussed above, the key to achieve
HBsAg loss is the modulation of immune responses. An important task is now to analyze which
part of the immune response is fundamental for these effects. In conclusion, the topic to stop long-term NA therapy seems to be very interesting but still controversial.  

StephenW

J Hepatol。 2017年3月15. pii：S0168-8278（17）30136-8。 doi：10.1016 / j.jhep.2017.03.002。 [打印前的电子版]
乙型肝炎表面抗原动力学通知策略停止抗病毒治疗有多好？
Brunetto M1，Cornberg M2，Chan HL3。
作者信息

1
    比萨大学临床和实验医学系 - 肝病病毒单位和肝炎病毒分子遗传学和病理学实验室 - 意大利比萨大学医院。电子邮件地址：[email protected]。
2
    胃肠病学，肝脏和内分泌科。汉诺威医学院;德国感染研究中心（DZIF），合作伙伴Hannover-Braunschweig，德国。电子地址：[email protected]。
3
    香港中文大学消化病学研究所医学与治疗学系，消化道疾病国家重点实验室。电子地址：[email protected]。
回复
我们同意W-J Jeng和Y-F Liaw的关键
自发性乙型肝炎表面的作用
抗原（HBsAg）血清清除率在临床上他的
乙型肝炎病毒（HBV）携带者的故事[1]
是HBV复制控制的标志
和从非活动转移到隐匿性感染
[2]。然而，报告的年度HBsAg清除率是高度可变的（0.31至3.2×100人/年），因为异质性的
研究人群[3-6]：感染模式，年龄
和种族是影响HBs的主要因素
Ag损失[5-8]。此外，病毒特征
HBV基因型可以发挥作用
降低基因型D的每年HBsAg下降
与基因型B / C感染的携带者（分别在38个月和9年中位随访期间分别为0.287和0.35log10IU / ml）
载体（在5年和3年前分别为0.53和0.751 log10 IU / ml血清HBsAg缺失）[9-12]。最后，不同的HBsAg动力学
根据残留病毒复制：进行性下降，直到HBsAg清除
在具有不可检测的HBV DNA的携带者中观察到与在具有可检测的病毒血症的携带者中大约2年前的HBsAg清除的尖锐HBsAg下降不同[8]。因此，a
通用阈值预测短期HBsAg
清除将需要大量的研究
感染不同基因型的患者队列
其中所有相关变量被分析：
人口统计学特征（年龄，性别和种族），病毒谱（HBeAg阳性史，
HBeAg /抗HBe血清转化时间，病毒载量），总体随访持续时间和每年的HBsAg
清除率。因此，在HBeAg阴性REVEAL队列上开发的评分系统
显示只有几个变量的组合
（年龄，BMI，HBsAg和HBV DNA血清
水平）可以以足够的精度预测单载波中HBsAg清除的概率
[8]。另一方面，可接受的阳性预测值和诊断精确度是可实现的
只有在非常低的HBsAg水平，作为100 IU / ml提出了几个研究在亚洲基因型B
和C HBV占优势[7,8,13-14]。事实上，当使用更高的HBsAg阈值（例如200IU / ml）时，必须将HBsAg动力学加入
提高诊断性能[11-12]。
这意味着需要监测HBsAg水平
时间。因此，使用后一种方法
不会修改目前的临床实践，因为需要进行血清HBsAg监测
无论如何预测和最终显示HBsAg清除。
W-J Jeng和Y-F Liaw也评论了HBsAg量化在上下文中的问题
核（t）类似物（NA）治疗。他们讨厌
d他们的数据表明HBsAg在NA期间下降
治疗在具有较高基线丙氨酸氨基转移酶（ALT;> 5x ULN）的患者中更强
更高的甲胎蛋白（AFP）水平。法新社反映
细胞更新和可能是另一个代理
免疫反应[15]。数据符合我们的讨论，免疫反应，但不是
NA的作用方式对于HBsAg是重要的
下降[16]。但是，基线的值
参数（ALT，AFP或IP-10）和治疗HBsAg水平，以决定何时停止NA
治疗在我们看来仍然有限。在不同地区有不同的停止NA方法。
APASL指南建议停止NA治疗
HBeAg阴性患者治疗后
至少2年无法检测的HBV DNA在三个不同的场合，6个月记录
[17]。这与EASL和AASLD指南形成鲜明对比
推荐治疗所有HBeAg阴性患者
直到HBsAg消失[2,18]。要求确定应该保持治疗或可能早停止的患者的临界值可能不同
不同地区。正如我们在我们的审查中讨论的，HBsAg水平<100IU / mL可能是好的
预测维持的HBV DNA抑制后
停止NA治疗[16]。其他研究者已经讨论了<150 IU / ml [19]或<200 IU / ml [20]的更高截止值。其他因素如
作为年龄[19]，以前的治疗，ALT水平的动力学或巩固治疗的持续时间
影响停止NA治疗后复发的风险[21]。在我们看来，目前的证据
不支持在该阶段在某个截止值处停止NA治疗的强烈推荐。
为了防止临床复发，我们建议较低
HBsAg截留<100IU / ml，和a
巩固治疗至少3年在我们的审查[16]。然而，另一个策略停止NA
治疗可以是诱导发亮和增加HBsAg率。 Hadziyannis等人已停止
阿德福韦和观察到的ALT爆发76％，随后39％的患者失去了HBsAg
长期随访[22]。 Hönerzu Siederdissen et al。停止后显示20％HBsAg消失
长期NA治疗在小队列的HBeAg阴性患者。有趣的是，不是HBsAg
在治疗停止时的水平，但是HBV的峰值水平
DNA和峰值ALT在复发期间
后期HBsAg下降的最佳预测因子。研究
也显示IP-10，IL-12，TNF和IL-10
停止NA治疗后显着诱导[23]。如上所述，实现的关键
HBsAg丢失是免疫应答的调节。一个重要的任务是分析哪个
部分免疫反应是这些效应的基础。总之，停止长期NA治疗的主题似乎非常有趣，但仍有争议。