乙肝前C区变异, 高病毒, 拉米夫丁抗药病例的研究文献

liver411

(谢谢有时间朋友帮网友翻译阅读)

[B]HBV Precore Mutants Associated with Higher HBV Replication in Patients with Lamivudine Resistance[/B]

By Brian Boyle, MD

Chronic hepatitis B virus (CHB) infection is a leading cause of liver disease and death worldwide. Hepatitis B e antigen (HBeAg) negative CHB results from the selection of hepatitis B virus (HBV) unable to secrete HBeAg. HBeAg-negative CHB has become the major form of HBV disease in many parts of the world.

Several mutations can cause HBeAg-negative CHB, the most common of which is a guanine to adenine transition at nucleotide position 1,896 (G1896A). This change, which creates a stop codon at codon 28 of the precore (PC) protein, causes premature termination of the PC protein.

The only therapeutic agents approved for treatment of HBV are interferon alfa, Epivir-HBV (lamivudine) and Hepsera (adefovir). Epivir-HBV and Hepsera are considered to be just as, if not more, effective as interferon alfa, but are safer and better tolerated.

Unfortunately, resistance to Epivir-HBV increases with the duration of therapy, rising to as high as 66% after 3 years. The YMDD (tyrosine-methionine-aspartate-aspartate) motif is most common mutation conferring Epivir-HBV resistance and affects the active site YMDD in the C domain of the HBV polymerase protein, causing the methionine (M) residue to be replaced with either isoleucine or valine.

Patients experiencing Epivir-HBV failure usually have an acute exacerbation of their liver disease and long-term data indicate that liver histology worsens in conjunction with the rising HBV viral loads.

During Epivir-HBV therapy for HBV, drug resistance develops at a similar rate in patients with HBeAg positive or HBeAg negative disease. In the absence of PC mutations, Epivir-HBV resistant HBV mutants have been shown to replicate inefficiently in vitro; however, it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. In a study published in Hepatology, a recombinant HBV baculovirus system was used in an effort to address these issues.

In the study, HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and Epivir-HBV resistant backgrounds, resulting in a panel of 6 related recombinant HBV baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with Epivir-HBV and Hepsera (adefovir) and to compare relative replication yields.

These assays indicated that the PC mutation does not significantly affect sensitivities to either Hepsera or Epivir-HBV. Wild-type HBV and PC mutant HBV showed similar levels of replication, whereas the replication levels of the Epivir-HBV resistant mutants were greatly reduced in HBeAg positive HBV. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the Epivir-HBV resistant mutants, increasing the replication yields of each virus.

The authors conclude, "These observations have direct clinical relevance in the setting of lamivudine therapy for HBeAg negative CHB. In a recent study of Greek patients with HBeAg negative CHB, Hadziyannis et al. noted that virological breakthrough because of the development of HBV resistance to lamivudine was almost invariably followed by serum alanine aminotransferase elevations.

"The elevations exceeded baseline values in almost 75% of patients and reached greater than 8 times the upper limit of normal in the majority of cases, increases that were more characteristic of acute hepatitis. The restoration of the replication yield for the lamivudine-resistant HBVs also containing the G1896A precore stop codon provides a possible basis for the disease exacerbation observed in these patients.

"Because the G1896A precore mutant is an "immune elimination escape" mutant, HBeAg negative lamivudine-resistant HBVs, which replicate more efficiently and produce higher viral loads, may become directly cytopathic. Alternatively, the selection of these viruses means that new viral epitopes may now be presented to the immune system, resulting in increases in necroinflammatory activity.

"Closer virologic and biochemical monitoring of HBeAg negative CHB patients undergoing long-term lamivudine monotherapy would appear warranted. Taken collectively, the clinical and virologic data strongly support the case for the use of alternative drugs and combination chemotherapy. Such strategies can be expected to minimize the long-term risk for the development of drug resistant virus, especially in the setting of HBeAg negative CHB."

01/03/03

Reference
R Chen and others. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology 2003; 37:27-35.


Copyright 2002 by HIV and Hepatitis. All Rights Reserved.

(内部交流)

lxa_008

用金山快译看吧

lxa_008

用金山快译看吧

lion8210

不要急，我尽快翻译出来

lion8210

明天译完，我马上吃饭就去干了

可可

lion8210的译文:


对拉米有抗药性的病人HBV前C区突变并且有高的HBV病毒复制
慢性hbv（CHB）感染是目前世界范围内肝脏疾病和死亡的一个最主要的因素。HBeAg阴性的CHB是由于一种选择引起的，在这种选择中，HBV病毒不能分泌HBeAg。在世界上许多地方，HBeAg阴性的CHB已经成为HBV疾病的主要形式。
很多突变能导致HBeAg阴性CHB，在此之中，最常见的是鸟嘌呤在核苷的G189A位置转变成腺嘌呤。这个转变在前C区蛋白质的第28密码处产生一个病毒停止复制密码，从而导致了前C区蛋白质的过早的死亡。
唯一经过批准的可用于治疗HBV的药物有α－干扰素，拉米和Hepsera（即adefovir）。拉米和Hepsera的效果被认为和α－干扰素差不多，但是比较安全和有容忍性。
不过不幸的，拉米的抗药性随着用药时间的延长而增加，三年后高达66％。YMDD变异是最主要的变异，其赋予了病人对拉米的抗药性并且感染HBV聚合酶蛋白C区的活性YMDD，YMDD变异还会导致残余的蛋氨酸（M）被异亮氨酸或者缬氨酸所取代。
使用拉米后失败的病人通常都会有肝脏疾病的急剧恶化，并且长时间的数据表明，在HBV病毒负担加重的同时，肝脏在组织学上会恶化。
在用拉米治疗HBV过程中，无论是HBeAg阳性还是阴性的病人，他们对拉米的抗药性是以相同速度发展的。在没有前C区变异的情况下，对拉米有抗药性的HBV突变异种在试管中复制得不是很有效；然而，我们并不知道前C区变异的存在是否影响病毒的复制效率或抗原的敏感性。在一篇已经出版的肝脏学研究里，做为一种尝试，一个重组HBV baculovirus 系统已经被用来处理这些问题。
在这个研究中，编码为G1896A 前C区病毒停止复制密码突变的HBV baculoviruses是在抗WT和抗拉米的背景下产生的，由此导致了一个由6个重组HBV baculovirus组成的病毒系列。在试管内，已经进行化验来比较拉米和Hepsera产生的前C区突变病毒的敏感性并且比较它们的相对病毒复制量。
这些化验表明前C区变异对Hepsera或者拉米的敏感性而言都没有显著的影响。WT型HBV和前C区突变异种的HBV有相似水平的病毒复制，但是在HBeAg阳性HBV中，对拉米有抗药性的变异病毒的复制水平大大降低了，不过也不要高兴得太早，前C区变异被发现是用来弥补每一个抗拉米变异病毒复制的不足，从而增加了每一个病毒的复制量。
作者下结论说：“这些观察有直接的临床关联性，这个关联性存在于对HBeAg阴性CHB患者采取拉米治疗的背景下。最近，在一个对希腊的HBeAg阴性CHB患者的研究中，由于HBV对拉米的抗药性的发展之后，几乎一成不变随之而来的就是谷丙转氨酶的升高，Hadziyannis et al. 指出了这个病理学上的突破。
“75％的病人的转氨酶都超过了基准值，并且在大多数病例中达到了正常水平上限的8倍还多，转氨酶的升高比急性肝炎的还要显著。对拉米有抗药性的HBV病毒复制量的恢复中也包含有G1896前C区病毒停止复制密码，其给这些看护的病人的疾病恶化提供了一个可能的基准。、抗拉米HBV病毒，其复制更加有效并且产生更高的病毒负担，可能直接导致了细胞病变。不过，换一个角度来看，这些病毒的选择意味着新的抗原现在可能存在于免疫系统之中，引起坏死炎性组织活性的增加。
对那些长时间来仅用拉米治疗的HBeAg阴性CHB病人的进一步的病理学和生物化学的监控将是正当的、应该的（即我们应该对那些长时间仅用拉米治疗的HBeAg阴性CHB病人进行监控）。总而言之，临床上的和病理学上的数据都强烈地支持在治疗中采取复合化学疗法和使用多种药物。这些策略能够期待使病毒的抗药性发展的长期风险最小化，特别是在HBeAg阴性CHB的背景下（即那些HBeAg阴性CHB患者要特别注意，不能仅仅使用拉米治疗）。

liver411

谢谢lion8210. 辛苦了. 谢谢可可组织.

漏掉一句话补充进去:
"Because the G1896A precore mutant is an "immune elimination escape" mutant,
因为G1896A前C区变异病毒是一个"免疫排除逃逸"变异病毒, 所以...

下面接lion翻译...
HBeAg negative lamivudine-resistant HBVs, which replicate more efficiently and produce higher viral loads, may become directly cytopathic. Alternatively, the selection of these viruses means that new viral epitopes may now be presented to the immune system, resulting in increases in necroinflammatory activity.
抗拉米HBV病毒，其复制更加有效并且产生更高的病毒量，并可能直接导致了细胞病变。不过，换一个角度来看，这些病毒的选择意味着新的抗原现在可能存在于免疫系统之中，引起坏死炎性组织活性的增加。

******

(其实, 无论您用没有用药物, 您有定期做肝脏穿刺检查吗? 这个非常重要)  

消灭HBV

郁闷

小伟

感谢 liver411 、lion8210 、可可！谢谢你们的辛勤劳动！
在这里，让我们看到了最新的资料。
多么希望能看到，完全控制HBV病毒的那一天，即使这一天让偶们苦苦等待.

zhangjinlong

我吃拉米10个月了，虽然由大三转为了小三，但是对于病毒的变异一直很担心。
不知道到时候能不能顺利停掉拉米，郁闷！
    还有如果病毒变异了，病情都会恶化吗？