不同的核苷（酸）在中国慢性乙型肝炎IDE类似物的抗病毒疗

StephenW

Comparison of the antiviral effects of different nucleos(t)ide analogues in chinese patients with chronic hepatitis B: A head-to-head study

Shu Yu, Qin Zhou, Xiao Miao Zhao, Min Yuan, Chang Tai Wang, Xiao Guang Cheng, Zhen Hua Zhang, Xu Li
Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China


Date of Submission    11-Aug-2014
Date of Acceptance    25-Sep-2014
Date of Web Publication    24-Nov-2014


   Abstract         

Background/Aims: To assess the antiviral efficacy of lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and lamivudine and adefovir dipivoxil (CLA) combination in previously untreated hepatitis B patients at different time points during a 52-week treatment period.

Patients and Methods: A total of 164 patients were included in this prospective, open-label, head-to-head study. Serum levels of alanine transaminase (ALT), hepatitis B virus (HBV) DNA, and hepatitis B e antigen (HBeAg) were measured at baseline, and at 12, 24, and 52 weeks of treatment.

Results: Median reductions in serum HBV DNA levels at 52 weeks (log 10 copies/mL) were as follows: LAM, 3.98; ETV, 3.89; LDT, 4.11; and CLA, 3.36. The corresponding HBV DNA undetectability rates were 83%, 96%, 91%, and 89%, respectively. These two measures showed no significant intergroup differences. Clinical efficacy appeared related to HBV DNA level reduction after 24 weeks of therapy. Patients were divided into three groups based on HBV DNA levels at week 24: Undetectable (<10 3 copies/mL), detectable but <10 4 copies/mL, and >10 4 copies/mL. Patients with levels below quantitation limit (QL) were analyzed at 52 weeks for HBV DNA undetectability rate (94%), ALT normalization rate (83%), and viral breakthrough rate (0%). The corresponding values in the QL-10 4 copies/mL group were 50%, 75%, and 13%, whereas those in the above 10 4 copies/mL group were 53%, 65%, and 18%. There were significant differences at week 52 for HBV DNA levels and viral breakthrough rate between the three groups.

Conclusions: Different nucleos(t)ide (NUC) analogues tested exhibited no significant differences in effectiveness for Chinese NUC-naive HBV patients during 1-year treatment period.

StephenW

不同的核苷（酸）在中国慢性乙型肝炎IDE类似物的抗病毒疗效比较：一个头对头研究

舒榆，秦洲，肖苗钊，闵元，张帝王某，小光程珍华哳嗯蓄力
传染病，安徽医科大学第一附属医院，合肥，中国科


提交11月，2014年的日期
受理日期25月，2014年
网络出版的24月，2014年的日期


   抽象

背景/目的：在52周的治疗拉米夫定评估的抗病毒疗效（LAM），恩替卡韦（ETV），替比夫定（LDT），和拉米夫定和阿德福韦酯（CLA）在以前未经治疗的乙肝患者在不同时间点的组合期。

患者与方法：共164例患者纳入该前瞻性，开放标签，头对头的研究。丙氨酸转氨酶（ALT），B型肝炎病毒（HBV）DNA和乙型肝炎e抗原（HBeAg）的血清水平测定在基线，并在12，24和52周的治疗。

结果：平均降低血清HBV DNA水平在52周（log10拷贝/毫升）依次为：LAM，3.98; ETV，3.89; LDT，4.11;和CLA，3.36。相应的HBV DNA不可检测率分别为83％，96％，91％，和89％，分别为。这两项措施均未见显著间差异。临床疗效出现在治疗24周后与HBV DNA水平下降。患者分为基于HBV DNA水平三组在24周：检测不到（<103拷贝/毫升），但检测到<104拷贝/ ml和>104拷贝/毫升。例低于定量限（QL）水平在52周的HBV DNA的不可检测率（94％），ALT正常化率（83％），和病毒突破率（0％）进行了分析。在QL-10 4拷贝/ ml组中的相应值分别为50％，75％和13％，而那些在上述10 4拷贝/ ml组为53％，65％，和18％。有52周的HBV DNA水平，三组间病毒学突破率显著的差异。

结论：不同的核苷（酸）IDE（NUC）测试类似物展出期间1年的治疗期为中国NUC天真HBV患者效果无差异显著。

StephenW

10 change from baseline values. LAM, lamivudine; ETV, entecavir; LDT, telbivudine; CLA, combination of lamivudine and adefovir dipivoxil" border="0">






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StephenW

EDITORIAL      
Year : 2014  |  Volume : 20  |  Issue : 6  |  Page : 331-332
Hepatitis B management: It is time to change the strategy

Waleed K Al-hamoudi
Associate Professor, Gastroenterology and Hepatology Unit (59), Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia


Date of Web Publication    24-Nov-2014


How to cite this article:
Al-hamoudi WK. Hepatitis B management: It is time to change the strategy. Saudi J Gastroenterol 2014;20:331-2

How to cite this URL:
Al-hamoudi WK. Hepatitis B management: It is time to change the strategy. Saudi J Gastroenterol [serial online] 2014 [cited 2014 Nov 25];20:331-2. Available from: http://www.saudijgastro.com/text.asp?2014/20/6/331/145313


Chronic hepatitis B (CHB) infection is a major global public health concern. The World Health Organization estimates that approximately 2 billion people worldwide have been infected with hepatitis B virus (HBV) and that approximately 350 million live with chronic infection. [1] CHB infection is a dynamic process that is influenced by immune, host, and virological factors. The aims of treating CHB with antiviral agents are to achieve sustained suppression of HBV replication and remission of the ongoing liver inflammation, with the ultimate goal of improving quality of life and survival by preventing cirrhosis and hepatocellular carcinoma (HCC). However, the current treatment options are far from ideal. The unique abilities of HBV to chronically persist in host hepatocytes due to the existence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes makes eradication very difficult. Furthermore, treatment of CHB became more complex with the long-term use of oral nucleos(t)ide analogs. Conventional interferon alpha (IFN-α), the only agent licensed in 1991, has been superseded by pegylated IFN-α. Five nucleos(t)ide analogs have been licensed since 1998. [2] The long-term use of oral nucleos(t)ide analogs has resulted in the selection of antiviral-resistant mutations. First-generation nucleos(t)ide analogs, including lamivudine, telbivudine, and adefovir, were associated with the highest drug resistance rate. Therefore, these agents are no longer considered as firstline treatment options for HBV infection in several of the recently published HBV management guidelines. Newer antiviral agents (entecavir and tenofovir) took over as firstline agents due to their superior potency and low drug resistance rate. [3],[4]

In this issue of the Journal, Yu et al report the antiviral efficacy of lamivudine, entecavir, telbivudine, and a combination of lamivudine and adefovir dipivoxil in previously untreated hepatitis B patients at different time points during a 52-week treatment period. The study reported no statistically significant differences in the effectiveness between the various nucleos(t)ide analogs when treating treatment-naive patients. [5] The researchers also confirmed the importance of early HBV suppression in achieving a better response after 52 weeks of treatment. This finding is in agreement with previously published reports.

Although there were no differences between the four groups in term of achieving a positive response at week 52 in treatment-naive patients, entecavir should be the firstline agent when choosing to treat treatment-naive patients. The other firstline agent that has gained popularity over the last few years is tenofovir, which was not included in this study. One of the important goals of treatment is to achieve prolonged suppression of the virus to decrease the negative viral effect on liver tissue. Entecavir and tenofovir are potent agents with no (tenofovir) or very low (entecavir)resistance rates. The major disadvantage of lamivudine is the high risk of developing antiviral resistance, approaching 70% at four years of treatment. This feature also limits the use of other antiviral agents due to cross-resistance, so lamivudine should not be used as a firstline agent anymore. [6] Similarly, relatively high resistance rates were reported with the use of telbivudine, and therefore, it is not considered as a firstline agent in recently published guidelines. [7] Adefovir is the least potent agent among all nucleos(t)ide analogs and does not achieve complete viral suppression in the first six months in the majority of patients. Additionally, this drug's resistance rate reaches 29% at 5 years, and the potential side effects, including nephrotoxicity, limit its use as a firstline agent, especially in patients with high viral loads. [8]

Therefore, tenofovir or entecavir is more likely to achieve the long-term goal of sustained viral suppression and should be considered as a firstline therapy for treatment-naive HBV patients. Additionally, multiple randomized controlled trials comparing the effects of newer antiviral agents with those of older agents showed a superior response to the second-generation agents. Lai et al. compared entecavir with lamivudine in CHB infection, and their study revealed that the rate of histological improvement, the virological response, and the normalization of liver enzymes were significantly greater with entecavir at 48 weeks. [9] Two other randomized trials conducted by Marcellin et al. and Hou et al. showed a superior antiviral effect with tenofovir compared with adefovir at 48 weeks. [10],[11]

In their study, Yu et al. showed excellent virological, biochemical, and HBeAg-loss rates at 52 weeks, although this study did not answer a more important question, which is what the post-treatment durability is. The authors, however, mentioned that a follow-up study assessing post-treatment durability will be conducted.

The authors also revealed that early viral suppression was linked to better clinical and virological responses at 52 weeks of treatment. However, the small number of patients enrolled in this study and the short follow-up period limit any solid conclusions. The authors did not classify the treatment response based on the stage of fibrosis, which would have added an important aspect to this study.

Despite the prospective nature of this study, its limitations are of major concern, limiting its clinical value. Furthermore, the epidemiology of HBV infection in China, including the mode of transmission, the age of infection, and the impact of genotypic differences, compared with other parts of the world makes generalization of the treatment response and outcome questionable.

In conclusion, the development of potent HBV drugs with high genetic barriers to resistance has resulted in significant suppression of viral replication over a longer period of time. As a result, overall patient survival has improved due to the prevention of disease progression to cirrhosis. Recent data showed regression of cirrhosis in 71 of 96 (74%) cirrhotic patients treated with tenofovir, which was confirmed by paired biopsies at baseline and after five years. [12] However, the preventive effect of these agents against HCC development is less clear. Therefore, the use of older-generation drugs, such as lamivudine, adefovir, and telbivudine, should be avoided when treating HBV in treatment-naive patients. For the time being, more potent drugs with high genetic barriers to resistance should be used as firstline agents until better treatment becomes available.

StephenW

社论
年份：2014年|体积：20|问题：6|页：331-332
乙型肝炎管理：是时候改变策略

瓦利德ķ铝hamoudi
副教授，胃肠病学和肝病单元（59），医学系，沙特国王大学，PO盒2925，利雅得11461，沙特阿拉伯


网络出版的24月，2014年的日期


如何引用这篇文章：
AL-hamoudi WK。乙型肝炎管理：是时候改变策略。沙特ĴGastroenterol2014;20：331-2

如何引用这个URL：
AL-hamoudi WK。乙型肝炎管理：是时候改变策略。沙特ĴGastroenterol[串行在线]2014年[引用2014年11月25日];20：331-2。可从以下http://www.saudijgastro.com/text.asp?2014/20/6/331/145313


慢性乙型肝炎（CHB）感染是一个主要的全球性公共卫生问题。据世界卫生组织估计，大约2十亿世界各地的人已经感染了乙型肝炎病毒（HBV）和大约3.5亿人患有慢性感染。 [1] CHB感染是由免疫，主机和病毒学因素影响的动态过程。治疗慢性乙型肝炎抗病毒制剂的目标是实现HBV复制和持续的肝脏炎症缓解持续抑制，通过防止肝硬化和肝细胞癌（HCC）改善生活和生存质量的最终目标。然而，目前的治疗选择是很不理想。 HBV对长期的独特的能力，由于共价闭合环状DNA在感染的肝细胞的细胞核的存在（cccDNA的），使根除很难坚持宿主肝细胞。此外，治疗慢性乙型肝炎的成为与长期使用口服核苷（酸）类似物更加复杂。常规干扰素（IFN-α），行货在1991年的唯一代理商，已经取代了聚乙二醇化干扰素α。自1998年[2]长期使用口服核苷（酸）类似物导致抗病毒耐药突变选择五种核苷（酸）类似物已被授权。第一代核苷（酸）类似物，包括拉米夫定，替比夫定，阿德福韦和，均与最高的耐药率。因此，这些药物都不再被视为在几个最近公布的HBV管理指引HBV感染FIRSTLINE治疗方案。较新的抗病毒药物（恩替卡韦和替诺福韦）接任代理FIRSTLINE由于其优越的效能和低耐药率。 [3]，[4]

在这个问题上的杂志，玉等人在52周治疗期间报告拉米夫定，恩替卡韦，替比夫定，拉米夫定和阿德福韦和酯在以前未经治疗的乙肝患者在不同时间点的组合的抗病毒疗效。该研究报告在治疗治疗过的病人时的各种核苷（酸）类似物的有效性无统计学差异显著。 [5]研究人员还证实了在实现治疗52周后，更好的响应早期抑制HBV的重要性。这一发现与先前公布的报告一致。

尽管在实现在52周治疗初治患者的积极响应的长远四组之间没有差异，恩替卡韦应选择治疗治疗过的病人时是FIRSTLINE剂。已得到普及，在过去几年中的其它FIRSTLINE剂是替诺福韦，这是不包括在本研究中。一种治疗的重要目标是实现病毒的长期抑制，以减少对肝组织的负面影响的病毒。恩替卡韦和替诺福韦是没有（替诺福韦）强效剂或非常低（恩替卡韦）的耐药率。拉米夫定的主要缺点是开发抗病毒耐药性，在四个年的治疗接近70％的高风险。这个特性也限制使用其它的抗病毒剂，由于交叉耐药性，所以拉米夫定不应再用作FIRSTLINE剂。 [6]同样，相对高的电阻率的报道与使用替比夫定的，因此，它不被认为是在最近发表的准则FIRSTLINE剂。 [7]阿德福韦是所有核苷（酸）类似物中最有力的代理人，不能达到完全抑制病毒在大多数患者的首六个月。另外，这种药物的耐药率达到5年的29％，以及潜在的副作用，包括肾毒性，限制了其作为FIRSTLINE剂使用，特别是在高的患者的病毒负荷。 [8]

因此，替诺福韦或恩替卡韦是更有可能实现持续的病毒抑制的长期目标，并应被视为FIRSTLINE疗法治疗过的患者HBV。另外，比较与旧代理新抗病毒剂的影响的多个随机对照试验表明于第二代试剂的优良的响应。 Lai等人。相比恩替卡韦与拉米夫定慢性乙型肝炎感染，他们的研究表明，组织学改善，病毒学应答，和肝酶正常化率分别为显著更大的恩替卡韦在48周。 [9]等两项随机试验由Marcellin等进行。和侯等人。表现出与替诺福韦优越的抗病毒效果与阿德福韦在48周相比。 [10]，[11]

在他们的研究中，俞等人。表现出优异的病毒学，生物化学和e抗原的损失率在52周，尽管这项研究并没有回答一个更重要的问题，这是后处理的耐久性是什么。作者，但是，提到一个后续研究评估后处理耐久性进行。

作者还透露，早期病毒抑制是有联系的更好的临床和病毒学反应在52周的治疗。然而，少数患者参加了这项研究，并短期随访期间限制任何可靠的结论。作者没有基于纤维化的阶段，这将增加的一个重要方面是本研究的治疗反应进行分类。

尽管本研究的潜在的性质，它的局限性是主要关注的问题，限制了它的临床应用价值。此外，HBV感染在中国，包括传播方式，感染的年龄，和基因型差异的影响的流行病学，与世界其他地区相比，使治疗反应和结果有疑问的泛化。

最后，强效HBV药物具有高耐药基因屏障的发展已导致病毒复制在一段较长的时间显著抑制。其结果是，总的患者存活已经由于疾病进展的预防肝硬化改善。最近的数据显示，肝硬化的回归在96（74％）的肝硬化与替诺福韦治疗的患者，这是由在基准成对活检证实的71和后五年。 [12]然而，对肝癌的发展，这些药物的预防效果还不太清楚。因此，利用老一代的药物，如拉米夫定，阿德福韦，替比夫定和，应当在治疗过的患者治疗的HBV时避免。暂时，更有效的药物具有高耐药基因屏障应作为FIRSTLINE代理，直到更好的治疗可用