国际肝病采访Morris Sherman教授

Hepatology Digest: This July, your article entitled “Entecavir Therapy for Lamivudine-Refractory Chronic Hepatitis B: Improved Virologic, Biochemical, and Serology Outcomes Through 96 Weeks” was published in Hepatology. According to this comparative study, through 96 weeks of treatment, 1mg of entecavir resulted in continued clinical benefit in lamivudine-refractory HBeAg-positive chronic hepatitis B patients, with a safety profile comparable to lamivudine. What about in the case of entecavir resistant patients? Can you give us some advice on how to treat those patients?

Prof. Sherman: There are really only two drugs that can be used for patients with entecavir resistance, and that’s adefovir and tenofovir.

Hepatology Digest: In your talk you mentioned lamivudine and it has a high rate of resistance. Are there any cases where you would favor it?

Prof Sherman: There are some cases. It depends very much on what you can do locally. Patients who start off with a very low viral load, say below one million copies, very often do very well on lamivudine. Lamivudine is not very potent, so it can not deal with very high viral loads, but it can certainly deal very well with patients who start off with a low viral load. Under those circumstances it can be used. It can be used for patients who are undergoing chemotherapy because they generally start off with a low viral load, so lamivudine is able to control that. So there are some circumstances where it can still be used. It is much less expensive than any of the other drugs and it should be used under those circumstances.

Hepatology Digest: How do you feel about using lamivudine in de novo combination therapy with another agent? It seems that the evidence isn’t really there to support it.

Prof. Sherman: No, the evidence is not there. The evidence that was shown had to do with lamivudine and adefovir and the rate of resistance was still higher than what you see with tenofovir or entecavir. That would not support that particular combination. If you are going to move to combination therapy, the only combination that makes sense is tenofovir plus something else. It might be tenofovir plus emtricitabine in the form of a drug called Truvada, which is a combination pill used for HIV, or tenofovir plus lamivudine, or tenofovir plus entecavir

Hepatology Digest: The Journal of the National Cancer Institute published your study about clinical trials for hepatocellular carcinoma entitled “Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma” in May of this year. In this article, you pointed out that the design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. What are the key issues in the design of clinical trials of HCC?

Prof. Sherman: What you are trying to do primarily is show that the drug you are giving works. So you can’t give that to a population who are going to die of their liver disease before the drug has an effect. That’s why the selection of patients is critical and you have to select patients whose liver disease is mild enough that you don’t expect them to die from liver disease over the course of the study. That’s an important point. The corollary of that is that when it comes to using these drugs, they’ve now only been tested in patients with good liver function, so can you use them in patients who have more advanced liver disease? That question is really not clear. That’s not to say that they shouldn’t be tested in patients with more advanced liver disease, but that is a later stage. It’s not for registration studies.

Hepatology Digest: You talked about people with various levels of disease. What is the most effective way that we can reduce the mortality for HCC?

Prof. Sherman: If the HCC is diagnosed when it is 3cm or higher, in the long run the chances are that the tumor will kill the patient. Not everybody obviously, but the majority. The best hope is to catch the tumor when it is very small, and for that you require screening, because you can cure virtually all 2cm lesions. Patients may get recurrent disease, second primaries, and so the risk of an additional tumor is there, but patients who have active disease can be treated with antivirals to reduce their risk. There are lots of things that can be done to treat the initial tumor provided you catch it early and to try and prevent a second tumor from developing by reducing the cell turnover in the liver.

Hepatology Digest: What would be the ideal screening method?

Prof. Sherman: At the moment, the ideal method without question is ultrasound. The trouble is that with ultrasound is that if you don’t have a good operator you may miss small tumors. It’s ideal in good hands but in the absence of good hands there’s no real ideal method.

Hepatology Digest: So training is essential?

Prof. Sherman: Training is essential. In many parts of the world, for example, when women have screening for breast cancer, the people who do the mammograms have to be certified. The same should apply for ultrasound screening for hepatoma.

Hepatology Digest: What is your view on the future of the use of biomarkers for the early diagnosis of HCC?

Prof. Sherman: There is no biomarker that is adequate for the diagnosis of very small ACC. All the biomarkers that have been looked at have all been looked at primarily in lesions larger than 2cm. When they have been looked at in smaller lesions, they really don’t perform very well. The commonly used biomarkers, which are the alpha-fetoprotein (AFP), L3 fraction of alpha-fetoprotein, and the DCP, are also all markers of more advanced disease. You can’t be a marker of early disease and late disease at the same time. When you have very good ultrasound and you can pick up a lesion on ultrasound that is 1cm in diameter, it’s hard to imagine that tiny little thing is going to produce enough of whatever biomarker you are looking at to be detectable in serum

Hepatology Digest: Presently, individualized treatment for patients with chronic hepatitis B is advocated. Could you give us some advice on how to go about individualizing treatment?

Prof. Sherman: I think it probably refers to the fact that it’s not like somebody with high cholesterol. In high cholesterol you give them a cholesterol lowering agent or in high blood pressure you give them something to reduce their blood pressure and it works. I think in hepatitis B you have to take into account a number of different factors. There are so many factors that you really do have to make an individual decision for each patient. For example, how old the patient is, what the viral load is, if they are e-antigen positive or negative, and what the biopsy looks like if you do a biopsy. Some young patients have advanced disease so you need to treat them. Some patients in their 40s or 50s have insignificant disease so maybe they don’t need treatment. All of those factors have to be taken into account.