[AASLD 2012]全球性随机临床试验(ARES研究)初步结果

2012-11-27 医脉通 医脉通

       恩替卡韦 (ETV) 是病毒复制的一种强效抑制剂,但是仅少数HBeAg阳性的慢性乙型肝炎 (CHB) 患者可以获得血清学应答,因此绝大多数患者需要长期治疗。ETV加用聚乙二醇干扰素 (PEG-IFN)治疗可以增加血清学应答率。        美国肝病研究学会(AASLD)第63届年会上,公布了全

       恩替卡韦 (ETV) 是病毒复制的一种强效抑制剂,但是仅少数HBeAg阳性的慢性乙型肝炎 (CHB) 患者可以获得血清学应答,因此绝大多数患者需要长期治疗。ETV加用聚乙二醇干扰素 (PEG-IFN)治疗可以增加血清学应答率。

       美国肝病研究学会(AASLD)第63届年会上,公布了全球性随机临床试验(ARES研究)初步结果。这项随机对照临床试验囊括了欧洲和中国的15个研究中心共纳入了184 例HBeAg 阳性代偿性肝病患者,并分配至ETV单药治疗48周,0.5 mg/d患者组或ETV单药治疗24 周后再联合PEG-IFN α-2a 180 ug/w治疗24周患者组。48周时评估治疗应答(HBeAg 消失伴HBV DNA < 200 IU/mL)获得应答的患者经过24周的巩固治疗后(72周)停药,并随访至96 周。目前展示的是治疗48周时的结果。

       该研究中共177例患者接受了治疗,93例接受ETV单药治疗,84例接受ETV加用PEG-IFN治疗。亚洲族裔的患者占61%,HBV基因型A/B/C/D的比例分别为7 /19 42/32%。到2012年6月,共计160例患者治疗已达48 周,其余患者2个月内也会完成。除HBsAg外,患者在基线时的一些重要的指标具有可比性。接受联合治疗的患者HBsAg水平较高(4.28 对4.03 log IU/mL,P = 0.05)。加用PEG-IFN患者组的应答率以及HBeAg消失率合为18%,而ETV单药治疗的患者组为8% (P = 0.07)。治疗48时加用PEG-IFN患者组HBV DNA (6.33对5.91 log IU/mL,P = 0.05),HBeAg (1.99对1.56 log IU/mL,P = 0.01) 和HBsAg (与 0.32 0.84 登录 IU/mL,P < 0.001)的水平下降更为显著。48周时仅一例患者(加用PEG-IFN治疗)获得了HBsAg的清除。校准基线时HBsAg水平后,加用PEG-IFN是治疗48周获得应答的独立相关因素(校准后的优势比:3.63,95 %CI: 1.24-10.7, P = 0.01)。加用PEG-IFN的耐受性好,且相关的副反应也并未增加。

       研究发现,24周时加用PEG-IFN可促进HBsAg的下降和 HBeAg的清除,并因此有可能增加HBeAg阳性的CHB患者服用ETV获得有限治疗疗程的几率。

研究背景:

       ARES研究,即"Augmenting Response to Entecavir With Peginterferon a-2a for the Treatment of HBeAg-positive Chronic Hepatitis B"研究,研究注册号
NCT00877760,该研究的目的是调查,通过使用暂时加用PEG-IFN策略,是否能增加HBeAg阳性的CHB患者的反应。

研究论文摘要:

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

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.
 

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