经α-干扰素和核苷（酸）类似物治疗的慢性乙型肝炎患者原发性肝癌发生率比较研究

doi:10.3969/j.issn.1672-5069.2017.04.019

摘要/Abstract

摘要： 目的分析比较应用干扰素α（IFN-α）和核苷（酸）类似物（NAs）治疗对慢性乙型肝炎患者肝细胞癌（HCC）发生率的影响差异。方法 2007年1月~2010年12月收治的30岁~60岁慢性乙型肝炎（CHB）患者,接受IFN-α2b治疗210例,治疗48~72 w,接受NAs治疗222例,长期应用和未抗病毒组136例。随访6年,观察疗效和HCC发生情况。应用SPSS 19.0统计软件分析。结果在治疗72周末,IFN-α2b治疗组HBeAg阳性患者比率显著低于NAs治疗组或未抗病毒组（P均<0.05）,但NAs治疗患者血清HBV DNA和ALT水平显著低于IFN-α2b治疗组或未抗病毒组（P均<0.05）;IFN-α2b治疗组与NAs治疗组血清肝纤维化标志物变化无显著性差异（P均>0.05）,但均比未抗病毒组低（P均<0.05）;随访6年,未抗病毒组HCC发生率为16.91%（23/136）,显著高于NAs治疗组的9.46%（21/222,x²=4.345,P=0.037）或IFN-α2b治疗组的0.0%（0/210,x²=38.044,P=0.000）,NAs治疗组HCC发生率显著高于IFN-α2b治疗组,具有统计学差异（x²=20.880,P=0.000）。结论 IFN-α2b和NAs抗病毒治疗均具有阻断HCC发生的作用,但IFN-α2b治疗在阻断HCC发生方面作用更强。

关键词: 肝细胞癌, 慢性乙型肝炎, 干扰素α, 核苷（酸）类似物, 治疗

Abstract: Objective The aim of this study is to compare the impact of interferon alpha and nucleos（t）ide analogues in treating patients with chronic hepatitis B on incidence of hepatocellular carcinoma. Methods A series of patients with chronic hepatitis B（CHB） aged 30 to 60 years old were enrolled between January 2007 and December 2010 in our hospital. 210 patients with CHB were treated with interferon alpha 2b（IFN-α2b） for 72 weeks, 222 with nucleos（t）ide analogues（NAs） as a long-term treatment and 136 cases didn’t received antiviral therapy. All the patients were followed-up for six years. All data were analyzed by SPSS 19.0 statistics software. Results At the end of 72 week treatment,serum HBeAg positivity rate in IFN-α2b-treated group was much lower than in NAs-treated or in non-antiviral group（P<0.05）,while serum HBV DNA and alanine aminotransferase levels in NAs-treated group were much lower than in IFN-α2b-treated group or in non-antiviral group（P<0.05）;serum chileglycine,collagen peptide Ⅲ,Ⅳ collagen,hyaluronic acid and laminin levels in IFN-α2b-or NAs-treated group were not significantly different（P>0.05）,while all were much lower than in non-antiviral group（P<0.05）;At the discontinuation of six year follow-up,the incidence of HCC in non-antiviral group was 16.91%（23/136）,much higher than 9.46%（21/222,x²=4.345,P=0.037） in NAs-treated or 0.0% （0/210,x²=38.044,P=0.000） in IFN-α2b-treated group,and the incidence of HCC in NAs-treated group was much higher than in IFN-α2b-treated group（x²=20.880,P=0.000）. Conclusions The efficacy of IFN-α2b therapy on HCC occurrence in patients with CHB is much stronger than NAs treatment.

Key words: Hepatocellular carcinoma, Hepatitis B, Interferon α, Nucleos（t）ide analogues, Therapy

汪顺才, 王兵, 马洁, 马久明, 周华, 虞腊青, 经继生. 经α-干扰素和核苷（酸）类似物治疗的慢性乙型肝炎患者原发性肝癌发生率比较研究[J]. 实用肝脏病杂志, 2017, 20(4): 455-459.

Wang Shuncai, Wang Bing, Ma Jie, et al.. A comparative study of impact of interferon alpha and nucleos(t)ide analogues in treating patients with chronic hepatitis B on incidence of hepatocellular carcinoma[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2017, 20(4): 455-459.

参考文献

[1] World Health Organization. Guidelines for the prevention,care and treatment of persons with chronic hepatitis B infection[Books & Documents]. WHO press,2015 Mar. www.who.int/about/licensing/copyright_form/en/index.html.
[2] Dandri M,Petersen J. Mechanism of hepatitis B virus persistence in hepatocytes and its carcinogenic potential. Clin Infect Dis,2016,62（S4）:S281-288.
[3] Tan ZM,Sun BC. Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence,World J Gastroenterol,19 （2013）8895-8901.
[4] Baran B. Nucleos（t）ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma. World J Hepatol,2015,7（13）:1742-1754.
[5] Hiramatsu N,Yamada R,Takehara T. The suppressive effect of nucleos（t）ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. J Gastroenterol Hepatol,2016,31（3）:546-552.
[6] Kim SK,Kim SR,Imoto S,et al. Recent advances in the management of chronic hepatitis B including suppression of hepatocellular carcinoma by entecavir and interferon. Oncology, 2015,89 （Suppl 2）:60-69.
[7] Lin SM,Sheen IS,Chien RN,et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.Hepatology,1999,29:971-975.
[8] Chen G,Lin W,Shen F,et al. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol,2006,101:1797-1803.
[9] 中华人民共和国卫生部. 原发性肝癌诊疗规范（2011年版）. 临床肿瘤学杂志,2011,16（10）：929-946.
[10] Ching RHH,Sze KMF,Lau EYT,et al. C-terminal truncated hepatitis B virus X protein regulates tumorigenicity,self-renewal and drug resistance via STAT3/Nanog signaling pathway. Oncotarget,2017,[Epub ahead of print].
[11] Wang J,Chenivesse X,Henglein B,et al. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature,1990,343:555-557.
[12] Tan YJ. Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol,2011,17: 4853-4857.
[13] Aoki H,Kajino K,Arakawa Y,et al. Molecular cloning of a rat chromosome putative recombinogenic sequence homologous to the hepatitis B virus encapsidation signal. Proc Natl Acad Sci USA,1996,93:7300-7304.
[14] Fallot G,Neuveut C,Buendia MA. Diverse roles of hepatitis B virus in liver cancer. Curr Opin Virol,2012,2:467-473.
[15] Ng SA,Lee C. Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol,2011,46:974-990.
[16] Forgues M,Difilippantonio MJ,Linke SP,et al. Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol,2003,23:5282-5292.
[17] Xu X,Fan Z,Kang L,et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest,2013,123:630-645.
[18] Kapoor NR,Ahuja R,Shukla SK,et al. The HBx protein of hepatitis B virus confers resistance against nucleolar stress and anti-cancer drug-induced p53 expression. FEBS Lett,2013,587:1287-1292.
[19] Michailidis E,Kirby KA,Hachiya A,et al. Antiviral therapies:focus on hepatitis B reverse transcriptase. Int J Biochem Cell Biol,2012,44（7）:1060-1071.
[20] Wu CY,Lin JT,Ho HJ,et al. Association of nucleos（t）ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B:a nationwide cohort study. Gastroenterology,2014,147:143-151.
[21] Yasunaka T,Ikeda F,Wada N,et al. Entecavir reduces hepatocarcinogenesis in chronic hepatitis B patients. Acta Med Okayama,2016,70（1）:1-12.
[22] Pei RJ,Chen XW,Lu MJ. Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways. World J Gastroenterol,2014,20（33）:11618-11629.
[23] Belloni L,Allweiss L,Guerrieri F,et al. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest,2012,122: 529-537.
[24] Haller O,Staeheli P,Kochs G. Interferon-induced Mx proteins in antiviral host defense. Biochimie,2007,89:812-818.
[25] Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev,2001,14:778-809.
[26] Lucifora J,Xia Y,Reisinger F,et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science,2014,343:1221-1228.
[27] Biron CA. Role of early cytokines,including and interferons （IFN-α）,in innate and adaptive immune respones to viral infections. Semin. Immunol. 2001,5:383-390.
[28] Lin SM,Sheen IS,Chien RN, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology,1999,29:971-975.
[29] Chen CJ,Yang HI,Su J,et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA,2006,295（1）:65-73.
[30] Joseph K,BSa H,Yang HI,et al. Lower liver cancer risk with antiviral therapy in chronic hepatitis B patients with normal to minimally elevated ALT and no cirrhosis. Medicine（Baltimore）,2016,95（31）::e4433.
[31] Yang HI,Yuen MF,Chan HL et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B （REACH-B）: development and validation of a predictive score. Lancet Oncol,2011,12:568-574.
[32] Liang KH,Hsu CW,Chang ML,et al. Peginterferon is superior to nucleos（t）ide analogues for prevention of hepatocellular carcinomain chronic hepatitis B. J Infect Dis,2016,213（6）:966-974.