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肝胆相照论坛 论坛 学术讨论& HBV English [AASLD 2012]长效干扰素可让慢乙肝患者实现安全停药 ...
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[AASLD 2012]长效干扰素可让慢乙肝患者实现安全停药 [复制链接]

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发表于 2012-12-7 13:58 |只看该作者 |倒序浏览 |打印
本帖最后由 cwy121 于 2012-12-7 13:59 编辑

慢性乙肝患者在服用口服抗病毒药物的基础上,加(换)用长效干扰素治疗,可使乙肝的表面抗原消失,达到临床治愈的目的。

       近日,首都医科大学附属北京佑安医院陈新月教授在2012年第63届美国肝病研究学会 (AASLD) 年会期间向与会媒体解读了这一研究成果。该研究(即SWITCH研究,是国际上首个针对口服抗病毒患者加 (换) 用长效干扰素的多中心临床研究 )结果显示,口服抗病毒药物治疗疗效较好的慢性乙肝患者 (病毒复制水平低,e抗原水平低的患者), 在原有治疗的基础上加 (换) 用长效干扰素,在48周的有限疗程内,10%的患者出现表面抗原消失,实现临床治愈,而继续使用口服抗病毒药物的患者没有一例达到这一目标。原先使用口服抗病毒药物治疗过程中e抗原消失且表面抗原水平低的患者疗效更好,加 (换) 用长效干扰素后达到表面抗原清除的几率更高,可达19%。


  在现实生活中,有不少慢性乙肝患者觉得长期服药是一个很大的困扰,因此迫切渴望能够停药。根据一项调查结果显示,超过90%的慢性乙肝患者希望能够安全停药,即停药后不复发;而63%的患者更是希望1-2年内能够实现这一目标。


  为更好的满足慢性乙肝患者的以上需求,陈新月教授强调,随着医学的进步以及临床上医生的抗病毒治疗实践经验的积累,通过改变治疗策略帮助部分患者尽早安全停药是可以实现的。慢性乙肝患者如何改变治疗策略,具体要采用何种治疗,陈新月教授建议可以从以下三个步骤来考虑。


明确慢性乙肝的治疗目标


  2012年最新欧洲肝病学会《慢性乙型肝炎病毒感染诊治指南》(以下简称《指南》)明确指出,慢性乙肝的治疗目标分为3个阶段。最基本的治疗目标是通过药物有效抑制病毒复制;其次是满意的治疗终点,实现e抗原血清学转换 (即血清指标从“大三阳”转为“小三阳”) ;最后是理想的治疗终点,实现表面抗原清除或同时表面抗体产生 (即达到临床治愈)。


  目前采用的慢性乙肝治疗药物主要有两大类,分别是口服抗病毒药物和干扰素类药物。口服抗病毒药物主要是通过抑制乙肝病毒DNA复制而降低病毒量。而干扰素,如聚乙二醇干扰素,一方面可以降低病毒水平,另一方面具有免疫调节作用,针对发病的机制,激发机体的免疫能力,经过有限疗程的治疗以后,机体能够在停药后仍然获得持久的免疫控制,实现停药后不复发。


  陈新月教授表示,对比两种药物的不同效果,长效干扰素和口服抗病毒类药物都可以实现抑制病毒复制,即达到最基本的治疗目标。但在达到满意的治疗终点上,长效干扰素实现e抗原血清学转换的比例要高于口服抗病毒药物。SWITCH研究显示,“大三阳”患者加 (换) 用长效干扰素实现e抗原血清学转换的机会比口服抗病毒药物患者增加了一倍。因此长效干扰素在维持停药后的持久疗效方面更有优势。而口服抗病毒药物一旦停药,病毒便会继续复制,复发的风险超过50%,部分患者还会面临耐药问题。在达到理想的治疗终点上,目前,只有干扰素,特别是长效干扰素能实现这一目标。此次SWITCH研究充分证实,长效干扰素在满意和理想的治疗终点上优于口服抗病毒药。


  2012年更新的欧洲《指南》明确推荐: 对于“大三阳”乙肝患者,实现 e抗原血清学转换的最佳治疗方案是接受长效干扰素治疗;而对于“小三阳”患者,实现有限疗程治疗停药后持久应答也推荐选择长效干扰素的治疗。


评估自身治疗方式的疗效


  陈新月教授表示,通常接受口服抗病毒药物治疗的患者处在治疗目标的最基本阶段,即实现了病毒抑制。作为一名乙肝患者,必须对乙肝治疗中具有风向标价值的e抗原、表面抗原两个抗原有所认识,并及时监测表面抗原定量水平的变化。


  在达到最基本的治疗目标以后,对e抗原阳性的患者而言,要争取实现e抗原的血清学转换,即从“大三阳”转成“小三阳”,这标志着疾病进入免疫控制期,处在免疫控制期的患者表面抗原水平相对较低,患者长期处于免疫控制期,可以降低肝硬化和肝癌的发生,提高长期生存率,同时也有利于实现表面抗原的清除,增加慢性乙肝临床治愈的机会。


  目前大多数患者认为慢性乙肝需要终身服药,或者对自己所能达到的治疗效果认识不清,从而错失了获得更好疗效甚至达到临床治愈的机会。陈新月教授鼓励患者在实现最基本的抗病毒治疗后,应该与医生积极沟通自己的状态,并尝试新的治疗方式,以争取更好的疗效。


调整治疗策略 实现更好的治疗目标


  为协助慢性乙肝患者改变策略达到最优的治疗目标,尽早实现安全停药,陈新月教授建议:在慢性乙肝治疗的开始阶段,如果条件允许,就应该优选长效干扰素治疗,以实现停药后持久免疫控制。由于聚乙二醇干扰素在免疫控制上更具优势,获得e抗原血清学转换即可停药,不用担心长期服药的困扰。


  而对于已用口服抗病毒药物的患者,特别是治疗后病毒已经阴转,e抗原、表面抗原水平已经降至较低的患者,更应该积极抓住加 (换) 用长效干扰素治疗的有利时机,积极调整治疗策略,抑制病毒同时调节机体免疫力,进而帮助患者达到停药后持久的e抗原血清学转换,降低停药后的复发率,同时有望达到表面抗原转阴。


  对于有些患者顾虑加用或换用长效干扰素是否会降低原本口服抗病毒药物所达到的疗效,以致前功尽弃,陈新月教授认为,加 (换) 用长效干扰素可以帮助慢性乙肝患者的疗效更上层楼,而不是降低原有的疗效,这点患者毋需顾虑。


  对此,中国工程院院士庄辉教授也建议,在慢性乙肝的治疗中,应根据患者的具体情况,明确治疗目标,建立正确的治疗策略,尽早取得更好的治疗效果。

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发表于 2012-12-7 22:43 |只看该作者
这是个好消息。

 而对于已用口服抗病毒药物的患者,特别是治疗后病毒已经阴转,e抗原、表面抗原水平已经降至较低的患者,更应该积极抓住加 (换) 用长效干扰素治疗的有利时机,积极调整治疗策略,抑制病毒同时调节机体免疫力,进而帮助患者达到停药后持久的e抗原血清学转换,降低停药后的复发率,同时有望达到表面抗原转阴。

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发表于 2012-12-7 22:49 |只看该作者
再看了一遍,大三阳,抗病毒取得阶段性成果(DNA阴,e抗原/表面抗原水平低)的时候,加用长效干扰素,得金牌概率高;

小三阳(dna阳,前C区变异病毒),抗病毒使dna阴后,加用长效干扰素,有安全停药的可能性。

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发表于 2012-12-8 00:02 |只看该作者
楼上摘要的很好,不过国内的研究受商业驱动很大

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才高八斗

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发表于 2012-12-8 09:49 |只看该作者
本帖最后由 StephenW 于 2012-12-8 09:52 编辑

这位教授引用一个临床研究(见下文),但他没有提供一个解释. 另一个临床(全球
ARES研究, 尚未完成) 注意HBsAg水平.

[tr][/tr]
CONTROL ID: 1414997


PRESENTATION TYPE: Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: New treatment strategy: switching from long-term entecavir to peginterferon alfa-2a induces HBeAg seroconversion/HBsAg clearance in patients with HBeAg-positive chronic hepatitis B
AUTHORS (FIRST NAME, LAST NAME): Qin Ning1, Meifang Han1, Yongtao Sun2, Jia-ji Jiang3, Deming  Tan4, Jinlin Hou5, Hong Tang6, Jifang  Sheng7, Mianzhi Zhao8
Institutional Author(s): Ning
INSTITUTIONS (ALL): 1. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Tangdu Hospital, the Fourth Military Medical University, Xi'an, China.
3. The First Hospital, Fujian Medical University, Fuzhou, China.
4. Xiangya Hospital, Central South University, Changsha, China.
5. Nanfang Hospital, Nanfang Medical University, Guangzhou, China.
6. West China Hospital, Sichuan University, Chengdu, China.
7. The First hospital, Zhejiang University, Hangzhou, China.
8. Shanghai Roche Pharmaceutical Co., Ltd, Shanghai , China.
ABSTRACT BODY: Study purpose: Nucleos(t)ide analog therapy in chronic hepatitis B patients can result in maintained HBV DNA suppression, but most patients (>50%) do not achieve a durable off-treatment response and therefore  potentially require life-long therapy. The study objective was to determine whether patients with maintained HBV DNA suppression on entecavir (ETV) can achieve HBeAg seroconversion/HBsAg clearance by switching to peginterferon alfa-2a (Peg-IFNα-2a).
Methods: This was a multicenter, randomized, open-label study in HBeAg(+) patients. Patients receiving ETV (0.5 mg QD) for 9–36 months, with HBV DNA <103 copies/mL + HBeAg <100 PEIU/mL, either switched to Peg-IFNα-2a (180 µg for 48 weeks) or continued ETV for a further 48 weeks. There was an 8-week overlap in the Peg-IFNα-2a arm. The primary endpoint was HBeAg seroconversion at end of treatment (week 48). Secondary endpoints included HBsAg clearance and HBV DNA <1000 copies/mL. Adverse events (AEs) were recorded.
Results: The mean age was 33 years in both arms. Mean HBV DNA, ALT, HBeAg and HBsAg levels at baseline were low and similar between arms. Mean duration of ETV treatment prior to switching to Peg-IFNα-2a was comparable between arms (20 months). HBeAg seroconversion and HBsAg clearance rates at week 48 were significantly higher with Peg-IFNα-2a than with ETV (table). HBeAg loss + HBsAg <3000 IU/mL at baseline resulted in 19% of patients achieving HBsAg clearance. On-treatment HBsAg decline from baseline to week 48 was significantly greater with Peg-IFNα-2a than ETV (–0.81 vs –0.06 log10 IU/mL; p<0.05). Some patients relapsed (HBV DNA ≥1000 copies/mL) when switched to Peg-IFNα-2a (23 patients, 24%), but median ALT levels were similar or lower in patients with relapse than those without. AEs and serious AEs were higher with Peg-IFNα-2a than ETV (AEs 69% vs 5%; serious AEs 6% vs 0%), but only 7% of Peg-IFNα-2a-treated patients discontinued therapy. AEs in patients switched to Peg-IFNα-2a were similar to treatment-naïve patients from previous studies.
Conclusion: Patients with maintained virologic response on ETV who switch to a finite course of Peg-IFNα-2a achieve significantly higher rates of HBeAg seroconversion/HBsAg clearance than continuing on ETV. HBeAg loss + HBsAg <3000 IU/mL at baseline resulted in a high rate of HBsAg clearance (19%).

Response, n (%)

Peg-IFNα-2a
N=97

ETV
N=100

p-value

HBeAg seroconversion

15 (15.5)

6 (6.0)

<0.05

HBeAg loss

63 (65.0)

59 (59.0)

>0.05

HBsAg loss

10 (10.3)

0

<0.05

HBsAg seroconversion

4 (4.1)

0

<0.05

HBV DNA <1000 copies/mL

62 (63.9)

90 (90.0)

<0.05



(No Image Selected)

Co-Author Disclosure Status
The following authors have completed their AASLD 2012 disclosure:
Qin Ning: Disclosure completed
Meifang Han: Disclosure completed
Yongtao Sun: Disclosure completed
Jia-ji Jiang: Disclosure completed
Deming  Tan: No Answer.
Jinlin Hou: Disclosure completed
Hong Tang: Disclosure completed
Jifang  Sheng: No Answer.
Mianzhi Zhao: Disclosure completed





[/table][table]









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才高八斗

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发表于 2012-12-8 09:58 |只看该作者
本帖最后由 StephenW 于 2012-12-8 10:07 编辑

[tr][/tr]
CONTROL ID: 1421510


PRESENTATION TYPE: Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
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. Sonneveld1, Qing Xie2, Ning-Ping Zhang3, Qin Zhang4, Fehmi Tabak5, Adrian Streinu-cercel6, Jiyao Wang3, Ramazan  Idilman7, Annikki de Niet8, Mircea. Diculescu9, Anneke J. van Vuuren1, Elke Verhey1, Bettina E. Hansen1, 10, Harry L. Janssen1
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.


(No Table Selected)
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Co-Author Disclosure Status
The following authors have completed their AASLD 2012 disclosure:
Milan  Sonneveld: Disclosure completed
Qing Xie: Disclosure completed
Ning-Ping Zhang: Disclosure completed
Qin Zhang: Disclosure completed
Fehmi Tabak: Disclosure completed
Adrian Streinu-cercel: Disclosure completed
Jiyao Wang: Disclosure completed
Ramazan  Idilman: Disclosure completed
Annikki de Niet: Disclosure completed
Mircea. Diculescu: Disclosure completed
Anneke van Vuuren: Disclosure completed
Elke Verhey: Disclosure completed
Bettina Hansen: Disclosure completed
Harry Janssen: Disclosure completed





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才高八斗

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发表于 2012-12-8 10:16 |只看该作者
最有意思的这个研究: PEG-INF减少肝内乙肝表面抗原的表达.

[tr][/tr]
CONTROL ID: 1422397


PRESENTATION TYPE: Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: Peginterferon Reduces Intrahepatic HBsAg and is Associated with Histologic Response in Chronic Hepatitis B
AUTHORS (FIRST NAME, LAST NAME): Pauline Arends1, Vincent Rijckborst1, Milan  J. Sonneveld1, Bettina E. Hansen1, 2, Harry L. Janssen1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Dept. of Gastroenterology & Hepatology, Erasmus MC, Rotterdam, Netherlands.
2. Dept. of Public Health, Erasmus MC, Rotterdam, Netherlands.
ABSTRACT BODY: Background. To date, there is limited knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B virus surface antigen (HBsAg) in chronic hepatitis B (CHB), and how it correlates with serum HBsAg and histological response in the terms of necroinflammation and fibrosis scores.
Methods. Fifty-two HBeAg positive CHB patients with paired liver biopsies taken at baseline and after 52 weeks of PEG-IFN therapy and 67 HBeAg negative CHB patients with paired liver biopsies taken at baseline and 24 weeks after 48 weeks of PEG-IFN therapy were studied. Necroinflammation and fibrosis were scored according to the Ishak scoring system. The degree of intrahepatic HBsAg expression was ranked on a scale of 0 to 5.
Results. Mean necroinflammatory score at baseline was 5.5 (± 2.2) and did not differ between HBeAg positive and -negative patients. Mean fibrosis score was 2.2 (± 1.4) and was comparable for HBeAg positive and -negative patients. Baseline degree of intrahepatic HBsAg did not differ between HBeAg positive and –negative patients and was not associated with necroinflammatory or fibrosis scores, nor with serum HBsAg.
After PEG-IFN the degree of intrahepatic HBsAg significantly reduced in HBeAg negative patients (p<0.001), and a trend was seen in HBeAg positive patients
(p=0.088). Patients with a decline in intrahepatic HBsAg had significantly more serum HBsAg decline at the end of follow-up (0.9 vs. 0.4IU/mL, p=0.031).
A reduction in necroinflammation (decrease ≥ 2 points) after PEG-IFN treatment was observed in 47% of HBeAg positive patients (P=0.002 compared with baseline) and in 52% of HBeAg negative patients (p<0.001 compared with baseline). Decline in intrahepatic HBsAg and a decrease in necroinflammation appeared to be associated (Spearman’s ρ0.159, p=0.096).
Improvement of fibrosis (decrease ≥ 1 point) after PEG-IFN therapy was found in 21% of HBeAg positive and 30% of HBeAg negative patients. However, a significant change in fibrosis score was only observed in HBeAg positive patients (p=0.050). There tended to be a correlation between a decline in intrahepatic HBsAg and fibrosis (Spearman’s ρ0.174, p=0.070).
Conclusion. PEG-IFN reduces expression of intrahepatic HBsAg as well as necroinflammation in both HBeAg positive and negative CHB. Decline in fibrosis was only found in HBeAg positive patients. Decline of HBsAg expression in hepatocytes after PEG-IFN was associated with a decline in serum HBsAg and showed a trend toward significance with decline in necroinflammation and fibrosis scores.


(No Table Selected)
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Co-Author Disclosure Status
The following authors have completed their AASLD 2012 disclosure:
Pauline Arends: Disclosure completed
Vincent Rijckborst: Disclosure completed
Milan  Sonneveld: Disclosure completed
Bettina Hansen: Disclosure completed
Harry Janssen: Disclosure completed





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发表于 2012-12-8 21:37 |只看该作者
一般接受核苷治疗的患者,多数转氨酶已经正常.之前的结论认为,在转氨酶正常的情况下使用干扰素,效果不好,因此骆抗先骆老不主张已经接受核苷治疗的患者再换干扰素.
病友交流,仅供参考.

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发表于 2012-12-9 10:14 |只看该作者
9病成医 发表于 2012-12-8 21:37
一般接受核苷治疗的患者,多数转氨酶已经正常.之前的结论认为,在转氨酶正常的情况下使用干扰素,效果不好,因 ...

治疗不能光看转氨酶
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我是忠肝义胆MP4。忠肝义胆-战友的天地
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发表于 2012-12-10 21:54 |只看该作者
本帖最后由 法海老禅师 于 2012-12-10 21:55 编辑

对大三阳的战友来说是个好消息。

结果显示,口服抗病毒药物治疗疗效较好的慢性乙肝患者 (病毒复制水平低,e抗原水平低的患者), 在原有治疗的基础上加 (换) 用长效干扰素,在48周的有限疗程内,10%的患者出现表面抗原消失,实现临床治愈,而继续使用口服抗病毒药物的患者没有一例达到这一目标。原先使用口服抗病毒药物治疗过程中e抗原消失且表面抗原水平低的患者疗效更好,加 (换) 用长效干扰素后达到表面抗原清除的几率更高,可达19%。
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