血清HBsAg动力学临床预测

StephenW

Serum HBsAg kinetics in clinical prediction
Wen-Juei Jeng
, Yun-Fan Liaw' Correspondence information about the author Yun-Fan LiawEmail the author Yun-Fan Liaw
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Article has an altmetric score of 3
DOI: http://dx.doi.org/10.1016/j.jhep.2017.01.036 |


To the Editor:

We read with great interest the review article “The role of quantitative hepatitis B surface antigen revisited” by Cornberg et al. in the Journal of Hepatology [1]. Indeed, it is a comprehensive update. However, the role of hepatitis B surface antigen (HBsAg) quantification in the prediction of spontaneous or antiviral therapy related HBsAg seroclearance and relapse after cessation of nucleos(t)ide analog (NUC) therapy was not well addressed. The studies mentioned in the review used an HBsAg level <100 IU/ml as a predictor for remote (6–10 years) HBsAg seroclearance but two studies on short-term prediction of HBsAg seroclearance within 1–3 years were not mentioned. One longitudinal study showed that serum HBsAg level ≤200 IU/ml had a negative predictive value for HBsAg seroclearance of 100% and 92% at 1 and 3 years, respectively, and the positive predictive value increased from 36% at 1 year and 49% at 3 year to 97% and 100%, respectively if combined with a ≥1 log10 IU/ml reduction in the preceding 2 years [2]. Another large case-control study also showed that HBsAg level <200 IU/ml was predictive of HBsAg seroclearance within 3 years and a patient with HBsAg <200 IU/ml and a 0.5 log10 IU/ml HBsAg decline in the next year may predict HBsAg seroclearance in 3 years with a sensitivity of 74% and a specificity of 89.4% [3]. Obviously, prediction of spontaneous HBsAg seroclearance within a much shorter period of 1–3 years is more desirable and useful in daily clinical practice.

Stronger HBsAg decline during NUC therapy associated with higher pretherapy alanine aminotransferase (ALT) was briefly mentioned in the review. Actually, patients with pretherapy ALT over 5× upper limit of normal (ULN) showed greater HBsAg decline not only at an ALT-level dependent manner but also at an alpha-fetoprotein (AFP) level-dependent manner, in which AFP dominated over ALT as a more powerful factor for early “rapid HBsAg decline” [4]. These findings are important because “rapid HBsAg decline” >0.5 log10 IU/ml by month 6 or >1 log10 IU/ml by month 12 of NUC therapy were found to be predictors for HBsAg seroclearance [5], and HBsAg decline ≥75% by week 24 of adefovir/tenofovir therapy was also predictive for HBsAg seroclearance [6]. A most recent study further showed that hepatitis flares (ALT >5× ULN) during pegylated interferon and tenofovir combination therapy in HBeAg positive patients was associated with HBsAg decline >1 log10 by week 12, which was an independent factor for HBsAg loss [7]. More studies on this issue are ongoing.

The issue of stopping NUC therapy in HBeAg-negative patients has attracted more and more attention in recent years. Studies have shown the lower the HBsAg level at the end of NUC therapy, the less chance of clinical relapse [[8], [9], [10]]. HBsAg <100 IU/ml seems to be the best predictive level but no consensus has been reached. This is also applicable in patients with liver cirrhosis who had discontinued NUC therapy, as such patients were included in these studies [[8], [9], [10]].

In conclusion, HBsAg quantification has a wide range of clinical applications. It is anticipated that the role of HBsAg kinetics in the natural course and during antiviral therapy in patients with chronic hepatitis B will remain a hot issue to be explored.

StephenW

血清HBsAg动力学临床预测
文ue eng
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台湾台北长庚大学医学院长庚纪念医院肝脏研究室
文章的高分为3分
DOI：http://dx.doi.org/10.1016/j.jhep.2017.01.036 |


编辑：

我们非常感兴趣地阅读了Cornberg等人的评论文章“定量乙型肝炎表面抗原的作用”。在“肝病杂志”[1]中。的确，这是一个全面的更新。然而，乙型肝炎表面抗原（HBsAg）定量在预测自发或抗病毒治疗相关HBsAg血清学和核苷（t）ide类似物（NUC）治疗停止后复发的作用尚未得到很好的解决。在评论中提到的研究使用HBsAg水平<100 IU / ml作为远程（6-10年）HBsAg血清白蛋白的预测因子，但没有提到两项关于1-3年内HBsAg血清清晰度短期预测的研究。一项纵向研究表明，血清HBsAg水平≤200IU / ml分别在1年和3年时HBsAg血清白蛋白阴性预测值分别为100％和92％，阳性预测值从1年的36％和49％在3年时，分别为97％和100％，如果结合前2年≥1log10 IU / ml减少[2]。另一项大型病例对照研究还显示，HBsAg水平<200 IU / ml可预测3年内的HBsAg血清清除率，HBsAg <200 IU / ml的患者和下一年的0.5 log10 IU / ml HBsAg下降可预测HBsAg 3年的血清清晰度，灵敏度为74％，特异性为89.4％[3]。显然，在1-3年的短时间内自发HBsAg血清清晰度的预测在日常临床实践中更为理想和有用。

在检查期间简要介绍了与更高治疗前丙氨酸氨基转移酶（ALT）相关的NUC治疗期间更强的HBsAg下降。实际上，ALT超过5倍（ULN）上限的患者ALT水平依赖性升高，而且甲胎蛋白（AFP）水平依赖性升高，其中AFP主要依赖于ALT作为早期“HBsAg快速下降”的更强大因素[4]。这些发现是重要的，因为在第6个月或6月10日期间，第6个月或12个月的“HBsAg下降”高于0.5log10 IU / ml，发现HBsAg血清白蛋白的预测因子[5]，HBsAg降低≥75％阿德福韦/替诺福韦治疗的第24周也预测HBsAg血清白蛋白[6]。最近的一项研究进一步表明，HBeAg阳性患者聚乙二醇干扰素和替诺福韦组合治疗期间，乙型肝炎病毒（ALT> 5×ULN）与第12周HBsAg降低> 1 log10相关，HBsAg损失是独立因素[7] 。有关这个问题的更多研究正在进行之中。

HBeAg阴性患者停止NUC治疗的问题近年来受到越来越多的关注。研究表明，NUC治疗结束时HBsAg水平越低，临床复发的机会越少[[8]，[9]，[10]]。 HBsAg <100 IU / ml似乎是最佳预测水平，但未达成共识。这也适用于已经停止NUC治疗的肝硬化患者，因为这些患者被纳入这些研究[[8]，[9]，[10]]。

总之，HBsAg定量测定具有广泛的临床应用。预计HBsAg动力学在慢性乙型肝炎患者自然病程和抗病毒治疗中的作用仍将是一个需要探索的热点问题。

StephenW

Reply to: “Serum HBsAg kinetics in clinical prediction”
Maurizia Brunetto
, Markus Cornberg
, Henry Lik-Yuen Chan  'Correspondence information about the author Henry Lik-Yuen Chan Email the author Henry Lik-Yuen Chan
Article has an altmetric score of 3
DOI: http://dx.doi.org/10.1016/j.jhep.2017.03.002 |


To the Editor:

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 history 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 × 100 persons/years) because of the heterogeneity of the studied populations [[3], [4], [5], [6]]: mode of infection, age and ethnicity are major factors influencing the HBsAg loss [[5], [6], [7], [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) when 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], [10], [11], [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 genotypes 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 variables (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; >5× 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 Asian Pacific Association for the Study of the Liver (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 to identify 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 effect. In conclusion, the topic to stop long-term NA therapy seems to be very interesting but still controversial.

StephenW

回复：“血清HBsAg动力学临床预测”
Maurizia Brunetto
，马克斯·康贝尔格
，Henry Lik-Yuen Chan“关于作者的信件信息Henry Lik-Yuen Chan Email给作者Henry Lik-Yuen Chan
文章的高分为3分
DOI：http://dx.doi.org/10.1016/j.jhep.2017.03.002 |


编辑：

我们同意WJ Jeng和YF Liaw关于自发性乙型肝炎表面抗原（HBsAg）血清清除在乙型肝炎病毒（HBV）携带者[1]的临床病史中的关键作用，因为它是HBV的控制标志复制和从非活动转变为隐匿感染[2]。然而，由于研究人群的异质性，报告的HBsAg清除年率是高度变化的（0.31〜3.2×100人/年）[[3]，[4]，[5]，[6]]：感染，年龄和种族是影响HBsAg损失的主要因素[[5]，[6]，[7]，[8]]。此外，与基因型B相比，HBV基因型的病毒特征可能起到基因型D感染携带者年龄低的HBsAg下降的意义（分别为388个月时分别为0.287和0.35 log10 IU / ml，分别为9年中位随访） / C感染的携带者（分别为0.53和0.751 log10 IU / ml，分别为5和3年血清HBsAg损失）[[9]，[10]，[11]，[12]]。最后，根据残留的病毒复制描述了不同的HBsAg动力学：在可检测的病毒血症携带者中HBsAg清除之前大约2年前，在具有不可检测的HBV DNA的携带者中观察到具有不可检测的HBV DNA的携带者中的HBsAg清除[8]。因此，鉴定预测短期HBsAg清除率的通用阈值将需要研究感染不同基因型的大量患者群体，其中分析所有相关变量：人口学特征（年龄，性别和种族），病毒概况（病史HBeAg阳性，HBeAg /抗HBe血清转化时间，病毒载量），总体随访时间和每年HBsAg清除率。因此，在HBeAg阴性REVEAL队列中开发的评分系统显示，只有几个变量（年龄，BMI，HBsAg和HBV DNA血清水平）的组合才能以足够的精度预测单载体中HBsAg清除的概率[8]。另一方面，可接受的阳性预测值和诊断准确度只有在非常低的HBsAg水平才可实现，如亚洲基因型B和C型HBV占主导地位的几项研究提出的100 IU / ml [[7]，[8] 13]，[14]]。事实上，当使用较高的HBsAg阈值（如200 IU / ml）时，必须添加HBsAg动力学以改善诊断性能[[11]，[12]]。这意味着需要随时间监测HBsAg水平。因此，使用后一种方法不会改变目前的临床实践，因为需要血清HBsAg监测来预测并最终显示HBsAg清除率。

W-J Jeng和Y-F Liaw也评论了在核苷类似物（NA）治疗的背景下HBsAg量化的问题。他们讨论了他们的数据，即NA治疗期间HBsAg下降的患者具有较高的基线丙氨酸氨基转移酶（ALT;> 5×ULN）和较高甲胎蛋白（AFP）水平。法新社反映细胞周转率，可能是免疫应答的另一替代方案[15]。数据符合我们的讨论，免疫反应而不是NA的作用方式对于HBsAg的降低是重要的[16]。然而，我们认为，基线参数（ALT，AFP或IP-10）的价值和治疗HBsAg水平决定何时停止NA治疗仍然有限。不同地区有不同的停止NA方法。亚太地区肝脏研究协会（APASL）指导意见表明，在治疗后至少2年的HBeAg阴性患者停用NA治疗，不可检测的HBV DNA记录在三个不同的时间，间隔6个月[17]。这与EASL和AASLD指南相反，EASL和AASLD指南强烈建议治疗所有HBeAg阴性患者，直到HBsAg损失[[2]，[18]]。要求临时确定应该维持治疗或可能早日停止的患者可能在不同地区有所不同。正如我们在我们的评论中所讨论的，HBsAg水平<100 IU / ml可能是停止NA治疗后维持HBV DNA抑制的良好预测因子[16]。其他研究者已经讨论了<150 IU / ml [19]或<200 IU / ml [20]的较高临界值。其他因素如年龄[19]，以前的治疗，ALT水平的动力学或巩固治疗持续时间可能会影响NA治疗后复发的风险[21]。我们认为，目前的证据不支持在此阶段停止NA治疗的强烈建议。为了防止临床复发，我们建议在我们的评论中，HBsAg的截止值低于100 IU / ml，巩固治疗至少3年[16]。然而，另一种阻止NA治疗的策略可能是诱发耀斑并增加HBsAg发生率。 Hadziyannis等人已经停止了阿德福韦酯，并观察到76％的ALT耀斑，随后39％的患者在长期随访中失去了HBsAg [22]。 Hönerzu Siederdissen等在HBeAg阴性患者的小队列中停止长期NA治疗后，HBsAg损失为20％。有趣的是，HBsAg水平在治疗停止时，HBV DNA的峰值水平和ALT峰值复发是HBsAg后期下降的最佳预测指标。该研究还显示，在停止NA治疗后，IP-10，IL-12，TNF和IL-10均明显诱导[23]。如上所述，实现HBsAg损失的关键是免疫反应的调节。现在一个重要的任务是分析哪些部分的免疫反应是这些影响的基础。总之，停止长期NA治疗的主题似乎是非常有趣但仍然有争议。