Long-Term Efficacy of Entecavir[long]

StephenW

http://www.hivandhepatitis.com/hepatitis-b/hepatitis-b-topics/hbv-treatment/3172-long-term-efficacy-of-entecavir-in-people-with-hbv
Long-Term Efficacy of Entecavir for People with Hepatitis B                                  Category: HBV Treatment  Published on Wednesday, 17 August 2011 00:00                                Written by James Learned               
                                                                                                

HBV © Russell Kightley

Long-term entecavir (Baraclude) monotherapy leads to a virological response in a large majority of nucleoside/nucleotide analog-naive patients, even those who still have detectable HBV DNA at 48 weeks.
In the August 2011 issue ofHepatology, Roeland Zoutendijk and colleagues with the VIRGIL Surveillance Study Group described the results of an analysis investigating the efficacy of entecavir for 1 year or more in nucleoside/nucleoside analog-naive and -experienced patients with chronic hepatitis B virus (HBV) infection.
The researchers explored baseline factors associated with partial virological response to entecavir in previously untreated patients and whether achieving a partial response during early treatment compromised long-term entecavir success.
In Phase 3 trials of lamivudine (Epivir-HBV) vs entecavir, entecavir has shown superior biochemical, virological, and histological efficacy. Genotypic resistance to entecavir is rare even after 5 years of treatment. But entecavir’s efficacy is seriously compromised in patients for whom lamivudine is no longer effective and whose HBV has extensive entecavir resistance mutations.
Current European hepatitis B treatment guidelines suggest a change in regimen for h patients who still have detectable viral load at week 48 -- whatever their previous treatment. But as the authors of the present study point out, evidence to support this recommendation is scare and based on data from studies using weaker nucleoside/nucleotide analogs.
This cohort study within the European Network for Vigilance against Viral Resistance (VIRGIL) included all adults with chronic hepatitis B treated with entecavir monotherapy between 2003 and 2010 at 10 large European centers.
Eligibility criteria included having an HBV DNA viral load of at least 2000 IU/ mL when starting entecavir and having taken entecavir monotherapy for at least 3 months. People with coinfections (HIV, hepatitis C virus, The analysis included 333 patients, although 20 (6%) were lost to follow-up. Of the 333 participants initially included, 75% were men, the median age was 43 years, and 43% were hepatitis B "e" antigen (HBeAg) positive; 48% were Caucasian, 28% were Asian, and the remaining 24% were classified as "other." HBV genotype was determined at start of entecavir therapy. The majority of the cohort had HBV genotype D (48%), followed by genotype A (21%), genotype C (14%), genotype B (9%), and other genotypes (7%).
Most participants (73%) were nucleoside/nucleotide analog-naive at baseline. Among the remainder, 22% had taken lamivudine previously, 11% had a history of lamivudine resistance, and 4% had lamivudine resistance at baseline. In addition, 15% of the cohort had taken adefovir (Hepsera) previously, 4% had a history of adefovir resistance, and 4% had adefovir resistance at baseline.
All participants took entecavir monotherapy for at least 3 months. They were seen every 3 months to test for alanine aminotransferase (ALT) levels, bilirubin, albumin, HBA DNA, HBeAg, and HBeAg antibodies.
Genotypic analysis was conducted at baseline for all nucleoside/nucleotide analog-experienced patients, in cases of virological breakthrough (an increase in HBV DNA > 1 log above nadir or lowest level at least twice following initial virological response), and in cases with HBV DNA > 200 IU/mL at the end of follow-up. For treatment-experienced patients, retrospective genotypic resistance was also assessed in stored serum samples obtained at the end of all previous nucleoside/nucleotide analog treatment regimens. If entecavir-resistant mutations were detected during follow-up, retrospective baseline genotypic analysis was performed for nucleoside/nucleotide analog-naive patients.
The primary outcome was virological response (HBV DNA < 80 IU/ml) during the on-treatment follow-up period. Secondary endpoints were HBeAg loss and seroconversion (in HBeAg positive participants), hepatitis B surface antigen (HBsAg) loss and seroconversion, emergence of entecavir-related mutations, and normalized ALT levels.
Results

• total of 243 nucleoside/nucleoside analog-naive participants were treated with entecavir monotherapy for a median of 19 months.
  
  
  • For HBeAg positive naive participants, the cumulative probabilities of achieving virological response were 48% at 48 weeks, 76% at 96 weeks, and 90% at 144 weeks.
  • HBeAg loss rates were 10%, 21%, and 34%, respectively.
  • Rates for HBeAg seroconversion were 8%, 16%, and 24%, respectively.
  • For HBeAg negative participants, the cumulative probabilities of achieving virological response were higher: 89% at 48 weeks, 98% at 96 weeks, and 99% at 144 weeks.
    
    
• Partial virological response at week 48 occurred in 36 (21%) of 175 nucleoside/nucleotide analog-naive participants who had at least 48 weeks of follow-up.
  
  
  • HBeAg positivity and having high HBV DNA at baseline were the only independent risk factors for partial virological response.
  • Of the 36 participants with partial virological response at 48 weeks, 29 (81%) went on to achieve complete virological response beyond 48 weeks of treatment.
  • 10 participants required more than 96 weeks of entecavir monotherapy to achieve complete virological response.
  • Participants who achieved complete virological response had lower HBV DNA at week 48 than those who did not respond with continued entecavir monotherapy.
  • A continuing decrease in HBV DNA was seen in 6 of 7 patients who had not achieved complete virological response at the end of follow-up.
    
    
• Of the nucleoside/nucleotide analog-experienced patients, 72 (80%) had previously taken lamivudine and 51 (57%) had taken adefovir; 12 had a history of adefovir resistance.
  
  
  • When adjusted for baseline HBV DNA and HBeAg status, response to entecavir was not influenced by prior adefovir treatment or adefovir resistance.
  • However, the presence of lamivudine resistance mutations at baseline and previous history of lamivudine resistance were significantly associated with a reduced probability of achieving virological response to entecavir.
    
    
• Adverse events during prolonged entecavir treatment included dizziness, headache, and loss of appetite in 3 participants.
• No participants developed clinically evident lactic acidosis and none had an increase in serum creatinine.
  
  

The researchers wrote, “The current multicenter study showed that [entecavir] is effective up to 3 years in [nucleoside/nucleotide analog-naive] patients, irrespective of having a virological response at week 48."
"The vast majority of [nucleoside/nucleotide analog-naive] patients with a [partial virological response] achieved undetectable HBV DNA through prolonged therapy without treatment adaptation," they continued. "Genotypic resistance to [entecavir] was not detected in any of the patients with a [partial virological response] at week 48.”
The study showed that continuing entecavir treatment appears to be safe and effective for patients with detectable HBV DNA at week 48, especially those with a lower viral load at that time, 95% of whom went on to achieved full virological response.
The researchers concluded, "[I]n contrast to what is suggested in recently published European Association for the Study of the Liver guidelines on the management of chronic hepatitis B, adjustment of [entecavir] monotherapy in [nucleoside/nucleotide analog-naive] patients with a [partial virological response] at week 48 is not necessary.”
They added that data from studies investigating drugs (like lamivudine) with a low barrier to resistance cannot be translated to more potent drugs such as entecavir and tenofovir.
Investigator affiliations: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Hepatology and Gastroenterology, Imperial College London, London, United Kingdom; Department of Hepatology, Hotel Dieu Hospital Lyon, Lyon, France; Department of Hepatology and Gastroenterology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; Liver Unit, IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany; 8Department of Hepatology, Hospital Vall de Hebron, Barcelona, Spain; Clinic of Infectious Diseases, University of Foggia, Foggia, Italy; Klinik und Poliklinik fur Gastroenterologie und Rheumatologie, Leipzig, Germany; and Department for Internal Medicine, University Medical Center, Hamburg-Eppendorf, Germany.
Supported by the Foundation for Liver and Gastrointestinal Research Rotterdam, the European Network of Excellence for Vigilance against Viral Resistance, and a research grant from Bristol-Myers Squibb.
8/16/11
Reference
R Zoutendijk, JGP Reijnders, A Brown, et al for the VIRGIL Surveillance Study Group. Entecavir Treatment for Chronic Hepatitis B: Adaptation Is Not Needed for the Majority of Naive Patients with a Partial Virological Response. Hepatology 54(2):443-451 (abstract). August 2011.

StephenW

谷歌翻译是不是100％正确，仅供参考使用。

长期恩替卡韦（博路定）单药治疗，导致在大部分的核苷/核苷酸类似物初治患者的病毒学应答，即使是那些仍然有48周检测HBV - DNA。

在2011年8月，Roeland Zoutendijk肝脏和维吉尔监测研究小组的同事的问题描述1年以上的慢性乙肝病毒核苷/核苷模拟天真和经验的患者，恩替卡韦的疗效分析结果调查（HBV）感染。

研究人员探索与恩替卡韦，部分病毒学应答，在以前未经治疗的患者，是否在损害长期恩替卡韦成功实现早期治疗，局部反应相关的基线因素。

在第3阶段试验中，恩替卡韦拉米夫定（Epivir - HBV）和恩替卡韦已经显示出卓越的生化，病毒学，和组织学疗效。恩替卡韦基因型耐药是罕见的，即使经过5年的治疗。但是，恩替卡韦的疗效是严重受损的患者，对他们来说，拉米夫定不再有效，其乙肝病毒具有广泛的恩替卡韦耐药突变。

欧洲目前的乙肝治疗指南提出一个方案仍然有48周时检测病毒载量为h患者在变化 - 不论他们以前的治疗。但作为本研究指出的作者，证据来支持这一建议是恐慌和基于使用较弱的核苷/核苷酸类似物的研究数据。

这在欧洲对病毒的抗性（维吉尔）警惕网络的队列研究包括2003年和2010年间在欧洲10个大型中心与恩替卡韦单药治疗治疗慢性乙型肝炎乙所有的成年人。

的资格准则，包括HBV - DNA病毒载量至少2000国际单位/毫升时，恩替卡韦和恩替卡韦单药治疗至少3个月。混合感染（感染艾滋病毒，丙型肝炎病毒，丁型肝炎病毒）和那些已做肝脏移植手术前开始替卡韦的人被排除在研究之外。

分析包括333例患者，20（6％）虽然失去了后续。最初包括333名学员中，75％为男性，年龄中位数为43岁，43％是B型肝炎的“e”抗原（HBeAg）阳性，48％为白人，28％是亚洲，其余24％列为“。” HBV基因型测定恩替卡韦治疗的开始。大多数人群HBV基因型D（48％），由基因型（21％），C基因型（14％），B型（9％），其他基因型（7％）。

大多数参与者（73％），核苷/核苷酸在基线模拟天真。其中，其余的22％，拉米夫定以前，11％的拉米夫定耐药的历史，和4％，在基线拉米夫定耐药。此外，15％的人群采取了阿德福韦（Hepsera）以前，4％的阿德福韦耐药的历史，和4％，在基线阿德福韦耐药。

所有参加了至少3个月的恩替卡韦单药治疗。他们看到，每3个月，谷丙转氨酶（ALT）水平，胆红素，白蛋白，HBA的DNA，HBeAg的，和e抗原抗体测试。

所有核苷/核苷酸类似物的患者在基线进行基因型分析，在病毒学突破的情况下（增加的HBV DNA> 1日志或以上的最低点至少两次的最低水平以下初始病毒学应答），并在与乙肝病毒DNA的情况下> 200 IU / mL的后续结束。对于治疗的患者，回顾性的基因型耐药还评估了所有先前的核苷/核苷酸类似物治疗方案最终获得的存储血清样本。如果恩替卡韦耐药突变检测随访期间，追溯基线基因型分析核苷/核苷酸类似物初治患者。

主要成果是病毒学应答（HBV - DNA <80 IU / ml）的在上的后续治疗期间。次要终点是HBeAg消失和血清转换（HBeAg阳性参与者），乙肝表面抗原（HBsAg）的损失和血清学转换，出现恩替卡韦相关的基因突变，并归ALT水平。

结果

     共243核苷/核苷类似物初治的参与者与恩替卡韦单药治疗中位数为19个月的治疗。
        对于HBeAg阳性的幼稚的参与者，实现病毒学应答的累积概率分别为48％， 在 48周，96周的76％，和90％在144周。
        HBeAg转阴率分别为10％，21％和34％。
        HBeAg血清转换率分别为8％，16％和24％，分别。
        对于HBeAg阴性的参与者，实现病毒学应答的累积概率：89％在48周，96周的98％，99％在144周。
    36（21％）175核苷/核苷酸类似物幼稚的参与者，他们有至少48周的后续部分发生在48周时的病毒学应答。
        在基线HBeAg阳性和HBV - DNA高，只对部分病毒学应答的独立危险因素。
        部分病毒学应答的36个48周，29（81％）的参与者，实现超过48个星期的治疗完全病毒学应答。
        10名学员所需的恩替卡韦单药治疗超过96周，以实现完整的病毒学应答。
        与会者取得了圆满的病毒学应答降低乙肝病毒DNA比那些没有回应，继续替卡韦单药治疗48周。
        一个持续下降的HBV DNA被认为没有达到完全病毒学应答的患者在随访结束6 7。
    核苷/核苷酸类似物的患者中，72（80％）此前采取的拉米夫定和51（57％）采取了阿德福韦; 12阿德福韦耐药的历史。
        基线HBV DNA和HBeAg状态调整时，恩替卡韦不前阿德福韦治疗或阿德福韦耐药的影响。
        但是，在基线和以前的历史拉米夫定耐药拉米夫定耐药突变的存在与减少的概率达到病毒学应答恩替卡韦的显着相关。
    长时间的恩替卡韦治疗期间不良事件包括头晕，头痛，食欲不振，3人参加。
    没有开发的参与者临床上明显的乳酸性酸中毒，并没有血肌酐增加。

研究人员写道，“目前的多中心临床研究显示，恩替卡韦]核苷/核苷酸类似物天真]的患者，48周时有一个的病毒学应答，不论是有效的，长达3年。”

“[核苷/核苷酸类似物天真] [部分病毒学应答]通过检测不到乙肝病毒DNA未经治疗的适应长期治疗的患者绝大多数，他们继续。” “基因型耐药[恩替卡韦]中没有检测到任何一个部分病毒学应答的患者在48周。”

研究表明，持续出现恩替卡韦治疗48周时检测到HBV DNA的患者，尤其是那些与当时的病毒载量较低的安全和有效的，其中95％实现了全面的病毒学应答。

研究人员得出结论，“[我] n的对比什么是欧洲肝脏慢性乙型肝炎管理指引，[恩替卡韦单药治疗的调整[核苷/核苷酸类似物，天真患者的研究协会最近公布的建议[部分病毒学应答] 48周时没有必要。“

他们补充说，从调查一个门槛低电阻的药物（如拉米夫定）的研究数据不能被转换为更有效的药物，如恩替卡韦和替诺福韦。

贵妃醉酒

Is hepatitis B virus genotype C independently associated with cirrhosis?

Hepatitis B virus (HBV) genotypes have distinct geographical distributions,
and have been shown to differ with regard to clinical outcome and prognosis.
However, the relationship between HBV genotypes and liver cirrhosis remains
controversial and no study on exploring the association between HBV genotypes
and subclinical cirrhosis in community-based population has been reported.
A research article to be published on January 21, 2010 in the World Journal of
Gastroenterology addresses this question. The research team led by Prof. Cao
from Department of Epidemiology, Second Military Medical University performed
a large epidemiological study with 10 167 community-based residents at the age
between 6 and 72 years in Eastern China. After excluding the subjects
co-infected with hepatitis C or hepatitis D viruses, the hepatitis B surface
antigen (HBsAg)-positive subjects were examined for HBV genotype, serum viral
load, alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg) status,
and ultrasonographic changes. Logistic regression models were used to
determine the factors independently associated with probable cirrhosis.
Of 634 HBsAg-positive subjects with HBV genotyped, 82 had probable cirrhosis.
Probable cirrhosis was only found in the HBeAg-negative subjects, and more
frequent in the subjects with genotype C than in those with genotype B. In
HBeAg-negative subjects, high viral load was frequently associated with
abnormal ALT level, while ALT abnormality was more frequent in those with
probable cirrhosis than those without. Ultrasonographic fatty liver was not
found in the subjects with probable cirrhosis. HBV genotype C, age (≥ 45
years), male sex, and ALT abnormality were demonstrated to be major risk
factors of probable cirrhosis for the residents chronically infected with HBV.
Clinical relevance and public health importance of HBV genotypes are different
in a given population. HBV genotype B and C are major HBV genotypes endemic in
East Asia. HBV genotype B is associated with acute hepatitis and tends to be
self-limiting and shorter lived. However, genotype C is associated with longer
duration of liver damage in the HBeAg-negative subjects, which may be the main
reason for liver cirrhosis. Genotype C HBV-infected male residents at the age
of 45 years or older should be routinely examined for active hepatitis and
early cirrhosis. Early intervention to the HBV-infected subjects with high
risks of cirrhosis might be effective for decreasing overall mortality of
liver cirrhosis.