AASLD2012:核苷类似物治疗 + 额外PEG IFN改进HBsAg的消失

StephenW

额外PEG IFN在核苷类似物治疗慢性乙型肝炎患者改进HBsAg的消失
*TITLE: *Improvement of HBsAg Loss by additional PEG IFN in Nucleosides Analogs treated Chronic Hepatitis B Patients

*AUTHORS (FIRST NAME, LAST NAME): *Zhongwen Wu^1 , Jifang Sheng^1 , _Lanjuan Li_^1

*Institutional Author(s): *

*INSTITUTIONS (ALL): *1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases,the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

*ABSTRACT BODY: *Background and Aim: Suppression of HBV-viral load by nucleos(t)ide analogs(NAs) treatment reduces disease progression but requires indefinite treatment. Hepatitis B surface antigen (HBsAg) loss or seroconversion is a rare event after long term treatment of NAs. PEG- IFN could induce sustained immune response and lead a significant decline of serum HBsAg., Our study aimed to explore whether NAs treated patients who have achieved sustained virological response (SVR, defined as HBV-DNA < 1000 copies/ml) and obvious decrease of HBsAg level, add on the treatment of peg interferon alpha-2a for 48 weeks could achieve high HBsAg declination and even got HBsAg loss.
Methods: 32 chronic hepatitis B patients have received NAs for 1.5-4 years, 65% of the patients achieved HBeAg seroconversion. all patients with HBV-DNA < 103 copies/ml, obvious decrease of HBsAg level 100-500 IU/ml (using time-resolved immunofluorometric assay) were enrolled into the study and divided into two groups: GroupA with 16 patints (M/F: 14/2, median age 31years, 5 HBeAg positive,) received additional peg-interferon alpha 2a (180ug/w) for 48 weeks; other 16 patients (M/F: 13/3, median age 34 years , 6 HBeAg positive) in Group B continued the NAs therapy for 48 weeks. Median baseline HBsAg was 209.64 IU/ml in Group A and 193.18 IU/ml in Group B.
Results: In GroupA, eight out of 16 patients (50%) had a continuous HBsAg decline which lead to HBsAg loss (<0.5 IU/ml), HBsAg seroconversion was observed in five of them (31.3%) . Quantitative HBsAg highly decreased to below 10IU/ml in twelve patients (75%). Two out of 5 HBeAg positive patients had HBeAg seroconversion, 1 had HBeAg loss, In Group B , no significant HBsAg decline was observed at week 48, even fluctuated round to the baseline level, and none of six HBeAg patients in group B achieved HBeAg loss or seroconversion.
Conclusions In chronic hepatitis B patients, with SVR and obvious decrease of HBsAg level after NAs treatment add on a finite course of peg interferon alpha-2a treatment could significantly drop the HBsAg level (75%) , even lead to HBsAg loss /seroconversion (50%) . This appears to be a promising approach for further investigation.

StephenW

*作者（名字，姓）：*仲文，孙吉芳盛^ 1 ^ 1，_Lanjuan吴Li_ ^ 1

*机构（作者）：*

*机构（ALL）：* 1。国家重点实验室的感染性疾病的诊断和治疗系的传染病，附属第一医院，浙江大学医学院，杭州，中国。

背景和目的：抑制核苷（酸）类似物治疗（NAS），HBV病毒载量减少了疾病的进展，但需要无限期治疗。 B型肝炎表面抗原（HBsAg）的损失或血清学转换后长期治疗的NAS是一种罕见的事件。 PEG-IFN可诱导持续的免疫反应，导致一个显着的下降，血清HBsAg，我们的研究旨在探讨是否来港接受治疗的患者都取得了持续病毒学应答（SVR，定义为HBV-DNA <1000拷贝/毫升），并明显减少HBsAg水平，增加聚乙二醇干扰素α-2a治疗48周，可达到较高的乙肝表面抗原偏角，甚至HBsAg消失。
方法：对32例慢性乙型肝炎患者已收到NAS为1.5-4年，65％的患者达到HBeAg血清转换。所有患者的HBV-DNA <103拷贝/ ml，明显减少，HBsAg水平100-500 IU /毫升（时间分辨免疫荧光分析）纳入研究，分为两组：A组有16个药品血（M / F ：14/2，年龄中位数31年，5 HBeAg阳性），获得额外的聚乙二醇干扰素α-2a干扰素（180ug / W），共48周;其他16例（男/女：13/3，平均年龄34岁，HBeAg阳性），B组继续NAS治疗48周。基线HBsAg的中位数为209.64 IU /毫升组A和193.18 IU / ml的B组。
结果：A组，8个的16例患者（50％）有一个持续的HBsAg下降，导致HBsAg消失（<0.5 IU / ml）的5人（31.3％），乙肝表面抗原血清学转换，观察。 HBsAg定量高度下降到低于10IU/ml中12例（75％）。两个5 HBeAg阳性患者HBeAg血清学转换，1例HBeAg转阴，B组，观察48周时没有显着的乙肝表面抗原下降，甚至轮的基线水平波动，而在B组的6个大三阳患者没有实现HBeAg消失或血清学转换。
结论慢性乙肝患者，SVR明显减少，HBsAg水平来港定居治疗后在一个有限的聚乙二醇干扰素α-2a治疗过程中可能会显着下降的HBsAg水平（75％），甚至导致HBsAg消失/血清学转换（50 ％）。这似乎是一个很有前途的方法作进一步调查。

咬牙硬挺

先核苷再干扰能祛除表面抗原吗？使用干扰素不是要求肝功是正常两倍左右吗？又有新用法了看来

xiangsiwuyong

我迷糊了，到底是怎么弄，小白鼠再次心碎

StephenW

回复 咬牙硬挺 的帖子

是的，他们在临床试验一些新的概念基于:
1. 长期使用替诺福韦/恩替卡韦 ,可以抑制血清HBV DNA“检测不到”
2. 长期血清HBV DNA“检测不到”, 可以让“精疲力竭”的免疫系统恢复

3个新概念:
1. 停止替诺福韦/恩替卡韦，HBVDNA反弹，刺激免疫系统，也许这一次免疫系统能够清除病毒.
2. 继续替诺福韦/恩替卡韦， 但添加干扰素, 干扰素可降低血清HBsAg，可以调节免疫系统 -
帮助免疫系统清除病毒.
3. 长期使用替诺福韦/恩替卡韦 ,可以抑制血清HBV DNA“检测不到”, 也许，也可能导致减少的乙型肝炎表面抗原（HBsAg）/ cccDNA?

StephenW

*TITLE: *Adding peginterferon alfa-2a to entecavir increases HBsAg decline and HBeAg clearance - first results from a global randomized trial (ARES study)

*AUTHORS (FIRST NAME, LAST NAME): *_Milan J. Sonneveld_^1 , Qing Xie^2 , Ning-Ping Zhang^3 , Qin Zhang^4 , Fehmi Tabak^5 , Adrian Streinu-cercel^6 , Jiyao Wang^3 , Ramazan Idilman^7 , Annikki de Niet^8 , Mircea. Diculescu^9 , Anneke J. van Vuuren^1 , Elke Verhey^1 , Bettina E. Hansen^1, 10 , Harry L. Janssen^1

*Institutional Author(s): *

*INSTITUTIONS (ALL): *1. Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
2. Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China.
3. Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
4. Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China.
5. Infectious Diseases, Cerrahpasa Medical School, Istanbul, Turkey.
6. National Institute of Infectious Disease, Bucharest, Romania.
7. Gastroenterology and Hepatology, University of Ankara, Ankara, Turkey.
8. Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
9. Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania.
10. Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands.

*ABSTRACT BODY: Background.*Entecavir (ETV) is a potent inhibitor of viral replication in HBeAg-positive chronic hepatitis B (CHB) patients, but serological response is infrequently achieved and indefinite therapy should therefore be anticipated in the majority of patients. Addition of peginterferon (PEG-IFN) to ETV may increase serological response rates.
*Methods.*In this investigator-initiated randomized controlled trial 184 HBeAg-positive patients with compensated liver disease were enrolled at 15 sites in Europe and China and allocated to either ETV 0.5mg daily alone for 48 weeks or a 24 week addition of PEG-IFN alfa-2a 180 ug weekly after 24 weeks of ETV monotherapy. Response (HBeAg loss with HBV DNA <200 IU/mL) was assessed at week 48, and responders were allowed to discontinue treatment after 24 weeks consolidation treatment (week 72), with subsequent off-treatment follow-up until week 96. Results at week 48 are presented here.
*Results.*177 patients received at least one dose of allocated treatment, 93 ETV alone and 84 ETV with PEG-IFN add-on. Sixty-one percent of patients were of Asian ethnicity and all major HBV genotypes were present (A/B/C/D in 7/19/42/32%). A total of 160 patients had reached week 48 by June 2012, and the remaining patients will do so within 2 months. Patients were comparable with regard to important baseline characteristics, except for HBsAg which was higher in patients receiving combination therapy (4.28 versus 4.03 log IU/mL, p=0.05). Response, as well as HBeAg loss alone, was achieved in 18% of patients who received PEG-IFN add-on, compared to 8% of patients treated with ETV alone (p=0.07). PEG-IFN add-on resulted in more decline of HBV DNA (6.33 versus 5.91 log IU/mL, p=0.05), HBeAg (1.99 versus 1.56 log IU/mL, p=0.01) and HBsAg (0.84 versus 0.32 log IU/mL, p<0.001) at week 48. Only one patient (who received PEG-IFN add-on) had clearance of HBsAg at week 48. After adjustment for the differences in baseline HBsAg levels, addition of PEG- IFN was independently associated with response at week 48 (adjusted odds ratio: 3.63, 95% CI: 1.24 -- 10.7, p=0.01). Add-on PEG-IFN was well- tolerated and no relevant safety concerns were raised.
*Conclusion.*A 24 week add-on of PEG-IFN treatment increases HBsAg decline and clearance of HBeAg and may therefore improve the chances of finite treatment in HBeAg-positive CHB patients treated with ETV.

StephenW

*标题：*添加聚乙二醇干扰素α-2a，恩替卡韦增加HBsAg的下降和HBeAg清除 - 从一个全球性的随机对照试验（ARES研究的第一个成果）

香港（姓氏，名字）：* _Milan J. Sonneveld_ ^ 1，清，谢^ 2，宁平张^ 3张，秦^ 4，费赫米塔巴克^ 5，阿德里安Streinu cercel ^ 6，基尧王^拉玛赞·Idilman 3，^ 7，Annikki Niet ^ 8，米尔恰。 Diculescu ^ 9 ^ 1安内克J.面包车Vuuren，Verhey埃尔克^ 1 ^ 1贝蒂娜E.汉森，10日，哈里L ^ 1扬森

*机构（作者）：*

*机构（ALL）：* 1。 ，Erasmus医学中心胃肠病学和肝病学大学医学中心的鹿特丹，鹿特丹，荷兰。
2。感染性疾病，瑞金医院，上海交通大学，中国。
3。胃肠病学和肝病学杂志，中山医院，复旦大学，上海，中国。
4。胃肠病学和肝病学杂志，上海公共卫生中心，复旦大学，上海，中国。
5。感染性疾病，医学院Cerrahpasa，伊斯坦布尔，土耳其。
6。国家传染病研究所，布加勒斯特，罗马尼亚。
7。胃肠病学和肝病学杂志，安卡拉大学，安卡拉，土耳其。
8。胃肠病学和肝病学，学术医疗中心，阿姆斯特丹，荷兰。
9。胃肠病学研究所，布加勒斯特，罗马尼亚Fundeni Cinical。
10。公共卫生，荷兰，鹿特丹Erasmus MC大学医学中心的鹿特丹。

*抽象的身体：背景。HBeAg阳性慢性乙型肝炎（CHB）患者，恩替卡韦（ETV）是一种强效抑制病毒的复制，但很少实现，不确定的治疗，因此，预计在广大患者的血清学反应。添加聚乙二醇干扰素（PEG-IFN）ETV可能会增加血清学反应率。
*方法*在这研究者发起的随机对照试验184例HBeAg阳性患者代偿性肝脏疾病患者在欧洲和中国的15个站点和分配为ETV 0.5毫克，每天单是48周或24周加PEG- IFNα-2a干扰素ETV单药治疗24周后每周180微克。 48周时应答（HBeAg消失，HBV DNA <200 IU /毫升）进行了评估和响应者被允许停止治疗，巩固治疗后24周（第72周），随后后续的处理，直到96周。结果在第48周。
*结果177例患者接受至少一剂分配的治疗，93 ETV PEG-IFN单独和84 ETV附加。 61％的患者为亚洲人种，所有主要的HBV基因型（A / B / C / D 7/19/42/32％）。 2012年6月，共有160名患者已经达到48周，其余患者2个月内将这样做。患者与重要的基线特征方面，除了对HBsAg为高在接受联合治疗的患者（4.28比4.03日志IU / mL的电话号码= 0.05）。反应，以及作为单独HBeAg消失，18％的患者接受PEG-IFN添加，取得了8％，仅恩替卡韦治疗的患者（P = 0.07）。 PEG-IFN添加的上导致更多的HBV DNA下降（6.33比5.91日志IU / mL时，P = 0.05）（1.99与1.56日志IU / mL时，P = 0.01），乙型肝炎e抗原和乙肝表面抗原（0.84比0.32日志IU /毫升，P <0.001），在第48周。只有一个病人（PEG-IFN附加）在48周时乙肝表面抗原清除。调整后基线HBsAg水平的差异，此外，PEG-IFN独立与反应在第48周（调整后的比值比：3.63，95％CI：1.24  -  10.7，P = 0.01）。 PEG-IFN的耐受性良好，并没有相关的安全问题提出了。
*结论：A 24周对PEG-IFN治疗e抗原HBsAg的下降和清除增加，因此可能提高的机会有限恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者的治疗。