HBeAg阴性患者临床治再治疗决策中的HBsAg动力学

StephenW

HBsAg Kinetics in Retreatment Decision for Off-Therapy Hepatitis B Flare in HBeAg-Negative Patients [url=]Yun-Fan Liaw[/url]
,  [url=]Wen-Juei Jeng[/url]
,  [url=]Ming-Ling Chang[/url]
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan

DOI:            https://doi.org/10.1053/j.gastro.2018.03.066 |

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Dear Editors:

A high rate of hepatitis B surface antigen (HBsAg) seroclearance after cessation of nucleos(t)ide analogue therapy has been reported previously in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.[url=]1[/url], [url=]2[/url], [url=]3[/url] More important, patients who were not retreated for clinical relapses off medication had a much higher HBsAg seroclearance rate than those who received retreatment.[url=]1[/url], [url=]3[/url] These findings have raised an important issue of how to differentiate a benign or beneficial alanine aminotransferase (ALT) flare that retreatment can be withheld from a detrimental one that requires retreatment.[url=]2[/url], [url=]3[/url] It is, therefore, crucial to define such a “stop-and-watch” strategy and optimal timing for retreatment that is not too soon to allow sufficient immune clearance response but not too late to prevent adverse outcomes.[url=]3[/url]

Hepatitis B flare, an event of ALT to >5× the upper limit of normal reflecting increasing endogenous immune response against hepatitis B virus (HBV), may be followed by sustained remission, persistent ALT elevation, or hepatic decompensation.[url=]4[/url] In patients with “effective immune clearance,” quantitative HBsAg levels surge before the ALT peak, and decrease along with ALT normalization to achieve remission. Conversely, quantitative HBsAg levels remain high or increase further in patients with “ineffective immune clearance”.[url=]4[/url] To test whether this combination of ALT and HBsAg kinetics can be used to make retreatment decisions for clinical relapse, we conducted a proof-of-concept case study using serial serum samples collected every 1 to 2 weeks from 2 patients treated with nucleos(t)ide analogue who were HBeAg-negative and had an off-therapy hepatitis flare of similar degree but with different outcomes. The results showed that, at the end of therapy, the quantitative HBsAg of patient A was 250 IU/mL, increased to 260 IU/mL upon virologic relapse, decreased to 146 IU/mL when ALT peaked at 356 U/L, followed by ALT normalization and a gradual quantitative HBsAg decrease to a level of 1.5 IU/mL, which is very close to HBsAg seroclearance (Figure 1A).

Figure 1The clinical course in 2 hepatitis B e antigen (HBeAg)-negative patients with hepatitis B flare after end of antiviral therapy (EOT). (A) No retreatment is needed in patients with successive HBsAg decline, whereas (B) retreatment is required in patient with increasing HBsAg levels. The horizontal dotted line indicates the upper limit normal of alanine aminotransferase (ALT; 36 U/L).

View Large Image | View Hi-Res Image | Download PowerPoint Slide

In contrast, the end of antiviral therapy quantitative HBsAg of patient B was 306 IU/mL, which decreased to 281 IU/mL at virologic relapse, surged to 5764 IU/mL when ALT flared to 247 U/L, followed by ALT fluctuation and increased quantitative HBsAg to 19,623 IU/mL when ALT increased to 238 U/L and HBV DNA to 4.42 × 107 IU/mL. He was then treated with a nucleos(t)ide analogue to prevent further possible deterioration (Figure 1B).

In clinical studies, quantitative HBsAg levels were measured every 3 to 6 months or even yearly. So far, only a small study of 15 HBeAg-negative patients monitored quantitative HBsAg every 4 weeks in the first 12 weeks after cessation of nucleos(t)ide analogue treatment, but not during a clinical relapse.[url=]5[/url] As shown in Figure 1, some of the quantitative HBsAg changes would not have been detected if it were assayed every 1 to 3 months. The serial HBsAg changes were different between these 2 HBeAg-negative patients with off-nucleos(t)ide analogue clinical relapse and hepatitis flare. Because quantitative HBsAg has been considered as a surrogate marker of infected hepatocyte,[url=]6[/url] the successive and profound HBsAg decrease after hepatitis B flare in patient A reflects an “effective immune clearance,” whereas the increasing HBsAg levels in patient B suggests that his immune response was ineffective or failed to control the HBV. It could be anticipated that if patient B had remained untreated, his ongoing hepatitis may lead to adverse outcome(s).

In conclusion, it seems appropriate to include quantitative HBsAg assay every 3 months in the off-nucleos(t)ide analogue monitoring plan and more frequently when ALT is increasing, at least before and after the peak of ALT. If HBsAg level is decreasing, retreatment can be withheld or is not necessary even in patients with hepatitis flare. In contrast, patients whose HBsAg is increasing and ALT remains elevated may need retreatment. Immediate retreatment is required if patients show signs of hepatic decompensation, such as increasing serum bilirubin and a prolonged prothrombin time. Further large studies are required to confirm the value of quantitative HBsAg monitoring in the proposed “stop-and-watch strategy,” which may increase HBsAg seroclearance rate.[url=]7[/url]

StephenW

HBeAg阴性患者临床治疗乙型肝炎疫苗再治疗决策中的HBsAg动力学
大三阳阴性患者临床治疗乙型肝炎疫苗再治疗决策中的乙肝表面抗原动力学
Yun-Fan Liaw
，文J J
，张明玲
台湾台北长庚大学医学院长庚医院肝脏研究室
DOI：https：//doi.org/10.1053/j.gastro.2018.03.066 |
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亲爱的编辑：

乙型肝炎e抗原（HBeAg）阴性的慢性乙型肝炎患者以前曾报道核苷（酸）类似物治疗停止后乙型肝炎表面抗原（HBsAg）血清学清除率较高。更重要的是，未因临床复发而停药的患者HBsAg血清清除率明显高于接受再治疗的患者[1,3]。这些研究结果提出了一个重要的问题，即如何区分良性或有益的丙氨酸转氨酶（ALT）因此，对于需要再次治疗的有害疾病应予以扣留.2,3因此，确定这种“停止并监视”策略和最佳再治疗时机是至关重要的，这种时机不能太快以至于不能提供足够的免疫清除反应，迟到以防止不良结果

乙肝表现为ALT> 5×正常上限，反映出增加对乙型肝炎病毒（HBV）的内源性免疫反应，可能会持续缓解，ALT持续升高或肝功能失代偿.4对于“有效的免疫清除“，定量HBsAg水平在ALT峰值之前激增，并伴随ALT正常化而减少以达到缓解。相反，对于“无效的免疫清除”患者，定量HBsAg水平仍然很高或进一步增加[4]。为了测试这种ALT和HBsAg动力学的组合是否可用于临床复发的再治疗决策，我们进行了概念验证案例研究使用从用核苷（酸）类似物治疗的2名患者（HBeAg阴性并且具有相似程度但是具有不同结果的脱离疗法肝炎闪光）每1至2周收集一次血清样品。结果显示，在治疗结束时，患者A的定量HBsAg为250 IU / mL，病毒学复发时升高至260 IU / mL，当ALT达到356 U / L时降至146 IU / mL，其次是ALT正常化和逐渐定量的HBsAg下降至1.5 IU / mL，这与HBsAg血清学清晰度非常接近（图1A）。
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图1

抗病毒治疗结束后乙型肝炎e抗原（HBeAg）阴性乙型肝炎患者的临床病程（EOT）。 （A）连续HBsAg下降的患者不需要再次治疗，而（B）HBsAg水平升高的患者需要再次治疗。水平虚线表示丙氨酸转氨酶的正常上限（ALT：36U / L）。

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与此相反，B型患者抗病毒治疗定量HBsAg的终点为306 IU / mL，在病毒学复发时降至281 IU / mL，ALT升至247 U / L时升至5764 IU / mL，随后出现ALT波动，当ALT升高至238 U / L和HBV DNA至4.42×107 IU / mL时，定量HBsAg升高至19,623 IU / mL。然后用nucleos（t）ide类似物治疗，以防止进一步恶化（图1B）。

在临床研究中，每3至6个月或甚至每年测量一次HBsAg定量水平。迄今为止，仅有一项对15例HBeAg阴性患者的研究在核苷类似物治疗停止后的头12周内每4周监测一次定量HBsAg，而不是在临床复发期间监测.5如图1所示，的HBsAg定量变化如果每1至3个月检测一次，就不会检测到。这2例HBeAg阴性患者的核 - 核酶类似物临床复发和肝炎爆发的连续HBsAg变化不同。由于定量HBsAg一直被认为是感染肝细胞的替代指标[6]，患者A发生乙型肝炎后，连续而深刻的HBsAg下降反映了“有效的免疫清除率”，而患者B中HBsAg水平升高表明他的免疫反应为无效或未能控制HBV。可以预料，如果患者B未得到治疗，他正在进行的肝炎可能导致不良后果。
总之，在核苷酸（t）类似物监测计划中每3个月应该包括一次定量的HBsAg检测，而且ALT越高越好，至少在ALT峰值之前和之后。 如果HBsAg水平下降，即使在肝炎病人中也可以停止再次治疗或不需要再次治疗。 相反，HBsAg升高且ALT升高的患者可能需要再次治疗。 如果患者出现肝功能失代偿的迹象，如增加血清胆红素和延长凝血酶原时间，则需要立即重复治疗。 需要进一步的大规模研究来证实拟定的“停止和观察策略”中定量HBsAg监测的价值，这可能会增加HBsAg血清学清除率.7

StephenW

https://www.gastrojournal.org/ar ... aven_jbs_etoc_email

齐欢畅

HBsAg Kinetics in Retreatment Decision for Off-Therapy Hepatitis B Flare in HBeAg-Negative Patients

Yun-Fan Liaw, Wen-Juei Jeng, Ming-Ling Chang
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
DOI: https://doi.org/10.1053/j.gastro.2018.03.066 |
showArticle Info
Abstract
Full Text
Images
References
Dear Editors:
A high rate of hepatitis B surface antigen (HBsAg) seroclearance after cessation of nucleos(t)ide analogue therapy has been reported previously in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.1, 2, 3 More important, patients who were not retreated for clinical relapses off medication had a much higher HBsAg seroclearance rate than those who received retreatment.1, 3 These findings have raised an important issue of how to differentiate a benign or beneficial alanine aminotransferase (ALT) flare that retreatment can be withheld from a detrimental one that requires retreatment.2, 3 It is, therefore, crucial to define such a “stop-and-watch” strategy and optimal timing for retreatment that is not too soon to allow sufficient immune clearance response but not too late to prevent adverse outcomes.3
Hepatitis B flare, an event of ALT to >5× the upper limit of normal reflecting increasing endogenous immune response against hepatitis B virus (HBV), may be followed by sustained remission, persistent ALT elevation, or hepatic decompensation.4 In patients with “effective immune clearance,” quantitative HBsAg levels surge before the ALT peak, and decrease along with ALT normalization to achieve remission. Conversely, quantitative HBsAg levels remain high or increase further in patients with “ineffective immune clearance”.4 To test whether this combination of ALT and HBsAg kinetics can be used to make retreatment decisions for clinical relapse, we conducted a proof-of-concept case study using serial serum samples collected every 1 to 2 weeks from 2 patients treated with nucleos(t)ide analogue who were HBeAg-negative and had an off-therapy hepatitis flare of similar degree but with different outcomes. The results showed that, at the end of therapy, the quantitative HBsAg of patient A was 250 IU/mL, increased to 260 IU/mL upon virologic relapse, decreased to 146 IU/mL when ALT peaked at 356 U/L, followed by ALT normalization and a gradual quantitative HBsAg decrease to a level of 1.5 IU/mL, which is very close to HBsAg seroclearance (Figure 1A).

Opens large image
Figure 1
The clinical course in 2 hepatitis B e antigen (HBeAg)-negative patients with hepatitis B flare after end of antiviral therapy (EOT). (A) No retreatment is needed in patients with successive HBsAg decline, whereas (B) retreatment is required in patient with increasing HBsAg levels. The horizontal dotted line indicates the upper limit normal of alanine aminotransferase (ALT; 36 U/L).

View Large Image | View Hi-Res Image | Download PowerPoint Slide
In contrast, the end of antiviral therapy quantitative HBsAg of patient B was 306 IU/mL, which decreased to 281 IU/mL at virologic relapse, surged to 5764 IU/mL when ALT flared to 247 U/L, followed by ALT fluctuation and increased quantitative HBsAg to 19,623 IU/mL when ALT increased to 238 U/L and HBV DNA to 4.42 × 107 IU/mL. He was then treated with a nucleos(t)ide analogue to prevent further possible deterioration (Figure 1B).

In clinical studies, quantitative HBsAg levels were measured every 3 to 6 months or even yearly. So far, only a small study of 15 HBeAg-negative patients monitored quantitative HBsAg every 4 weeks in the first 12 weeks after cessation of nucleos(t)ide analogue treatment, but not during a clinical relapse.5 As shown in Figure 1, some of the quantitative HBsAg changes would not have been detected if it were assayed every 1 to 3 months. The serial HBsAg changes were different between these 2 HBeAg-negative patients with off-nucleos(t)ide analogue clinical relapse and hepatitis flare. Because quantitative HBsAg has been considered as a surrogate marker of infected hepatocyte,6 the successive and profound HBsAg decrease after hepatitis B flare in patient A reflects an “effective immune clearance,” whereas the increasing HBsAg levels in patient B suggests that his immune response was ineffective or failed to control the HBV. It could be anticipated that if patient B had remained untreated, his ongoing hepatitis may lead to adverse outcome(s).

In conclusion, it seems appropriate to include quantitative HBsAg assay every 3 months in the off-nucleos(t)ide analogue monitoring plan and more frequently when ALT is increasing, at least before and after the peak of ALT. If HBsAg level is decreasing, retreatment can be withheld or is not necessary even in patients with hepatitis flare. In contrast, patients whose HBsAg is increasing and ALT remains elevated may need retreatment. Immediate retreatment is required if patients show signs of hepatic decompensation, such as increasing serum bilirubin and a prolonged prothrombin time. Further large studies are required to confirm the value of quantitative HBsAg monitoring in the proposed “stop-and-watch strategy,” which may increase HBsAg seroclearance rate.7

pourvivre

拜读

Hepbest

这个需要进一步研究啦

欢欢123

这个可以呀！

StephenW

回复 Hepbest 的帖子

是的, 我同意.

StephenW

回复 欢欢123 的帖子

只在一些患者中. 需要更好的预测因子.