预防B型肝炎病毒相关的肝癌抗病毒治疗

StephenW

http://onlinelibrary.wiley.com/doi/10.1002/hep.25937/full
Prevention of hepatitis B virus–related hepatocellular carcinoma with antiviral therapy†

    Ching-Lung Lai1,2,‡,*,
    Man-Fung Yuen1,2

Article first published online: 7 JAN 2013

DOI: 10.1002/hep.25937

Abstract

Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC). Primary prevention of hepatitis B infection by vaccination is effective in reducing the incidence of HCC. In persons with CHB infection, the two accepted treatment modalities are interferon alpha (IFN-α) given subcutaneously for a limited period and nucleoside/nucleotide analogs given orally on a long-term basis. These treatments are effective in suppressing viral activity and improving disease markers in short-term studies. The long-term effect on the development of liver cancers with these two forms of treatment appears to be different. However, there are no studies directly comparing IFN-α and nucleoside/nucleotide analogs. Comparisons across studies are inevitably limited by differences in the baseline characteristics of the study cohorts. Long-term follow-up studies of IFN-α therapy show inconsistent results. The beneficial effect in reducing the development of liver cancer is observed mainly in treatment responders who have preexisting cirrhosis of the liver. The long-term studies of lamivudine (and adefovir) show a consistent reduction in the development of liver cancers in patients with, and without, cirrhosis. This beneficial effect is blunted by the development of resistance. The effects of the newer nucleoside/nucleotide analogs, with higher potency and minimal risk of resistance development, are, as yet, unknown. (HEPATOLOGY 2013)

[extracts]
Other Risk Factors for Development of HCC

Other than viral replication, there are other important viral and host factors associated with development of HCC. These are not readily amendable to therapeutic interventions. Several viral genomic changes/mutations/polymorphisms have been found to be associated with a higher risk of development of HCC. These include HBV genotypes (especially genotype C), pre-S deletions, enhancer II mutations (T1653), and core promoter mutations (V1753, T1762, and A1764).33, 34

Host factors associated with higher risk of development of HCC include increasing age and male gender. Host response to HBV infection that results in progression to cirrhosis is also a major contributory risk factor. However, cirrhosis can currently be prevented and even reversed, to a certain extent, by prolonged antiviral therapy.35 Host genomic constitution may also influence the risk of development of HCC. Several recent genome-wide association studies (GWAS) have shown that single-nucleotide polymorphisms at different human genomic loci (e.g., chromosome 1p36.22, chromosome 6 of human leukocyte antigen [HLA]-DP and HLA-DQ loci, and chromosome 8p12) are associated with a higher chance of development of HCC in CHB patients.36, 37

The combination of viral and host factors exert synergistic effects on the development of HCC.34 Though total amelioration of HCC occurrence in CHB disease may not be achievable, maximal viral suppression by potent antiviral treatment is still the most effective way to reduce the occurrence of HCC.
Conclusions

Successful treatment of CHB can decrease the risk of HCC. The protective effect of IFN-α is likely to be limited to patients with cirrhosis who are sustained responders, a relatively small proportion of patients. The effect of IFN-α in patients without cirrhosis is unclear. Treatment with nucleoside analogs appears more effective in lowering the risk of HCC development, probably through more potent and persistent suppression of viral replication, though the effect may be blunted with the occurrence of resistance. Whether the current two first-line agents (entacavir and tenofovir), which have greater potency and lower resistance rates than lamivudine and adefovir, can further reduce the risk of development of HCC have yet to be proven.

StephenW

慢性乙型肝炎（CHB）感染是肝细胞肝癌（HCC）的主要病因。主要通过接种疫苗是预防乙肝病毒感染，有效地降低肝癌的发病率。在慢性乙型肝炎感染者中，这两个公认的治疗方法是α-干扰素（IFN-α），在有限的时间和一个长期的基础上口服核苷/核苷酸类似物皮下。这些治疗是有效抑制病毒活性，改善在短期研究中的疾病标志物。这两种形式的治疗肝癌的发展的长期影响是不同的。然而，也没有研究直接比较，IFN-α和核苷/核苷酸类似物。差异的研究队列的基线特征之间的比较研究，都不可避免地受到限制。长期IFN-α治疗的随访研究显示不一致的结果。降低肝癌的发展中观察到的有益作用主要有预先存在的肝硬化治疗有反应。拉米夫定（和阿德福韦）的长期研究显示出一致的减少在肝癌患者的发展，和无，肝硬化。这种有益的作用明显减弱，发展的阻力。的较新的核苷/核苷酸类似物，具有更高的效力和耐药性的发展的风险最小，是影响中，到目前为止，还未知。 （肝胆病2013年）

HCC发展的其他危险因素

除了病毒复制，还有其他一些重要的病毒和宿主因素与HCC的发展。这些都不是随时可修正治疗干预。一些病毒基因组的变化/突变/多态性被发现与发展的HCC的风险较高。这些措施包括（特别是C基因型）HBV基因型，前S缺失，增强II的突变（T1653）和核心启动子突变（V1753，T1762，A1764）.33，34

的HCC高风险的发展与宿主因素包括年龄的增加，男性。 HBV感染的宿主反应，在进展为肝硬化的结果也是一个主要的供款的风险因素。然而，目前防止肝硬化，甚至逆转，长期的抗病毒therapy.35宿主基因组构成，在一定程度上也可能影响发展的HCC的风险。最近的几个全基因组关联研究（GWAS）表明，单核苷酸多态性在不同的人类基因组位点（例如，染色体1p36.22，6号染色体的人类白细胞抗原HLA-DP，HLA-DQ位点，染色体8p12 ）相关，37在CHB patients.36中具有较高的HCC的发展机会

病毒和宿主因素的结合，发挥协同效应的发展HCC.34改善肝癌的发生在慢性乙肝疾病虽然可能无法实现，最大抑制病毒，通过有效的抗病毒治疗仍是最有效的方式，以减少肝癌的发生。
结论

成功的CHB治疗可以减少肝癌的危险。 IFN-α的保护作用可能是有限的肝硬化患者持续应答，一个相对较小的患者比例。在无肝硬化的患者IFN-α的影响目前还不清楚。出现与核苷类似物治疗更有效地降低HCC的发展的风险，可能是通过更有效和持久性的抑制病毒复制，但效果可以与电阻发生钝化。无论是目前的两个一线药物（entacavir和替诺福韦），具有更大的效力和较低的电阻率比拉米夫定和阿德福韦，可以进一步降低风险的HCC的发展还有待证明。