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回复 中国先生ws 的帖子
替诺福韦才8年, 长期来看仍是未知数.
4.2. Incomplete suppression of viral replication
Although clinical studies on the antiviral efficacy of nucleos(t)ide analogs under the variety of clinical conditions demonstrate striking reduction of viral load in peripheral blood, intrahepatic HBV core DNA and cccDNA are still detectable after long-term antiviral therapy36, 37 and 38. Moreover, sequential accumulation of drug resistance mutations during apparently effective nucleos(t)ide analog therapy provides additional evidence suggesting that residual HBV replication and de novo cccDNA synthesis occur under long-term DNA polymerase inhibitor therapy 57. Interestingly, analyses of viral DNA replication intermediates and core antigen-positive hepatocytes in the livers of WHV-infected woodchucks under the therapy of clevudine demonstrated that after more than 30 weeks of therapy, the predominant WHV DNA species in the liver is cccDNA. However, core-associated viral DNA replication intermediates, such as partial single-stranded DNA, are also clearly detectable. Intriguingly, while the vast majority of hepatocytes become core antigen-negative, a small fraction of hepatocytes expresses core antigen at the level similar to that in the pre-treated hepatocytes 40. This observation indicates that while majority of infected hepatocytes have been cured after long-term nucleoside analog therapy, the residual viral DNA replication and cccDNA synthesis occur in discrete hepatocytes. In another word, the failure to cure HBV infection is most likely due to a fraction of HBV infected cells that are refractory to nucleoside analog therapies.
Why should this be? Because the nucleoside analogs are prodrugs that require activation by host cellular nucleoside kinases in virally infected cells, it is thus possible that the cells refractory to the therapy are incapable of activating the nucleoside analogs. Alternatively, considering the important role of cell division in elimination of pre-existing cccDNA41, it is also possible that the refractory cells are long-live cells and have not divided during the therapy. Nevertheless, further understanding the biological feature of the refractory cell population is important for the treatment of chronic HBV infection.
4.3. Turnover of HBV host cells
The rate of infected cell turnover is one of the key parameters of HBV infection dynamics in vivo. Hepatocyte death, initiated through attack by antiviral cytotoxic T-lymphocytes (CTL), and compensatory hepatocyte proliferation, are both believed to be major contributing factors in the loss of virus DNA during immune resolution of transient infections. Although non-cytolytic cure of infected hepatocytes have been approved to occur, it is estimated that a minimum of 0.7–1 and approximately 2 complete random turnovers of the hepatocyte population of the liver occurs during the resolution of WHV infection in woodchucks 50 and HBV infection in chimpanzees 48, respectively. Hepatocyte turnover also plays an important role in viral pathogenesis and immune selection of hepatocytes infected with mutant strains of HBV and in the emergence of hepatocytes that appear refractory to HBV infection through clonal expansion. Under the condition of therapeutic inhibition of ongoing HBV DNA replication, the rate of HBV infected cell turnover is a critical determinant of cccDNA decay kinetics 41 and 58. Accordingly, hepatocyte turnover has been investigated on the variety of pathobiological conditions by either directly measuring hepatocyte proliferation activity from liver biopsies or mathematic modeling of viral dynamics. These studies from multiple laboratories reveal that while the half-life of hepatocytes in the healthy adult liver is approximately half a year, the median half-lives of infected hepatocytes in patients with chronic hepatitis B are 257 h (=10.7 days) (n=9, range 112–762 h) 59 and 7 days in patients with chronic hepatitis B under lamivudine treatment 60. The results thus imply the overall rate of hepatocyte turnover is significantly accelerated in patients with chronic hepatitis B, which should favor the eradication of cccDNA with viral replication inhibitor therapies.
4.2。病毒复制不完全抑制
虽然对核苷（酸）类似物在各种临床病症的抗病毒效力的临床研究表明撞击外周血减少病毒载量，肝内HBV核心DNA和cccDNA的仍然长期抗病毒therapy36，37和38之后可检测的。此外，耐药突变的过程中明显地有效核苷（酸）的IDE模拟治疗顺序积累提供了额外的证据表明下长期DNA聚合酶抑制剂治疗57.有趣残余HBV复制和从头cccDNA的合成发生，病毒DNA复制中间体的分析并在克拉夫定的治疗下WHV感染土拨鼠肝脏核心抗原阳性肝细胞中证实后超过30周的治疗，在肝脏中主要的WHV DNA种类是cccDNA的。然而，核心相关病毒DNA复制中间体，如部分单链DNA，也清楚地检测到。有趣的是，尽管肝细胞中的绝大多数成为核心抗原阴性，肝细胞的一小部分表示在水平核心抗原类似于在经预处理的肝细胞40这一观察表明，虽然大多数感染的肝细胞的长期之后被固化-term核苷类似物治疗，剩余的病毒DNA复制和cccDNA的合成发生在分立的肝细胞。换句话说，在未能治愈HBV感染是最有可能是由于HBV感染的细胞是难治核苷类似物治疗的一小部分。
这是为什么呢？因为该核苷类似物是那些需要在病毒感染的细胞的激活宿主细胞核苷激酶前体药物，它因此，有可能使细胞难治的治疗是不能激活的核苷类似物。或者，考虑到细胞分裂中消除预先存在cccDNA41的重要作用，它也有可能是在耐火细胞是长活细胞和治疗过程中未划分。然而，进一步理解耐火细胞群体的生物学特征是慢性HBV感染的治疗很重要。
4.3。乙肝病毒的宿主细胞的营业额
受感染的细胞更新的速度是HBV感染动力学体内的关键参数之一。肝细胞死亡，通过攻击抗病毒细胞毒性T淋巴细胞（CTL）和代偿肝细胞增殖发起的，都认为是主要因素在病毒DNA的瞬态期间感染的免疫分辨率的损失。虽然感染的肝细胞的非细胞溶解的固化已获准发生，据估计，最小的肝的肝细胞群体的0.7-1和约2完全随机失误WHV感染在土拨鼠50和HBV感染的分辨率期间发生在黑猩猩分别48。肝细胞周转还在病毒致病和免疫选择感染HBV的突变株，并在出现难治HBV感染通过克隆扩增肝细胞的出现肝细胞中起重要作用。在持续的HBV DNA复制的抑制治疗的情况下，乙肝病毒感染的细胞周转率是cccDNA的衰变动力学的一个关键决定因素41和58。因此，肝细胞的营业额已经研究在各种条件病理学通过直接测量肝细胞增殖活动从肝活检或病毒动力学数学模型。从多个实验室这些研究揭示，尽管肝细胞在健康成人肝脏的半衰期是约半年，感染的肝细胞的治疗慢性乙型肝炎的中位数的半衰期是257小时（10.7天）（N =因此9，范围112-762八）59和7天的患者在拉米夫定治疗60慢性乙型肝炎的研究结果意味着肝细胞周转率整体治疗慢性乙型肝炎显著加快，这应该有利于消灭了的cccDNA与病毒复制抑制剂的疗法。 |
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楼主: 中国先生ws
发表于 2015-7-13 20:18
