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。会上国立台湾大学医学院高嘉宏教授就乙肝治疗终点及实现方法阐述了自己的观点。
高嘉宏教授
“治疗的最终目标不只是清除乙肝病毒DNA或逆转肝硬化。”
从乙型肝炎病毒感染史中，我们知道有几种标志物。因此，一些治疗的终点来自这种疾病的自然史：首要目标，次要目标和最终目标。首要目标是是乙肝病毒DNA检测不到，其次是乙肝病毒e抗原阳性的患者的HBeAg血清转换。次要目的包括肝纤维化和肝硬化的逆转。有时我们可以发现乙肝表面抗原转阴。然而，作为一名临床医生，我们不只是治疗疾病本身，我们要把患者作为一个整体进行治疗。这意味着我们将有一个更好的最终结果。因此，最终目标包括阻止肝癌的发生、延长患者的生存期和减轻肝性失代偿。当然，我们也想提高患者的生存质量。
免疫系统调节剂（例如干扰素）或直接抗病毒药物——核苷（酸）类似物都能实现主要治疗终点。干扰素治疗后，大约经过1年左右的时间，30%-40%的患者会出现乙肝e抗原转阴。然而，30%-40%的乙肝e抗原阴性的患者，在停用干扰素后会复发。核苷（酸）类似物治疗是一个长期的过程，大约需要3-5年，有时候也不一定，比如有些患者会出现肝硬化。一些数据显示，患者的纤维化程度减轻，甚至肝硬化出现逆转。此外，来自日本、香港和台湾的一些数据显示，长期应用核苷（酸）类似物可以降低肝细胞癌的发生率。
“对于影响慢性乙型肝炎患者疾病进展的宿主基因因素，我们知之甚少。”
宿主基因因素对慢性乙型肝炎患者的作用仍然是个迷。有数据显示，有些基因与急性乙型肝炎患者的慢性化有关。第一个报道来自日本，Chayama教授的研究组进行的试验，报道提及了HLA-DPA1 和 DPB1。也有一些SNP或基因型与病毒的持续感染和清除有关。它们是从急性感染到慢性感染过度的核心。我们组的研究显示，HLA-DPA1 和 DPB1基因型与慢性乙型肝炎患者表面抗原转阴有关。然而，没有明确的数据显示宿主基因因素与慢性肝炎进展为肝硬化有关。来自中国的研究者们应用全基因组关联研究对肝细胞癌易感基因进行定位。目前定位有两个基因与肝细胞癌有关：KIF-1B 和CRHR2。目前只有两种基因与乙肝病毒相关性肝细胞癌有关。我们需要进行更多的试验来弄清这一灰色区域。
“基线和治疗中病毒因素对治疗应答有影响。”
病毒因素比刚才提及的宿主因素更加清楚，关于病毒因素有多个回顾性研究，其中一篇是我自己写的。他们报道对发病因素和治疗有影响的病毒因素包括血清乙肝病毒DNA、乙肝e抗原持续阳性和病毒基因型。亚洲最常见的基因型为B型和C型，基因型为B型的乙肝病毒可以导致严重的肝病，例如肝细胞癌。有越来越多的证据显示，核心启动子突变与肝细胞癌有关，也与肝硬化的发展有关。
一些基线和治疗中的病毒因素对治疗效果有影响。基线病毒因素包括乙肝病毒DNA水平的升高。乙肝病毒DNA水平越高的患者，抗病毒治疗的效果越差，意味着需要进行长期的治疗。基因型对干扰素的治疗效果也有影响。我们以前的研究显示，基因型为C型的乙肝病毒对干扰素治疗不敏感。一些荟萃分析显示，与基因型为C型或D型的乙肝病毒相比，基因型为A型或B型的乙肝病毒对干扰素治疗更敏感。
我们现在要进一步阐明治疗中的病毒因素（例如乙肝表面抗原）对治疗效果的预测作用。治疗12周或24周后乙肝表面抗原水平的下降，对乙肝e抗原阴性或阳性的患者应用干扰素后血清转化率或持续病毒学应答率产生影响。核苷（酸）类似物的治疗，大多数数据都是关于乙肝病毒DNA的基础水平的。只有大约10%的应用核苷酸类似物治疗的患者乙肝表面抗原会随着乙肝病毒DNA的快速下降而降低。这些患者可能会恢复内源性抗感染免疫活动。这些患者的预后最好，乙肝表面抗原可能会完全消失。
原文阅读》》》Endpoints for Anti-Hepatitis B Therapy: What Are They and How Do We Reach Them?
“The ultimate goal for therapy lies beyond HBV DNA levels or reversal of cirrhosis. ”
From the natural history of viral HBV infection, we know there are several landmarks. Therefore, some therapeutic endpoints are derived from this natural history: the primary, intermediate, and the ultimate goals. The primary goals are making the HBV DNA undetectable, followed by HBeAg seroconverion for HBeAg (+) patients. The intermediate aim includes the regression of hepatic fibrosis or some reversal of liver cirrhosis. Sometimes we can see the loss of HBsAg. However, as a clinician, we do not just treat the disease itself; we treat the patient as a whole. That means we would like to have a better final outcome. So when it comes down to the ultimate goal, it includes the prevention of l iver cancer, prolonging pat ient survival, and decreasing hepatic decompensation. Of course, we also want to improve the quality of life of our patients.
Immune system modulators, such as interferon or direct antiviral drugs—nucleos(t)ide analogues (NUCs)—both achieve the primary endpoint. After IFN-based therapy, which has a finite duration of around one year, 30%-40% of the patients may reach HBeAg seroconversion. However, in HBeAg (-) patients, 30%-40% have a high relapse rate after stopping IFN. Therapy with NUCs is a prolonged therapy, of 3-5 years, sometimes indefinitely, as with patients with liver cirrhosis. There is some data that shows that histological improvements in fibrosis, and even reversal of liver cirrhosis has been observed. Furthermore, there are some new data from Japan, Hong Kong, and Taiwan showing that we can reduce the incidence of HCC in patients receiving long-term NUC treatments.
“We know very little about the host genetic factors that affect the disease progression in patients with chronic hepatitis B.”
Host genetic factors remain a mystery in terms of their effect on patients with chronic hepatits B. There are data showing that some genes may be associated with chronicity in acute HBV patients. The first report is from Japan, by Prof. Chayama’s group, which mentions HLA-DPA1 or DPB1. There are also some SNP or genotypes associated with viral persistence and clearance. These are central to the transition from acute to chronic infections. My group has shown that the HLA-DPA1 or DBP1 genotypes are associated with surface antigen loss in chronic hepatitis B patients. However, there are no clear data on host genetic factors associated with disease progression from chronic hepatitis to liver cirrhosis. Researchers from China have used a GWAS (Genome-Wide Association Study) to locate HCC susceptible genes . They have currently located two genes associated with HCC: KIF-1B and CRHR2. Those are the only two genes mentioned as of now that are related with HBV-associated HCC. We need more studies to clarify this grey zone.
“Baseline and on-treatment viral factors can affect treatment response.”
Viral factors are clearer than the host genetics just mentioned and there are several review articles, including one written by myself. They report viral factors that affect pathogenesis and treatment: serum HBV DNA, persistence of HBeAg, and viral genotype. Genotypes B and C are the most common in Asia and genotype B is associated with more severe l iver diseases, l ike HCC. There is increasing evidence showing that the core promoter mutations are associated with HCC and are even associated with cirrhosis development.
Some baseline and on-treatment viral factors can affect treatment response. Basel ine factors, for example, include high HBV DNA. The higher the HBV DNA, the poorer the response to anti-viral treatment, implying that a longer treatment course is needed. Also, in the case of genotype, the response to IFN is affected. Our previous studies have shown that genotype C has a low response rate to IFN. Some meta-analyses show that genotypes A and B are better responders to IFN compared with genotypes C and D.
We are now further elucidating the on-treatment factors, like surface antigen kinetics, to predict outcomes. Declines in HBsAg levels, either at 12 weeks or 24 weeks of therapy, may affect the seroconversion rate or SVR to IFN in HBeAg (+) or HBeAg (-) patients. For treatment with NUCs, most of the data refers to baseline HBV DNA. Only a small proportion (around 10%) of NUC- treated patients can have a rapid decline of surface antigen during treatment due of the rapid reduction of HBV DNA. These patients may even restore their endogenous immune activity against infections. These patients have the best results, and may have complete loss of the HBsAg.
来源：APASL 2014 daily news
