Expert Insight Into: Nucleos(t)ide Analog Therapy in Patients with Decompensated

StephenW

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Expert Insight Into:
Nucleos(t)ide Analog Therapy in Patients with Decompensated Chronic Hepatitis B Liver Disease (Part 5 of Series)

Based on the Article:
Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72.
(Course HBV6.13)
Published on October 06, 2011 Article Review
Expert Faculty: Helen S. Te, MD
Medical Writer: Shawn E. Kuhmann, PhD


Clinical Insights

    This phase II study demonstrates that in CHB patients with decompensated liver disease, tenofovir and emtricitabine/tenofovir had similar tolerability and renal safety when compared with entecavir.
    Both entecavir and tenofovir appear to be safe and effective in this difficult-to-treat population, but more studies will be required to confirm these results, with particular attention paid to renal parameters and lactic acidosis.

PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.

In chronic hepatitis B (CHB) patients with compensated liver disease, sustained suppression of hepatitis B virus (HBV) DNA, in order to prevent worsening liver disease, is the goal of antiviral therapy. These treatments include five oral nucleos(t)ide analogs as well as interferon alfa (standard and pegylated). Entecavir and tenofovir are the preferred first-line nucleos(t)ide analogs because of their efficacy and barriers to resistance. Oral nucleos(t)ide analogs are also recommended for CHB treatment in patients with decompensated liver disease, based on studies with lamivudine and adefovir showing improved clinical outcomes in decompensated CHB patients.

A study of entecavir in 144 compensated and 55 decompensated patients showed that entecavir was similarly effective in both populations and that Child-Turcotte-Pugh scores were improved, generally within 6 months, in decompensated patients. Another study compared entecavir to adefovir in decompensated CHB and found that entecavir had superior virologic efficacy, but that 1-year survival rates were similar. Entecavir has reduced efficacy in patients with lamivudine-resistant HBV, and entecavir resistance may develop in these patients. Renal impairment has been reported with tenofovir use, mostly in human immunodeficiency virus patients, and renal dysfunction is common in decompensated liver disease. Because of the limited safety and efficacy data with entecavir and tenofovir in this patient population, a phase II trial was performed to assess the safety and tolerability of tenofovir, emtricitabine/tenofovir, and entecavir in patients with decompensated CHB.

The global study randomized 112 patients to receive tenofovir (300 mg; n = 45), emtricitabine/tenofovir (200 mg/300 mg; n = 45), or entecavir (0.5 mg for patients with <6 months lamivudine exposure and no lamivudine resistance mutations, otherwise 1.0 mg; n = 22). At the investigator's discretion, patients were allowed to switch to open-label emtricitabine/tenofovir if they did not have an HBV DNA decrease ≥2 log10 at week 8, had virologic breakthrough, or had HBV DNA >400 copies/mL at week 24. There were no significant differences in baseline demographics between the groups. The study results through 48 weeks were presented.

The primary endpoints of the study were tolerability and safety based on renal parameters. Tolerability failure—permanent discontinuation due to adverse events—occurred in 7 patients: 3 receiving tenofovir (6.7%), 2 receiving emtricitabine/tenofovir (4.4%), and 2 receiving entecavir (9.1%), all while receiving blinded study drug.

Table 1. Summary of tolerability failures in a study of tenofovir, emtricitabine/tenofovir, and entecavir therapies in CHB patients with decompensated liver disease
Patient      Study drug    Considered related to study drug                 Outcome
1 Emtricitabine/tenofovir  No Died within 30 days of last dose of study drug: liver failure secondary to cirrhosis and sepsis.
2 Tenofovir                    No Died within 30 days of last dose of study drug: endstage liver disease.
3  Entecavir                   No Died within 30 days of last dose of study drug: disease deterioration/exacerbation of hepatitis B.
4 Entecavir                    No Died within 30 days of last dose of study drug: septic shock.
5 Tenofovir                    No Discontinued study with renal failure following liver transplantation. Study drug had not been resumed following transplantation.
6 Emtricitabine/tenofovir Yes Grade 2 allergic reaction following first dose of study drug that resolved after second and final dose.
7 Tenofovir                    No Interrupted study drug with hepatic encephalopathy and hepatorenal syndrome. Did not resume study drug and died 2 days following final dose.

Confirmed renal parameters meeting the safety threshold—increase in serum creatinine ≥0.5 mg/dL above baseline or serum phosphorus levels <2.0 mg/dL—were observed in 8 patients: 4 receiving tenofovir (8.9%), 3 receiving emtricitabine/tenofovir (6.7%), and 1 receiving entecavir (4.5%). One of the confirmed increases in serum creatinine in the tenofovir group occurred after the patient switched to open-label emtricitabine/tenofovir. The difference between the combined tenofovir-containing treatment groups and the entecavir group was not significant for either tolerability or renal parameters (P = .622 and P = 1.00, respectively).

During blinded treatment, adverse events occurred in 82.2% of the patients in the tenofovir group, 93.3% of patients in the emtricitabine/tenofovir group, and 77.3% of patients in the entecavir group; grade 3 or 4 laboratory abnormalities occurred in 46.7%, 51.1%, and 45.5% of patients, respectively. Adverse events and laboratory abnormalities were consistent with advanced liver disease. The percentage of patients with adverse events related to study drug were low and similar among the groups (17.8%, 15.6%, and 9.1% for tenofovir, emtricitabine/tenofovir, and entecavir, respectively). Six deaths occurred, but none were considered related to study drug. No cases of lactic acidosis were reported.

HBV DNA levels were <400 copies/mL in 70.5%, 87.8%, and 72.7% of patients in the tenofovir, emtricitabine/tenofovir, and entecavir groups, respectively at 48 weeks of treatment; ALT was normalized in 46.2%, 64.0%, and 41.2% of patients. In the tenofovir and emtricitabine/tenofovir groups, hepatitis B e antigen (HBeAg) loss occurred in 21.4% and 26.7% of patients, and HBeAg seroconversion occurred in 21.4% and 13.3% of patients, respectively. HBeAg loss or seroconversion was not observed in the entecavir group. Decreases in Child-Turcotte-Pugh score of ≥2 points occurred in 25.9%, 48.0%, and 41.7% of patients in the tenofovir, emtricitabine/tenofovir, and entecavir groups, respectively. One patient in the emtricitabine/tenofovir group had an increase of ≥2 points in the Child-Turcotte-Pugh score. The median change from baseline in model for endstage liver disease (MELD) scores was -2.0 in all groups. Six liver transplants were performed: 2 in the tenofovir group, 4 in the emtricitabine/tenofovir group. No transplant patients experienced HBV recurrence. Two of the three patients in the entecavir group who entered the study with lamivudine resistance mutations switched to open-label emtricitabine/tenofovir due to an incomplete response at week 24; all three patients had a complete response at week 48. No resistance to tenofovir or entecavir was observed in the study.

The study's authors concluded that the tenofovir-containing regimens were well tolerated and showed no significant difference in renal safety parameters compared with entecavir in patients with decompensated CHB. Although the study was not designed to compare efficacy between the treatment groups, all three treatments demonstrated efficacy with regards to virologic, biochemical, and clinical outcomes.

Reference

Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72.

StephenW

专家洞察：
核苷（酸）IDE模拟治疗失代偿期慢性乙肝肝病患者（系列5部）

基于条：
disoproxil富马酸泰诺福韦（TDF），恩曲他滨/ TDF，并在失代偿期慢性乙肝肝病患者恩替卡韦。出处： 2011; 53:62-72。
（课程HBV6.13）
发布于2011年10月06逐条审查
专家学院：海伦S. TE，医学博士
医学作者：肖恩E. Kuhmann，博士


临床见解

    第二阶段的研究表明，在失代偿性肝病，替诺福韦和恩曲他滨/替诺福韦慢性乙型肝炎患者用恩替卡韦相比，也有类似的耐受性和肾安全。
    恩替卡韦和替诺福韦都出现在此难以治疗人群的安全有效，但将需要更多的研究来确认这​​些结果，特别注意肾功能参数和乳酸性酸中毒。

请注意：每篇文章是由选定的新数据的科学价值的教员。这是一个捆绑系列的文章，作为一个群体，提供了一个全面和平衡的观点的一部分。

在慢性乙型肝炎（CHB）代偿期肝病，持续抑制乙肝病毒（HBV）DNA，为了防止肝脏疾病恶化的患者，抗病毒治疗的目标。这些治疗包括五个口服核苷（酸）以及IDE类似物干扰素（标准和聚乙二醇）。恩替卡韦和替诺福韦的首选第一线的核苷（酸）IDE类似物，由于其疗效和耐药性的障碍。在失代偿性肝病患者慢性乙型肝炎治疗的口服核苷（酸）IDE类似物还建议，基于拉米夫定和阿德福韦在失代偿期慢性乙肝患者改善临床结果显示的研究。

补偿的研究恩替卡韦在144和55失代偿期患者显示，恩替卡韦在两个群体中也同样有效，儿童特科特- Pugh分级的分数进行了改进，在失代偿期患者，一般6个月内。另一项研究相比，恩替卡韦在失代偿期慢性乙肝阿德福韦，发现恩替卡韦有优越的病毒学疗效，但1年生存率相似。恩替卡韦与拉米夫定耐药HBV患者减少疗效，恩替卡韦的耐药性可能在这些患者中发展。肾损害报告使用替诺福韦，大多是在人类免疫缺陷病毒的患者，肾功能不全是常见于失代偿性肝病。因为有限的安全和疗效与恩替卡韦和替诺福韦在这个病患族群的数据，第二阶段的试验是评估替诺福韦，恩曲他滨/替诺福韦的安全性和耐受性，并在失代偿期慢性乙肝患者恩替卡韦。

全球研究随机112例患者接受替诺福韦（300毫克; N = 45），恩曲他滨/替诺福韦（200 mg/300毫克; N = 45），或恩替卡韦（<6个月的拉米夫定暴露患者和0.5毫克，没有拉米夫定耐药突变，另有1.0毫克; N = 22）。在研究人员的自由裁量权，病人被允许到开关开放标签恩曲他滨/替诺福韦，如果他们没有在8周一个乙肝病毒的DNA下降≥2 log10的病毒学突破，或有乙肝病毒的DNA> 400拷贝/ 24周毫升。在组与组之间的基线人口统计学没有显著差异。通过48周的研究结果。

这项研究的主要终点为耐受性和安全性的基础上肾功能参数。由于耐受性故障永久停止不良事件发生在7例患者接受替诺福韦（6.7％），接受恩曲他滨/替诺福韦（4.4％），2，接受恩替卡韦（9.1％），同时接受盲法研究药物。

表1。替诺福韦，恩曲他滨/替诺福韦和恩替卡韦与失代偿性肝病慢性乙型肝炎患者的治疗研究中的耐受性失败的总结
病患 研究药物 审议了有关研究药物 成果
1 恩曲他滨/替诺福韦 无 内死亡30天的最后一个剂量研究药物：肝功能衰竭，继发肝硬化和败血症。
2 泰诺福韦               无 30天的最后一个剂量研究药物：终末期肝病内死亡。
3 恩替卡韦               无 在30天的最后一剂研究药物而死亡：病情恶化/ B型肝炎发作
4 恩替卡韦               无 内死亡30天的最后一个剂量研究药物：感染性休克。
5 泰诺福韦               无 停产的研究与肾功能衰竭肝移植。研究药物没有被移植后恢复。
6 恩曲他滨/替诺福韦 是 二级以下，解决后第二次，也是最后一次剂量研究药物剂量的过敏反应。
7泰诺福韦                无 肝性脑病和肝肾综合征中断研究药物。没有恢复研究药物和最后一剂后2天死亡。

肾功能参数证实会议的安全阈值的增加血清肌酐≥0.5毫克/升以上基准或血磷水平<2.0毫克/升，在8例患者中观察到：4接受替诺福韦（8.9％），3接受恩曲他滨/替诺福韦（6.7 ％），并接受恩替卡韦（4.5％）。确认发生后，病人的替诺福韦组血肌酐增加一个开关打开标签恩曲他滨/替诺福韦。联合替诺福韦治疗组和恩替卡韦组之间的差异不耐受或肾功能参数的显著性（P = 0.622和P = 1.00）。

双盲治疗期间，不良事件发生在82.2％的在替诺福韦组患者，恩曲他滨/替诺福韦组患者的93.3％，和77.3％的患者在恩替卡韦组; 3或4级实验室检查异常发生在46.7％， 51.1％，45.5％的患者分别。不良事件和实验室异常与晚期肝病一致。与研究药物有关的不良事件的患者比例很低，类似的群体（17.8％，15.6％和9.1％为替诺福韦，恩曲他滨/替诺福韦，和恩替卡韦，分别）之间。发生6人死亡，但没有被认为是与研究药物。乳酸性酸中毒的病例报告。

70.5％，87.8％和72.7％的患者在替诺福韦，恩曲他滨/替诺福韦和恩替卡韦组HBV DNA水平<400拷贝/ ml，分别在48个星期的治疗; ALT为46.2％，64.0％归， 41.2％的患者。替诺福韦和恩曲他滨/替诺福韦组，B型肝炎e抗原（HBeAg）的损失发生在21.4％和26.7％的患者，和，分别为21.4％和13.3％的患者出现HBeAg血清转换。在恩替卡韦组没有观察到HBeAg消失或血清转换。儿童特科特- Pugh分级评分≥2分的跌幅分别为25.9％，48.0％和41.7％的患者在替诺福韦，恩曲他滨/替诺福韦和恩替卡韦组，在发生。恩曲他滨/替诺福韦组患者在儿童特科特- Pugh评分增加≥2分。中位数从基线为终末期肝病模型（MELD）的变化，各组分数是-2.0。 6个肝脏移植：恩曲他滨/替诺福韦组在替诺福韦组，4 2。没有移植患者乙肝复发。在恩替卡韦组患者进入拉米夫定耐药突变的研究的两个开关开放标签恩曲他滨/替诺福韦由于不完全反应在第24周，所有患者在48周的完整的响应。没有替诺福韦或恩替卡韦的耐药性研究中观察到。

这项研究的作者得出结论，耐受性良好，含有替诺福韦方案和肾的安全参数没有表现出与失代偿期慢性乙肝患者恩替卡韦相比显着性差异。虽然这项研究并没有设计比较治疗组之间的疗效，所有三个治疗方面病毒学，生化和临床结果证明的疗效。

参考

    廖施雅风，光泽，李CM，等。 disoproxil富马酸泰诺福韦（TDF），恩曲他滨/ TDF，并在失代偿期慢性乙肝肝病患者恩替卡韦。出处： 2011; 53:62-72。