失代偿乙肝患者肝: 恩替卡韦 v 阿德福韦

StephenW

http://www.hivandhepatitis.com/hbv-treatment/approved-hbv-drugs/3102-entecavir-vs-adefovir-in-hepatitis-b-patients-with-liver-decompensation
Entecavir vs Adefovir in Hepatitis B Patients with Liver Decompensation
恩替卡韦与阿德福韦在乙型肝炎患者肝功能失代偿

Category: Approved HBV Drugs  
Published on Tuesday, 26 July 2011 00:00  Written by James Learned               
                                                                                                

HBV © Russell Kightley

                                       
               
               
In a head-to-head comparison, entecavir (Baraclude) demonstrated superior virological efficacy compared to adefovir (Hepsera) in hepatitis B patients with decompensated liver disease.
In the July 2011 issue of Hepatology, Yun-Fan Liaw and colleagues described a randomized, open-label Phase 3 study to assess the safety and efficacy of entecavir vs adefovir in people with chronic hepatitis B virus (HBV) infection and decompensated liver disease. Decompensation refers to the liver’s inability to function properly, usually due to severe scarring (advanced fibrosis or cirrhosis).
        In various studies, the 5-year survival rate for people with HBV and decompensated cirrhosis is significantly lower than rates reported for people with compensated cirrhosis (14%-35% vs 80%-86%). Interferon is generally considered to be contraindicated in people with decompensated liver disease due to the risk of serious adverse events, and most data on nucleoside/nucleotide analog therapy in patients with decompensation have come from non-comparative or uncontrolled studies of lamivudine (Epivir-HBV) and adefovir.
        Entecavir has been shown to have superior virological and biochemical benefits after 48 weeks of treatment compared to lamivudine or adefovir in nucleoside-naive patients, including people with advanced fibrosis or cirrhosis.
        A variety of factors led the researchers to conduct the present study: lamivudine’s high resistance rates, adefovir’s suboptimal potency and potential for kidney toxicity, international HBV guidelines that recommend beginning nucleoside/nucleotide treatment as soon as possible in patients with hepatic decompensation, and a lack of comparative studies looking at the safety and efficacy of entecavir in this population.
        In this head-to-head study participants with chronic hepatitis B and hepatic decompensationwere randomly assigned to receive 1.0 mg/day entecavir (n=100) or 10 mg/day adefovir (n=91), both taken orally once-daily. The adefovir dose was chosen because the trial included both lamivudine-experienced and nucleoside/nucleotide-naive participants. Although the study continued for up to 96 weeks, the Hepatology article reported efficacy during the study’s first 48 weeks, as well as cumulative safety.
        Safety analyses included cumulative rates of on-treatment adverse events, serious adverse events, discontinuations due to adverse events, death, hepatocellular carcinoma (HCC), renal impairment, and hepatic flares (large increases in liver enzymes).
        The primary efficacy endpoint was mean reduction in HBV DNA viral load at week 24. Secondary endpoints included mean change from baseline in HBV DNA at week 48; proportion of participants with HBV DNA < 300 copies/mL; alanine aminotransferase (ALT) normalization; improvement in total bilirubin, prothrombin time, albumin, and platelets; improvement in Model for End-Stage Liver Disease (MELD) scores; and improvement in Child-Turcotte-Pugh (CTP) status.
        Beginning in 2003, a total of 191 participants were recruited from 52 sites worldwide and followed for 96 weeks. All participants had hepatitis B with hepatic decompensation. Most (74%) were men, 54% were Asian, 33% were white, and 35% had evidence of lamivudine resistance. Participants had detectable hepatitis B surface antigen (HBsAg) for at least 6 months; 54% were hepatitis B "e" antigen (HBeAg) positive.
        At baseline, the mean HBV DNA level was 7.83 log copies/mL, ALT was at least 15 times the upper limit of normal (mean 99.6 times), serum creatinine was below 2.5 mg/dL, mean CTP score was 8.6, and they had no liver masses suggesting HCC. People coinfected with HIV, hepatitis C, hepatitis D, or other known liver diseases were excluded.
        Participants were nucleoside/nucleotide-naive, with the exception of some who had taken or were taking lamivudine; 35% had genotypic evidence of lamivudine resistance. Participants on lamivudine at the time of screening stopped taking it upon randomization to entecavir or adefovir.
        Results

• Participants taking entecavir had a greater decrease in HBV DNA than those taking adefovir at all time points through week 48.
• At weeks 24 and 48, more study participants on entecavir achieved HBV DNA < 300 copies/mL than those on adefovir (49% vs 16% and 57% vs 20%, respectively).
• At week 24, entecavir demonstrated superiority to adefovir in terms of decreased HBV DNA.
• 37 participants met the criteria for resistance testing at week 48 (5 on entecavir and 32 on adefovir), but none showed resistance to their assigned drug.
• The same number met the criteria for resistance testing beyond week 48:
  
  • 3 of 5 entecavir recipients had entecavir resistance detected at week 144 or beyond;
  • 6 of 27 adefovir recipientshad adefovir resistance beyond week 48 (2 between weeks 48 and 96, 2 between weeks 96 and 144, and 2 at or beyond week 144.
    
• The proportion of participants with ALT normalization was significantly higher in the entecavir group at weeks 24 and 48.
• HBeAg loss and seroconversion rates were higher among participants on adefovir at week 24, but became comparable to those on entecavir by week 48.
• 5 participants taking entecavir showed HBsAg loss by week 48, compared with no participants taking adefovir.
• Both treatment groups had improved MELD and CTP scores at week 48:
  
  • the mean change from baseline in MELD scores at week 48 was -2.6 for the entecavir group and -1.7 for the adefovir group;
  • the difference was at least partly due to the difference in baseline MELD scores, which were higher in the entecavir group;
  • about two-thirds of participants in each group had either an improvement or stabilization of CTP scores;
  • about one-third of participants in each group had a reduction of at least 2 points in their CTP score and/or improvement in CTP class.
    
• Through week 48 both groups experienced improvement in liver function as measured by changes in total bilirubin, prothrombin time, albumin, and platelets; degree of improvement was comparable across both groups.
• Frequencies of adverse events, serious adverse events, and grade 3 or 4 adverse events were comparable between the 2 treatment groups:
  
  • the most frequently reported serious adverse events were liver failure or complications of decompensated cirrhosis, as expected in this population;
  • 10 entecavir-treated patients (11%) and 1 adefovir-treated patient (1%) required dose reductions due to changes in kidney function while on treatment;
  • 7 entecavir-treated patients (7%) and 5 adefovir-treated patient (6%) discontinued treatment because of adverse events;
  • ALT flares were not observed in any participants during the first 48 weeks of the study, but 3 participants experienced flares after week 48.
    
• The cumulative rates of HCC were 12% (12 of 102) in the entecavir arm and 20% (18 of 89) in the adefovir arm.
• The mean time to development of HCC did not differ between the 2 groups, however.
• 8 of 12 entecavir recipients (67%) and 4 of 18 adefovir recipients (22%) diagnosed with HCC had HBV DNA < 300 copies/mL at the time of their diagnosis.
• Of the 57 deaths reported at the time of this analysis, 52 occurred in treated participants (23% on entecavir and 33% on adefovir; the other 5 deaths occurred prior to randomization).
• Most deaths were the result of liver failure.
  

        “The present study differs from other recently reported clinical trials conducted in this population in that the study enrolled patients with more severe liver disease,” the authors wrote. “The results from this week 48 analysis demonstrated that entecavir and adefovir are effective, safe, and well tolerated in this population.”
        “Although the virologic superiority of entecavir over adefovir did not translate into a comparable hepatic improvement, this observation might be related to the baseline severity of disease in this study population and the time required to reverse severe fibrosis once it is established.
        In conclusion, the researchers wrote, “[T]he current study demonstrates that entecavir is superior to adefovir in suppressing HBV DNA and achieving ALT normalization through week 48.”
        Initial data from this study were presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in 2009 and in October 2010 led to U.S. Food and Drug Administration (FDA) approval of entecavir for the treatment of chronic hepatitis B patients with decompensated liver disease, a particularly hard-to-treat population.
        Investigator affiliations:
        Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Second Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India; Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; China Medical University Hospital, Taichung, Taiwan; Liver Unit, University of Calgary, Calgary, Alberta, Canada; Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY; Miami Veterans Affairs Medical Center, Miami, FL; John A. Burns School of Medicine, University of Hawaii, Honolulu, HI; Department of Infectious Diseases, Medical University, Lodz, Poland; Research and Development, Bristol-Myers Squibb Co., Wallingford, CT.
        7/26/11
        References
        Y Liaw, M Raptopoulou-Gigi, H Cheinquer, et al. Efficacy and Safety of Entecavir Versus Adefovir in Chronic Hepatitis B Patients With Hepatic Decompensation: A Randomized, Open-Label Study. Hepatology 54(1):91-100 (abstract). July 2011.
        Y Liaw, M Raptopoulou-Gigi, H Cheinquer, et al. Efficacy and Safety of Entecavir Versus Adefovir in Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. October 30-November 1, 2009. Abstract 422.

        

StephenW

谷歌翻译是不是100％，仅作为参考使用。

恩替卡韦（博路定）在头比较，表现出卓越的病毒学疗效相比，B型肝炎与失代偿性肝病患者的阿德福韦（Hepsera）。

在2011年7月肝病问题，廖运范和他的同事描述了一个随机，开放标签第3阶段研究，以评估恩替卡韦与阿德福韦酯的安全性和疗效与慢性乙型肝炎病毒（HBV）感染和失代偿性肝病的人。代偿是指肝脏无法正常工作，通常是由于严重的疤痕（先进的肝纤维化或肝硬化）。

在各项研究中，对乙肝和肝硬化失代偿期的人的5年生存率明显高于代偿期肝硬化的人（14％-35％和80％-86％）率较低。干扰素是由于严重不良事件，并在模拟治疗失代偿患者的核苷/核苷酸大多数数据的风险与失代偿性肝脏疾病的人通常被认为是禁忌的，来自非比较或不受控制的研究拉米夫定（Epivir - HBV ）和阿德福韦。

已经显示出恩替卡韦治疗48周后，在核苷初治患者，其中包括先进的肝纤维化或肝硬化的人，拉米夫定或阿德福韦相比有优越的病毒学和生物化学效益。

各种因素，研究人员以进行本研究：拉米夫定的高电阻率，阿德福韦的最理想的效力和潜在的肾毒性，国际乙肝病毒的指引，建议开始与肝功能失代偿患者核苷/核苷酸治疗为尽快尽可能，并缺乏在这一人群中，恩替卡韦的安全性和疗效的比较研究。


在此与慢性B型肝炎和肝功能失代偿头的研究参与者被随机分配接受恩替卡韦为1.0毫克/天（N = 100）或10毫克/天阿德福韦（N= 91），内服，每日一次。阿德福韦剂量的选择，因为试验包括拉米夫定经验和核苷/核苷酸天真的参与者。虽然持续长达96周的研究，肝病文章在研究的第48周的疗效，以及累积安全。

安全分析，包括累计治疗的不良事件，严重不良事件，因不良反应事件，死亡，肝细胞癌（HCC），肾功能不全，肝耀斑（肝酶大量增加）停药率。

主要疗效终点是24周时的HBV DNA病毒载量平均减少。次要终点包括平均48周的HBV DNA与HBV - DNA的参与者的比例从基线的变化<300拷贝/毫升，谷丙转氨酶（ALT）正常化;总胆红素，凝血酶原时间，白蛋白，及血小板的改善;在模型的改进终末期肝病患者（MELD）评分和改善儿童特科特- Pugh分级（CTP）的状态。

从2003年开始，共191人参加，来自全球52网站招聘和随访96周。所有参加者有B型肝炎，肝功能失代偿。大多数（74％）为男性，54％是亚洲人，33％是白人，35％，拉米夫定耐药的证据。与会者至少6个月检测到乙肝表面抗原（HBsAg），54％是乙肝“e”的抗原（HBeAg）阳性。

基线时，平均HBV DNA水平为7.83日志拷贝/毫升，谷丙转氨酶是至少15倍正常上限（平均99.6倍），血清肌酐低于2.5毫克/升，平均CTP评分为8.6，和他们无肝群众建议肝癌。与艾滋病毒，丙型肝炎，丁型肝炎，或其他已知的肝脏疾病合并感染的人被排除在外。

与会者核苷/核苷酸天真，有些人已采取或服用拉米夫定的除外; 35％拉米夫定耐药基因型的证据。放映时间拉米夫定与会者在停止服用后，随机对恩替卡韦或阿德福韦。

结果

.服用恩替卡韦的参与者比那些在所有时间点，通过48周的阿德福韦的HBV - DNA的更大的跌幅。
.在24周和48周，对恩替卡韦的研究参与者达到HBV - DNA <300拷贝比阿德福韦（49％对16％和57％对20％，分   别）/毫升。
.24周时，恩替卡韦展示优势阿德福韦降低乙肝病毒DNA。
.37与会者会见电阻测试的标准，在48周（5恩替卡韦和阿德福韦32），但没有抵抗分配给他们的药物。
相同数量的满足电阻超过48周的测试标准：
       . 5恩替卡韦受助3恩替卡韦的阻力在144周或以后发现;
       . 27阿德福韦recipientshad超过48周（2个星期之间48和96，2 96周和144周之间，和2个达到或超过144本周的阿德福韦耐药6。
.ALT正常化的参与者的比例显着高于恩替卡韦组在24周和48周。
.HBeAg消失和血清转换率较高，在24周的阿德福韦参与者，但与那些对恩替卡韦48周。
.5参与者服用恩替卡韦表明HBsAg消失，48周相比，没有参与者服用阿德福韦。
    两个治疗组的改善，48周时的MELD和CTP的分数：
        在48周时的MELD评分分数从基线的平均变化的恩替卡韦组和阿德福韦组-1.7 -2.6;
        差异至少部分是由于MELD评分，在恩替卡韦组在基线的差异;
        约三分之二的人参加各组的改善或稳定的CTP评分;
        约三分之一参加各组的CTP评分和/或改进的CTP类减少了至少2分。
.通过48周的两组测量总胆红素，凝血酶原时间，白蛋白，及血小板，改善肝功能的改善程度在两组相媲美。
    不良事件，严重不良事件，3或4级不良事件的频率分别为2个治疗组之间的比较：
        最常报告的严重不良反应肝功能衰竭或肝硬化失代偿期的并发症，如预期般在这个人口;
        10恩替卡韦治疗的患者（11％）和1阿德福韦治疗的患者（1％）由于肾功能的变化，而对治疗所需的剂量减少;
        7恩替卡韦治疗的患者（7％）和5阿德福韦治疗的患者（6％）因不良事件中止治疗;
        ALT突增，没有观察到任何参与者在第48周的研究，但3参与者经历了48周后的耀斑。
.HCC的累积率分别为12％（12 102）在恩替卡韦组20％（89 18）阿德福韦手臂。
.肝癌发展的平均时间没有差异，但两组之间。
.恩替卡韦收件人8 12（67％）和4 18阿德福韦与肝癌诊断的受助人（22％）在诊断时HBV DNA <300拷贝/ ml。
.在这一分析的时间报道的57人死亡，52起发生在治疗的参与者（23％恩替卡韦和阿德福韦的33％，其他5人死亡，之前发生的，以随机）。
.大多数死亡是导致肝功能衰竭。

“目前的研究不同，在这个人口在该研究纳入了更严重的肝脏疾病患者进行临床试验等最近报道，”作者写道。 “这48周的分析结果表明，恩替卡韦和阿德福韦有效，安全，并在这一人群中的耐受性良好。”

“虽然恩替卡韦对阿德福韦病毒学优势并没有转化成可比的肝功能改善，这个观察可能在本研究人群中的基线疾病的严重程度和扭转严重纤维化，一旦成立所需的时间。

总之，研究人员写道，“[T]的他目前的研究表明，恩替卡韦优于阿德福韦抑制HBV DNA和实现通过48周的ALT正常化。”

在第60届美国肝病（美国肝病学会）在2009年和2010年10月研究协会的年度会议上提出这项研究的初步数据，导致美国食品和药物管理局（FDA）批准恩替卡韦治疗慢性乙型肝炎B组患者失代偿性肝病，特别难以治疗的人群。

调查背景：

肝研究组，长庚医院，长庚大学医学院，台北，台湾内科二部，萨洛尼卡，希腊塞萨洛尼基亚里士多德大学;联邦大学，南里奥格兰德州，巴西的阿雷格里港;部消化科，GB潘特医院，新德里，印度; Siriraj医院内科部，玛希隆大学，曼谷，泰国;雅丽氏何妙龄那打素医院，香港，中国，台湾中国医药大学附设医院，台中，肝脏单位，卡尔加里大学，阿尔伯塔省卡尔加里，加拿大，纽约州，纽约哥伦比亚大学医学中心肝脏疾病和移植中心，迈阿密退伍军人事务医疗中心，佛罗里达州迈阿密，夏威夷大学医学院的约翰A ·伯恩斯，檀香山，喜;部传染病，波兰罗兹医科大学，研究和开发，施贵宝公司，沃灵，CT。