Tenofovir and Entecavir Are Safe and Effective in Hepatitis B Patients with Deco

StephenW

http://www.hivandhepatitis.com/hep_b/news/2011/0118_2010_a.html

Tenofovir  and Entecavir Are Safe and Effective in Hepatitis B Patients with Decompensated Cirrhosis

		SUMMARY:  The nucleotide analog tenofovir   (Viread) and the nucleoside analog entecavir   (Baraclude) were both well-tolerated and produced  good hepatitis B virus (HBV) suppression in patients  with decompensated liver disease, with little evidence  of kidney problems, according to an international study published in the January 2011 issue of Hepatology. Adding emtricitabine (Emtriva) to tenofovir increased the likelihood of achieving undetectable viral load and HBeAg loss.

                                       
By Liz Highleyman
  
Over years or decades, chronic hepatitis B can lead to decompensated  liver disease, characterized by symptoms such as ascites  (abdominal fluid accumulation), portal vein hypertension, and hepatic encephalopathy.
People with advanced liver disease are considered difficult to treat, but this population has an urgent need for effective  therapy to control viral replication and slow further progression  of liver damage. A growing body of research has looked at  antiviral therapy for patients with end-stage liver disease.

Yun-Fan Liaw from Chang Gung Memorial Hospital in Taiwan and colleagues
conducted a study to compare the safety and tolerability of tenofovir, tenofovir plus emtricitabine (the 2 drugs  in the Truvada  coformulation approved for HIV treatment), and entecavir.
This Phase 2 study included 112 chronic hepatitis B patients  with decompensated liver disease. At baseline the median  Child-Turcotte-Pugh (CTP) score was 7 and median MELD scores    ranged from 10.5 to 13.0. Most participants (84%) were men, the median age was 52 years, just over half were Asian,and 65% were initially hepatitis B "e" antigen (HBeAg) negative. About one-third had creatinine clearance suggesting impaired kidney function at baseline; advanced  liver disease is a risk factor for kidney dysfunction and tenofovir can cause kidney problems in at-risk individuals.
Participants were randomly allocated (2:2:1) to the 3 treatment arms. None had previously used the study drugs; entecavir recipients who previously used or were resistant to lamivudine  (Epivir-HBV) took a higher dose. The investigators primarily looked at safety, in particular "tolerability failure"  -- adverse events that resulted in permanent treatment discontinuation -- and markers of kidney function.
They  also assessed response based on HBV viral load suppression, ALT liver enzyme normalization, and HBeAg loss and seroconversion.  Patients with insufficient viral suppression (> 400 copies/mL) at weeks 8 or 24 or later could begin open-label tenofovir/emtricitabine, but were considered "failures"        for the 48-week efficacy analysis.
Results

	Tolerability  failure was infrequent and statistically similar in all study arms: 6.7% with tenofovir monotherapy, 4.4% with tenofovir/emtricitabine, and 9.1% with entecavir.
	Overall,  8 patients taking tenofovir, 3 taking tenofovir/emtricitabine, and 3 taking entecavir discontinued their assigned study  drug prior to week 48; 10 switched to open-label tenofovir/emtricitabine.
	Protocol-defined  kidney impairment was also uncommon, occurring in 8.9%,  6.7%, and 4.5%, respectively -- not a significant difference.
	Most   participants across all study arms reported adverse events, but adverse event profiles and laboratory abnormalities were consistent with advanced liver disease, with no  unexpected safety signals.
	6 patients died (no deaths considered related to study drugs) and 6 received liver transplants with no HBV recurrence.
	At week 48, similar proportions of patients taking tenofovir (70.5%) and entecavir (72.7%) had HBV DNA < 400 copies/mL, rising to 87.8% in the tenofovir/emtricitabine combination arm.
	These proportions rose to 76.7%, 87.8%, and 85.7%, respectively, when participants who switched to open-label tenofovir/emtricitabine  were included.
	Similarly, 57% taking tenofovir and 55% taking entecavir had normal  ALT, rising to 76% in the combination arm.
	21% of tenofovir recipients and 27% of tenofovir/emtricitabine  recipients experienced HBeAg loss, compared with none of the entecavir recipients.
	Corresponding rates of HBeAg seroconversion were 21%, 13%, and 0%,  respectively.
	CTP and MELD scores improved in all treatment arms.
	No participants developed resistance to any study drug.

Based on these findings, the authors wrote, "All treatments  were well tolerated in patients with decompensated liver  disease due to chronic hepatitis B with improvement in virologic, biochemical, and clinical parameters."
"Although  the study was not designed to detect differences in efficacy among the 3 treatment regimens, standard chronic hepatitis B efficacy assessments (e.g., viral suppression, normalization  of ALT, HBeAg/HBsAg loss, and seroconversion) were generally  improved at 48 weeks in the majority of patients in each treatment group, as were measures of severity of liver disease  and dysfunction (CTP and MELD scores)," they elaborated  in their discussion. "As anticipated, each treatment  arm produced reductions in serum HBV DNA and normalization of ALT levels consistent with results obtained in chronic  hepatitis B patients without decompensation."
"The percentages of patients with confirmed changes in serum creatinine and/or serum phosphorus were not significantly different among patients who received [tenofovir] compared to [entecavir], suggesting similar renal [kidney] safety,"  they added.
"In summary, both [tenofovir]-containing regimens were well tolerated in these decompensated chronic hepatitis B patients, with no significant differences compared to [entecavir]  with respect to tolerability failures or confirmed changes in renal parameters," the researchers concluded. "These  data demonstrate the safety of these treatments through 48 weeks in patients with decompensated chronic hepatitis B and evident therapeutic benefit in all groups."
Investigator affiliations: Liver Research Unit, Chang Gung Memorial Hospital,Chang Gung University College of Medicine, Taipei, Taiwan;  Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Ege Universitesi Tip Fakultesi  Hastanesi, Izmir, Turkey; Ippokration General Hospital of   Athens, Athens, Greece; Toronto General Hospital, Toronto,Ontario, Canada; National Chen Kun University Hospital, Tainan, Taiwan; Hospital of Infectious Diseases, Warsaw,  Poland; Virginia Mason Medical Center, Seattle, WA; Gordon and Leslie Diamond Centre, Vancouver, BC, Canada; Hospital General Universitari Vall d'Hebron, Barcelona, Spain; Hospital  La Fe, Valencia, Spain; Charite Campus Virchow-Klinikum,  Berlin, Germany; Gilead Sciences, Durham, NC; University      of Miami School of Medicine, Miami, FL.
1/18/11
Reference
Y-F Liaw, I-S Sheen, C-Mo Lee, and others. Tenofovir  disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir  in patients with decompensated chronic hepatitis B liver disease. Hepatology 53(1): 62-72 (Abstract).  January 2011.



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StephenW

替诺福韦和恩替卡韦是安全和有效的乙型肝炎失代偿期肝硬化患者


摘要：核苷酸类似物泰诺福韦（VIREAD的）和核苷类似物恩替卡韦（博路定）均良好的耐受性，产生了良好的乙型肝炎病毒（HBV）的抑制与失代偿期肝病患者，肾脏问题的证据有限，根据一项国际在2011年1月发表的研究报告的肝脏问题。添加恩曲他滨（Emtriva），以实现泰诺福韦增加了不到病毒载量和HBeAg的损失的可能性。




由Liz Highleyman

过去几年或几十年，慢性乙肝可导致失代偿性肝病，特点的症状，如腹水（腹部积水），门静脉高压症，肝性脑病。

拥有先进的肝脏疾病的人被认为是难以治疗，但是这个人口已经成为迫切需要有效的治疗，以控制病毒复制和肝脏损害进一步缓慢的进展。越来越多的研究机构有看的终末期肝病患者的抗病毒治疗。

廖运范从长庚医院在台湾和他的同事
进行了一项研究，比较安全和替诺福韦，替诺福韦和emtricitabine耐受性（在Truvada coformulation 2艾滋病毒治疗药物的批准），和恩替卡韦。

这个第2期研究包括112慢性肝炎失代偿期肝病乙肝患者。在儿童中位数基准，特科特- Pugh分级（CTP）的得分为7，中位数由10.5 MELD分数不等13.0。大多数与会者（84％）为男性，平均年龄为52岁，刚刚超过一半是亚洲人，65％最初乙型肝炎“e”的抗原（HBeAg）阴性。约三分之一已在基线肌酐清除提示肾脏功能受损，先进的肝脏疾病是肾功能不全和替诺福韦可导致危险的个人肾脏疾病的风险因素。

受试者被随机分配（2:2:1）的3治疗组。没有以前使用的药物研究;收件人谁以前使用恩替卡韦或拉米夫定有抗药性（拉米乙肝）占较高的剂量。研究者主要看安全，特别是“耐受性的失败” - 不良事件导致永久性停药 - 和肾功能指标。

他们也评估的基础上的反应抑制乙肝病毒载量，肝酶ALT键正常化和HBeAg血清转换损失和。不足的患者病毒抑制（“400拷贝/毫升）或24或8周后可以开始开放标签替诺福韦/恩曲他滨，但被认为是”失败“的48个星期的疗效分析。

结果
耐受性故障不常见，在所有类似的统计研究武器：6.7％的替诺福韦单药治疗，4.4％和替诺福韦/恩曲他滨，恩替卡韦和9.1％。
总体而言，8例服用泰诺福韦，3注意到替诺福韦/恩曲他滨，服用恩替卡韦和3分配给他们的研究药物终止前48周，10转开放标签替诺福韦/恩曲他滨。
协议定义的肾损害也屡见不鲜，8.9％，6.7％和4.5％，分别发生 - 没有显着差异。
在所有研究的大部分武器报告的不良事件的参与者，但不良事件概况和实验室异常符合晚期肝癌病不出意外的安全信号。
6例死亡（无死亡病例，研究审议了有关毒品）和6收到无HBV复发肝移植手术。
48周时，患者服用泰诺福韦（70.5％）和恩替卡韦（72.7％）的比例有类似乙肝病毒DNA的<400拷贝/毫升，上升至87.8％的替诺福韦/恩曲他滨联合治疗组。
这些比重上升到76.7％，87.8％和85.7％，分别切换到谁当参与者开放标签替诺福韦/恩曲他滨都包括在内。
同样，57％服用替诺福韦和55％服用恩替卡韦有ALT正常，联合组上升到76％。
21％的受助人及27泰诺福韦替诺福韦/恩曲他滨受助％发生HBeAg转阴，恩替卡韦与受助人的事。
HBeAg血清转换率分别为21％，13％和0％，分别为。
CTP和MELD评分改善，所有的治疗武器。
没有参加任何研究开发的抗药物。

基于这些发现，作者写道：“所有的治疗耐受性良好的失代偿期肝病患者，由于在病毒学，生化，临床指标改善慢性乙型肝炎患者。”

“尽管这项研究并不是用来检测的3种治疗方法的疗效差异，慢性乙型肝炎疗效标准评估（例如，抑制病毒，血清ALT，e抗原/ HBsAg转阴正常化，血清转化），一般在48周改善，在各治疗组患者大多数，都是肝脏疾病和功能障碍（CTP和MELD分数）的严重性措施，“他们阐述他们的讨论。 “正如预期的，每个治疗组血清HBV DNA的生产减少的ALT水平与慢性乙型肝炎患者没有得到代偿的结果一致，规范化。”

“与血清肌酐和/或血清磷证实改变了患者的患者比例分别为没有谁收到[泰诺福韦]相比，[恩替卡韦]，说明类似的肾[肾脏]安全显着不同，”他们补充道。

“总之，无论是[泰诺福韦]含方案的耐受性良好，这些失代偿期慢性乙型肝炎患者相比，耐受性方面的失败[恩替卡韦]或证实肾参数的变化无显着差异，”研究人员得出结论。 “这些数据表明在慢性乙肝失代偿期和明显的各组患者的治疗效果，通过这些治疗48周的安全。”

调查背景：肝研究单位，长庚医院，长庚大学医学院，台湾台北，内科，长庚纪念医院，高雄医学中心，长庚大学医学院，高雄，台系;爱琴Universitesi提示Fakultesi Hastanesi，伊兹密尔，土耳其; Ippokration雅典，雅典，希腊总医院，多伦多总医院，多伦多，安大略省，加拿大，国立大学医院陈坤，台南，台湾，传染病医院，华沙，波兰;弗吉尼亚梅森医学中心，华盛顿州西雅图，戈登和莱斯利钻石中心，温哥华，不列颠哥伦比亚省，加拿大;医院总务Universitari瓦尔德希伯伦，巴塞罗那，西班牙;医院拉铁，巴伦西亚，西班牙; Charite校园菲尔绍- Klinikum，柏林，德国; Gilead Sciences公司，达勒姆，数控;的医学，迈阿密，佛罗里达州迈阿密学院大学。

1/18/11

参考
Y型F廖，我- S的光泽，ç钼李等。富马酸泰诺福韦disoproxil（教师发展论坛），恩曲他滨/华盈，和恩替卡韦与失代偿期慢性乙型肝炎患者的肝脏疾病。肝胆病53（1）：62-72（摘要）。 2011年1月。