慢性乙肝患者HBsAg/抗-HBs共存与肝癌发生风险的研究
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摘要
目的探讨慢性乙型肝炎(chronic hepatitis B, CHB)患者HBsAg/抗-HBs共存的血清学模式与肝细胞癌(hepatocellular carcinoma, HCC)的关系。方法在病例对照研究中,选取2017年1月至2018年3月首都医科大学附属北京佑安医院收治的CHB患者412例,分为G1组(HBsAg/抗-HBs共存)和G2组(HBsAg阳性、抗-HBs阴性),每组206例,对HCC发生风险进行logistic回归分析。在队列研究中,选取2010年9月至2013年11月的CHB患者260例,分为G3组(HBsAg/抗-HBs共存)和G4组(HBsAg阳性、抗-HBs阴性),每组130例,采用生存分析法分析两组HCC累计发生率的差异。结果病例对照研究中,年龄≥50岁(OR=4.486,95%CI:2.592～7.762,P <0.001),男性(OR=3.683,95%CI:2.025～6.699,P <0.001),HBsAg/抗-HBs共存(OR=2.063,95%CI:1.259～3.382,P=0.004)均可增加HCC发生风险。队列研究中,随访期间85.8%(223/260)的患者接受了规范抗病毒治疗,两组抗病毒治疗患者的比例差异无统计学意义(P=0.214)。基线高病毒载量患者,HBsAg/抗-HBs共存可能增加其HCC发生风险(Log-rank P=0.018),而低载量患者两组差异无统计学意义(Log-rank P=0.902)。结论基线高病毒载量的CHB患者,HBsAg/抗-HBs共存可能增加HCC发生风险。该模式与病毒突变有关,对乙肝患者的预后评估有提示作用。建议联合检测反映肝内病毒模板含量的指标及HBV突变位点来评估肝癌风险,拟定治疗及随访策略。
Objective To illustrate the association between the serological pattern of coexisting of HBsAg and anti-HBs and hepatocellular carcinoma(HCC) in patients with chronic hepatitis B(CHB). Methods In the case-control study,206 patients with coexistence of HBsAg and anti-HBs(G1 group) and 206 patients with HBsAg alone(G2 group) were selected. The risk of HCC was analyzed by univariate analysis and multivariate logistic regression analysis. In the cohort study, 130 patients with coexistence of HBsAg and anti-HBs(G3 group) and 130 patients with HBsAg alone(G4 group) were recruited to estimate the cumulative incidence of HCC by Kaplan-Meier analysis. Results In the case-control study, age ≥ 50 years(OR = 4.486, 95% CI:2.592-7.762, P<0.001), male(OR = 3.683, 95% CI:2.025-6.699, P<0.001), coexistence of HBsAg and anti-HBs(OR = 2.063, 95% CI:1.259-3.382, P = 0.004) were risk factors for HCC development. In the cohort study, during the follow-up period, 85.8%(223/260) of the patients received antiviral therapy, and there was no significant difference in the proportion of antiviral therapy between the two groups(P = 0.214). The serological pattern of coexistence of HBsAg and antiHBs significantly increased the risk of HCC in CHB patients with high HBV load at baseline(Logrank P = 0.018). However,the significance was not showed in patients with low HBV load at baseline(Logrank P = 0.902). Conclusions The serological pattern of coexistence of HBsAg and anti-HBs may increase the risk of HCC in CHB patients with high HBV load. This model is associated with viral mutations and has a promising role in the evaluation of prognosis in CHB patients. It is suggested that the risk of HCC should be assessed by combining the indicators reflecting the content of viral template and the detection of HBV mutation sites, and the treatment and follow-up strategies should be formulated.
Objective To illustrate the association between the serological pattern of coexisting of HBsAg and anti-HBs and hepatocellular carcinoma(HCC) in patients with chronic hepatitis B(CHB). Methods In the case-control study,206 patients with coexistence of HBsAg and anti-HBs(G1 group) and 206 patients with HBsAg alone(G2 group) were selected. The risk of HCC was analyzed by univariate analysis and multivariate logistic regression analysis. In the cohort study, 130 patients with coexistence of HBsAg and anti-HBs(G3 group) and 130 patients with HBsAg alone(G4 group) were recruited to estimate the cumulative incidence of HCC by Kaplan-Meier analysis. Results In the case-control study, age ≥ 50 years(OR = 4.486, 95% CI:2.592-7.762, P<0.001), male(OR = 3.683, 95% CI:2.025-6.699, P<0.001), coexistence of HBsAg and anti-HBs(OR = 2.063, 95% CI:1.259-3.382, P = 0.004) were risk factors for HCC development. In the cohort study, during the follow-up period, 85.8%(223/260) of the patients received antiviral therapy, and there was no significant difference in the proportion of antiviral therapy between the two groups(P = 0.214). The serological pattern of coexistence of HBsAg and antiHBs significantly increased the risk of HCC in CHB patients with high HBV load at baseline(Logrank P = 0.018). However,the significance was not showed in patients with low HBV load at baseline(Logrank P = 0.902). Conclusions The serological pattern of coexistence of HBsAg and anti-HBs may increase the risk of HCC in CHB patients with high HBV load. This model is associated with viral mutations and has a promising role in the evaluation of prognosis in CHB patients. It is suggested that the risk of HCC should be assessed by combining the indicators reflecting the content of viral template and the detection of HBV mutation sites, and the treatment and follow-up strategies should be formulated.
引文
[1]World Health Organization(WHO).Global Hepatitis Report 2017.Geneva:World Health Organization,2017:7-13.
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[11]Seo SI,Choi HS,Choi BY,et al.Coexistence of hepatitis B surface antigen and antibody to hepatitis B surface may increase the risk of hepatocellular carcinoma in chronic hepatitis B virus infection:a retrospective cohort study[J].J Med Virol,2014,86:124-130.
[12]Jang JS,Kim HS,Kim HJ,et al.Association of concurrent hepatitis Bsurface antigen and antibody to hepatitis B surface antigen with hepatocellular carcinoma in chronic hepatitis B virus infection[J].J Med Virol,2009,81:1531-1538.
[13]Chen CJ,Yang HI,Su J,et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[J].JAMA,2006,295:65-73.
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[15]Brunetto MR.Chance and necessity of simultaneous HBsAg and antiHBs detection in the serum of chronic HBsAg carriers[J].J Hepatol,2014,60:473-475.
[16]Kohno H,Inoue T,Tsuda F,et al.Mutations in the envelope gene of hepatitis B virus variants co-occurring with antibody to surface antigen in sera from patients with chronic hepatitis B[J].J Gen Virol,1996,77:1825-1831.
[17]Weinberger KM,Zoulek G,Bauer T,et al.A novel deletion mutant of hepatitis B virus surface antigen[J].J Med Virol,1999,58:105-110.
[18]Huang X,Qin Y,Zhang P,et al.PreS deletion mutations of hepatitis B virus in chronically infected patients with simultaneous seropositivity for hepatitis-B surface antigen and anti-HBS antibodies[J].J Med Virol,2010,82:23-31.
[19]Pollicino T,Cacciola I,Saffioti F,et al.Hepatitis B virus PreS/S gene variants:pathobiology and clinical implications[J].J Hepatol,2014,61:408-417
[20]Papatheodoridis GV,Manolakopoulos S,Touloumi G,et al.Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s)starting with lamivudine monotherapy:results of the nationwide HEPNET.Greece cohort study[J].Gut,2011,60:1109-1116.
[21]Lai MW,Huang SF,Hsu CW,et al.Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy[J].Antivir Ther,2009,14:249-261.
[2]Arnold W,Hess G,Meyer zum Büschenfelde KH,et al.Simultaneous occurrence in the serum of hepatitis B surface antigen(HBsAg)and antibodies against HBsAg(anti-HBs)of different subtypes.Serologic and fluorescence histologic studies[J].Verh Dtsch Ges Inn Med,1976,82:405-407.
[3]Dienstag JL.Concurrent hepatitis B surface antigen and antibody and the clonal selection theory of antibody diversity[J].Gastroenterology,1987,93:899-904.
[4]PondéRA.The underlying mechanisms for the“simultaneous HBsAg and anti-HBs serological profile”[J].Eur J Clin Microbiol Infect Dis,2011,30:1325-1340.
[5]Gerlich WH.The enigma of concurrent hepatitis B surface antigen(HBsAg)and antibodies to HBsAg[J].Clin Infect Dis,2007,44:1170-1172.
[6]中华医学会肝病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].中国病毒病杂志,2015,31:1941-1960.
[7]中华人民共和国卫生和计划生育委员会医政医管局.原发性肝癌诊疗规范(2017年版)[J].中华消化外科杂志,2017,16:635-647.
[8]中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊治指南(2018年版)[J].中华临床感染病杂志,2018,11:401-410.
[9]Zhang JM,Xu Y,Wang XY,et al.Coexistence of hepatitis B surface antigen(HBsAg)and heterologous subtype-specific antibodies to HB-s Ag among patients with chronic hepatitis B virus infection[J].Clin Infect Dis,2007,44:1161-1169.
[10]Lada O,Benhamou Y,Poynard T,et al.Coexistence of hepatitis B surface antigen(HBsAg)and anti-HBs antibodies in chronic hepatitis Bvirus carriers:influence of“a”determinant variants[J].J Virol,2006,80:2968-2975.
[11]Seo SI,Choi HS,Choi BY,et al.Coexistence of hepatitis B surface antigen and antibody to hepatitis B surface may increase the risk of hepatocellular carcinoma in chronic hepatitis B virus infection:a retrospective cohort study[J].J Med Virol,2014,86:124-130.
[12]Jang JS,Kim HS,Kim HJ,et al.Association of concurrent hepatitis Bsurface antigen and antibody to hepatitis B surface antigen with hepatocellular carcinoma in chronic hepatitis B virus infection[J].J Med Virol,2009,81:1531-1538.
[13]Chen CJ,Yang HI,Su J,et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[J].JAMA,2006,295:65-73.
[14]Iloeje UH,Yang HI,Su J,et al.Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J].Gastroenterology,2006,130:678-686.
[15]Brunetto MR.Chance and necessity of simultaneous HBsAg and antiHBs detection in the serum of chronic HBsAg carriers[J].J Hepatol,2014,60:473-475.
[16]Kohno H,Inoue T,Tsuda F,et al.Mutations in the envelope gene of hepatitis B virus variants co-occurring with antibody to surface antigen in sera from patients with chronic hepatitis B[J].J Gen Virol,1996,77:1825-1831.
[17]Weinberger KM,Zoulek G,Bauer T,et al.A novel deletion mutant of hepatitis B virus surface antigen[J].J Med Virol,1999,58:105-110.
[18]Huang X,Qin Y,Zhang P,et al.PreS deletion mutations of hepatitis B virus in chronically infected patients with simultaneous seropositivity for hepatitis-B surface antigen and anti-HBS antibodies[J].J Med Virol,2010,82:23-31.
[19]Pollicino T,Cacciola I,Saffioti F,et al.Hepatitis B virus PreS/S gene variants:pathobiology and clinical implications[J].J Hepatol,2014,61:408-417
[20]Papatheodoridis GV,Manolakopoulos S,Touloumi G,et al.Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s)starting with lamivudine monotherapy:results of the nationwide HEPNET.Greece cohort study[J].Gut,2011,60:1109-1116.
[21]Lai MW,Huang SF,Hsu CW,et al.Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy[J].Antivir Ther,2009,14:249-261.