| [ISVHLD2012]核苷（酸）类似物治疗乙型肝炎的长期结局：耐药、有效性和安全性——Prof.Eugene R. Schiff专访 -----
来源： 作者：E.R.Schiff 发布时间：2012-7-17 14:00:46 阅读：4
在美国，目前已经出台一项政策，需对1945年至1965年出生的人进行HCV筛查，眼下这些年龄在47至67岁的人生活在美国的各个地方。为什么呢？因为这些人群占到目前病人的70%。
Dr Schiff: In the United States， they have just instituted a policy where they want to screen anyone who was born from 1945 to 1965. Right now these people are anywhere from 47 to 67 years of age. Why? Because that is where 70% of the patients we see are. Why is that? In the United States， clearly a big factor was young people experimenting with drugs; they weren’t hardcore addicts but this was back in the time of flower children during the Vietnam War era. They shared needles. They had no idea that they picked up hepatitis C and some 40 or 50 years later they are wondering how something they did back then could have an impact now.
希夫博士：在美国，目前已经出台一项政策，需对1945年至1965年出生的人进行HCV筛查，眼下这些年龄在47至67岁的人生活在美国的各个地方。为什么呢？因为这些人群占到目前病人的70%。这是为什么呢？在美国，显然最大的因素是吸毒的年轻人，他们并不是铁杆吸毒者，但是他们在越战时期正好处于花样孩童期。他们共用针头。他们没有想到患上了丙型肝炎。他们其中的一些人，在大约40年或50年后，他们想知道他过去做过什么对现在造成的影响。
Hepatology Digest: One of the reasons it is hard to focus on both chronic hepatitis B and C is that they are silent diseases. Just recently， the WHO created a separate program to tackle viral hepatitis and it has taken them so long to do so because it was difficult to build awareness because the disease course is so long.
《国际肝病》：因为慢性乙型和丙型肝炎是“沉默的疾病”，所以很难引起人们的注意。就在最近，世界卫生组织专门针对病毒性肝炎设立一个项目，但是设立这一项目花费了很长的时间，因为这些疾病的病程太长，很难引起足够的重视。
Dr Schiff: Indeed. I remember when HIV was first recognized， it was associated with all of these opportunistic infections as a result of acquiring immune deficiency. I was involved in a big study where we followed people who received a blood transfusion and we watched the natural history evolve. There was no treatment and it was tragic. So there was an awareness particularly amongst the people who legislate; an awareness that this was a disease that rapidly killed people and there were measures introduced to control HIV. In contrast， both hepatitis B and hepatitis C are insidious but both cause significant worldwide mortality from either decompensated liver disease or liver cancer， but it may take thirty or forty years to get to that point. That is the big difference. Right now there is much more awareness.
希夫博士：的确如此。我记得当首次发现艾滋病毒时，因为获得性免疫缺陷，它与所有这些机会性感染均有一定的关系。我参与了一个大型的研究，该研究对输注血制品的患者进行了随访，从这项研究我们观察了整个疾病的自然史。那时没有治疗方法，结局相当悲惨。因此，引起了大家的警觉，尤其是那些具有法律意识的人士；人们认识到这是一种疾病，并且能快速导致死亡；后来人们找到控制HIV的措施。相比之下，乙肝和丙型肝炎则是“阴险”的，两者在世界范围内导致因失代偿期肝病或者肝细胞癌死亡率显著升高，但是我们用了30至40年才达到目前的高度。这是非常大的差别。现在越来越受到重视。
Hepatology Digest: One of the issues we have with hepatitis B that you mentioned earlier is that whereas with hepatitis C we have cure rates， there is not a cure for hepatitis B.
《国际肝病》：您刚才提到，对于丙型肝炎有治愈率，而HBV的治疗则没有，这是为什么呢？
Dr Schiff: Nevertheless， with treatment and particularly with the oral nucleoside/nucleotide analogs， you can render the patient HBV DNA negative without side effects. When you do that， you see an associated decrease or cessation of necroinflammation which stops new fibrosis and moreover， you can see regression of fibrosis and even so-called early cirrhosis. The liver may be a little nodular but you don’t have significant portal hypertension associated it， but it is well established that we can see reversal of cirrhosis. The problem， and the reason we say there isn’t a cure， is when we stop this daily oral treatment in most of these people， it reactivates. Why does it reactivate? Because within the hepatocytes there is a residual of hepatitis B called cccDNA (covalently closed circular DNA) which sits dormant in the hepatocyte. But if you do not continue suppression with the nucleotide/nucleoside analogs it reactivates and therefore we haven’t cured it. If the patient is on the drugs indefinitely they do well but there are several problems that arise from that. One is compliance. When patients think of this as an infectious type of disease， they think of antibiotics and when they see they are HBV DNA negative and the virus is undetectable they wonder why they need to keep taking this medicine. Even fairly intelligent people stop their medication. Indefinite treatment is necessary for hyperlipidemia， glucose intolerance and hypertension and people accept that. But with an infectious disease like hepatitis B， many can’t comprehend that they have to keep taking their medicine. Secondly there is the issue of cost. If the patient needs to take something indefinitely， who will be paying for that? This is one of the reasons why there is enthusiasm for finite treatment， for example with interferon. My personal opinion and others would disagree is that around the world， the vast majority of patients with hepatitis B are not being treated with interferon because it has side effects and many patients do not want it or can’t tolerate it and many physicians feel the same way.
希夫博士：的确如此，不过HBV患者经过治疗特别是口服核苷/核苷酸类似物治疗后，HBVDNA可转阴，而且没有什么副作用。当达到这些目标后，你会发现肝脏坏死性炎症减轻或者消失，你会发现肝脏纤维化逆转，甚至所谓的早期肝硬化得到逆转。肝脏可能仅存在很小的结节，而不存在显著的门脉高压症，但是公认的是肝硬化得到逆转。问题是，当我们停止口服药物治疗后，大部分患者可能会复发，这就是乙肝不能治愈的原因。为何出现复发呢？主要是因为在肝细胞内仍然会残存乙肝病毒，即cccDNA（共价闭合环状DNA），它主要存在于肝细胞内。但是如果停止服用抗病毒治疗药物，就可能出现复发，因此我们并不能治愈乙肝。如果患者服用抗病毒药物的期限不固定，即使他们做得很好，仍然可能出现一些问题。其中一点就是依从性。通常患者会认为乙肝是一种感染性疾病，并常与抗菌素相类比，当HBVDNA转阴，同时病毒检测不出来的时候，他们会想为什么还要服用抗病毒药物呢？甚至相当聪明的患者可能会停药。高血脂症、糖尿病以及高血压的长期治疗目前也是不确定，但是人们却能接受。但是当面临感染性疾病，例如HBV，许多患者并不能理解为何要长期服药。其次，就是成本问题。当患者需要长期服用某种药物时，谁来买单？这就是为何目前热衷于有限治疗方案的原因之一，例如干扰素治疗。下面是我个人的观点，其他人可能并不认同：在世界范围内，绝大部分乙肝患者并没有采用干扰素治疗方案，部分是因为其副作用，许多患者不能接受或者不能耐受，而且许多医生也是这么认为的。
Hepatology Digest: So do you think the nucleotide/nucleoside analogs are the treatment of the future?
《国际肝病》：那么你认为核苷酸/核苷类似物是抗病毒治疗的希望吗？
Dr Schiff: I think right now we are still questioning the treatment but what we want is something that can clear cccDNA. They are looking at different ways to do that and there are several presentations at this meeting on the topic. That is one of the challenges for the future and I think it will happen. When you clear out cccDNA， from a practical standpoint you have cured the disease.
希夫博士：我认为目前我们仍然在质疑治疗，但是我们需要的是能够清除cccDNA的药物。目前正在寻找不同的治疗方法，在这次会议上也有相关的演讲。这是未来的挑战之一，并且我认为它会发生。当你成功清除cccDNA，从治疗的角度上讲，你就治愈了这种疾病。
Hepatology Digest: At the moment though， as you said， cost is a big issue especially here in Asia so there is a lot of compromise. The Asian guidelines still suggest starting therapy with lamivudine.
《国际肝病》：正如您所说，抗病毒治疗成本是一个大问题，尤其是在亚洲，所以有很多折中的治疗方案。亚洲公布的指南仍推荐拉米夫定作为开始抗病毒治疗的药物选择。
Dr Schiff: Lamivudine was one of the first successful nucleoside analogs. It turns out that it is safe， it is relatively inexpensive and it is effective. The downside is that the majority of people who continue to use lamivudine develop resistant mutations and if you stay on the drug in the face of these emerging resistant mutations， the mutation becomes the predominant virus and can cause progressive liver injury rather than sustained remission. In fact， I was involved in a big study where we salvaged these people who were waiting for liver transplants， at that time with adefovir. If you take lamivudine and if you become HBV DNA negative and with time you stay that way， i.e. you are in the group that does not develop a resistant mutation， you can keep taking it and that is going to be inexpensive. Unfortunately， most people do not fall into that category. Much more in the past than now but it still happens， is the use of alternative types of medications which are usually inexpensive and herbal and sadly do not really do much and the disease will progress. That is something that certainly has gone on and is going on in China but it happens worldwide. Most of the time it does nothing other than giving the patient the false security that something is happening.
希夫博士：拉米夫定是第一个成功应用于临床的核苷类似物。事实证明，它相当安全，并且物美价廉。它的主要副作用是当大多数人继续使用拉米夫定后，可能出现耐药变异，如果继续服用这种药物，耐药株成为优势株的时候，就可能导致渐进性的肝脏损伤，而不是持续缓解。事实上，我曾经参与过一项大型研究，对需要等待进行肝移植的患者进行挽救治疗，我们使用的是阿德福韦酯。当你服用拉米夫定并且如果HBVDNA转阴时，并且持续保持这种状态，例如始终未出现病毒变异，你可以继续服药，而且治疗价格非常便宜。然而，不幸的是许多患者并不是如此的。另外有部分患者可能会采取一些替代治疗方案，例如草药治疗，这些方案通常价格低廉，但是治疗效果不好，疾病可能还会进展，这种情况在过去较为常见，但现在依然存在。这些情况在中国已经发生，或者正在发生，但是在全世界都是如此。在大部分时间，这些治疗方案只是安慰治疗，给患者以虚假的安全。
Hepatology Digest: If you have a patient on lamivudine， how often would you be checking for resistance and how soon would you be switching medication?
《国际肝病》：如果你有一位服用拉米夫定的病人，您多长时间会去检测耐药？多长时间后会考虑换药？
Dr Schiff: In the beginning I would probably check every three months. But when someone remains HBV DNA negative at around two years， I would still check but maybe every six months. Regardless of what they are on， I will be checking them for liver cancer. The best non-invasive and least expensive way is ultrasound. Even in patients you have rendered HBV DNA negative and with normal liver biochemistry， they can develop hepatocellular carcinoma. The ones who are most likely to do that are those that develop cirrhosis along the way. Nevertheless， and this is true for hepatitis B more so than hepatitis C， about 20% of patients who get liver cancer don’t have cirrhosis. You can render them negative on treatment and they think they are home free. The reason they can develop cancer is that early in the natural history of this disease， they have developed a malignant transformation at a molecular level within the hepatocytes which is not outwardly recognizable. This is the challenge， to be able to recognize this malignant transformation. All of the guidelines for hepatitis B say not to treat people who are immunotolerant. These are young people， usually below the age of thirty， who have a very high viral load but normal ALT. Typically they have very little if any fibrosis and if you follow them over years， most of them will spontaneously seroconvert and end up as inactive carriers. They are HBsAg positive but with very little circulating virus and normal enzymes and may stay that way for decades and do well. On the other hand， within that group are those who are going to develop liver cancer. What we want， and this has been addressed by Anna Lok， is some kind of marker probably of a genetic nature， that says this person should be treated now even though they are immunotolerant because later on in life they are at risk for cancer. This is the situation in many disease conditions these days. Can we characterize a person from a genetic standpoint as far as risk for certain diseases is concerned? Knowing they are in that category means we can intervene much earlier. Looking at it not from a scientific point of view but as a physician who treats patients， we need to individualize treatment. We look at risk versus benefit， we look at quality of life， and we look at the particular individual in front of us. For example， if we take a patient with hepatitis C and it is relatively mild and knowing that there are major advances right now where you won’t even need interferon and there is a high cure rate， if that patient is so preoccupied with their disease that they are on the internet daily and feel in their own mind they will need a liver transplant， then from a practical standpoint to help that person function in society without hurting themselves， you will want to treat them. That will allow them to refocus back on their lives and function normally in society. This is something that you don’t read about as an indication but that is individualized treatment. Keep in mind that guidelines are just that – guidelines. They give you boundaries but within those guidelines， you have to use clinical judgment and weigh risk versus benefit. That is the key.
希夫博士：在开始的时候，我可能每隔3个月检测一次。但是当患者HBVDNA保持持续阴性2年以上时，我可能将监测的频率改为6个月一次。不管怎样，我都会去监测肝癌。最佳的非侵入性的和最便宜的方式是超声波检查。即使取得病毒转阴，而且肝脏生化学检查正常，他们仍然可能发生肝细胞癌。特别是发生了肝硬化的患者更需如此。尽管如此，大约有20%的患者可能在没有肝硬化的情况下发生肝癌，而且HBV患者较HCV患者常见。他们发生肝癌的原因是因为在疾病的自然史中，肝细胞已经发生了在分子水平内的恶性转变，这是无法从外表进行辨认。如何去早期识别这种恶性转变，是我们面临的挑战。所有的指南均认为在免疫耐受期不建议进行抗病毒治疗，他们通常是年轻人，年龄在30岁以下，病毒载量高，但是ALT 正常。通常情况下，他们很少或者无肝纤维化，如果对其进行随访观察的话，大部分患者可能发生自发血清转换，最终成为非活动性携带者。他们乙肝表面抗原阳性，但是循环中仅存在少量病毒，转氨酶正常。他们可能维持这种状况许多年，并且身体状况良好。另一方面，这部分人群也是肝癌的好发人群。我们所希望做的，正如Anna Lok所讲的那样，就是寻找某种遗传性特征的标记，也就是说在这些免疫耐受的患者也需要进行治疗，因为他们可能发生肝癌。这同现今其他许多疾病的状况类似。我们能否从遗传角度来分析个体患某种疾病的风险？因为只有知道他们属于哪类，我们才有可能进行更早的介入。如果不从科学的角度去看这个问题，但作为一名医生治疗患者的时候，我们应该采取个体化的治疗方案。我们关注治疗的风险与收益，我们关注生活质量，我们需要关注面前的每一个个体。例如，如果我们治疗一位丙肝患者，他们可能相对病情非常轻，而且知道目前的重大进展并且治愈率较高，但是你可能不会选择干扰素治疗；如果患者太关注他们的疾病，每天都上网检索资料，并且自认为需要进行肝移植治疗，你可能对他们进行治疗，以帮助他们恢复社会功能并不至于伤害自己。这样可能有助于帮助他们重新回归生活，并保持正常的社会功能。这些你不会在说明书上看到，但是的确是个体化的治疗策略。一定要确记，指南就是指南而已。指南会给边界，但是在指南内，你需要进行临床判断，并且衡量风险和收益。这才是关键所在。
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发表于 2012-7-17 15:28
