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乙型肝炎抗病毒治疗中的几个问题：耐药处理、联合治疗、优化治疗——土耳其安卡拉大学医学院Cihan Yurdaydin教授专访

　　慢性乙肝患者长期使用核苷/核苷酸类似物抗病毒治疗有发生耐药的风险。您能给我们一些关于如何降低耐药的建议吗？

Issues During Antiviral Treatment of Hepatitis B: Drug Resistance， Combination Treatment and Optimization Therapy

如何降低长期使用核苷（酸）类似物抗病毒治疗患者的耐药风险？ Prof. Yurdaydin: One way of avoiding drug resistance is to use nucleoside analogues that have potent antiviral activity and drugs that have high genetic barriers to resistance such as entecavir and tenofovir in treatment naïve patients. This is why the EASL Guidelines and the American Guidelines have recommended the use of these drugs for first-line treatment in chronic hepatitis B When considering nucleoside or nucleotide analogue treatment. If you have to give lamivudine， for example， because the patient cannot afford these other drugs， then I would consider using lamivudine in patients who have low HBV DNA to start with and with high ALT， as the possibility of achieving undetectability of HBV DNA at week 24 of treatment is rather high and this would also decrease the likelihood of resistance in a substantial manner. Yurdaydin教授：避免耐药的一种途径是在治疗初治患者中使用那些具有强大抗病毒活性和具有较高基因耐药屏障的药物，如恩替卡韦和替诺福韦酯。这也是为什么EASL和AASLD指南建议在慢性乙型肝炎患者中考虑核苷（酸）类似物治疗时采用这些药物作为一线用药的原因。如果因患者买不起其他药物，我们不得不给予拉米夫定时，我将考虑在那些具有较低HBV DNA载量和较高ALT水平的患者中使用拉米夫定，这种方法实现用药24周HBV DNA检测不出的可能性相当高，同时也会减少发生拉米夫定耐药的可能性。 对于证实存在多个抗病毒耐药的慢性乙型肝炎患者，我们应该如何应对？ Prof. Yurdaydin: One thing is to prevent resistance and to prevent resistance we have learned to avoid sequential treatment which refers to: when you start with one drug and when resistance develops， you stop that drug and start the second drug. That is not good. Maybe with tenofovir， sequential therapy might be a viable option but until we have robust data to show that， we should never consider sequential therapy. If we have resistance， we should use the add-on strategy for the time being. The other point is， we see patients with multiple resistant mutations and in those patients where the resistant mutations have been defined and we know which drug is effective for this resistant mutation， this information should be used. However， in the case that there is a resistant mutation which has not been defined， we should of course look for the answer from a reference laboratory where they can do phenotypic assays to check which nucleoside or nucleotide analogue is best suited for treatment of this new mutation. Yurdaydin教授：一方面是预防耐药，我们已经知道，应该避免序贯治疗方法，即当用一种药物治疗时发生耐药，就停止使用这种药物并且启用第二种药物。这样做是不好的。以替诺福韦序贯治疗可能是可行的，但是，除非有充分的数据证明这种方法的可行性，否则绝不应该考虑。如果产生了耐药，目前采用的是加药策略。另一方面，有些患者有多重耐药突变，并且这些患者的耐药突变已经明确，从中我们也就可以知道哪种药物对这些患者是有效的。然而，有时，我们不能发现明确的耐药位点，我们也应该从参考实验室中寻找答案，在那里，他们可以做一些表型检测，可以挑选出最适合于这些新的突变的核苷（酸）类似物。 联合治疗是增加抗病毒效果和减少或延迟耐药发生的一种治疗策略吗？ Prof. Yurdaydin: Combination therapy was always a reliable option in chronic hepatitis B with the use of nucleoside or nucleotide analogues especially from the experience we gathered in the HIV field. But time has told us that， first of all， we do not have the right combination treatments and secondly， with the recent， very potent antiviral drugs， we are probably not in need of combination treatment strategies. Today， I would not consider combination of any oral antivirals in the naïve patient. In terms of combinations of pegylated interferon with nucleoside/nucleotide analogues， this is another issue， because while combinations of nucleoside analogues is a combination of drugs acting on the same target， with pegylated interferon you have different targets. This combination could potentially work， although it has been reported that combinations between pegylated interferon and nucleoside analogues is not different from monotherapy. You have to remember that at the end of treatment there was a significant greater decline of DNA with combination treatments and currently studies are underway to look at the effect of combination treatment of pegylated interferon with tenofovir and I hope that we will have good news for the patients with this combination. If it works， it could be influential in shortening treatment duration with a greater increase in HBsAg clearance but we have to wait and see for the results. Yurdaydin教授：联合治疗在慢性乙型肝炎患者的核苷（酸）类似物治疗中常常被认为是一种可靠的选择，尤其是来自抗HIV领域的实践支持这一策略。但是，时间已经告诉我们：首先，我们尚无正确的联合治疗方案；其次，近年来，一些强大抗病毒活性的药物不需要联合治疗策略。现在，在初治患者中我都不会考虑任何口服抗病毒药物的联合应用。但PEG-IFN与核苷（酸）类似物的联合则不同。因为，核苷（酸）类似物的联合针对的是同一个靶点，而与PEG-IFN的联合则是针对的不同靶点。尽管已经有报道显示PEG-IFN与核苷（酸）类似物的联合治疗与单药治疗并无不同，但是这种联合或许会产生较强的作用。我们必须记住，联合治疗结束时病毒载量要有较明显的下降。目前正在进行PEG-IFN与替诺福韦酯的联合治疗试验，我希望这个联合治疗能给广大用药患者带来好的消息。如果有效，那么在有限的治疗期限内取得较高的HBsAg清除率，这将是非常有影响力的发现，我们需要等待结果的公布。 如何优化治疗策略来提高IFN治疗HBeAg阴性患者的持久应答？ Prof. Yurdaydin: Interferon therapy has limited use in HBeAg-negative patients owing to relapse after discontinuation of therapy， but despite this， interferon somehow remains an attractive treatment possibility in HBeAg-negative chronic hepatitis B. Why? Because in HBeAg-negative hepatitis B， only interferon leads to the optimal endpoint and that is HBsAg clearance. The problem is the number of patients reaching this optimal endpoint in HBeAg-negative chronic hepatitis B with interferon is still seen as too low. One way to increase interferon efficacy is to increase the duration of treatment. If you go for interferon for two years of treatment， you definitely have less relapse and a better sustained viral response. The other thing is， you can attempt to predict those patients who will have a response， and there are studies that have shown that on-treatment week 12 quantitative HBsAg levels can be used for this approach， but we probably need more data and more appreciation of already published and in-press data to see its action in clinical practice. Yurdaydin教授：尽管由于IFN治疗HBeAg阴性患者容易出现停药后复发，而使其在这类患者中应用较少，但是IFN在HBeAg阴性慢性乙型肝炎患者的治疗选择中仍然具有吸引力。其原因是因为对于HBeAg阴性的慢性乙型肝炎患者，只有IFN才能产生理想的治疗终点，即HBsAg的清除。目前的问题是对于使用IFN治疗的HBeAg阴性的慢性乙型肝炎患者能达到这一良好治疗终点的患者仍然很少。提高IFN治疗效果的一个途径是延长治疗疗程。如果将IFN治疗延长至两年，就会发现复发明显减少，同时持续病毒学应答率提高。另一个途径是尝试预测那些可能会有应答反应的患者，已有研究显示，治疗12周HBsAg的定量水平可以用于预测应答。但我们仍需要更多数据，对于已经或即将发表的研究进行评价来探讨这一策略在临床实践中的作用。