编者按：如果从1963年Baruch S. Blumberg教授发现HBsAg算起，人类对抗HBV的历史已经有半个多世纪。在第28届亚太肝病学会年会（APASL2019）的特邀“State-of-the-Art”演讲环节，中国香港天下仁心医疗集团主席廖家杰教授回顾了这场没有硝烟但人类必须获得胜利的战争。我们取得了哪些阶段性的成绩？胜利的曙光在何方？一起来从演讲的精彩内容中获得启示。

 

作为一位在亚太地区执业三十多年的肝病专家，临床中最令人痛苦的是，临床上有很多患者没有得到及时诊断和治疗，就诊时已处于肝病晚期、甚至是终末期肝癌（HCC），他们中间有很多在中年时就因肝病不幸离世。

 

1963年，诺贝尔奖获得者Baruch S. Blumberg教授发现了乙肝表面抗原（即“澳大利亚抗原”；JAMA,1965[1]）。随后，Beasley RP教授（Lancet，1981[2]）和Chen DS教授的大规模流行病学研究（Science，1993[3]）以及随后证实乙肝疫苗接种能大幅减少HCC的研究（Chang MW NEJM 1997[4]），明确了慢性乙型肝炎和HCC的因果关系。

 

此外，慢性HBV感染也是终末期肝硬化及其并发症的罪魁祸首，并且乙型肝炎再激活——无论是自发性的，还是由于使用免疫抑制剂治疗诱发的，都可能导致暴发性肝衰竭。因此，从临床角度来看，治疗慢性乙型肝炎的终点应该是减少HBV感染相关的发病率和死亡率，即减少肝细胞癌、终末期肝硬化以及由于乙型肝炎再激活所导致的暴发性肝衰竭的发生（APASL慢性乙型肝炎治疗指南，2015）。

 

随着对病毒生命周期的理解和对HBV感染中宿主免疫的重要性的认识，两种干扰素（普通干扰素和聚乙二醇化干扰素）和7种核苷（酸）类似物：拉米夫定、替比夫定、恩替卡韦、克拉夫定（韩国获批），阿德福韦酯、富马酸替诺福韦二吡呋酯以及富马酸丙酚替诺福韦，已在全球多个国家和地区获批用于治疗慢性乙型肝炎。

 

这些药物的获批是基于精心设计的随机对照临床试验。这些试验使用了替代治疗终点（surrogate marker），如：HBeAg血清学转换、血清HBV DNA水平降低、HBsAg转阴和/或HBsAg血清学转换（出现抗-HBs）和肝脏硬度改善。达到这些替代治疗终点被认为“等同于”HBV相关肝病发病率和死亡率降低。

 

与此一致，一项长期的、精心设计的随机对照研究证明，拉米夫定长期治疗能够有效地降低肝病相关的发病率和死亡率（Liaw YF，NEJM，2004[5]）。

 

然而，这二十余年的临床实际情况是，HBV相关的发病率和死亡率并未如预期下降。近期的系统性回顾研究（Anna Lok，Hepatology，2016[6]）分析了73项研究，其中59项（15项随机对照临床试验和44项观察性研究）报道了临床结果，仅有中等质量级别的证据支持“慢性乙型肝炎患者接受抗病毒治疗能减少肝硬化、失代偿期肝病以及HCC”。

 

2018年，肝癌（至少80%是HCC）仍然是全球癌症死亡的第四大原因，全球有841,000例新发病例和782,000例死亡病例（死亡率/发病率为0.93）。每年，超过50%的新诊断肝癌病例（90%以上与HBV感染相关）和肝癌死亡病例发生在中国。另一方面，由于免疫抑制剂在肿瘤性疾病、免疫相关疾病和器官移植等患者人群中的应用增加，与HBV再激活相关的暴发性肝衰竭的发生率也在升高。

 

科学和现实临床之间的联系，缺少了什么？最近，主要的研究工作集中在实现乙肝“治愈”——HBsAg转阴伴或不伴出现抗-HBs以及清除肝内cccDNA。这是基于前期的观察发现：在慢性乙型肝炎患者进展至肝硬化之前实现HBsAg转阴，将大大降低HCC的发病率。

 

从实现消除HBV相关的肝脏发病率和死亡率的终点出发，这种类型的“治愈”在有效率、安全性和成本方面（随着价格低廉的仿制药广泛使用），与长期乃至终生核苷（酸）类似物治疗或有限疗程的干扰素治疗相比，是否会是更好的解决方案？

 

我们真正需要的是，开发基于基因组学和蛋白质组学的技术平台（Jiang Y，Nature，2019[7]），实现肝癌的早期诊断（从而使局部根治或者移植成为可能）；提高社会公众和医疗专业人员对慢性乙型肝炎的认识；设计更加行之有效的方案来进一步减少HBV的新发感染；以及剖析可能使HBV相关肝病发病率和死亡率升高的原因并加以纠正。

 

只有多学科共同努力，并在社区和监管部门的帮助下，清楚认识真正的“治疗终点”，我们才能减轻慢性乙型肝炎患者的痛苦。

 

参考文献:

 

1. B.S. Blumberg, H.J. Alter, S. Visnich, JAMA 191 (1965) 541–546.

 

2. Beasley RP, et al. Lancet 1981,2(8256):1129-1133 

 

3. Chen DS. Science. 1993 Oct 15;262(5132):369-70

 

4. Chang MH, et al. N Engl J Med. 1997, 26;336(26):1855-9.

 

5. Liaw YF, et al, N Engl J Med. 2004, 7;351(15):1521-31.

 

6. Lok AS, et al. Hepatology. 2016 Jan;63(1):284-306.

 

7. Jiang Y, et al. Nature, research letter, https://doi.org/10.1038/s41586-019-0987-8

 

专家简介

 

廖家杰（George Lau） 

 

中国香港内科医学院院士，中国香港大学内科医学博士，英国皇家内科医学院院士，中国香港大学内外全科医医学士，中国香港医学专科医学院院士（肠胃及肝脏科），爱丁堡皇家内科医学院荣授院士，伦敦大学皇家内科医学院荣授院士

 

中国香港天下仁心医疗集团主席，中国香港天下仁心胃肠及肝脏中心主任，中国人民解放军总医院第五医疗中心联合中国香港天下仁心医疗集团丙肝诊断治疗中心共同主任，中国人民解放军总医院第五医疗中心联合肝病转化医学研究所共同所长

 

Decades of research in chronic hepatitis B infection-Have we reached the endpoint?

 

Being a practicing hepatologist in Asia for almost thirty years, my most distressing clinical experience is the need to confront patients with chronic hepatitis B (CHB) infection, being undiagnosed and presented with advanced/late hepatocellular carcinoma (HCC). Many of these patients subsequently died at their middle-age. 

 

With the discovery of hepatitis B surface antigen (as Australian antigen), by Nobel Prize winner Baruch S. Blumberg in 1963 coupled with subsequent large scale epidemiology study (Beasley RP 1981, Chen DS, Sung JL 1977) and the demonstration of substantial reductions of HCC with universal hepatitis B vaccination (Chang MW 1997) the causal relationship of CHB with HCC, has been clearly established.?

 

In addition, CHB infection is also the major culprit of end-staged liver cirrhosis and its reactivation, either spontaneously or with the use of immunosuppressive therapy could lead to fulminant liver failure. Hence, from the clinical perspective, the ultimate endpoint for the treatment of CHB should be a reduction of its related morbidity and mortality i.e. HCC, end-staged liver cirrhosis and fulminant hepatic failure due to its reactivation. 

 

In addition, CHB infection is also the major culprit of end-staged liver cirrhosis and its reactivation, either spontaneously or with the use of immunosuppressive therapy could lead to fulminant liver failure. Hence, from the clinical perspective, the ultimate endpoint for the treatment of CHB should be a reduction of its related morbidity and mortality i.e. HCC, end-staged liver cirrhosis and fulminant hepatic failure due to its reactivation. 

 

With the understanding of viral life cycle and the importance of host immunity, two interferon (IFN, standard and pegylated) and seven nucleos(t)ide analogues: lamivudine, telbivudine, entecavir, clevudine (in South Korea), adefovir, tenofovir and tenofovir alafenamide, have been approved by various regulatory authority for the treatment of CHB. 

 

These medications were approved based on well-designed randomized controlled trials (RCTs), using surrogate treatment endpoints, such as e-seroconversion, reduction of serum HBV DNA level, loss of hepatitis B surface antigen (HBsAg) with or without development of hepatitis B surface antibody (anti-HBs) and improvement of liver stiffness, which are believed to be “equivalent” to reduction of HBV-related liver morbidity and mortality.

 

In keeping with this, long-term carefully designed and controlled studies with the use of lamivudine has been shown to be effective in reducing liver-related mortality and morbidity (Liaw 2004). 

 

However, in real-life over the past two decades, HBV-related morbidity and mortality has not been reduced as expected. In a recent systemic review, which included 73 studies, of which 59 (15 RCTs and 44 observational studies) reported clinical outcomes, only moderate-quality evidence supported the effectiveness of antiviral therapy in CHB patients in reducing the risk of cirrhosis, decompensated liver disease and HCC. 

 

By 2018, liver cancer (at least 80% being HCC) remains the fourth leading cause of cancer death worldwide, with about 841,000 new cases and 782,000 deaths annually (mortality/incidence ratio of 0.93). Annually, over 50% of all newly diagnosed liver cancer cases (> 90 % related to HBV) and deaths occurred in China. On the other hand, due to the increase use of immunosuppressive agents for treatment of various forms of cancer, immune-related diseases and in patients who received transplantation, there is an increasing incidence of fulminant liver failure due to HBV reactivation. 

 

What is the missing link between science and real life? Recently, major research effort has been focused to achieve loss of HBsAg with or without development of anti-HBs and eradication of intrahepatic cccDNA as a form of “cure” in CHB. This is supported by the previous observation that in CHB patients, loss of HBsAg before the development of liver cirrhosis will drastically reduce the incidence of HCC. 

 

Will this type of “cure” be a better solution in terms of efficacy, safety and cost (with the widespread utility of much cheaper generic agents) as compared to life-long nucleos(t)ide or finite therapy with IFN (though only a minority could have sustained disease remission), to achieve the ultimate endpoints with elimination of HBV-related liver morbidity and mortality？

 

What we really need is perhaps methods for early detection of HCC (to allow curative local ablation therapy or transplantation) based on the new technology platform in genomics and proteinomics, raise of public and health-care professional awareness of CHB, designation of more effective algorithm to further reduce incidence of new infection and to understand and to correct the other comorbidity factors which can aggravate CHB-related morbidity and mortality. 

 

Only with conjoint multi-disciplinary effort, with the support of our community and governance agency, with clear understanding of the real “end-point”, will we be able to alleviate the suffering of mankind from CHB infection.