第24届亚太地区肝脏研究协会年会（APASL 2014）于2014年3月12～15日在澳大利亚布里斯班召开。鉴于围绕着新型抗-HCV药物突出成绩的正面新闻，香港中文大学 Henry Chan教授从目前HBV治疗方案局限性方面给我们指出了一个更发人深省的观点。
Henry Chan教授
目前对于慢性乙型肝炎患者只有两种治疗方式：聚乙二醇化干扰素和核苷（酸）类似物。对于前一种治疗来说，目标是持续治疗，至无病毒应答。然而，这种治疗方案仍然难以实现。
由于治疗负担以及持续应答只发生在30%～40%的患者中，选择哪类患者最有可能从这种治疗方案中获益是很有必要的。这可以通过三种基线预测进行。“从本质上讲，”Chan教授解释，“我们需要知道HBV基因型，ALT水平和HBV DNA。”
在最佳情况下，GT-A具有较高的应答率（60%左右），尽管这些在GT-B和C中下降了一半，GT-D组中跌到了17%。增加ALT和HBV DNA的浓度，这些应答率全部下降。另一个因素，HBeAg阴性，尽管出现在很多患者中，但是一个没有验证的预测因子。
如果一种无应答被预测到，患者根本不能接受治疗。即使在那些未能满足治疗终止规定的患者中，甚至对易于治疗的GT-A来说，应答率仍然在50%以下。
而对于核苷（酸）类似物（NUC）的治疗，对治疗反应的目标是持久不变的。无法检测到HBV DNA对阻止肝病进展是必要的，然而我们如何确定无应答的患者以及部分应答的患者？
Chan教授给出的数据显示，在12个月时HBV DNA应答有最大预测值。当提及终止治疗规定时，每一个肝脏协会使用不同的标志。对于HBeAg(+)患者，APASL定义血清转化和检测不到病毒DNA为停止治疗的充分条件。针对HBeAg(-)患者，为期两年的治疗，再联合每隔6个月3次检测不到DNA，被认为是符合条件的。这有别于AASLD和EASL指南，其中规定HBsAg清除作为治疗终点。
Chan教授认为，这种终点尽管完美，但难以实现。在最好的情况下，替诺福韦只能给10%的患者提供表面抗原清除。然而，HBsAg浓度可以用来预测，HBsAg低浓度（<100 IU/mL）和显著降低（>1 log IU/mL）可认为核苷（酸）类似物治疗表现良好。
聚乙二醇化干扰素有限的疗效、不佳的基线预测以及较低的HBsAg清除率，和NUC治疗的复发风险，都表明要赶上HCV目前的治疗现状，慢性乙型肝炎治疗还有很长的路要走。
原文阅读》》》Limitations of HBV Antiviral Therapy
Given the positive press surrounding the substantial achievements of new anti-HCV drugs, Prof.Henry Chan gave us a more sobering perspective on the limitations of current HBV regimens.
There are currently only two treatment modalities for those with chronic hepatitis B: pegylated interferon and nucleos(t)ide analogues.In the former,the goal is sustained, off-treatment viral response.However,this remains elusive.
Given the burden of treatment,and that sustained response occurs in only 30-40% of patients,it is essential to choose which patients will most likely benefit from therapy. This can come done to three baseline predictors.“Essentially,” explains Dr.Chan,“all we need to know is HBV genotype,ALT levels,and HBV DNA.”
In best-case scenarios,GT-A has much higher response rates (around 60%),though these are halved in GT-B and -C,and drop to 17% in GT-D.Add high levels of ALT and HBV DNA and these rates drop across the board.Another factor,HBeAg negativity,has little validation as a predictor,despite being present in many patients.
If a null response is predicted,patients will simply not receive therapy.Even in those who do not fulfill the stopping rule, response rates remain below 50% even for the easy-to-treat GT-A.
In NUC therapy,the goal is sustained,on-treatment response.Undetectable HBV DNA levels are essential to halt the progression of liver disease,yet how do we identify patients who will not respond?What about the partial responders?
Dr. Chan presented data showing that HBV DNA response at 12 months had the greatest predictive value.When it comes to stopping rules,each liver society uses different markers. In HBeAg(+)patients,APASL defines seroconversion and undetectable DNA as sufficient for stopping treatment.For HBeAg(-)patients, therapy for two years plus undetectable DNA at 3 times,6 months apart,is considered sufficient.This differs from AASLD and EASL guidelines,which set HBsAg clearance as the endpoint.
Dr.Chan argues that this end point, while ideal, is difficult to achieve.At best,tenofovir can only give 10% of patients surface antigen clearance.However,HBsAg levels can be used for prognosis,as those low levels(<100 IU/mL)and significant decreases(>1 log IU/mL)perform well with NUC therapy.
Peginterferon’s limited efficacy and poor baseline predictors,combined with low rates of HBsAg clearance and risk of relapse in NUC therapy, show that current treatments for chronic hepatitis B have a long way to go to catch up to their HCV counterparts.
