DDW 2003：替诺福韦和恩替卡韦有效地抑制乙肝病毒

StephenW

DDW 2003: Tenofovir and Entecavir Effectively Suppress Hepatitis B Virus

   
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    Category: HBV Treatment   
    Published on Thursday, 06 June 2013 00:00
    Written by Liz Highleyman



The newer antivirals tenofovir (Viread) and entecavir (Baraclude) inhibit hepatitis B virus (HBV) replication more effectively than older agents, but good adherence is needed to maintain long-term viral suppression, according to a set of studies presented at the Digestive Disease Week meeting (DDW 2013) last month in Orlando.

A range of nucleoside/nucleotide analogs are active against HBV, but the virus can develop drug resistance that compromises long-term efficacy. Tenofovir disoproxil fumarate and entecavir have a higher barrier to resistance than the older lamivudine (Epivir-HBV) and adefovir (Hepsera).
Clinical Practice

Mindie Nguyen from Stanford University and colleagues evaluated the effectiveness of tenofovir and entecavir in routine clinical use, comparing this to efficacy seen in pivotal trials that supported the drugs' approval. Participants in clinical trials often do better because they are highly motivated, may be selected for favorable response characteristic, and are closely monitored and supported around adherence and side effect management.

This analysis included 845 treatment-naive patients undergoing treatment at 3 U.S. liver clinics between January 2001 and January 2011. Two-thirds were men, almost all were Asian, the mean age was 47, and 63% were hepatitis B "e" antigen (HBeAg) negative. A total of 93 received lamivudine, 198 took adefovir, 447 took entecavir, and 107 received tenofovir.

After 12 months of treatment, rates of complete viral suppression were significantly higher for people taking entecavir (75%) or tenofovir (81%) compared with lamivudine (39%) or adefovir (54%); response to entecavir and tenofovir was statistically similar. Patients in the entecavir and lamivudine groups had similar median ALT and mean HBV DNA levels. Virologic breakthrough was less common with entecavir (2.5%) than with tenofovir (8.6%), and in all cases was attributed to poor adherence.

"Treatment outcomes were clearly favorable with newer agents ([entecavir] and [tenofovir]) compared to old agents ([lamivudine] and [adefovir])," the researchers concluded.

"Antiviral therapy with either [entecavir] or [tenofovir] is highly effective in suppressing HBV viral replication, and non-adherence is the primary cause of treatment failure," they added. "Further patient education and close clinical monitoring by care providers are needed to improve patient adherence to anti-HBV therapy, which is long-term or even life-long in the majority of cases."
Long-term Entecavir

Watcharasak Chotiyaputta from Mahidol University in Bangkokevaluatedthe safety, effectiveness, and antiviral resistance among nucleoside/nucleotide-naive patients receiving entecavir monotherapy in clinical practice in Thailand.

This chart review included records from 535 chronic hepatitis B patients treated with entecavir for at least 1 year. About 60% were men, the mean age was 52 years, 65% were HBeAg negative, and 37% had liver cirrhosis.

Over an average 40 months of follow-up, more than 90% of both HBeAg positive and negative patients reached undetectable HBV viral load by year 5. No cases of viral breakthrough occurred and no drug resistance mutations were detected. HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss were uncommon, however, at 11% and 2%, respectively. There were no serious adverse events and serum creatinine levels (a potential indicator of kidney toxicity) remained unchanged.

Among 337 patients without cirrhosis at baseline, 20 (6%) developed cirrhosis according to imaging tests during follow-up, but none experienced clinical decompensation. Among 198 patients with cirrhosis at study entry, 5 (3%) developed clinical decompensation. Further, 12 patients (2%) developed hepatocellular carcinoma over 5 years.

"[Entecavir] was safe and effectively suppressed hepatitis B virus without virological breakthrough throughout 5 years of treatment," the investigators concluded.
Entecavir vs Tenofovir

Linyi Gao, also with the Stanford group, and colleagues compared the efficacy of entecavir and tenofovir in chronic hepatitis B patients with high HBV viral load at baseline, a group at risk for liver disease progression.

This retrospective case-control study included 62 consecutive treatment-naive participants at 3 U.S. medical centers with baseline HBV DNA >1,000,000 IU/mL who started treatment with tenofovir. They were matched with 199 control subjects treated with entecavir. About 60% were men, the average age was about 42 years, about one-third were HBeAg negative, and 8% had cirrhosis.

Among HBeAg negative participants, there was no significant difference in rates of viral suppression between tenofovir and entecavir recipients. Among HBeAg positive patients, however, those taking tenofovir achieved viral suppression significantly faster than those taking entecavir. Viral suppression rates in the tenofovir arm were 16% at 6 months, 50% at 12 months, and 71% at 18 months, compared with 11%, 31%, and 39%, respectively, in the entecavir arm.

"[Tenofovir] is significantly more effective than [entecavir] for achieving complete viral suppression in HBeAg positive, treatment-naive hepatitis B patients with HBV DNA >1,000,000 IU/mL," the researchers concluded. "Moreover, the difference between [tenofovir] and [entecavir] becomes more and more pronounced with increasing treatment time."
Tenofovir Kidney Function

While tenofovir is highly effective against HBV,it has the potential to cause kidney toxicity in susceptible individuals; to date this has mostly been studied in people with HIV (tenofovir is effective against both viruses).

Nghi Ha form the University of California at San Francisco and colleagues looked at changes in renal function among treatment-naive chronic hepatitis B patients who at baseline had either normal kidney function, defined as estimated glomerular filtration rate (eGFR) > 80 mL/minute, or mildly impaired function, defined as 50-80 mL/minute.

This case-control study included 72 participants who received 300 mg once-daily tenofovir disoproxil fumarate and 72 patients matched for age, sex, and baseline eGFR who instead used 1 mg once-daily entecavir. Two-thirds were men, the mean age was 45 years, and 86% had unimpaired kidney function.

The researchers saw no significant difference in kidney function changes between patients exposed to tenofovir and those taking entecavir. The likelihood of worsening function was similar in both groups, and rates of reclassification to a category of worse function were 12.9 and 12.5 cases per 100 person-years, respectively. In a multivariate analysis that included demographic characteristics, baseline eGFR, diabetes, and hypertension, tenofovir use was not significantly associated with renal dysfunction. Older age and impaired function at baseline were significant predictors for worsening function over time.

"Renal function of HBV patients on antiviral therapy with either [tenofovir] or [entecavir] should be monitored, especially in those who are older and/or with known impaired renal function," they recommended.

6/6/13

References

L Gao, HN Trinh, J Li, et al. Tenofovir Is More Effective Than Entecavir for Achieving Rapid Viral Suppression in HBeAg-Positive Chronic Hepatitis B Patients With High HBV DNA Levels. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1009.

W Chotiyaputta, P Charatcharoenwitthaya, SP Chainuvati, et al. Entecavir Is Safe and Highly Effective for Long-Term Treatment of Chronic Hepatitis B Patients: a Single Center Experience. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1011.

MH Nguyen, HN Trinh, KT Chaung, et al. Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1006.

NB Ha, KC Ku, NB Ha, et al. Renal Function in Chronic Hepatitis B (CHB) Patients Treated With Tenofovir Dipivoxil Fumarate (TDF) Monotherapy -- a Matched Case Cohort Study. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1010.

StephenW

较新的抗病毒药物替诺福韦（Viread的）和恩替卡韦（博路定）抑制B型肝炎病毒（HBV）复制更有效地比早期版本的代理，但良好的依从性是需要维持长期抑制病毒，根据一系列研究，在消化疾病为期一周的会议（DDW 2013）上个月在奥兰多。

一系列核苷/核苷酸类似物抗HBV活跃，但该病毒可以发展耐药性，损害长期疗效。富马酸替诺福韦酯和恩替卡韦具有较高的耐药屏障比旧的拉米夫定（拉米HBV）和阿德福韦（阿德福韦酯）。
临床实践

阮Mindie从斯坦福大学和同事评估了在常规临床使用替诺福韦和恩替卡韦的有效性，这疗效比较看出，在关键试验药物的批准支持。在临床试验中的参与者往往做的更好，因为他们积极性都很高，可以选择良好的响应特性，并密切监察，并围绕坚持和副作用管理支持。

这种分析包括845治疗初治患者接受治疗3 2001年1月至2011年1月的美国肝病诊疗。三分之二为男性，几乎所有的亚洲，平均年龄为47岁，63％为B型肝炎的“e”抗原（HBeAg）阴性。 93共收到198了拉米夫定，阿德福韦，有447名服用恩替卡韦，107收到替诺福韦。

12个月的治疗后，完整的病毒抑制率显着高于拉米夫定（39％）或阿德福韦（54％）相比，服用恩替卡韦或替诺福韦（81％）（75％）的人，恩替卡韦和替诺福韦是类似的统计。恩替卡韦和拉米夫定组患者中也有类似的ALT中位数和平均HBV DNA水平。病毒学突破是不太常见的比替诺福韦（8.6％），恩替卡韦（2.5％），在所有情况下，是由于依从性差。

“治疗结果是明显占优，新制剂（恩替卡韦和替诺福韦），比旧代理（[拉米夫定和阿德福韦），”研究人员得出结论。

“抗病毒治疗与任[恩替卡韦]或[替诺福韦]在抑制乙肝病毒的复制是非常有效的，和不粘附治疗失败的原因是主要的，”他们补充道。 “更多的耐心教育和保健提供者需要密切的临床监测，提高病人的依从性，抗乙肝病毒治疗，这是长期或在大多数情况下，甚至终身。”
恩替卡韦长期

Watcharasak Chotiyaputta Bangkokevaluatedthe安全性，有效性和抗病毒药物的耐药性核苷/核苷酸天真的接受恩替卡韦单药治疗的患者，在临床实践中在泰国玛希隆大学。

此图审查包括从535慢性乙型肝炎患者，恩替卡韦治疗至少1年的记录。大约有60％为男性，平均年龄为52岁，65％为HBeAg阴性，37％有肝硬化。

在平均40个月的随访中，超过90％的HBeAg阳性和阴性患者达不到HBV病毒载量5年。病毒突破无案件发生，无耐药性突变检测。 HBeAg血清转换和乙肝表面抗原（HBsAg）的损失是非常少见，不过，在11％和2％，分别。没有严重的不良事件和血清肌酐水平（潜在的肾毒性指标）保持不变。

其中337例患者在基线时无肝硬化，20（6％）开发的肝硬化可根据影像学检查随访过程中，但没有经历过临床失代偿。其中开发临床研究项目，5（3％）198例肝硬化失代偿。此外，12例（2％），肝癌5年以上。

“恩替卡韦是安全的，有效抑制乙肝病毒，整个治疗5年无病毒学突破，研究人员得出结论。
恩替卡韦和替诺福韦

临沂高，也与斯坦福集团，和同事相比，恩替卡韦和替诺福韦在慢性乙型肝炎患者在基线HBV病毒载量高，一组在肝脏疾病进展的风险的功效。

这种回顾性病例对照研究包括62个连续3美国医疗中心治疗天真的参与者与基线HBV DNA> 1,000,000 IU / mL的人开始替诺福韦治疗。他们匹配与199用恩替卡韦治疗的对照组受试者。约60％为男性，平均年龄约42岁，约三分之一为HBeAg阴性，8％有肝硬化。

其中HBeAg阴性参与者，替诺福韦和恩替卡韦受助人之间的病毒抑制率无显着差异。其中HBeAg阳性患者，然而，那些服用替诺福韦取得显著抑制病毒的速度比那些服用恩替卡韦。替诺福韦臂病毒的抑制率分别为16％在6个月内，50％在12个月和18个月的71％，分别为11％，31％和39％，恩替卡韦组相比。

“泰诺福韦]比[恩替卡韦]为实现完整的病毒抑制HBeAg阳性，治疗初治乙肝患者HBV DNA> 1,000,000 IU /毫升，”研究人员得出结论明显更有效。此外，之间的差异[替诺福韦，恩替卡韦变得更加显着增加处理时间。“
替诺福韦肾功能

虽然替诺福韦抗HBV是非常有效的，它有可能造成肾毒性易感个体，迄今大多被研究人感染艾滋病毒（替诺福韦是有效对抗这两种病毒）。

尼奇厦形式，在加州大学旧金山和同事看着肾功能的变化在治疗初治慢性乙肝患者基线定义无论是肾功能正常，估计肾小球滤过率（eGFR）> 80毫升/分钟，或轻度受损的功能，定义为50-80毫升/分钟。

该病例对照研究共纳入72与会者谁收到300毫克，每日一次替诺福韦酯富马酸和72例患者的年龄，性别匹配，和基线eGFR的，而不是谁用1毫克，每日一次，恩替卡韦。三分之二为男性，平均年龄为45岁，86％有肾功能未受损伤。

研究人员发现暴露tenofovir和那些服用恩替卡韦的病人肾功能变化之间没有显着差异。功能恶化的可能性是在两组相似，并重新分类为一类功能更差率分别为12.9％和12.5宗，分别每100人年。在多变量分析，包括人口特征，基线表皮生长因子受体，糖尿病和高血压，替诺福韦的使用没有明显伴有肾功能不全。年龄较大，功能受损基线时显着恶化的预测功能随着时间的推移。

“要么替诺福韦抗病毒治疗的乙肝患者的肾功能]或[恩替卡韦]应该被监控，尤其是在那些谁是老年人和/或与已知的肾功能受损，”他们建议。

13年6月6日

参考文献

L高，HN郑氏，J，等。泰诺福韦是更有效地比实现快速抑制病毒HBeAg阳性慢性乙型肝炎患者的HBV DNA水平高的恩替卡韦。消化疾病周（DDW 2013年）。奥兰多，2013年5月18-21日。摘要Sa1009。

W Chotiyaputta，P Charatcharoenwitthaya，SP Chainuvati，等。恩替卡韦是安全，高效的用于长期治疗的慢性乙型肝炎患者：一个单中心的经验。消化疾病周（DDW 2013年）。奥兰多，2013年5月18-21日。摘要Sa1011。

MH阮，HN郑氏，KT弘昌等人。在常规临床实践治疗初治慢性乙型肝炎（CHB）的口服抗病毒药物治疗的有效性。消化疾病周（DDW 2013年）。奥兰多，2013年5月18-21日。摘要Sa1006。

KC古哈，NB，NB哈，等。肾功能的慢性乙型肝炎（CHB）患者富马酸替诺福韦酯（TDF）单药治疗 - 配对病例队列研究。消化疾病周（DDW 2013年）。奥兰多，2013年5月18-21日。摘要Sa1010。