[ISVHLD2012]治愈乙型肝炎有必要吗？有可能吗？——Prof.Timothy M

StephenW

[ISVHLD2012]治愈乙型肝炎有必要吗？有可能吗？——Prof.Timothy M. Block专访               

来源： 作者：Timothy.M.Block 发布时间：2012-6-21 15:31:50   阅读：25

                    
You will be giving a talk entitled “Is a Cure for Chronic Hepatitis B Necessary? Is It Even Possible?”
                    
Hepatology Digest: You will be giving a talk entitled “Is a Cure for Chronic Hepatitis B Necessary? Is It Even Possible?”
　　
Prof. Block: Those recommended for treatment by current guidelines are at a very significant risk for death due to liver disease， so I do agree that they do need to be treated. In an analysis done by Alison Evans， a population scientist， if you fall within the treatment guidelines - elevated DNA， elevated liver function tests - and are above the age of 40， your risk of death in the next 10 years is 30-40%. That is pretty significant. There is no question those people should be treated， but what about the people who fall outside the treatment guidelines - very low viral DNA levels， reasonably normal liver function tests? What is their risk of death? We deliberately chose an unsubtle outcome so there would not be a lot of argument about our definition of adverse clinical outcomes. The risk of being dead within 10 years is 3-9%. That is not acceptable. And for this population there are no drugs. It makes no sense to give them a DNA synthesis inhibitor because they do not have much viral DNA. New drugs are needed and a cure is needed.
　　The next question is: Do I think a cure is possible? We now see that chronic hepatitis C is curable， which certainly makes you think that it may be possible for chronic hepatitis B (CHB). I will be talking about some strategies that we are taking. I will not have time to cover all the approaches currently being taken. Our work suggests to me that some of the new antiviral strategies offer the best hope ever for a durable antiviral effect that attacks the heart of the hepatitis B virus - the persistence of covalently closed circular DNA (cccDNA). I will be talking about new methods - pharmacologic agents - that appear to suppress cccDNA expression and levels. Here at our center Ju-Tao Guo， Haitao Guo， and Andrea Cuconati have developed methods to screen from drugs that suppress cccDNA or affect HBsAg secretion. I will show the activity of those drugs in tissue cultures. Dr. Yumei Wen’s lab has a program that has had some success in generating immunological response in chronic carriers. Our hope is that our approach will complement the immunological approach.
　　People have tried looking at combination approaches using interferons and the polymerase inhibitors. So far these combinations have not shown to be statistically better than either of those drugs alone. There are studies in the US now to determine if there are more rational ways to combine those two therapies - altering timing， for instance - but what we are going need is something that reactivates the immunological recognition of the virus in chronic carriers. Interferon alone is not enough to do that.
　　I believe newer drugs may be able to derail HBV perseverance. Most individuals with CHB have a humoral response to HBsAg. The hope is， if you can rapidly eliminate HBsAg or suppress the viral cccDNA， you will leave unmasked antibody. That is the hope. It is my conjecture. There are studies that show rapid antiviral response is a very strong predictor of sustained viral response (SVR) to HCV. There is also some evidence that people who have reasonably rapid antiviral responses to HBV with interferon - HbsAg levels dropping quickly - then these people are the most likely to have SVR. This suggests to me that virological phenomenology similar to what is happening in hepatitis C could be happening in CHB. In other words， possibly， the more rapid the reduction， the more vulnerable the virus is. Now， it could be that people who are able to attain SVR are also able to produce rapid virological response. It is possible that pharmacologically inducing a rapid reduction will not allow activation people’s immune systems. We are not certain how applicable our experience with HCV is to HBV. The evidence is certainly not strong yet. But there is some evidence that people who have quicker reductions in HBsAg with interferon are more likely to have SVR， so maybe what was true with HCV will be true with HBV.
                                                
                    

StephenW

来源：作者：Timothy.M.Block发布时间:2012-6-21 15时31分50秒阅读：25

您将给予讲座，题为“是一种治疗慢性乙型肝炎治疗的必要吗？它甚至有可能吗？“

肝病：您将给予讲座，题为“是一种治疗慢性乙型肝炎治疗的必要吗？它甚至有可能吗？“

教授座：用于治疗由目前的指导方针的建议是非常显着，在因肝病死亡的风险，所以我不同意，他们确实需要来对待。在完成由艾莉森·埃文斯，人口学家，如果你属于治疗指南分析 -  DNA的升高，肝功能测试 - 和40岁以上的是，你在未来10年内死亡的风险是30-40％ 。这是相当显着。有没有问题，但这些人应被视为怎么样的人属于外治疗指引 - 病毒DNA水平非常低，合理的肝功能正常，测试？什么是他们的死亡风险？我们特意选择了一个unsubtle结果，所以不会有很多对我们不利的临床结果的定义参数。在10年内死亡的风险为3-9％。这是不能接受的。和对这个群体有没有毒品。这是没有意义的，给他们的DNA合成抑制剂，因为他们没有太多的病毒DNA。需要新的药物和治疗需要。
接下来的问题是：我认为治愈是可能的吗？我们现在看到，慢性丙型肝炎是可以治愈的，这当然使你认为它可能是慢性乙型肝炎（CHB）的可能。我会说，我们正在采取一些策略。我不会有时间来涵盖所有目前正在采取的做法。我们的工作，我建议，一些新的抗病毒药物策略提供了最好的希望，为有史以来持久的抗病毒效果，攻击B型肝炎病毒的核心 - 共价闭合环状DNA（cccDNA）的持久性。我将谈论的新方法 - 药物制剂 - 出现抑制cccDNA的表达和水平。在这里我们的中心菊郭涛，郭海涛，和安德烈Cuconati的开发方法，屏幕从cccDNA的药物抑制或影响HBsAg的分泌。我将表明这些药物在组织培养的活动。玉梅文博士的实验室有计划，已取得了一些成功产生慢性携带者的免疫反应。我们的希望是，我们的做法将补充免疫的方法。
人们试图寻找在使用干扰素和聚合酶抑制剂的组合方式。到目前为止，这些组合没有显示出有统计学比单靠这些药物之一。有在美国的研究，以确定是否有更合理的方式结合这两种疗法 - 改变的时机，例如 - 但我们需要去重新激活免疫识别病毒慢性携带者的东西。干扰素单独做到这一点是不够的。
我相信新的药物可能是能够脱轨HBV毅力。慢性乙型肝炎患者中的大多数人有一个对HBsAg体液免疫反应。希望是，如果你能迅速消除HBsAg或抑制病毒cccDNA的，你会离开东窗事发抗体。这是希望。这是我的猜想。有研究表明抗病毒反应迅速的持续病毒应答（SVR），丙型肝炎病毒是非常强的预测。也有一些证据表明，有合理快速的抗病毒药物干扰素对HBV  -  HBsAg水平迅速下降的人 - 那么这些人是最有可能有SVR的。这表明我的病毒学什么是丙型肝炎的发生类似现象可以发生在CHB。换言之，可能的话，更快速的减少，更容易受到病毒。现在，它可能是，也能产生快速病毒学应答的人是能够实现的SVR。这是可能的药物诱导迅速减少，将不允许激活人的免疫系统。我们不能确定如何适用于我们的经验与丙型肝炎病毒是乙型肝炎病毒。证据肯定是不强。但有一些证据表明，有更快的削减与干扰素乙肝表面抗原的人更容易有SVR的，也许是真实的丙型肝炎病毒会真正与HBV。

suanjiuzi

回复 StephenW 的帖子

翻译的太糟了！

这篇文章的大意是：1.肝脏有炎症反应，病毒阳性且大于四十岁的人未来十年的死亡率是30-40%。肝功正常，病毒载量低的且年龄大于四十岁的人未来四年死亡率为3-9%，而且，对这部分人目前没有任何药物可以提供治疗（耸人听闻）。
2.在干扰素治疗中，病毒载量或hbsag下降的越快说明治愈的可能性越大。
3.这个教授对将来能攻击cccDNA的药物持乐观态度。
4.对提升感染者对病毒的免疫力来说，干扰素作用远远不够。但联合用药，目前并没有统计上的药效提升。

咬牙硬挺

楼上英语水平好啊，这个教授真有点夸张了

tonychant

Good news from Prof Block:Novel Inhibitors of Hepatitis B Virus Surface Antigen
http://www.hbvhbv.com/forum/thread-1093494-1-1.html

0914

看的我怕怕

StephenW

回复 0914 的帖子

Liver Cancer and Hepatitis Viruses                                                                                                                                                                 Paul F. Engstrom, MD                                                         Senior Vice President for Population Science Alison A. Evans, ScD Associate Member W. Thomas London, MD                                                         Senior Member Alison A. Evans, ScD, Associate Member W. Thomas London, MD, Senior Member Paul F. Engstrom, MD, Senior Vice President for Population Science Fox Chase Cancer Center Philadelphia, PennsylvaniaThe most common form of liver cancer, hepatocellular carcinoma (HCC), has become a disease of increasing importance in the US and other Western countries as the numbers of affected individuals increase. In fact, the HCC incidence rates doubled between 1985 and 1998 in the US, reaching just over 4 cases per 100,000 people in 2000, with a proportionally greater increase in the incidence rates in younger age groups. Worldwide, liver cancer is the third most common cause of cancer death, with approximately 550,000 annual deaths. The American Cancer Society estimates that there will be 15,420 deaths from liver cancer in the US in 2005, of which 70%--80% will be HCC.  Liver cancer is the eighth most frequent cause of cancer mortality in US men and the twelfth in women.   The highest incidence rates are found among Asian-Americans, who have about double the risk of African-Americans and Hispanics and four times the risk of Caucasians. Chronic infection with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) is associated with the majority of HCC cases.  Recent estimates for the US have attributed 47% of cases to HCV alone, 15% to HBV alone, and 5% to coinfection with both viruses.  The other 33% of cases appear to be due to nonviral causes.  Internationally, HBV is responsible for a far greater proportion of HCC cases than it is in the US, reflecting the higher prevalence of HBV in many developing countries.   Currently, an estimated 1.3 million Americans are chronically infected with HBV and 2.7 million chronically infected with HCV.  These individuals are at high risk for the occurrence of HCC, a malignancy for which long-term survival rates are poor.  The development of prevention programs targeting this population may be the best hope to reduce the increasing public health impact of HCC. HBV and HCV are both highly contagious. Chronic HBV infection can be transmitted through exposure to infected blood or blood-containing body fluids via a cut on the skin or a tear in the mucous membranes. It can also be spread among individuals sharing contaminated needles or through sexual intercourse with an infected person. HBV also can be transmitted from an infected pregnant woman to her newborn child at birth.   For reasons that are not completely understood, Asian mothers are much more likely to transmit HBV to their babies than mothers of other ethnic groups.  All pregnant women should be screened for HBV infection during pregnancy so that, if they are infected, steps can be taken to prevent the transmission of the virus to their infants. HCV, in contrast, is rarely passed from mother to baby.  About 60% of chronic HCV infections are due to contaminated needles, with approximately 15% due to sexual transmission and 10% resulting from blood transfusions prior to the now routine screening of blood for hepatitis viruses. Early symptoms of both HBV and HCV infection are similar and can include jaundice (yellowing of the skin or eyes), tiredness, pain in the abdomen, loss of appetite, nausea, and dark urine.  About 80% of people infected with HCV and 30% infected with HBV, however, never show early symptoms of their infection.   The only certain way to diagnose these infections is with blood tests. HBV and HCV are liver viruses that can cause chronic infections.  These infections of long duration (often lasting many decades), which lead to chronic active hepatitis, liver cirrhosis, and HCC. Nonetheless, there a few biological similarities between the two viruses.  Table 1 summarizes the characteristics of HBV and HCV. Table 1 Comparison of HCV and HBV as Risk Factors for HCC                         HCV HBV Number chronically infected (US) 2.7 million 1.3 million Number chronically infected (world) 170 million 350 million Lifetime risk of HCC if chronically infected About 10%--25% About 1%--5% Number of associated HCC cases/year (US) About 5,000-5,600 About 1,800-2,000 Prevalence of cirrhosis in HCC About 100% About 80%--90% Time from infection to HCC 20--30 years, shorter with older age at infection 20--70 years, varies by population Prevention strategies Infection control, anti-viral therapies, early detection Infection control, vaccination, anti-viral therapies, early detection                 HCV = hepatitis C virus; HBV = hepatitis B virus; HCC = hepatocellular carcinoma.The association of chronic HCV infection with development of HCC is well-established; this nearly always occurs in the presence of cirrhosis. About 80% of persons infected with HCV will develop a chronic infection, and 15%--20% will develop serious liver disease, often many decades later.  Among those who develop cirrhosis, 1%--4% per year will develop HCC.  Several important cofactors, such as alcohol consumption and older age at infection, are known to affect the probability of developing HCC among persons chronically infected with HCV. The most effective means available for prevention of viral hepatitis-associated HCC is prevention of the initial viral infection.  A vaccine against HBV has been available since 1982, and early childhood vaccination programs have been the most effective strategy for reducing the prevalence of infection, particularly in high-risk populations.  The global impact of childhood HBV infection programs is beginning to be seen.  In Taiwan, where universal newborn vaccination began in 1984, HCC incidence rates have begun to decline in young people.   In the US, universal infant HBV vaccination has been recommended since 1991 after the previous strategy of targeting only high-risk individuals failed to reduce the incidence of HBV infection.  Vaccination remains the best means of protection against HBV infection, and all persons at risk of exposure (e.g., health care workers, first responders, household contacts of chronic carriers) should be urged to get vaccinated. Prevention of HCV infection is more difficult due to the lack of a vaccine or effective post-exposure prophylaxis.  Universal precautions against exposure to bloodborne infectious agents are the primary means of prevention.   In the US, these measures have led to a reduction in the number of new infections per year from an average of 240,000 in the 1980s to about 25,000 in 2001.  At present, the majority of new HCV infections in the US occur because of needle sharing among drug abusers.  The best way for individuals to protect themselves from HCV infection is to avoid contact with infected blood and body fluids. Effective secondary prevention of HCC depends upon early detection of small tumors.  The most commonly used blood serum marker for identifying affected individuals, known as alphafetoprotein, is produced by 40%--80% of HCCs and can be detected by a blood test.  Patients with chronic viral hepatitis or cirrhosis of any origin are candidates for semiannual or annual screening with alphafetoprotein and ultrasound examination of their livers to detect early tumors. Such screening programs have shown that identification of small, asymptomatic lesions is possible, but a consequent reduction in HCC mortality has not always been evident.  The cost-benefit ratio of alphafetoprotein plus ultrasound screening versus ultrasound alone is still a subject of debate. Antiviral therapies for both HCV and HBV have shown promise in the reduction of HCC risk for those whose disease is amenable to such treatment. Current antivirals, however, are not effective in all chronically infected persons and are generally most useful in those who already have biochemical and/or histologic evidence of active liver disease.  Cancer chemoprevention strategies that focus on other portions of the etiologic pathways for HCC may be a fruitful avenue for future prevention efforts, particularly in the reduction of immune-mediated liver damage.

StephenW

楼上论文发表在2005年, 没有提及“30-40％”的风险.我会尝试获得更多的信息.