在聚乙二醇干扰素α-2a的视为闲置乙肝表面抗原携带者乙肝

StephenW

World J Hepatol. 2016 May 28;8(15):637-43. doi: 10.4254/wjh.v8.i15.637.
Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a.Li MH1, Xie Y1, Zhang L1, Lu Y1, Shen G1, Wu SL1, Chang M1, Mu CQ1, Hu LP1, Hua WH1, Song SJ1, Zhang SF1, Cheng J1, Xu DZ1.
Author information

• 1Ming-Hui Li, Yao Xie, Lu Zhang, Yao Lu, Ge Shen, Shu-Ling Wu, Min Chang, Cai-Qin Mu, Lei-Ping Hu, Jun Cheng, Dao-Zhen Xu, Liver Disease Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
  

AbstractAIM: To examine the association between interferon (IFN) therapy and loss of hepatitis B surface antigen (HBsAg) in inactive HBsAg carriers.
METHODS: This was a retrospective cohort study in inactive HBsAg carriers, who were treatment-naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBsAg, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group.
RESULTS: Thirteen (65.0%) of 20 treated patients achieved HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 ± 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 ± 25.58 IU/mL at baseline to 17.11 ± 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation.
CONCLUSION: IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations.


KEYWORDS: Chronic hepatitis B surface antigen carriers; Hepatitis B surface antigen loss/seroconversion; Inactive hepatitis B surface antigen carriers; Interferon; Peginterferon alfa-2a

StephenW

世界肝脏病学杂志。 2016年5月28日; 8（15）：637-43。 DOI：10.4254 / wjh.v8.i15.637。
在聚乙二醇干扰素α-2a的视为闲置乙肝表面抗原携带者乙肝表面抗原的清除。
李MH1，谢Y1，张L1，Y1路，沉G1，吴SL1，常M1，万亩CQ1，胡LP1，华WH1，宋SJ1，张SF1，程J1，徐DZ1。
作者信息

    1Ming慧丽，姚燮，张璐，姚璐葛慎，吴淑玲，闵昌彩秦牧，雷平胡，郡城，道沟镇许，肝病中心，北京地坛医院，首都医科大学，北京100015，中国。

抽象
目标：

审查非活动HBsAg携带者干扰素（IFN）治疗和B型肝炎表面抗原（HBsAg）的损失之间的关联。
方法：

这是在非活动性HBsAg携带者，谁是治疗天真，与血清HBsAg水平<100 IU / mL和检测不到乙肝病毒（HBV）DNA水平（<100 IU / mL）的回顾性队列研究。所有的20个治疗的患者接受皮下注射PEG-IFNα-2A 180微克/周72周及随后随访24周。共有40 96周的观察匹配的未经处理的控制。血清HBsAg，乙型肝炎病毒DNA和丙氨酸转氨酶进行了监测，治疗组中的每3个月，每3-6莫对照组中使用。
结果：

20治疗的患者十三（65.0％）达到HBsAg消失，其中12人取得了乙肝表面抗原血清学转换。平均水平的HBsAg治疗的患者从26.22±33.00 IU / mL的基线水平下降至6.69±13.04 IU / mL的治疗后24周。血清HBV DNA水平在研究期间的所有治疗的患者仍然检测不到（<100国际单位/毫升）。对照组的HBsAg水平从25.72±25.58国际单位/毫升在96周（p = 0.108）降低基线到17.11±21.62国际单位/毫升。在对照组中，没有患者出现HBsAg消失/血清学转换，和两个（5.0％）发生HBV再激活。
结论：

干扰素治疗结果HBsAg消失和血清转换在非活动性HBsAg携带者低浓度的HBsAg相当大的比例。
关键词：

慢性乙肝表面抗原携带者;乙型肝炎表面抗原损失/血清转化;非活动乙肝表面抗原携带者;干扰素;聚乙二醇干扰素α-2a的

StephenW

HBsAg level reflects the transcriptional activity of the cccDNA and is used as a proxy measure of HBV infection and for treatment guidance[19-21]. HBsAg declines during treatment and its level at the end of treatment can predict HBeAg seroconversion in HBeAg-positive patients[22-24] and sustained viral response in HBeAg-negative patients[25-27]. Thus, inactive HBsAg carriers were not recommended for antiviral therapy[1-3]. However, this inactive state was not always sustained. A long-term follow-up study showed cumulative probabilities of hepatitis relapse in inactive HBsAg carriers of 10.2%, 17.4%, 19.3%, 20.2% and 20.2% after 5, 10, 15, 20 and 25 years of follow-up, respectively, with an annual rate of 1.55%[28]. Another long-term longitudinal study (up to 23 years) showed that 1%-17% of inactive carriers reverted back to HBeAg-positive chronic hepatitis[4]. Cirrhosis and HCC may still develop in some inactive HBsAg carriers[28-30]. In contrast, no cirrhosis or HCC occurred in patients with HBsAg loss after IFN treatment, indicating that HBsAg clearance is currently the only parameter associated with an excellent long-term prognosis[10], and the strongest factor predicting excellent long-term outcome in HBV infected individuals is HBsAg loss, spontaneously or after treatment[10]. Therefore, it could be speculated that inactive HBsAg carriers can get further improvement in outcomes if HBsAg loss could be achieved after IFN treatment.

This study contained all participants who were inactive carriers with HBsAg < 100 IU/mL and wished to achieve HBsAg clearance by PEG-IFN alfa-2a treatment during the study period. Despite the lack of liver pathology for diagnosis, the patients could be considered as inactive for having undetectable HBV DNA and persistent normal ALT for 2 years, serum HBV DNA < 100 IU/mL and HBsAg < 100 IU/mL at enrollment. It has been reported that HBsAg < 1000 IU/mL with HBV DNA < 2000 IU/mL can distinguish inactive from active carriers with a diagnostic accuracy of 94.3%, sensitivity of 91.1%, specificity of 95.4%, positive predictive value of 87.9%, and negative predictive value of 96.7%[31]. Although the present study was not a randomized controlled study, all treated inactive carriers with HBsAg < 100 IU/mL and matched controls according to age, sex, and HBsAg and ALT levels were included for eliminating the bias.

Effects, including the probability of HBsAg clearance, can be enhanced by extended therapy with PEG-IFN alfa-2a[32]. In our study the patients were given 72 wk of treatment. After 12 wk of treatment with PEG-IFN alfa-2a, HBsAg levels decreased significantly compared with baseline levels. Furthermore, at the end of study, HBsAg loss occurred in most of treated patients, and HBsAg levels in the remaining seven treated carriers who did not achieve HBsAg loss decreased significantly. In contrast, mean HBsAg level of the control group remained constant during 96 wk of observation and no patients experienced HBsAg loss. These results suggest that inactive HBsAg carriers could benefit from PEG-IFN alfa-2a treatment.

In the present study, all participants had HBsAg < 100 IU/mL and they may have a good long-term clinical outcome, even HBsAg loss, after long-term follow-up. However, it was reported that spontaneous HBsAg loss in patients with HBsAg < 100 IU/mL occurred in a mean period of 86.6 ± 29 mo (range, 26-115) after the baseline visit with an annual rate of 1.6%[33], and in the present study after 72 wk treatment of PEG-IFN alfa-2a, HBsAg clearance occurred in 65% of treated objects. In a study by Tseng et al[34], HBsAg level < 10 IU/mL at baseline was the strongest predictor of HBsAg loss. However, the rate of HBsAg loss was only 7.4 per 100 persons per year and it occurred in a mean period of 5.8 ± 4.2 years. Although half of the subjects included in this study had HBsAg < 10 IU/mL and undetectable HBV DNA, 80% (8/10) of them achieved HBsAg loss after 72 wk of IFN treatment, suggesting that PEG-IFN alfa-2a treatment can make inactive carriers achieve HBsAg clearence in a short-term period compared with spontaneous HBsAg loss occurring in the nature history. Although Chen et al[35] reported in a case-control study that the positive predictive value of HBsAg level of 200 IU/mL in predicting HBsAg loss occurring within 1 year was 36%, their study design was different from ours. The aim of their study was to observe the difference in HBsAg decrease between 46 patients who underwent spontaneous HBsAg loss and 46 patients who had no HBsAg loss during the same observation course. The aim of our study was to compare the rate of HBsAg clearance in patients treated with PEG-IFN alfa-2a compared with untreated patients, and the result showed that the rate of HBsAg clearance was significantly higher in patients treated with PEG-IFN alfa-2a than in untreated patients. The results of our study suggested that inactive carriers can receive PEG-IFN alfa-2a therapy to increase the probability of HBsAg clearance and shorten the time compared with that occurring spontaneously.

In conclusion, our study demonstrated that treatment with PEG-IFN alfa-2a produced a high rate of HBsAg loss/seroconversion in inactive carriers with low HBsAg levels. However, whether inactive carriers with HBsAg levels more than 100 IU/mL could benefit from PEG-IFN alfa-2a treatment needs further study.

StephenW

的HBsAg水平反映了的cccDNA的转录活性，并用作HBV感染的一个代理度量和用于治疗指导[19-21]。在治疗过程中HBsAg的下降及其在治疗结束等级可以在HBeAg阳性患者[22-24]预测HBeAg血清转换和持续的HBeAg阴性患者[25-27]病毒学应答。因此，不建议抗病毒治疗[1-3]非活动性HBsAg携带者。然而，该非活动状态并不总是持续。一项长期随访研究分别在5，10，15，20年和25年的随访，结果显示乙肝复发的10.2％，17.4％，19.3％，20.2％和20.2％，非活动性HBsAg携带者的累积概率，用1.55％[28]的年增长率。另一个长期的纵向研究（长达23年）显示，1％的非活动性携带者的17％恢复到HBeAg阳性慢性肝炎[4]。肝硬化和HCC仍可能发展一些非活动性HBsAg携带者[28-30]。与此相反，没有肝硬化或肝癌患者发生干扰素治疗后HBsAg消失，表明HBsAg清除当前预测HBV优良的长期结果具有优异的长期预后[10]相关联的唯一参数，和最强的因子被感染的个体是HBsAg消失，自发或治疗[10]后。因此，它可以推测，无活性的HBsAg携带者可以得到进一步改善的结果，如果HBsAg的损失可能干扰素治疗后实现。

这项研究包含谁是非活动性携带者乙肝表面抗原与<100 IU / mL的所有参与者，并希望实现在研究期间通过PEG-IFNα-2a中治疗HBsAg清除。尽管缺乏肝脏病理诊断的，患者可以被认为是不活动的具有不可检测HBV DNA和持久ALT正常为2年，血清HBV DNA <100国际单位/毫升与HBsAg <100国际单位/毫升的注册。已经报道了HBsAg的<1000国际单位/毫升与HBV DNA <2000国际单位/毫升可从活动载波区分不活动以94.3％的诊断准确性，91.1％的灵敏度，95.4％的特异性，87.9％的阳性预测值，和96.7％，阴性预测值[31]。虽然本研究不是随机对照研究中，所有处理过的非活动载波用HBsAg <100国际单位/毫升，并根据年龄，性别匹配的对照，和HBsAg和ALT水平被包括用于消除偏差。

影响，包括HBsAg清除的概率，可以通过用PEG-IFNα-2a中[32]扩展疗法来增强。在我们的研究中，患者均给予72周的治疗。用PEG-IFNα-2a中治疗12周后，HBsAg水平下降显著与基线水平相比。此外，在研究结束时，HBsAg的损失发生在大多数治疗的患者，而在其余七个治疗载体HBsAg水平谁没有达到HBsAg消失显著下降。与此相反，对照组的平均值的HBsAg水平期间96周的观察保持不变，没有患者出现HBsAg消失。这些结果表明，不活动的HBsAg携带者可从PEG-IFNα-2a中治疗中获益。

在本研究中，所有的参与者有乙肝表面抗原<100 IU / mL和他们可能有一个良好的长期临床疗效，甚至HBsAg消失，经过长期随访。然而，据报道，自发HBsAg消失的患者用HBsAg <100国际单位/毫升发生在基线就诊后86.6±29个月（范围，26-115）的平均周期为1.6％[33]的年增长率，并在72周治疗PEG-IFNα-2a的后本研究中，HBsAg清除发生在处理对象的65％。在曾国藩等人[34]，乙肝表面抗原水平的研究<10 IU / mL的基线是HBsAg消失最强的预测因子。然而，HBsAg消失率为每年7.4％100只者和它发生在5.8±4.2岁，平均周期。虽然科目的一半纳入本次研究的HBsAg <10 IU / mL和检测不到HBV DNA，80％（8/10），其中后IFN治疗72周实现HBsAg消失，这表明PEG-IFNα-2a中可以治疗使得在自然历史中发生自燃HBsAg消失相比，非活动性携带者乙肝表面抗原实现在clearence短期期。虽然陈等人[35]在一项病例对照研究报告指出，在预测1年以内发生HBsAg消失200 IU / mL时的HBsAg水平的阳性预测值为36％，他们的研究设计是与我们的不同。他们研究的目的是观察46例谁接受自发性HBsAg消失和46例谁相同的观察过程中无HBsAg消失之间的HBsAg下降的差异。我们研究的目的是HBsAg清除率比较与未处理的患者相比PEG-IFNα-2a中治疗的患者，结果表明，HBsAg清除率为与PEG-IFN治疗的患者显著更高alfa- 2A比未经治疗的病人。我们研究的结果表明，不活动的运营商可以接收PEG-IFNα-2a中治疗，以增加HBsAg清除的可能性，并缩短与发生自发相比的时间。

总之，我们的研究表明，用PEG-IFNα-2a中处理所产生的HBsAg损失/血清转换与低HBsAg水平不活动载波的高速率。然而，无论是与HBsAg水平非活动性携带者超过100国际单位/毫升可从PEG-IFNα-2A治疗中获益尚需进一步研究。

StephenW

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