Entecavir v Entecavir + Tenofovir

StephenW

                                     Expert Insight Into:
Combination Nucleos(t)ide Analog Therapy vs Nucleos(t)ide Analog Monotherapy in Patients with Chronic Hepatitis B
                                                               
                                                                                                             Based on: Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naïve patients with chronic hepatitis B. Gastroenterol. 2012;143:619-628.                                                 (Course HBV7.08)                                                
Published on November 07, 2012 Article Review                                                                                       
            Expert Faculty: Helen S. Te, MD
Medical writer: Kate Revill, PhD
            
                                                                              

                    
                                                   
                                                                                                                                                                      Clinical Insights

• Clinicians should consider HBeAg positive patients with HBV DNA ≥108 IU/mL as possible candidates for the combination of tenofovir disoproxil fumarate with entecavir
• In this study, mutations conferring resistance to entecavir or tenofovir were not observed in either the combination or monotherapy arm, likely due to the high barrier to resistance generally observed with entecavir or tenofovir monotherapy. However, the study was not of sufficient duration to evaluate resistance rates over a longer-term period
  

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.

   

Unchecked hepatitis B virus (HBV) infection can lead to liver failure and/or death as a result of increased risk of cirrhosis and hepatocellular carcinoma (HCC). Conventional treatment of chronic HBV (CHB) is with nucleos(t)ide analogue (NA) monotherapy over a long duration to reduce the viral load. Both entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are approved NAs with potent antiviral activities. Since treatment with NAs to achieve rapid, maximum suppression of hepatitis viral replication over a sustained period of time is required to achieve a successful outcome, a treatment strategy combining both ETV and TDF may improve upon viral suppression achieved with monotherapy alone and reduce the likelihood of acquired drug resistance over time.

   

In this study, the efficacy and safety of combining ETV with TDF as opposed to ETV therapy alone was assessed in a randomized, open-label, multi-center study of 379 NA-naïve patients with hepatitis B e antigen (HBeAg) positive (n=264) or HBeAg negative (n=115) CHB. The treatment groups were similar in baseline demographics and disease characteristics, with approximately 50:50 Asian:white patients and 70% HBeAg positive and 30% HBeAg negative patients in both arms. Mean HBV DNA level was 7.5 log10 IU/mL in both arms and approximately 2 log10 IU/mL higher among HBeAg positive patients than in HBeAg negative patients. In the combination therapy arm, baseline ALT levels were slightly higher (158 U/L vs 127 U/L) and there were slightly more male patients (74.1% vs 63.7%) than in the monotherapy arm.

Patients were randomized 1:1 to receive ETV 0.5 mg plus TDF 300 mg daily (n=197) or ETV 0.5 mg (n=182) once daily for 100 weeks. Primary endpoint was the proportion of patients achieving an HBV DNA level <50 IU/mL at week 96. Secondary endpoints included HBV DNA <50 IU/mL at week 48, as well as HBV DNA <50 IU/mL by HBeAg status, ALT normalization (≤1xULN), HBeAg loss and HBeAg seroconversion (in HBeAg positive patients), and HBsAg loss at weeks 48 and 96. Safety was assessed through week 96 and also during 24 weeks of off-treatment follow-up.

Although a slightly higher number of patients achieving HBV DNA levels <50 IU/mL was observed at week 48 in the combination treatment arm compared to the monotherapy arm (80.2% vs 70.3%, respectively, P = 0.026), no significant difference in the number of patients with HBV DNA levels of <50 IU/mL was seen at week 96 between treatment arms in the full patient cohort (83.2% vs 76.4%, respectively; P = .088). Stratification by HBeAg status revealed that HBeAg positive patients had a better response to combination therapy compared to monotherapy, with an HBV level <50 IU/mL at week 48 (74.6% vs 61.1%; P = 0.018) and at week 96 (80.4% vs 69.8%; P = .046). In contrast, no significant difference in HBV DNA suppression was observed in HBeAg negative patients at week 48 (93.2% vs 91.1%, P = .67) and week 96 (89.8% vs 91.1%, P = .82). In addition, 79% of HBeAg positive patients with a baseline HBV DNA level of more than or equal to 108 IU/mL achieved an HBV DNA level <50 IU/mL at week 96 when receiving combination therapy, compared to 62% when receiving ETV monotherapy (P = 0.018). Comparable results in both treatment arms were observed in patients with lower baseline HBV DNA levels <108 IU/mL, indicating that combination therapy may provide a benefit in suppressing HBV replication only in HBeAg positive patients with higher viral load.

Normalization of serum ALT levels occurred in more patients receiving ETV therapy alone than in combination therapy with TDF at week 96 (P = .004). No significant differences in HBeAg loss and seroconversion were observed between HBeAg positive patients receiving combination therapy or monotherapy. Similar low rates of HBsAg loss and HBsAg seroconversion were seen in both treatment groups.

Virologic breakthrough, an indicator of resistance to therapy, was observed in 3.6% of patients treated with combination therapy and 1% of patients treated with monotherapy. However, mutations in HBV previously associated with resistance to ETV or reduced TDF susceptibility were not detected in these patients, indicating that breakthrough was due to non-adherence. Safety profiles were similar between treatment arms (Figure 1). The three deaths reported were all within the combination therapy arm, of which one was due to liver failure. This  patient was a 70-year-old Asian woman who experienced breakthrough at week 48 (and therefore may not have been adhering to the treatment strategy), and despite remaining on combination therapy, died after 100 weeks.

Figure. Safety Profiles of Monotherapy vs Combination Therapy

   
Click to Enlarge

Superior viral suppression with ETV plus TDF combination therapy was observed only in HBeAg positive patients with baseline HBV DNA levels of ≥108 IU/mL but not in patients with lower baseline HBV DNA levels. These results suggest that combining TDF with ETV may benefit those patients with a viral load ≥108 IU/mL to achieve a more rapid suppression of viral replication and decreasing the opportunity for resistance to arise.

Reference

Lok AS, Trinh H, Carosi G, et al. Efficacy of Entecavir With or Without Tenofovir Disoproxil Fumarate for Nucleos(t)ide-Naïve Patients With Chronic Hepatitis B. Gastroenterology. 2012;143:619–628.

StephenW

专家洞察：
联合核苷（酸）IDE模拟治疗与核苷（酸）IDE模拟单药治疗慢性B型肝炎患者

：带或不带富马酸替诺福韦酯的核苷（酸）IDE初治患者与慢性B型肝炎胃肠病学杂志恩替卡韦的疗效。 2012年143:619-628。
（课程HBV7.08）
发表于2012年11月7号条评论
专家教授：海伦S.特，MD
医学作家：凯特雷维利，博士


临床见解

    临床医师应考虑HBeAg阳性患者HBV DNA≥108 IU / mL作为可能的候选相结合，富马酸替诺福韦酯，恩替卡韦
    在这项研究中，未观察到突变的耐恩替卡韦或替诺福韦组合或单药治疗组，可能是由于高耐药屏障一般恩替卡韦或替诺福韦单药治疗观察。然而，这项研究并没有足够的时间来评估一个长期的耐药率超过

请注意：每篇文章的教师对新数据的科学价值选择。这是其中的一部分捆绑的系列文章，作为一个群体，提供全面和平衡的角度。

未经检查的B型肝炎病毒（HBV）感染可导致肝功能衰竭和/或死亡的风险增加肝硬化和肝细胞癌（HCC）的结果。常规治疗的慢性乙肝（CHB）是核苷（酸）类似物（NA）单药治疗在很长的时间，以降低病毒载量。恩替卡韦（ETV）和富马酸替诺福韦酯（TDF）被批准NAS具有强大的抗病毒活性。由于NAS在一段持续的时间内实现快速，最大抑制肝炎病毒复制的治疗需要取得圆满成功，治疗策略相结合，ETV和TDF提高后，仅实现单药治疗的病毒抑制和减少的可能性随着时间的推移获得性耐药。

在这项研究中，ETV与TDF相结合的疗效和安全性，而不是ETV治疗单独进行评估的随机，开放标签，多中心研究，379 NA初治患者与B型肝炎e抗原（HBeAg）阳性（N = 264）或HBeAg阴性组（n = 115）CHB。治疗组在基线人口统计学和疾病特征相似50:50亚洲：白色的患者e抗原阳性，30％和70％的HBeAg阴性患者的双臂。平均HBV DNA水平为7.5 log10的国际单位/毫升的双臂，高约2个log10 IU / mL的HBeAg阳性患者比HBeAg阴性患者之间的。中西医结合治疗手臂，基线ALT水平略高（158 U / L和127 U / L）和，有稍微男性患者比单药治疗组（74.1％对63.7％）。

患者随机接受ETV 0.5 mg加TDF每天300毫克组（n = 197）或ETV 0.5毫克组（n = 182），每天一次为100周。主要终点是达到HBV DNA水平的患者比例<50 IU / mL的96周。次要终点包括HBV DNA <50 IU / mL的48周时，HBV DNA <50 IU / ml的HBeAg状态，ALT复常（≤1xULN），HBeAg消失和HBeAg血清转换（HBeAg阳性患者），HBsAg和损失在48和96周。安全性评估到第96周和24周的场外治疗随访期间。

虽然略高一些患者的HBV DNA水平<50 IU / mL的48周观察到联合治疗组相比，单药组（80.2％对70.3％，P = 0.026），无显着差异，与HBV DNA水平<50 IU / mL的患者数在96周治疗组在全组患者（分别为83.2％和76.4％，P = 0.088）之间。分层显示，HBeAg阳性患者HBeAg状态有一个更好的响应联合治疗与单药治疗相比，与HBV水平<50 IU / mL的48周（74.6％比61.1％，P = 0.018）和96周（80.4％比69.8％，P = 0.046）。相反，HBV DNA抑制无显着差异，观察HBeAg阴性患者在第48周（93.2％比91.1％，P = 0.67）和96周（89.8％比91.1％，P = 0.82）。此外，实现了79％的HBeAg阳性患者HBV DNA的基线水平大于或等于108 IU / mL的HBV DNA水平<50 IU / mL的接受联合治疗96周时相比，62％时，接受ETV单药治疗（P = 0.018）。比较的结果在两治疗组在与低基线HBV DNA水平的患者中观察到108 IU / mL时，表明联合治疗可能提供的好处只在抑制乙肝病毒复制的HBeAg阳性患者具有较高的病毒载量。

血清ALT水平正常化发生在更多的患者接受ETV治疗，仅比与TDF中西医结合治疗96周（P = .004）。之间无显着差异，HBeAg消失和血清转换HBeAg阳性患者接受联合治疗或单一。类似的HBsAg转阴率和乙肝表面抗原血清学转换主要出现在两个治疗组低。

病毒学突破，抵抗治疗的指标，联合治疗与单药治疗的患者和1％的患者中观察到3.6％。然而，在HBV的突变与电阻ETV或TDF敏感性降低的在这些患者中未检测到，表明突破是由于不遵守。安全性是相似的治疗武器（图1）。死亡的报道西医结合治疗臂内，其中一个是由于肝功能衰竭。患者是一名70岁的亚裔女子在经历了突破48周（因此可能不会一直秉承的治疗策略），尽管余下的联合治疗，死亡后100周。

图。单药治疗和联合治疗的安全性
图片1
点击查看大图

ETV的高级病毒的抑制与加TDF联合治疗，观察在HBeAg阳性患者基线HBV DNA水平≥108 IU /毫升，但不与低基线HBV DNA水平的患者。这些结果表明，TDF恩替卡韦相结合可能受益的患者的病毒载量≥108 IU / mL的，实现了更快速的抑制病毒复制，并降低电阻产生的机会。

参考

乐AS卡罗西的Trinh H，G，等。带或不带核苷（酸）IDE初治患者的慢性B型肝炎，胃肠病学富马酸替诺福韦酯，恩替卡韦的疗效。 2012年143:619-628。

咬牙硬挺

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