回顾 策略来控制乙肝：公共政策，流行病学，疫苗和药品

StephenW

Review
Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs

    Stephen Locarnini1, , , Angelos Hatzakis2, Ding-Shinn Chen3, Anna Lok4

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        doi:10.1016/j.jhep.2015.01.018
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Summary

The last 50 years of hepatitis B research has resulted in the development of effective screening assays for surveillance, vaccines for prevention and antiviral drugs that significantly improve patient clinical outcomes. Not surprisingly then, the global epidemiology of hepatitis B virus (HBV) is set to change dramatically over the next decade. For example, the success and the high coverage of universal HBV vaccination and the ageing cohorts of patients with chronic hepatitis B (CHB) will result in reductions of incidence and prevalence of chronic hepatitis, cirrhosis and probably hepatocellular carcinoma. This will be further accelerated by the impressive progress in the treatment outcomes for patients with CHB. In spite of this success, challenges remain, such as planning for the impact of migration from countries with high prevalence rates to those countries with low rates of HBV infection. The recent establishment of the World Health Organisation Global Hepatitis Program with the provision of a framework for global action has become the cornerstone for all countries to now frame their own particular national responses to control hepatitis B. An effective policy framework can prevent new infections, ensure people can access clinical care, and in doing so reduce the burden of infection at an individual, country and regional level. These developments present a real opportunity to reduce the significant, social and economic burden of global hepatitis B, ultimately the critical next steps to render the world hepatitis B free.
Keywords

    Epidemiology; Prevention; Hepatitis B vaccine; Acute hepatitis B; Chronic hepatitis B; Treatment; Chronic liver disease; Hepatocellular carcinoma; Public policy; WHO

StephenW

回顾
策略来控制乙肝：公共政策，流行病学，疫苗和药品

    斯蒂芬Locarnini1，，安吉洛Hatzakis2，鼎希恩Chen3，安娜Lok4

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        DOI：10.1016 / j.jhep.2015.01.018
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总结

在过去50年乙肝研究已导致有效筛选试验发展监测，疫苗预防和抗病毒的药物，显著改善患者的临床结果。不出意外的话，B型肝炎病毒的流行病学全球（HBV）设置为极大地改变未来十年。例如，成功和高覆盖率普遍乙肝疫苗和治疗慢性乙型肝炎（CHB）老化同伙将导致发病率和慢性肝炎，肝硬化和肝癌可能是癌患病率降低的。这将通过在治疗结果慢性乙型肝炎患者的令人印象深刻的进展进一步加快。尽管这一成功，挑战依然存在，如规划，从国家的高发病率与HBV感染率低迁移影响的国家。最近成立的世界卫生组织全球肝炎计划与提供的全球行动框架已成为基石所有国家现在帧自己特定的国家应对控制乙肝的有效的政策框架，可以预防新感染，确保人们可以访问的临床护理，并在这样做减少在个人，国家和区域层面感染负担。这些发展带来了真正的机会，以减少全球乙肝显著，社会和经济负担，最终的关键下一步渲染世界乙肝免费。
关键词

    流行病学;预防;乙肝疫苗;急性乙型肝炎;慢性乙型肝炎;治疗;慢性肝病;肝癌;公共政策;世卫组织

StephenW

Extract:

Progression to cirrhosis and HCC is very slow in the inactive carrier state (<1% per year), while progression to cirrhosis may occur at a rate of 2–10% per year in the immune reactive and reactivation phases. Progression from cirrhosis to HCC may occur in 2–4% of patients per year. The incidence of cirrhosis appears to be 2-fold higher in HBeAg-negative compared to HBeAg-positive patients. In cirrhotic patients the 5-year cumulative risk of HCC is 17% in East Asia, 10% in Western Europe and USA, and 5-year related death is 14% in East Asia and 15% in Europe [6]. Progression rates are mainly determined by the age of infection, gender, extent of HBV replication, particular HBV genotypes and variants, coinfection with HCV, HDV or HIV, alcohol, exposure to aflatoxin B1, host genetic factors and probably co-morbidities including metabolic syndrome, diabetes, obesity and tobacco smoking. Studies in Asia suggest a faster progression to cirrhosis and HCC if infected with genotype C compared to genotype B HBV. Studies in Europe and North America reveal that genotype D CHB has a higher progression to cirrhosis and HCC than genotype A [6], [8], [10] and [11].

The main risk factors for HBV progression to HCC include HBeAg positivity and HBV DNA levels. Seminal studies from Taiwan established these associations [12], [13] and [14]. The incidence of HCC was 1169/100,000 person-years for HBsAg and HBeAg-positive persons, 324/100,000 person-years for HBsAg positive, HBeAg-negative and 39/100,000 person-years for those who were HBsAg negative. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease (REVEAL-HBV) study established HBV DNA levels as the main determinant of progression to HCC. However, even HBsAg positive carriers with low levels of HBV DNA and normal ALT had an almost 5-fold greater risk for HCC than HBsAg negative controls [13] and [15].


Did you mean: Extract: Progression to cirrhosis and HCC is very slow in the inactive carrier state (<1% per year), while progression to cirrhosis may occur at a rate of 2–10% per year in the immune reactive and reactivation phases. Progression from cirrhosis to HCC may occur in 2–4% of patients per year. The incidence of cirrhosis appears to be 2-fold higher in HBeAg-negative compared to HBsAg-positive patients. In cirrhotic patients the 5-year cumulative risk of HCC is 17% in East Asia, 10% in Western Europe and USA, and 5-year related death is 14% in East Asia and 15% in Europe [6]. Progression rates are mainly determined by the age of infection, gender, extent of HBV replication, particular HBV genotypes and variants, coinfection with HCV, HDV or HIV, alcohol, exposure to aflatoxin B1, host genetic factors and probably comorbidities including metabolic syndrome, diabetes, obesity and tobacco smoking. Studies in Asia suggest a faster progression to cirrhosis and HCC if infected with genotype C compared to genotype B HBV. Studies in Europe and North America reveal that genotype D CHB has a higher progression to cirrhosis and HCC than genotype A [6], [8], [10] and [11]. The main risk factors for HBV progression to HCC include HBeAg positivity and HBV DNA levels. Seminal studies from Taiwan established these associations [12], [13] and [14]. The incidence of HCC was 1169/100,000 person-years for HBsAg and HBeAg-positive persons, 324/100,000 person-years for HBsAg positive, HBeAg-negative and 39/100,000 person-years for those who were HBsAg negative. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease (REVEAL-HBV) study established HBV DNA levels as the main determinant of progression to HCC. However, even HBsAg positive carriers with low levels of HBV DNA and normal ALT had an almost 5-fold greater risk for HCC than HBsAg negative controls [13] and [15].
摘录：

发展为肝硬化和肝癌处于非活动载波状态非常慢（<1％，每年），而可能发生在每年2-10％的免疫反应性和再活化阶段的速度发展为肝硬化。级数从肝硬化至肝癌可能发生在每一年的病人2-4％。肝硬化的发生率似乎是2倍的HBeAg阴性较高相比，HBeAg阳性患者。在肝硬化患者肝癌的5年累积风险是东亚17％，在西欧和美国的10％，而5年期相关的死亡是在东亚地区的14％，在欧洲[6] 15％。升学率主要是由感染，性别，乙肝病毒的复制，尤其是HBV基因型和变异，同时感染了HCV，HDV或HIV，酗酒，接触黄曲霉毒素B1程度的年龄决定，宿主遗传因素和可能合并症，包括代谢综合征，糖尿病，肥胖和吸烟。研究表明亚洲较快发展为肝硬化和肝癌，如果感染上C型相比，B型HBV。研究在欧洲和北美揭示D基因型CHB具有更高发展为肝硬化和肝癌比基因型A [6]，[8]，[10]和[11]。

主要风险因素为乙肝进展为肝癌包括e抗原阳性和HBV DNA水平。来自台湾精囊炎研究建立这些协会[12]，[13] [14]。肝癌的发病率为1169/10万人年HBsAg和HBeAg阳性者，324/10万人年为HBsAg阳性，HBeAg阴性和39/10万人年对于那些谁是HBsAg阴性。病毒载量提升风险评估及相关肝病（REVEAL-HBV）研究建立HBV DNA水平作为发展的主要决定因素肝癌。然而，即使HBsAg的乙肝病毒DNA的水平低和ALT正常阳性携带者肝癌除HBsAg阴性对照[13]和[15]的几乎5倍的风险更大。

StephenW

Prospects for cure

Eradicating HBV in patients who are chronically infected maybe an unachievable goal but a “functional cure” may be possible and should be pursued. While long-term entecavir or tenofovir is convenient, fairly safe, with negligible risk of drug resistance and cost is expected to decline in the coming years with the availability of generic drugs, there remains a small risk of adverse reactions and the cost of indefinite treatment will remain unaffordable for many patients as well as health departments in countries with socialized health care. Furthermore, adherence to treatment tends to diminish over time.

A multi-prong approach with antiviral drugs targeting different steps of the HBV replication cycle combined with immunotherapy to restore immune responsiveness to HBV will be needed for patients to remain in a state of “functional cure” [75]. Currently available NUCs only target the HBV reverse transcriptase/polymerase. Recent identification of a bile salt transporter – sodium taurocholate cotransporting polypeptide (NTCP) as the host receptor for HBV created opportunities to evaluate compounds that can block viral entry [76]. One example, Myrcludex B is being tested in phase 2 clinical trials. Other approaches aim at eradication or functional silencing of cccDNA through epigenetic modifications, dysregulation of nucleocapsid assembly or inhibition of virion secretion. Previous attempts of immunotherapy have failed to restore immune responsiveness to HBV in patients with chronic HBV infection even though some of these approaches were effective in uninfected volunteers. However, recent studies showed that immune response to HBV can be restored in patients who undergo HBeAg spontaneously or following antiviral treatment, and more so in those who achieve HBsAg loss [77]. These data indicate that restoration of immune response to HBV is possible particularly after HBV replication has been suppressed and HBsAg production decreased.


展望治愈

消除乙肝病毒在谁是慢性感染，也许是无法实现的目标，而是一个“功能性治愈”是可能的，应当继续进行病人。虽然长期恩替卡韦或替诺福韦是方便，相当安全，具有耐药性和成本的风险可以忽略不计，预计在未来几年与仿制药的供应下降，但仍然不良反应小的风险和不确定的治疗费用仍然买不起很多患者以及卫生部门与社会卫生保健的国家。此外，坚持治疗往往会随着时间逐渐褪去。

与靶向不同步骤的HBV复制周期结合免疫的抗病毒药物的多叉股的方法来恢复免疫反应对HBV将需要的患者留在“功能治愈”[75]的状态。目前市面上只有NUCs针对乙肝病毒逆转录酶/聚合酶。最近鉴定胆盐转运 - 牛磺胆酸钠cotransporting多肽（NTCP）作为HBV宿主受体创造了机会，以评估可以阻止病毒进入[76]的化合物。一个例子中，Myrcludex B被在第2阶段的临床试验中被测试。其他的方法旨在消除或cccDNA的通过表观遗传修饰功能沉默，核衣壳组装或抑制病毒分泌失调。以前的尝试免疫治疗都未能恢复免疫反应对HBV慢性HBV感染者，尽管其中的一些方法是有效的未感染的志愿者。然而，最近的研究表明，对HBV的免疫反应可以自发谁或以下的抗病毒治疗，更使发生在大三阳那些谁达到HBsAg消失[77]患者的恢复。这些数据表明，恢复对HBV的免疫应答是可能的特别后HBV复制被抑制和HBsAg的产量下降。

StephenW

整篇文章:
http://www.sciencedirect.com/sci ... i/S0168827815000495