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标题: HBV可以治愈吗？谈谈拉米夫丁（3TC）对cccDNA的作用(2005.5) [打印本页]

作者: zasxz 时间: 2005-5-12 22:19 标题: HBV可以治愈吗？谈谈拉米夫丁（3TC）对cccDNA的作用(2005.5)

Is HBV Curable: effect of lamivudine (3TC) on cccDNA


  "Effect of Lamivudine Therapy on the Serum Covalently Closed-Circular (ccc) DNA of Chronic Hepatitis B Infection"

The American Journal of Gastroenterology
May 2005

Man-Fung Yuen, M.D. 1 , Danny Ka-Ho Wong, Ph.D. 1 , Simon Siu-Man Sum, M.Phil. 1 , He-Jun Yuan, Ph.D. 1 , John Chi-Hang Yuen, B.Sc. 1 , Annie On-On Chan, M.D. 1 , Benjamin Chun-Yu Wong, M.D. 1 , and Ching-Lung Lai, M.D. 1

Before reporting on this study here are links to additional reports on cccDNA in HBV:

PegIFN+Adefovir Combination for HBV: cccDNA, seroconversion
http://www.natap.org/2005/EASL/easl_9.htm (EASL Report, April 2005)

Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir therapy (Gastroenterology journal)
http://www.natap.org/2004/HBV/062204_09.htm - 22 Jun 2004

New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA (Journal of Hepatology, March 2005)
http://www.natap.org/2005/HBV/021605_03.htm - 16 Feb 2005

Adefovir Reduced HBV Viral Reservoir & HBsAg in Parallel
http://www.natap.org/2004/DDW/ddw_07.htm - 20 May 2004 (DDW Report, May 2004)

Hepatitis B Report: adefovir; Pegasys (EASL 2002)
http://www.natap.org/2002/easl/day3.htm -- 04 Aug 2004

Quantitation of covalently closed circular hepatitis B virus DNA in chronic hepatitis B patients (Hepatology 2004)
http://www.natap.org/2004/HBV/090304_03.htm - 03 Sep 2004

BACK TO STUDY- Lamivudine & cccDNA

ABSTRACT
OBJECTIVE: To determine the effect of 1-yr lamivudine treatment on serum covalently closed-circular DNA (cccDNA) level.

PATIENTS AND METHOD: Serum total HBV DNA and cccDNA levels at baseline, week 24, and week 52 were measured in 82 lamivudine-treated patients, 17 of whom received 1-yr placebo and acted as controls.

RESULTS: There was a significant reduction in the cccDNA levels from baseline (median 3.0 x 106 copies/ml) to week 24 (33,476 copies/ml) and week 52 (48,694 copies/ml) (p< 0.001 for both). The median reduction in cccDNA level at week 24 and 52 were 2.21 and 2.12 logs, respectively, which were significantly greater than those of controls (0.31 log, p< 0.001; 0.2 log, p< 0.001, respectively). Fifteen patients (18.3%) developed YMDD mutations by week 52. Compared to patients without YMDD mutations, patients with YMDD mutations had significantly less median reduction of total HBV DNA level (4.44 vs 3.65 logs, respectively, p = 0.02) and cccDNA level (2.27 vs 1.65 logs, respectively, p = 0.016) at week 24 and significantly less median reduction of cccDNA at week 52 (2.35 vs 0.8 logs respectively, p< 0.001).

CONCLUSIONS: One-year lamivudine treatment decreased serum cccDNA level by 2 logs. The chance of YMDD mutations at week 52 was related to the magnitude of viral suppression at week 24.

INTRODUCTION
The replication cycle for hepadnaviurses has been fully characterized. Once hepatitis B virus (HBV) enters hepatocytes, the relaxed-circular DNA (rcDNA) of the HBV will convert into covalently closed-circular DNA (cccDNA) inside the nuclei of the infected hepatocytes (1). This process takes place within 24 h upon the inoculation of HBV in the duck model (2, 3). HBV replicates through reverse transcription of the pregenomic RNA produced from the cccDNA template to form a partially double-stranded rcDNA. This in turn either replenishes the depleted cccDNA pool or is secreted outside the hepatocyte as a complete virion after further processing at the endoplasmic reticulum. Since cccDNA does not undergo semiconservative replication, all the cccDNA inside the hepatocytes is derived from viral DNA produced in the cytoplasm. The production of cccDNA is controlled by a negative feedback mechanism dependent on the amount of envelope proteins inside the hepatocytes (4-6). Therefore, complete eradication of HBV not only relies on the inhibition of the active viral replication that will prevent infection of new hepatocytes, but also requires a total elimination of cccDNA in order to prevent the synthesis of new HBV. In cell cultures with undividing hepatocytes as well as in duck HBV studies, cccDNA is found to have high stability (7, 8).

Studies have shown that cccDNA is detectable in the culture medium of 2.2.15 cells-derived from HEPG2 cells, serum of HBV infected rats and serum of HBV patients (9-11). Recently, we have confirmed that cccDNA can be measured in serum of chronic hepatitis B (CHB) patients by using an invader assay (12). The invader assay has also been fully and carefully validated in our previous study (12). More importantly, serum cccDNA levels are found to correlate well with intrahepatic cccDNA levels. This allows for serial assessment of intrahepatic cccDNA levels without the necessity of repeated liver biopsies.

One-year lamivudine treatment is associated with 3 logarithmic reductions of total HBV DNA levels (13, 14). According to studies in woodchuck and duck models, lamivudine in combination with another nucleoside analog or immunomodulator can reduce the cccDNA levels (8, 15). The reduction of cccDNA by lamivudine alone in another woodchuck study is demonstrated to be caused by the loss of hepatocytes rather than an actual decrease in cccDNA content inside the hepatocytes (7). To date, the effect of lamivudine therapy on cccDNA in man is unknown. Yet, clinical relapse of CHB after cessation of therapy is probably due to the reactivation of viral replication from the residual cccDNA inside the hepatocytes (16).

We sought to determine the effect of 1-yr lamivudine treatment on the serum cccDNA levels that may reflect its effect on the intrahepatic cccDNA.

AUTHOR DISCUSSION

It is likely that the majority of cccDNA in the serum originates from infected hepatocytes, which upon cell death release the cccDNA into the circulation. Some other contributions to serum cccDNA may be coming from extrahepatic infected cells such as peripheral blood lymphocytes (19-21).

There were no significant changes in the serum cccDNA levels over a period of 52 wk in the patients receiving placebo. This suggests that the HBV infection was in an equilibrium state in which the rate of replenishment and depletion of cccDNA from hepatocyte cell death were more or less equal.

Studies with the duck and woodchuck models demonstrate that cccDNA levels decrease with lamivudine therapy (8, 15). The decline in cccDNA level is the result of cell death of the hepatocytes in which the active viral replication is halted by lamivudine. Other studies also suggest that cccDNA inside the hepatocytes will also be lost during the process of mitosis (7, 22). To our knowledge, the present study is the first human study to demonstrate that serum cccDNA levels decreased in CHB patients who received lamivudine. Lamivudine probably disrupts the equilibrium state of cccDNA by decreasing the rate of replenishment through inhibition of viral replication in infected hepatocytes. Moreover, nucleoside analogues are also effective in suppressing viral replication in extrahepatic infected cells (23). Irrespective of the sources of serum cccDNA, inhibition of viral replication can be achieved by lamivudine resulting in a significant reduction of serum cccDNA level.

The present study showed that, over a treatment period of 52 wk, the serum cccDNA level decreased by approximately 2 logs. This probably reflects a similar trend of reduction of intrahepatic cccDNA content after 52 wk of lamivudine treatment since we have demonstrated in our previous study that serum cccDNA levels correlate very well with intrahepatic cccDNA levels (12). The measurement of serum cccDNA together with the conventional total serum HBV DNA gives a clearer picture of the decline of HBV replication with nucleoside analogue therapy. Studying the levels of both total HBV DNA and cccDNA in the serum would allow some insight into the decline of both the replicative and nonreplicative form of the virus without the necessity of performing liver biopsies. Since clearance of cccDNA is one of the ultimate aims of the treatment of CHB, estimation of serum cccDNA may provide some indications for the duration of therapy.

The serum total HBV DNA levels increased when YMDD mutations developed though to levels lower than the pretreatment levels. Similarly serum cccDNA levels at week 52 in the 15 patients with YMDD mutations also increased. The median cccDNA level at week 52 for these 15 patients (173,539 copies/ml) was lower than the median level at baseline (924,671 copies/ml), though this was not statistically significant probably due to the small number of patients. This finding is in agreement with the fact that YMDD mutants are less replication competent than YMDD wild type (24, 25). The 67 patients who did not develop the YMDD mutants continued to have further decrease in HBV DNA and cccDNA levels.

Patients with less viral suppression by lamivudine as reflected by lower logarithmic reduction of both the total HBV DNA and cccDNA at week 24 (Table 2& Fig. 2) are associated with a significantly higher chance of development of YMDD mutations at week 52. According to our previous study, high viral load (total HBV DNA level) at 24 wk of lamivudine treatment is associated with a higher chance of subsequent development of YMDD mutation (12). Nucleotide analogue treatment for HBV should target at an early maximal viral suppression to reduce the chance of subsequent development of drug-resistant mutations in the future.

In conclusion, the present study demonstrated that cccDNA could be quantified in serum with significant changes during lamivudine therapy as well as after the development of YMDD mutations. Lamivudine resulted in a decrease in the cccDNA levels by a magnitude of 2 logs. The chance of emergence of YMDD mutations at week 52 was closely related to the magnitude of viral suppression at week 24 of lamivudine therapy. Serum cccDNA monitoring is a potential tool for monitoring antiviral therapy in the future. A reduction to undetectable levels may signify total, or near total, eradication of HBV, though this may require confirmation by intrahepatic cccDNA in liver biopsies.

PATIENTS and METHODS
Patients

A total of 82 patients with CHB infection were recruited in the present study. These patients were from three previous clinical trials NUCB3009, NUCB3018, and NUCB4003, sponsored by GlaxoSmithKline research laboratories. These 3 trials randomized a total of 187 patients to different regimes including lamivudine 25 mg daily for 1-2 yr, famciclovir 500 mg three times daily for 12 wk followed by lamivudine 100 mg daily, or lamivudine 100 mg daily at entry into the trials. Seventeen patients were randomized to receive placebo for 1 yr followed by lamivudine 100 mg daily. The 82 patients recruited in the present study were selected because they were either given lamivudine 100 mg daily at the entry into the trials or placebo for 1 yr followed by lamivudine 100 mg daily. These selection criteria were chosen in order to obtain a homogenous population who received either lamivudine 100 mg daily or placebo. The entry criteria for trial NUCB3009/3018 were: patient >=16 yr old, positive hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) for at least 6 months, HBV DNA levels >=1.4 x 106 copies/ml by solution-hybridization assay (Abbott Diagnostics, Chicago, IL) and ALT levels <= 10 x upper limit of normal (ULN) (13). The entry criteria for trial NUCB4003 were: patient >= 16 yr old, positive HBsAg and HBeAg for at least 6 and 3 months, respectively, detectable HBV DNA levels by branched DNA assay (Bayer Corporation, NJ) (lower limit of detection 0.7 x 106 copies/ml), and ALT levels between 1.3-10 x ULN (17). All three trials were approved by the Ethics Committee of the University of Hong Kong, Hong Kong, and were conducted in the Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Sixty-five of these patients were randomized on lamivudine 100 mg daily at the beginning of the trial. The remaining 17 patients were randomized to receive placebo during the first 52 wk and subsequently received lamivudine 100 mg daily. Total HBV DNA and cccDNA levels of these 17 patients during the initial 52 wk on placebo acted as control for comparison with the values obtained during 52 wk of lamivudine treatment (that is the second year data of these 17 patients receiving lamivudine 100 mg for the first time after week 52 together with the initial 52-wk data from the other 65 patients).

The clinical profiles and liver biochemistry of the patients were monitored. Serum taken and stored at -70¡C at baseline (before the first dose of lamivudine), week 24, and week 52 were thawed to measure total HBV DNA and cccDNA levels.

Measurement of Serum Total and cccDNA Levels

The serum total HBV DNA levels were measured by the Cobas Amplicor HBV Monitor test (Roche Diagnostics, Branchburg, NJ) (lower limit of detection of 200 copies/ml).

The serum cccDNA was measured by the Invader¨ HBV DNA assay (Third Wave Technologies, Inc., Madison, WI), which has a lower limit of detection of 104 copies/ml. The detailed methodology was described in a previous paper (12).

Determination of YMDD Mutations

The mutations of the tyrosine, methionine, aspartate, aspartate (YMDD) motif [methionine either substituted by isoleucine (rtM204I) or valine (rtM204V)] in the C domain and leucine substituted by methonine (rtL180M) in the B domain of the HBV DNA polymerase gene were determined in all the lamivudine-treated patients at week 52 by the line probe assay (INNO-LiPA HBV DR, Innogenetics NV, Belgium) as described in our previous study (18).

Statistical Analysis

The data was analyzed by the Mann-Whitney test for the continuous ordinal data, chi 2 test with Yates' correction, and Fisher exact test for the association between two qualitative variables. The differences in paired samples were tested by Wilcoxon signed ranks test. p-Values of less than 0.05 were considered as statistically significant.

Demographics

The demographic data and the liver biochemistry of the 82 patients (65 on lamivudine 100 mg daily from the start of the trials, and 17 on placebo for 52 wk followed by lamivudine 100 mg daily) are listed in Table 1. There were no differences in the parameters between the two groups of patients (all p = NS).

Total HBV and cccDNA Levels on Placebo

For the 17 patients on placebo for 52 wk, there were no significant changes in the median total HBV DNA level and cccDNA level from baseline to week 24 and to week 52 [total HBV DNA: 7.7 x 107 (range 1.7 x 105 to 3.5 x 1011) vs 3.2 x 106 (range 18,500 to 2.9 x 1011) and vs 5.1 x 108 (range 17,000 to 5.1 x 1011) respectively, p = 0.41 and 0.49 respectively; cccDNA: 4.9 x 106 (range 0 to 7.3 x 107) vs 1.8 x 105 (range 0 to 3.7 x 107) and vs 8.6 x 105 (range 0 to 2.6 x 107) respectively, p = 0.10 and 0.11, respectively].

Total HBV and cccDNA Levels of Patients on Lamivudine for 52 Wk

For the 82 patients receiving lamivudine, there was a significant reduction in the total HBV DNA levels from a median level of 1.58 x 109 (range 17,600 to 5.3 x 1011) copies/ml at baseline to a median level of 66,600 (range <200 to 2.52 x 1010) copies/ml at week 24 (p< 0.001) and a median level of 169,000 (range <200 to 2.45 x 1010) copies/ml at week 52 (p< 0.001). There was also a significant reduction in the cccDNA level from a median level of 3.0 x 106 (range <10,000 to 6.15 x 107) copies/ml at baseline to a median level of 33,476 (range <10,000 to 1.63 x 107) copies/ml at week 24 (p< 0.001) and a median level of 48,694 (range <10,000 to 5.6 x 106) copies/ml at week 52 (p< 0.001).

Comparisons of HBV DNA and cccDNA Levels between Patients on Lamivudine and Placebo

The median total HBV DNA and cccDNA levels at baseline, week 24, and week 52 in lamivudine treated patients and control patients are plotted in logarithmic scale in Figure 1. Patients receiving lamivudine had a significantly greater reduction of median logarithmic total HBV DNA levels at week 24 and week 52 compared to those of control patients [4.4 (range -0.55 to 7.07) vs 0.64 (range -0.78 to 2.86), respectively, p< 0.001 at week 24; 4.1 (range -0.76 to 7.64) vs 0.13 (range -3.63 to 2.19), respectively, p< 0.001 at week 52]. Similarly, lamivudine treated patients had a significantly greater reduction of median logarithmic cccDNA levels at week 24 and week 52 compared to those of control patients [2.21 (range -2.1 to 7.45) vs 0.31 (range -0.84 to 7.87) respectively, p< 0.001 at week 24; 2.12 (-0.93-7.35) vs 0.20 (range -1.07 to 3.05) respectively, p< 0.001 at week 52].

Effects of YMDD Mutations on cccDNA Levels

Fifteen patients (18.3%) developed YMDD mutations by 52 wk. Of these, six patients (40%) also had the concomitant mutations of rtL180M. The median logarithmic reduction of cccDNA at week 52 was significantly less in patients with YMDD mutations compared to patients without YMDD mutations [0.80 (range -0.58 to 6.17) vs 2.35 (range -0.64 to 7.35), respectively, p< 0.001] (Fig. 2). Though the median cccDNA level at week 52 in the 15 patients with YMDD mutations was less than that at baseline [173,539 (range <10000 to 3,551,992) vs 924,671 (range 108,149-31,209,948) copies/ml respectively], the difference was not statistically significant (p = 0.36). Patients with subsequent development of YMDD mutations by week 52 in fact already had a lower median logarithmic reduction of cccDNA at week 24 than patients without YMDD mutations [1.65 (range -0.27 to 6.17) vs 2.27 (range -0.21 to 7.35) respectively, p = 0.015] (Fig. 2).

Effects of Total HBV and cccDNA Reduction at 24 Wk on the Development of YMDD Mutations

Compared to patients without YMDD mutations at week 52, patients with YMDD mutations at week 52 had a significantly lower median logarithmic reduction of total HBV DNA levels and cccDNA levels at week 24 [total HBV DNA: 4.44 (range -0.24 to 7.07) vs 3.65 (-0.55 to 6.84), respectively, p = 0.02; cccDNA: 2.27 (-0.21 to 7.45) vs 1.65 (range -0.07 to 6.17), respectively, p = 0.016)]. The chances of YMDD mutations at week 52 for patients with respect to the different magnitude of logarithmic reduction in the total HBV DNA levels and cccDNA levels at week 24 are listed in Table 2. These data suggest that greater viral suppression as reflected by total HBV DNA and cccDNA at week 24 was associated with a lower chance of YMDD mutations at week 52.

REFERENCES

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作者: baobao7676 时间: 2005-5-19 14:07

太好了。完全符合我的预期！预感只要能够用序贯疗法，5年后我的HBV必除！

作者: 特深沉 时间: 2005-5-19 14:43

恐怕5年的时间太短，而且靠抑制根除也不现实，还是要想办法启动自身免疫机制，

或者能够复制抗体输入。

作者: zhangmy 时间: 2005-5-20 00:18

晕，跟看天书一样，有中文的吗？麻烦您给简单介绍一下可好。多谢

作者: baobao7676 时间: 2005-5-20 09:13

5年常规抑制复制治疗未必可以清除。但通过加强免疫机制，把体内的清除速度加快3倍是很容易做到的。如此一来，5年后的cccDNA就只有1000以内了。到时候身体内的抗体可以产生，阻止细胞间的HBV渗透，HBV就真正痊愈了。

作者: 特深沉 时间: 2005-5-20 12:43

我相信可以让cccDNA少到一定程度，但“到时候身体内的抗体可以产生”，可不一定吧，

怎样的机制来产生抗体呢？

作者: baobao7676 时间: 2005-5-20 13:17

抗体的产生其实是一直进行的。一般有几个办法可以产生抗体：

一是让抗原突然放量，刺激人体免疫系统让抗体激增，老王的故意停拉米就有这样的含义，随后在加拉米镇压，抗原减少后，抗体就出现了剩余；

二是逐步减少抗原的数量，抗体从被耗竭，转成逐渐出现盈余。许多小山羊战友就是这种情况，但要HbsAg的抗体出现，需要平均5年时间。拉米的大规模应用至今不过4年，侥幸躲过变异的少之有少，相信今后几年会有更多的战友报告胜利的喜讯；

三是注射大量抗原，人为刺激人体应激反应，最终产生抗体。大量注射疫苗、乙克等就是类似的思路。这一类的应用条件是体内的抗原浓度不高。

作者: 特深沉 时间: 2005-5-20 14:44

"抗体的产生其实是一直进行的" ,这个结论有出处吗？

是你自己的猜测还是医学界的共识？我怎么没看到过这种论断呢？

作者: hanfeng118 时间: 2005-5-20 23:12

。。。。。。

作者: 黑山羊 时间: 2005-5-21 00:28

以下是引用特深沉在2005-5-20 1:44:12的发言：
"抗体的产生其实是一直进行的" ,这个结论有出处吗？

是你自己的猜测还是医学界的共识？我怎么没看到过这种论断呢？

想请问一下特板，5年后的cccDNA就只有1000以内了。最长时间打乙肝球蛋白，能把HBV灭了吗？

作者: 特深沉 时间: 2005-5-21 01:17

至少目前没有任何证据表明，cccDNA少到一定程度，抗原会自动消失，或者抗体会自动产生。

不过，也没有长期使用核苷贯序疗法的经验，毕竟阿迪夫为才刚上市，一切都还刚开始。或许

今后才知道长期抑制病毒的远期效果。

作者: starlight 时间: 2005-5-21 04:34

目前还没有能将ccc-dna减少到一定数量的确切手段，所以当然无法证明 “cccDNA少到一定程度，抗原会自动消失，或者抗体会自动产生。”

但是

1、每年有少量小三阳转阴，产生抗体

2、几乎所有的乙肝携带者肝穿检查都有不同程度的炎症表现

可以作为 "抗体的产生其实是一直进行的" 的间接证据。

作者: 特深沉 时间: 2005-5-21 12:38

我过去就跟王震宇的贴子说过: 炎症反应,不一定是免疫机制的因素, 病毒感染本身可造成细胞坏死, 导致炎症.

作者: 特深沉 时间: 2005-5-21 12:40

如果炎症进展是自身免疫作用,那么, 就有希望在长期抑制病毒后,达到一个拐点.

作者: 特深沉 时间: 2005-5-21 12:41

如果这样说,还是有清除的一天.

作者: starlight 时间: 2005-5-21 22:39

以下是引用特深沉在2005-5-20 23:37:42的发言： 我过去就跟王震宇的贴子说过: 炎症反应,不一定是免疫机制的因素, 病毒感染本身可造成细胞坏死, 导致炎症.

我不这么看。

如果是病毒感染本身可造成细胞坏死, 导致炎症，那么炎症反应应该与病毒量呈正相关，然而事实并非如此。有的人体内病毒量长期维持高水平，却仍然肝功正常，仅肝穿检查发现炎症反应。

我认为炎症反应应该与免役功能有关。要是有一种检测手段能检测出免役复合物，即可作为一个直接证据。

作者: 特深沉 时间: 2005-5-22 00:35

如果我们也有免疫反应，但抗体数量不足，那么，经过长时间的抑制病毒，

也许有拨乱反正的一天。

作者: 候月 时间: 2005-5-22 11:32

问题是我们有什么办法能够达成长时间抑制病毒呢？我总觉得，如今有了阿迪之后，大可以如此一试：（拉米）9个月+（阿迪）3个月=N。只要DNA长阴，数年之后必有奇迹。

作者: baobao7676 时间: 2005-5-23 12:15

不好意思。抗体一直在产生，是我的推断。

目前在医学界没有人体内大分子的代谢图谱。关于抗原在体内的消失机制，已知的只有这一种：和抗体结合成抗原-抗体复合物，最后被巨噬分子清除。从这一点我推测体内的抗体产生速度和抗原产生速度一样！否则抗原就会一直增加。而一个病情平稳的人，抗原浓度在相当长的时间内是稳定的。

作者: 特深沉 时间: 2005-5-23 13:27

“否则抗原就会一直增加。而一个病情平稳的人，抗原浓度在相当长的时间内是稳定的。”

这个推断比较有意思。是什么在限制抗原的浓度持续增加呢？显然存在一个制约因素。

也许是抗体吧。我再想想还会有什么机制在限制抗原的持续增长。

作者: starlight 时间: 2005-5-23 21:09

以下是引用特深沉在2005-5-23 0:27:29的发言：
“否则抗原就会一直增加。而一个病情平稳的人，抗原浓度在相当长的时间内是稳定的。”

这个推断比较有意思。是什么在限制抗原的浓度持续增加呢？显然存在一个制约因素。

也许是抗体吧。我再想想还会有什么机制在限制抗原的持续增长。

竞争。病毒之间的竞争。

人体内的抗体既然不能在病毒量低的情况下抑制，当然更不可能在病毒量高的情况下抑制。

作者: starlight 时间: 2005-5-23 22:15

天然免疫应答与清除HBV有关

解放军第302医院病毒性肝炎和艾滋病重点实验室王福生博士报告了天然免疫应答在清除HBV中的作用。

人体抗病毒感染的天然免疫应答可能决定病毒感染的临床结局和预后。浆细胞样树突状细胞DC(pDC)是人体天然免疫应答的主要组成部分。

王福生等进行的研究显示，在HBV慢性感染患者(120例)中，pDC细胞数量和功能明显降低，与健康人群相比有显著的差异(P<0.05)。而在急性肝炎患者血液中pDC水平相对较高(但是也低于健康人群)。

慢性乙肝经过拉米夫定抗病毒治疗后，病毒载量降到检测水平以下时，pDC细胞数量升高。由此可见，pDC在机体受到病毒感染的过程中可能有重要的防御作用。

慢性肝炎患者均有不同程度的pDC数量和功能的下降，后者是机体发生机会性感染的必要条件。因此，HBV慢性感染患者的特异性免疫应答和天然免疫均受到严重的损伤，从而使病毒不断复制，形成HBV持续感染，导致病程慢性化。

王福生等进行的研究还显示，慢性重型乙肝和肝癌合并慢性乙肝患者外周血中宿主调节性CD4+CD25+ T淋巴细胞(Treg)数量增加，其中慢性乙肝患者肝组织中浸润的Treg数量增加更明显。慢性乙肝合并肝癌患者外周血Treg细胞FOXP3表达水平升高，并可部分抑制CD3抗体介导的淋巴细胞增殖反应，提示慢性乙型肝炎患者对HBV产生免疫耐受可能与调节性T细胞有关。

深入了解关于抗病毒性肝炎的天然免疫应答，不仅有助于阐明HBV的免疫致病机制，而且还能够指导临床科学地开展抗病毒药物治疗，同时对建立新型免疫细胞治疗方案也有直接的帮助。

作者: baobao7676 时间: 2005-5-24 11:18

楼上所谓的免疫应答最终清除病毒的机制仍旧是清除被感染细胞，并不能解答抗原往何处去的问题。

抗原浓度在体内的相当长时间内维持稳定，充分说明他的产生速度等于清除速度。如果一种机制能够抑制抗原的生成或降低生成速度，抗体就会多出来。我深信大三只要不变异，持续拉米后变小三是必然的，小三阳持续拉米转阴也是必然的。

作者: starlight 时间: 2005-5-24 22:32

病毒的复制不可能是无限制的。随着病毒量的增多，对于复制原料的需求就增大，然而供给并不会随之增大，当需求与供给达到平衡时，病毒量也就恒定了。

同时，病毒可能会产生一种物质来抑制别的病毒的复制，当这种物质达到一定浓度时，就起到了抑制作用。（纯属猜测）

人体内产生的抗体数量之小，可忽略不计，且产生多少就被病毒中和多少。在病毒量很高且能源源不断产生的情况下，提高免疫力是没有意义的，除非提高的免疫力能超过病毒的复制能力。但是如果病毒的复制被抑制在一个很低的水平，跟免疫力相当，这时提高免疫力就有非常大的意义。但各人的情况不同，有的人免疫力足够高，可以清除病毒，有的人免疫力不够高，就只能长期抗战了，即使这时病毒已被抑制在一个极低水平。

作者: shimboo 时间: 2005-5-25 01:56

好贴！

抗原浓度在体内的相当长时间内维持稳定，应该是竞争和人体的免疫反应都有功劳的。无论是否能彻底清除HBV，续惯疗法都是一个值得尝试的方法。

作者: as100200 时间: 2005-5-25 06:30

我总觉得要转阴、产生抗体，必需速战速决（半年时间左右）。治疗时间一长，问题就多了。

我所了解的，急性感染后转阴、某些慢性乙肝急性发作后转阴以及拉米或干扰素治疗后转阴的大多是约半年时间迅速治愈。

作者: ardejiang 时间: 2005-5-28 02:50

以前也看到相类似的统计。但是又有谁愿意拖这么长时间呢。如果能有效缩短治疗时间该多好！！！

作者: 蓝芝 时间: 2005-5-30 05:06

那么（1阳，4阳，5阳），变为（1阳，4弱阳，5阳）

在不用药的情况下是不是因为自身抗体在清除病毒呢？

[此贴子已经被作者于2005-5-29 16:06:51编辑过]

作者: 候月 时间: 2005-5-31 05:16

看来，“地丁合一”（阿地＋贺普丁）似乎令长期抗病毒成为可能。国内的商家是否可以考虑把它们做成一粒药呢？明年专利期一到，就抛出来，另起名，售价每粒10元左右，那就相当不错。

作者: jackwen 时间: 2005-5-31 12:01

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