麻烦翻译一下. 谢谢.

liver411

这是个52岁ALT正常, HBV DNA稍微高...的患者...的病例探讨...不错的...我放上一点点字明天. 花猫可以翻译...

Case Study A: History and Physical

Dr. Afdhal: Clinical medicine, like baseball, throws you a lot of curves, and it is not always as easy as the algorithms presented and the data that we have seen may suggest. Many times the decisions are much more complex than that

[upload=jpg]uploadimages/20058/200581016530464.jpg[/upload]

Dr. Afdhal: I am going to use 2 cases to illustrate many of the issues that were brought up by the other faculty to see how we can use evidence-based medicine and some of our clinical knowledge to deal with true patient cases.

[upload=jpg]uploadimages/20058/200581016530630.jpg[/upload]

Dr. Afdhal: The first case is a 52-year-old male, born in China, who was diagnosed with hepatitis B virus (HBV) infection 5 years previously; he is completely asymptomatic and not taking any other medications.

[upload=jpg]uploadimages/20058/200581016530535.jpg[/upload]

Dr. Afdhal: He works as a teacher. His brother and sister both have documented HBV infection; one is on treatment. There is no history of liver cancer in the family.

[upload=jpg]uploadimages/20058/200581016531132.jpg[/upload]

Dr. Afdhal: He was seen by his referring doctor, who had documented, over a period of approximately 6 months, several occasions when the alanine aminotransferase (ALT) varied between 224 and 160 IU/L. His physical examination was completely unremarkable. As was appropriate, the doctor referred him for evaluation by a specialist.

[upload=jpg]uploadimages/20058/20058101653171.jpg[/upload]

Dr. Afdhal: Surprisingly, when we saw him, his ALT was 23 IU/L. His aspartate aminotransferase (AST) was 21 IU/L. He was HBV early antigen (e-antigen) negative and HBV e-antigen antibody (anti-Hbe) positive. Data were not available to us from before. His HBV DNA was low -- lower than the 10⁴ copies/mL cutoff, as discussed by Dr. Schiff -- at 5000 copies/mL. His hepatitis A virus (HAV) antibody test was positive; his hepatitis C virus (HCV) and human immunodeficiency virus (HIV) test were negative. As Dr. Dieterich said, you have to check for the other viruses.

We were in a dilemma. Is this a recent seroconversion -- high transaminases and now e-antigen negative and anti-Hbe positive -- or is this a nonreplicating precore mutant? Dr. Schiff, what do you think?

Dr. Schiff: On physical examination, could you feel his liver?

Dr. Afdhal: No. His physical examination was unremarkable.

Dr. Schiff: If you felt his liver, in a man like this, and it was firm and enlarged, you would know that he is flip flopping; this is part of the natural history of HBV, particularly in Asia. Someone caught him when he had enzyme elevation; When Dr. Afdhal gets him, he is e-antigen negative and has normal enzymes. I would definitely treat him; I would most likely biopsy him, but I would not argue with somebody who did not.

Someone may say, "I'll observe and wait until he reactivates." When you say that, you had better be following him because sometimes patients do not come back until they get jaundice.

I would be very concerned about him; I would want to treat him. But, if you do not, you have to observe him closely. You might want a liver biopsy here, because this man is probably going to have significant scarring.

Dr. Afdhal: Dr. Schiff is forgetting to mention, and the algorithm clearly states, that in this case -- with e-antigen negative, a low viral load, and a normal ALT -- we should observe. We followed the algorithm, and we observed this patient, as we should have.[br]

[此贴子已经被作者于2005-8-11 8:40:02编辑过]

liver411

[upload=jpg]uploadimages/20058/2005810161214991.jpg[/upload]

Dr. Schiff: This is what happened?

Dr. Afdhal: No, this is not what happened. This is merely to remind us how the antigen is processed; how it is processed is part of the replication of the virus. As we transcribe the core gene, the e-antigen is secreted into the serum; and there is the subgroup of patients who are e-antigen negative, but have active viremia.

[upload=jpg]uploadimages/20058/2005810161214220.jpg[/upload]

Dr. Afdhal: The patient did return, and when he came back, he was somewhat symptomatic, complaining of pain, fatigue, and some nausea. He had, at this time, a mildly enlarged liver. His ALT was 179 IU/L; his AST was 136 IU/L. He was still e-antigen negative -- not flip flopping, as is obviously a concern -- and still anti-HBe positive. His HBV DNA at this time had climbed from the prior 5000 copies/mL to 50 million copies/mL (7.7 log₁₀ copies/mL). Dr. Schiff, what do you think is happening now?

Dr. Schiff: There is no question, I would treat him. I would probably biopsy him, too.

[upload=jpg]uploadimages/20058/2005810161214314.jpg[/upload]

Dr. Afdhal: We felt, yes, this was exactly what we should do. We did a liver biopsy, and it showed some liver disease with grade 1, stage 1 disease, and ground-glass hepatocytes showing active viral replication. The ground-glass hepatocytes are filling up the cytoplasm of the hepatocytes

[upload=jpg]uploadimages/20058/2005810161214896.jpg[/upload]

Dr. Afdhal: One of the issues that the patient wanted to know, and we wanted to know: is this a flare of wild-type HBV, or is this a precore mutant? It is easy to talk about precore mutants and core promoter mutants, but we do not really have clinical tests that tell us whether patients have these; we have to go on clinical judgment. This is an important decision, because it is going to affect what treatment we use in terms of the treatments available to us, as listed. Dr. Keeffe, are we dealing with a precore mutant or somebody who is flip-flopping and flaring back, or a wild type?

Dr. Keeffe: To recheck the e-antigen and the anti-HBe might help to see whether he is e-antigen positive. My guess is that this is a precore-core promoter mutant. The dilemma is one that we all face. Is this an inactive carrier -- as evidenced the first time that you saw this patient -- or is this a patient who is an e-antigen negative chronic HBV patient, who we know has fluctuating liver enzymes and DNA levels? You caught him at a nadir; then he comes back, and he is active. My guess is that he is a precore-core promoter mutant who was in an inactive phase when you first saw him.

Dr. Dieterich: Dr. Keeffe, would the biopsy have helped at that point?

Dr. Keeffe: There are 2 options. When you first saw the patient, you could have jumped in and done a biopsy to see if there is disease. Or, you could have had serial visits over the course of a year to get a sense of whether it is inactive or whether it is a precore mutant.

Dr. Schiff: But clearly, he is not asymptomatic because you already had the information. His ALT levels have been up for 6 months, so you know that he was fluctuating.

Dr. Keeffe: Yes, and for that reason, you could have jumped in right from the start.

Dr. Afdhal: Yes, even with a low viral load, we considered that because of the high ALT. This clearly demonstrates that you have to follow these patients and that they do have "yo-yoing" ALTs. He was still persistently e-antigen negative and anti-HBe positive. Because the clinical decision -- whether this is a precore mutant -- is an important one, we felt that we should call this a precore mutant when we came to our treatment decisions.

This is important. Because of that, I want to review briefly some of the data we have on the clinical trials in precore mutants.

[upload=gif]uploadimages/20058/2005810161214900.gif[/upload]

Dr. Afdhal: These are the interferon data from a meta-analysis of the e-antigen negative presumed precore mutants. With 6 to 12 months of interferon therapy, compared with controls, there is an ability to reduce HBV DNA below the lower limits of quantification -- which in these studies was at the 10⁵ copies/mL level and, obviously, is an issue with these studies -- and you can normalize ALT to below the upper limit of normal. You can achieve both in about 24% of patients, and in some patients, there is even associated HB surface antigen loss.

[此贴子已经被作者于2005-8-11 8:44:27编辑过]

wwqm

以下是引用liver411在2005-8-10 14:41:53的发言：

Case 2.病理二

The second Chinese patient was a 17-year-old male randomized to receive 500 mg famciclovir three times a day in September 1997 for 12 weeks, followed by 100 mg of lamivudine daily. He was found to be HBsAg positive by screening his blood for donation at age 16.

第二名中国患者是一名17岁男性, 自1997年9月被任选临床试药服用泛昔洛韦500毫克每天三次, 为期12周, 之后改用拉米夫定100毫克每天一次. 他是在16岁一次献血筛检中检查到HBeAg阳性.

He had HBV genotype C. The pretreatment liver biochemistry was as follows: albumin, 50 g/liter; bilirubin, 8 umol/liter; ALT, 59 U/liter. The HBV DNA level measured by the Cobas Amplicor HBV Monitor test was 6.7 x 10 6 copies/ml. The HBV DNA level decreased to 2.1 x 10 4 copies/ml at month 6 of therapy. He had follow-up every 8 weeks under the trial protocol till week 48. From then onwards, he had regular follow-up every 3 to 6 months in our Hepatitis Clinic, Queen Mary Hospital, The University of Hong Kong.

他感染的HBV病毒基因是C型. 治疗前肝脏生化为: 白蛋白50g/liter, 单红素8umol/liter, ALT59U/liter. HBV DNA水平使用Cobas Amplicor HBV Monitor方法检验是6.7X 10 6 拷贝/毫升. HBV DNA水平在治疗后6个月时减低至2.1X10 4 拷贝/毫升. 之后, 根据试药规定每8周检查一次, 直到第48周为止. 从48周起, 他每3-6个月去香港大学附属皇后玛丽医院肝脏诊所复查一次.

He had fluctuating ALT levels, ranging from 29 to 132 U/liter before achieving HBeAg seroconversion at month 15 of therapy (December 1998). The HBV DNA level was undetectable at the time of HBeAg seroconversion. HBsAg became negative at 27 months (at 19.3 years of age; December 1999). Lamivudine was maintained after HBeAg seroconversion but was stopped after 30 months of therapy on the patient's own initiative (March 2000). Anti-HBs was detectable at the titer of 421.2 MU/liter at the last follow-up (71 months; at 22.9 years of age; August 2003).

在第15个月HBeAg转阴(1998年12月)前, 他的ALT属于上下波动, 持续在29-132U/liter之间. HBV DNA在HBeAg转换的时候监测不到. HBsAg在第27个月的时候(19.3岁, 1999年12月)转阴. 拉米在HBeAg转阴后继续服用, 直到30月时候在患者的要求下停药(2000年3月). HBsAb在最后一次检查(第71个月, 在22.9岁, 2003年8月)时候为421.2MU/liter.

He had persistent normal ALT levels till the last follow-up. The latest liver biochemistry was as follows: albumin, 11 umol/liter; ALT, 12 U/liter. The serum HBV DNA was undetectable. The option of liver biopsy was declined by the patient. 其ALT直到上次检查时候维持正常. 最后一次肝脏生化检查为: 白蛋白11umol/liter, ALT12U/liter. HBV DNA为监测不到. 给与患者感穿检查的机会被患者拒绝.

奇怪的是最后一次的白蛋白是否正确, 11? 应该求证那个Dr之后改掉再发表.

抱歉, 是我打字错误. 应该是白蛋白43 g/liter, 胆红素11 umol/liter, ALT, 12 U/liter. 我已经把相关的地方改过来了. 再次表示感谢.

wwqm

411先生提供了这么多好文章, MAYMAY要是翻译过来我会把他们放到病友交流的置顶帖中的. 但是411先生和MAYMAY都应该注意休息. 再次致谢.

彩虹玫瑰

谢谢411先生的翻译

真惭愧，今天我试着去翻译的时候，一些词语，我根本无法查到它的意思

正准备让一位学医的朋友帮忙翻译

谢谢对英文版的支持

流浪花猫

以下是引用liver411在2005-8-10 15:28:29的发言：

SORRY! You may do this one, pretty good article...

Highlights in Hepatitis B Therapy -- Clinical Efficacy and Patterns of Viral Resistance

B型肝炎治疗会议文献——临床效益和病毒模式

Disclosures

George V. Papatheodoridis, MD

Boston, Massachusetts; Monday, November 1, 2004 -- Researchers and clinicians from all over the world presented many exciting original studies during this year’s meeting of the American Association for the Study of Liver Diseases. The management of chronic hepatitis B, which is a rapidly evolving field in hepatology, was the main focus of several emerging presentations. This commentary explores the key issues of these clinically important reports on the management of chronic hepatitis B, as presented during the core meeting proceedings.

马萨诸塞州，波士顿，2004年11月1日星期一，来自全球的临床医师和研究人员在今年的美国肝脏疾病研究协会的会议提出很多令人激动的新颖研究。慢性B型肝炎的处理， 这在肝脏病学里将是一个迅速逐步形成的领域， 介绍几个独特的主要焦点。会议核心审理评论探讨临床医生处理关于慢性乙型肝炎重要报告的关键问题。

Clinical Efficacy

临床效应

The development and approval of oral anti-hepatitis B virus (HBV) agents, lamivudine, and more recently adefovir dipivoxil, revolutionized the treatment of chronic hepatitis B and has offered effective therapeutic options for almost all patients with this disease. In addition to these 2 drugs, several newer agents are currently under evaluation, but today’s sessions only included the results of 2 studies on the clinical efficacy of anti-HBV agents, and therefore this commentary will address these reports.

正式批准用于治疗病毒性B肝（HBV）的药物，拉米夫定，和近期的阿德福韦，绝大部分B型慢性肝炎可在临床治疗上提示有效。
另外两只药，NEWER AGENTS仍在评估，但当日会议仅包括在抗-HBV的 2项研究的结果临床效应？（什么意思）因此这项评估加入报告。

Shouval and colleagues^[1] presented the results of a 48-week, phase 3 trial of entecavir vs lamivudine in 648 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Entecavir (0.5 mg/day) compared with lamivudine (100 mg/day) was associated with more frequent histologic improvement (70% vs 61%; P = .014), greater reductions in serum HBV-DNA < 400 copies/mL (91% vs 73%; P < .0001), and with achievement of the composite endpoint (HBV-DNA < 700,000 Eq/mL and alanine aminotransferase [ALT] normalization [84% vs 78%; P = .04]). There was similar fibrosis improvement (36% vs 38%, entecavir vs lamivudine, respectively) among both treatment groups. No resistance to entecavir was detected. Thus, entecavir appears to offer a benefit over lamivudine in the treatment of HBeAg-negative chronic hepatitis B.

HOUVAL 和其同事提供一项48周的结果，在648位B型慢性肝炎，E抗原 (HBeAg)阴性患者的恩卡韦对拉米夫定的三个试药状态。恩卡韦每天0。5MG联合拉米夫定每天100MG发生组织改善，（70%VS61%），血清HBV-DNA < 400 copies/mL (91% vs 73%; P < .0001), 复合的终点？结果(HBV-DNA < 700,000 Eq/mL以及ALT正常。[84% vs 78%; P = .04]). 纤维化改善(36% vs 38%,分别为恩卡韦VS拉米夫定，）没有发现恩卡韦抗药性，因此，恩卡韦在B型慢性肝炎E抗原阴性治疗上有效益于拉米夫定。

Adefovir has been approved for the treatment of chronic hepatitis B in western countries, but is not yet approved in China. The initial results of a 5-year controlled trial of this agent in 480 Chinese patients with HBeAg-positive chronic hepatitis B were reported by Zeng and colleagues.^[2] At 12 months, treatment with adefovir (10 mg/day) achieved reductions in serum HBV-DNA by 4.5 log₁₀ copies/mL; HBV-DNA response (< 100,000 copies/mL) was achieved in 98% of patients, and ALT normalization was achieved in 79% of patients. Thus, the efficacy of adefovir was confirmed in Chinese patients with chronic hepatitis B, a population that is considered to represent a difficult-to-treat HBV clinical setting.

阿德福韦已在西方国家批准用于治疗慢性B型肝炎，但在中国仍未被核准。Zeng 和 同事的最初5年在480位中国B型慢性肝炎E抗原阳性患者试验结果报告上。阿德福韦每天10MG，治疗12个月，血清HBV DNA减少达到4.5 log10 copies/mL，患者HBV DNA应答达98%，ALT复常达79%，因此，证实阿德福韦对中国B型慢性肝炎患者有效。

Issues in HBV Resistance

The primary disadvantage of antiviral agents is that they have to be administered for long periods. In particular, in HBeAg-negative chronic hepatitis B, antiviral agents may have to be given indefinitely in order to maintain on-therapy remission, because relapses are observed in the majority of patients who discontinue treatment. Any form of long-term antiviral therapy, however, may be associated with development of viral resistance. The problem of resistance is very frequent and progressively increases with prolongation of lamivudine therapy (> 50% at 3 years), but is infrequent with adefovir therapy (approximately 6% at 3 years). Because emergence of resistant HBV mutants is the main factor limiting the efficacy of antiviral therapy, many investigators focus on the elucidation of this clinical issue.

In this setting, resistance to adefovir has been associated with emergence of the rtN236T or rtA181V mutation in the HBV polymerase gene, but the effects of these mutations on viral sensitivity have not been clarified. Locarnini and colleagues^[3] used site-directed mutagenesis and created a panel of HBV mutants containing rtN236T or rtA181V with either wild or mutant (G1896 stop codon mutation) precore region. Both mutations caused small decreases in sensitivity to adefovir; the rtN236T mutation decreased sensitivity by 6.7-fold irrespective of the precore region and the rtA181V mutation by 1.6-fold in precore wild, and by 3.6-fold in precore mutant strains. All of these HBV strains remained relatively sensitive to lamivudine or tenofovir, with the rtN236T precore mutant strain being the least sensitive.

Bartholomeusz and colleagues^[4] analyzed the mechanism of adefovir resistance using molecular modeling and in vitro functional analysis. They showed that adefovir resistance mutations clustered into 3 regions of the polymerase gene (D and A, B, C-D domain), which have differential effects on the structure of the HBV polymerase and its interaction with adefovir. All of these observations are expected to assist the clinician in selecting new and more effective anti-HBV agents.

Cross-resistance to lamivudine and adefovir has not been detected to date. To investigate the possibility of the emergence of an HBV strain with polymerase mutations conferring resistance to both of these agents, Brunelle and colleagues^[5] constructed an HBV strain harboring the L180M+M204V+N236T mutations, which demonstrated resistance to both lamivudine and adefovir in vitro. In addition, they reported that they isolated such an HBV strain from a liver transplanted patient who had been treated with combination adefovir plus lamivudine for 42 months after development of lamivudine resistance. Based on these findings, it appears that multiple drug resistance may emerge more frequently in the future, with the more wide and prolonged use of combination therapies.

M204V or M204I and L180M are the most common HBV mutations associated with lamivudine resistance. In an in vitro study, Delaney and colleagues^[6] determined the cross-resistance profiles of lamivudine, adefovir, and a number of other currently evaluated antiHBV agents. All L-nucleoside analogues (lamivudine and the unapproved/investigational agents [for HBV indication], emtricitabine, clevudine, L-deoxy-thymidine, L-deoxy-cytidine, L-deoxy-adenosine) demonstrated > 100-fold resistance to all lamivudine-resistant strains, while entecavir demonstrated variable resistance (37- to 471-fold) with M204I strains, exhibiting the greatest fold reduced susceptibility to entecavir. In contrast, acyclic phosphonate nucleotides (adefovir and the unapproved/investigational agents [for HBV indication] tenofovir and alamifovir) showed consistent activity against the wild-type and all patterns of lamivudine-resistant HBV strains.

There are very limited data regarding HBV resistance to entecavir, which was very recently described to be associated with rtM250V +/- I169T or rtT184G + rtS202I mutations of the HBV polymerase. Two sequential reports presented during these meeting proceedings set out to further address this issue. Warner and colleagues^[7] showed that the first class of entecavir resistance mutations (rtM204V, rtI169T) affects the interaction between the incoming dNTP and the primer strand of HBV-DNA, whereas the second class (rt T184G, rtS202I) results in altered geometry of the nucleotide binding pocket of the polymerase near the YMDD motif. Moreover, these investigators found that all of these mutations interact cooperatively with the rtM204V/rtI LMV resistance mutation, which may explain the cross-resistance between the 2 agents. In the second study, Tenney and colleagues^[8] reported that 4 or more combined mutations were required for maximal entecavir resistance and that such mutations emerged in a small proportion (6%) of chronic hepatitis B patients with preexisting lamivudine resistance treated with entecavir for 48 weeks, whereas no entecavir resistance was detected in 432 treatment-naive chronic hepatitis B patients receiving entecavir for 1 year or more.

Collectively, these data suggest that HBV resistance may affect the efficacy of all antiviral agents if they are given for a long enough period. Therefore, monotherapies, or, most probably, combinations of antiviral agents with potent antiviral efficacy and low resistance profiles, will have priority over other oral antiviral drugs, particularly in patients with advanced liver disease.

Concluding Remarks

It is hoped that the above discussion sheds light on the current challenges facing the physician treating the patient with chronic hepatitis B. Emergence of drug-resistant HBV is an ongoing clinical problem, as evidenced by the many studies presented above, and the path forward will require additional elucidation of these mechanisms to better optimize and individualize therapy.

References

1. Shouval D, Lai C-L, Cheinquer H, et al. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside-naive HBeAg(-) chronic hepatitis B: results of phase III trial ETV-027. Hepatology. 2004;40:728A. [Abstract #LB 07]
2. Zeng MD, Yao GB, Wang YZ, et al. One year results from a multi-centre, double-blind, placebo (PLA)-controlled 5 year study of adefovir dipivoxil (ADV) in Chinese patients with HBeAg positive chronic hepatitis B (CHB). Hepatology. 2004;40:730A. [Abstract #LB 11]
3. Locarnini S, Shaw T, Sozzi T, et al. HBV mutants associated with clinical resistance to adefovir dipivoxil display only small decreases in antiviral sensitivity in vitro. Hepatology. 2004;40:244A. [Abstract #182]
4. Bartholomeusz A, Locarnini SA, Ayres A, et al. Molecular modelling of hepatitis B virus polymerase and adefovir resistance identifies three clusters of mutations. Hepatology. 2004;40:246A. [Abstract #185]
5. Brunelle M-N, Jacquard A-C, Pichoud C, et al. Susceptibilty to antivirals of an HBV strain harboring polymerase mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2004;40:265A. [Abstract #229]
6. Delaney IV W, Yang H, Qi X, et al. In vitro cross-resistance testing of adefovir, lamivudine, telbivudine (L-DT), entecavir and other anti-HBV compounds against four major mutational patterns of lamivudine-resistant HBV. Hepatology. 2004;40:244A. [Abstract #181]
7. Warner N, Locarnini SA, Edwards R, et al. Molecular modelling of entecavir resistant mutations in the hepatitis B virus polymerase selected during therapy. Hepatology. 2004;40:245A. [Abstract #183]
8. Tenney DJ, Langley DR, Oliver AJ, et al. Hepatitis B virus resistance to entecavir involves novel changes in the viral polymerase. Hepatology. 2004;40:245A. [Abstract #184]

Copyright © 2004 Medscape.

55th Annual Meeting of the American Association for the Study of Liver Diseases

411老大，我译得错漏百出，也要试着学习啊，今天就学习这么多先，下次再来看。请老大修正。

流浪花猫

WWQM斑竹，您可能认错人了。我只是三脚花猫。[em03]

liver411

以下是引用流浪花猫在2005-8-11 2:17:34的发言：
WWQM斑竹，您可能认错人了。我只是三脚花猫。[em03]

Tri leg cat is pretty hard to find.

wwqm

以下是引用liver411在2005-8-11 8:20:02的发言：

Tri leg cat is pretty hard to find.

I fully agree. [em02]

liver411

[upload=gif]uploadimages/20058/200581185834770.gif[/upload]

Dr. Afdhal: The problems with interferon are illustrated here. The pros are that you can get away with a fixed course of treatment. For an e-antigen negative person, 12 months is clearly better than 6 months. The cons are also quite clear. It is injectable; it is expensive; it has a poor side effect profile. Most important, the relapse rates for e-antigen negative patients are extremely high at 50% to 70% -- much higher than that seen with e-antigen positive patients who are treated with interferon. And one cannot use interferon as chronic, long-term, suppressive therapy. This is a tough choice, to use this agent.

[upload=gif]uploadimages/20058/200581185834548.gif[/upload]

Dr. Afdhal: Summarizing the data that we have on lamivudine, the pros are that you do see virologic and ALT responses in a large number of patients, and that has been associated with appropriate histologic improvement. The cons are that an even higher proportion of patients who are e-antigen negative will have relapse, almost 90%. In this subgroup of patients, lamivudine resistance with the tyrosine-methionine-aspartate-aspartate (YMDD) mutation is a common finding

[upload=gif]uploadimages/20058/20058119050708.gif[/upload]

Dr. Afdhal: I want to review some data on adefovir based on the study of e-antigen negative patients that was published in 2003. This is longer follow-up data than was in the publication; this is 96 weeks. The study design is shown. It is a trial of adefovir vs placebo; the first year, 2:1 randomization with a crossover phase at the end of year 1 -- some patients continue on adefovir, some are switched from adefovir to placebo, and the placebo patients all switch to adefovir. This is a continuous, ongoing study with a planned follow-up for a total of 5 years.

[upload=gif]uploadimages/20058/20058119050376.gif[/upload]

Dr. Afdhal: This shows the effects on HBV DNA. Let us focus first on the adefovir/adefovir group: 1 year of adefovir, and continued a second year on adefovir, for a total of 96 weeks. There is effective suppression of virus below the lower limit of detection, at 10³ copies/mL, and continued effective suppression.

Look at the patients on placeb year 1 on placebo, no real reduction in viral load, followed by switching to adefovir, where there is an effective suppression of virus -- that, again, is persistent through the year of follow-up. What about the subgroup that was initially on adefovir and then crossed over to placebo? There we see a relapse in these patients, with the recurrence of HBV DNA.

[upload=gif]uploadimages/20058/20058119050781.gif[/upload]

Dr. Afdhal: The ALT pattern mirrors the HBV DNA pattern almost exactly and follows those findings -- a reduction in ALT in the patients who are on the active treatment with adefovir, 10 mg once daily.