干扰素治疗B、C基因型慢性乙型肝炎临床效果差异的Meta分析
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摘要
目的综合评价干扰素治疗B、C基因型慢性乙型肝炎(CHB)患者的疗效差异。方法计算机检索PubMed、Web of Science、The Cochrane Library、CNKI、万方和VIP数据库截止到2018年11月发表的关于干扰素治疗B、C基因型CHB患者疗效差异的文献。2位研究者独立筛选文献、提取资料并评价所纳入文献的质量,然后进行Meta分析。结果共纳入20篇研究文献,Meta分析结果显示,干扰素治疗B基因型CHB患者的HBV DNA阴转率、HBeAg清除率、HBeAg血清学转换率、HBsAg清除率,以及ALT复常率均明显高于C基因型CHB患者(比值比分别为2. 95、3. 16、1. 83、2. 59、2. 31,95%可信区间分别为2. 22～3. 91、2. 38～4. 20、1. 44～2. 33、1. 05～6. 38、1. 69～3. 16,P值均<0. 05)。亚组分析结果显示,干扰素在B、C基因型CHB患者中的疗效差异不受干扰素种类的影响。结论干扰素的抗病毒效果受到HBV基因型的影响,B基因型抗病毒效果优于C基因型,因此,HBV基因型是预测干扰素疗效的重要因素。
Objective To investigate the clinical effect of interferon(IFN) in the treatment of genotype B or C chronic hepatitis B(CHB)patients. Methods PubMed,Web of Science,The Cochrane Library,CNKI,Wanfang Data,and VIP were searched for articles on IFN in the treatment of genotype B or C CHB patients published up to November,2018. Two researchers performed screening,data extraction,and quality assessment of the articles independently,and then a meta-analysis was performed. Results A total of 20 articles were included.The results of the meta-analysis showed that compared with the genotype C CHB patients,the genotype B CHB patients had significantly higher HBV DNA clearance rate(odds ratio [OR]= 2. 95,95% confidence interval [CI]: 2. 22-3. 91,P < 0. 05),HBeAg clearance rate(OR = 3. 16,95% CI: 2. 38-4. 20,P < 0. 05),HBeAg seroconversion rate(OR = 1. 83,95% CI: 1. 44-2. 33,P < 0. 05),HBsAg clearance rate(OR = 2. 59,95% CI: 1. 05-6. 38,P < 0. 05),and alanine aminotransferase normalization rate(OR = 2. 31,95% CI: 1. 69-3. 16,P < 0. 05). The subgroup analysis showed that the clinical effect of IFN in genotype B or C CHB patients was not affected by the type of IFN. Conclusion The antiviral effect of IFNs is affected by HBV genotype,and the patients with genotype B CHB have a better antiviral outcome than those with genotype C CHB. Therefore,HBV genotype is an important factor for predicting the clinical effect of IFN therapy.
Objective To investigate the clinical effect of interferon(IFN) in the treatment of genotype B or C chronic hepatitis B(CHB)patients. Methods PubMed,Web of Science,The Cochrane Library,CNKI,Wanfang Data,and VIP were searched for articles on IFN in the treatment of genotype B or C CHB patients published up to November,2018. Two researchers performed screening,data extraction,and quality assessment of the articles independently,and then a meta-analysis was performed. Results A total of 20 articles were included.The results of the meta-analysis showed that compared with the genotype C CHB patients,the genotype B CHB patients had significantly higher HBV DNA clearance rate(odds ratio [OR]= 2. 95,95% confidence interval [CI]: 2. 22-3. 91,P < 0. 05),HBeAg clearance rate(OR = 3. 16,95% CI: 2. 38-4. 20,P < 0. 05),HBeAg seroconversion rate(OR = 1. 83,95% CI: 1. 44-2. 33,P < 0. 05),HBsAg clearance rate(OR = 2. 59,95% CI: 1. 05-6. 38,P < 0. 05),and alanine aminotransferase normalization rate(OR = 2. 31,95% CI: 1. 69-3. 16,P < 0. 05). The subgroup analysis showed that the clinical effect of IFN in genotype B or C CHB patients was not affected by the type of IFN. Conclusion The antiviral effect of IFNs is affected by HBV genotype,and the patients with genotype B CHB have a better antiviral outcome than those with genotype C CHB. Therefore,HBV genotype is an important factor for predicting the clinical effect of IFN therapy.
引文
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[11]LI CY.Analysis of HBV gene distribution in patients with chronic hepatitis B virus e antigen positive and different antiviral therapies[J].J Beihua Univ:Nat Sci,2017,18(6):773-776.(in Chinese)李春杨.慢性乙型肝炎病毒e抗原阳性患者HBV基因分布及抗病毒治疗研究[J].北华大学学报:自然科学版,2017,18(6):773-776.
[12]SHI GY,GUO XW,YANG LL,et al.The effects of different genotypes of hepatitis B virus PEG-INF-a-2a in Xinjiang[J].J Xinjiang Med Univ,2015,38(9):1124-1127.(in Chinese)石光英,郭新文,杨丽丽,等.聚乙二醇干扰素α-2a治疗新疆地区不同HBV基因分型乙肝患者的临床疗效[J].新疆医科大学学报,2015,38(9):1124-1127.
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[15]LIU SR,SU Y.The relationship between HBV genotypes and antiviral treatments[J/CD].Chin J Front Med Sci:Electronic Version,2014,6(5):139-141.(in Chinese)刘士荣,苏毅.乙型肝炎病毒基因型与抗病毒治疗的关系研究[J/CD].中国医学前沿杂志:电子版,2014,6(5):139-141.
[16]CHEN CH,LEE CM,HUNG CH,et al.Hepatitis B virus genotype B results in better immediate,late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients[J].J Gastroenterol Hepatol,2011,26(3):461-468.
[17]LI ZQ,YU ZJ,WU SH,et al.Comparison of antiviral effects of interferon-alpha on different genotypes of hepatitis B virus[J].J Shandong Univ:Med Sci,2010,45(3):526-528.(in Chinese)李志勤,余祖江,武淑环,等.干扰素α对不同基因型乙型肝炎病毒抗病毒疗效比较[J].郑州大学学报:医学版,2010,45(3):526-528.
[18]CHEN SJ,ZHU CL,FANG ZR,et al.Analysis of the correlation between the therapeutic effect of interferon on chronic hepatitis B and HBV genotype[J].J Navy Med,2010,31(2):114-115.(in Chinese)陈尚军,朱春雷,方志荣,等.干扰素治疗慢性乙型肝炎疗效与HBV基因型相关性分析[J].海军医学杂志,2010,31(2):114-115.
[19]CAI YP,HUANG YC,ZHANG MZ,et al.Relationship between hepatitis B virus genotype and efficacy of interferon alpha-2b in Wuhan[J].Chin J Integr Tradit West Med Liver Dis,2010,20(2):83-85.(in Chinese)蔡艳萍,黄元成,张美珍,等.乙肝病毒基因型对武汉地区慢性乙型肝炎患者干扰素α-2b疗效的影响[J].中西医结合肝病杂志,2010,20(2):83-85.
[20]XIAO Y,ZHOU YJ,ZHENG JL,et al.Effect of hepatitis B virus genotypes and rapid virological reponse to interferon-α2b on the efficacy of patients with chronic hepatitis B receiving interferon therapy[J].J Prac Hepatol,2009,12(1):23-24,80.(in Chinese)肖扬,周岳进,郑金莉,等.乙型肝炎病毒基因型和早期病毒学应答对干扰素-α2b治疗慢性乙型肝炎疗效的预测价值[J].实用肝脏病杂志,2009,12(1):23-24,80.
[21]SHEN JK,HOU JL,PAN XN,et al.Correlation of HBV genotypes to the therapeutic effect of PEG-interferon and the pathological changes of the liver of chronic hepatitis B patients[J].J South Med Univ,2008,28(7):1217-1218,1222.(in Chinese)沈建坤,侯金林,潘兴南,等.HBV基因型与聚乙二醇干扰素疗效关系及病理变化[J].南方医科大学学报,2008,28(7):1217-1218,1222.
[22]ZOU HB,ZHU LM,ZHAO GM,et al.The relationship between HBV genotypes and the efficacy of antiviral therapies in hepatitis B e antigen-positive patients[J].Chin J Hepatol,2007,15(6):425-427.(in Chinese)邹怀宾,朱理珉,赵桂鸣,等.E抗原阳性慢性乙型肝炎患者感染病毒的基因型与抗病毒治疗疗效的关系[J].中华肝脏病杂志,2007,15(6):425-427.
[23]ZHAO H,KURBANOV F,WAN MB,et al.Genotype B and younger patient age associated with better response to lowdose therapy:A trial with pegylated/nonpegylated interferonalpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China[J].Clin Infect Dis,2007,44(4):541-548.
[24]LUO K,HE H,LIU Z,et al.No significant differences in histology and response to interferon treatment in hepatitis B carriers of genotypes Cand recombinant B[J].J Viral Hepat,2007,14(6):419-425.
[25]MA JC,WANG LW,LI XJ,et al.Relationship between HBV genotypes and anti-viral therapeutic efficacy of interferon-alpha[J].Hepatobiliary Pancreat Dis Int,2007,6(2):166-171.
[26]WANG CY,YANG YG,LIU CY,et al.The relationship between hepatitis B virus genotypes and the efficacy of interferon-a2b therapy in patients with chronic hepatitis B[J].J Prac Hepatol,2007,10(6):373-374.(in Chinese)王春颖,杨友国,刘成永,等.乙型肝炎病毒基因型与干扰素-α2b疗效的关系[J].实用肝脏病杂志,2007,10(6):373-374.
[27]LAU GK,PIRATVISUTH T,LUO KX,et al.Peginterferon Alfa-2a HBe Ag-Positive Chronic Hepatitis B Study Group.Peginterferon Alfa-2a,lamivudine,and the combination for HBe Ag-positive chronic hepatitis B[J].N Engl J Med,2005,352(26):2682-2695.
[28]XU ZJ,YANG H,CHEN Z,et al.Study on the relationship between hepatitis B virus genotypes and effect of alpha 1b interferon therapy[J].Chin J Gastroenterol Hepatol,2005,14(1):92-94.(in Chinese)许正锯,杨红,陈真,等.乙型肝炎病毒基因型与干扰素α1b疗效关系的研究[J].胃肠病学和肝病学杂志,2005,14(1):92-94.
[29]WU XY,ZHANG Y,ZHANG GH.Relationship between HBVgenotype and curative effect interferon and lamifudine[J].Chin J Clin Health Care,2004,7(4):278-280.(in Chinese)吴晓荫,张洋,张国虎.乙型肝炎病毒基因型与干扰素及拉米夫定疗效的关系[J].中国临床保健杂志,2004,7(4):278-280.
[30]NAKAYOSHI T,MAESHIRO T,NAKAYOSHI T,et al.Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands:a prospective study[J].J Med Virol,2003,70(3):350-354.
[31]WAI CT,CHU CJ,HUSSAIN M,et al.HBV genotype B is associated with better response to interferon therapy in HBe Ag(+)chronic hepatitis than genotype C[J].Hepatology,2002,36(6):1425-1430.
[32]KAO JH,WU NH,CHEN PJ,et al.Hepatitis B genotypes and the response to interferon therapy[J].J Hepatol,2000,33(6):998-1002.
[2]World Health Organization.Global hepatitis report 2017[M/OL].(2017-10-18)[2018-12-17].http://www.who.int/iris/handle/10665/255016.
[3]OTT JJ,STEVENS GA,GROEGER J,et al.Global epidemiology of hepatitis B virus infection:New estimates of age-specific HBsAg seroprevalence and endemicity[J].Vaccine,2012,30(12):2212-2219.
[4]YAN YP,SU HX,JI ZH,et al.Epidemiology of hepatitis B virus infection in China:Current status and challenges[J].JClin Transl Hepatol,2014,2(1):15-22.
[5]KONG LN,QIN B,MA Q,et al.Relationship between hepatitis Bvirus genotype B and C and response to interferon therapy in HBe Ag positive chronic hepatitis B patients:A meta-analysis[J].J Gastroenterol Hepatol,2014,29(7):1387-1395.
[6]LIMOTHAI U,CHUAYPEN N,KHLAIPHUENGSIN A,et al.Association of interferon-gamma inducible protein 10 polymorphism with treatment response to pegylated interferon in HBe Ag-positive chronic hepatitis B[J].Antivir Ther,2016,21(2):97-106.
[7]MAO QG,PAN JS,FANG KN,et al.Precise prediction model and simplified scoring system for sustained combined response to interferon-alpha[J].World J Gastroenterol,2010,16(27):3465-3471.
[8]SUN KX,LI J,YAN L,et al.Distribution of hepatitis B virus genotypes and subgenotypes in Chinese patients with chronic hepatitis B virus infection[J].Chin J Viral Dis,2011,1(3):177-182.(in Chinese)孙奎霞,李杰,闫玲,等.中国慢性乙型肝炎病毒感染者病毒基因型及基因亚型分布[J].中国病毒病杂志,2011,1(3):177-182.
[9]Chinese Society of Hepatology and Chinese Society of Infectious Disease,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[10]STANG A.Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses[J].Eur J Epidemiol,2010,25(9):603-605.
[11]LI CY.Analysis of HBV gene distribution in patients with chronic hepatitis B virus e antigen positive and different antiviral therapies[J].J Beihua Univ:Nat Sci,2017,18(6):773-776.(in Chinese)李春杨.慢性乙型肝炎病毒e抗原阳性患者HBV基因分布及抗病毒治疗研究[J].北华大学学报:自然科学版,2017,18(6):773-776.
[12]SHI GY,GUO XW,YANG LL,et al.The effects of different genotypes of hepatitis B virus PEG-INF-a-2a in Xinjiang[J].J Xinjiang Med Univ,2015,38(9):1124-1127.(in Chinese)石光英,郭新文,杨丽丽,等.聚乙二醇干扰素α-2a治疗新疆地区不同HBV基因分型乙肝患者的临床疗效[J].新疆医科大学学报,2015,38(9):1124-1127.
[13]CHEN X,CHEN X,CHEN W,et al.Extended peginterferon alfa-2a(Pegasys)therapy in Chinese patients with HBe Agnegative chronic hepatitis B[J].J Med Virol,2014,86(10):1705-1713.
[14]FENG JF,GAO GS,YAN HD,et al.Viral factors influencing HBe Ag seroconversion in patients with HBe Ag-positive chronic hepatitis B treated with Peg-interferonα[J].Chin Arch Tradit Chin Med,2014,32(4):758-760.(in Chinese)冯家飞,高国生,颜华东,等.病毒学因素对聚乙二醇干扰素α治疗HBe Ag阳性慢性乙型肝炎e抗原血清学转换的影响[J].中华中医药学刊,2014,32(4):758-760.
[15]LIU SR,SU Y.The relationship between HBV genotypes and antiviral treatments[J/CD].Chin J Front Med Sci:Electronic Version,2014,6(5):139-141.(in Chinese)刘士荣,苏毅.乙型肝炎病毒基因型与抗病毒治疗的关系研究[J/CD].中国医学前沿杂志:电子版,2014,6(5):139-141.
[16]CHEN CH,LEE CM,HUNG CH,et al.Hepatitis B virus genotype B results in better immediate,late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients[J].J Gastroenterol Hepatol,2011,26(3):461-468.
[17]LI ZQ,YU ZJ,WU SH,et al.Comparison of antiviral effects of interferon-alpha on different genotypes of hepatitis B virus[J].J Shandong Univ:Med Sci,2010,45(3):526-528.(in Chinese)李志勤,余祖江,武淑环,等.干扰素α对不同基因型乙型肝炎病毒抗病毒疗效比较[J].郑州大学学报:医学版,2010,45(3):526-528.
[18]CHEN SJ,ZHU CL,FANG ZR,et al.Analysis of the correlation between the therapeutic effect of interferon on chronic hepatitis B and HBV genotype[J].J Navy Med,2010,31(2):114-115.(in Chinese)陈尚军,朱春雷,方志荣,等.干扰素治疗慢性乙型肝炎疗效与HBV基因型相关性分析[J].海军医学杂志,2010,31(2):114-115.
[19]CAI YP,HUANG YC,ZHANG MZ,et al.Relationship between hepatitis B virus genotype and efficacy of interferon alpha-2b in Wuhan[J].Chin J Integr Tradit West Med Liver Dis,2010,20(2):83-85.(in Chinese)蔡艳萍,黄元成,张美珍,等.乙肝病毒基因型对武汉地区慢性乙型肝炎患者干扰素α-2b疗效的影响[J].中西医结合肝病杂志,2010,20(2):83-85.
[20]XIAO Y,ZHOU YJ,ZHENG JL,et al.Effect of hepatitis B virus genotypes and rapid virological reponse to interferon-α2b on the efficacy of patients with chronic hepatitis B receiving interferon therapy[J].J Prac Hepatol,2009,12(1):23-24,80.(in Chinese)肖扬,周岳进,郑金莉,等.乙型肝炎病毒基因型和早期病毒学应答对干扰素-α2b治疗慢性乙型肝炎疗效的预测价值[J].实用肝脏病杂志,2009,12(1):23-24,80.
[21]SHEN JK,HOU JL,PAN XN,et al.Correlation of HBV genotypes to the therapeutic effect of PEG-interferon and the pathological changes of the liver of chronic hepatitis B patients[J].J South Med Univ,2008,28(7):1217-1218,1222.(in Chinese)沈建坤,侯金林,潘兴南,等.HBV基因型与聚乙二醇干扰素疗效关系及病理变化[J].南方医科大学学报,2008,28(7):1217-1218,1222.
[22]ZOU HB,ZHU LM,ZHAO GM,et al.The relationship between HBV genotypes and the efficacy of antiviral therapies in hepatitis B e antigen-positive patients[J].Chin J Hepatol,2007,15(6):425-427.(in Chinese)邹怀宾,朱理珉,赵桂鸣,等.E抗原阳性慢性乙型肝炎患者感染病毒的基因型与抗病毒治疗疗效的关系[J].中华肝脏病杂志,2007,15(6):425-427.
[23]ZHAO H,KURBANOV F,WAN MB,et al.Genotype B and younger patient age associated with better response to lowdose therapy:A trial with pegylated/nonpegylated interferonalpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China[J].Clin Infect Dis,2007,44(4):541-548.
[24]LUO K,HE H,LIU Z,et al.No significant differences in histology and response to interferon treatment in hepatitis B carriers of genotypes Cand recombinant B[J].J Viral Hepat,2007,14(6):419-425.
[25]MA JC,WANG LW,LI XJ,et al.Relationship between HBV genotypes and anti-viral therapeutic efficacy of interferon-alpha[J].Hepatobiliary Pancreat Dis Int,2007,6(2):166-171.
[26]WANG CY,YANG YG,LIU CY,et al.The relationship between hepatitis B virus genotypes and the efficacy of interferon-a2b therapy in patients with chronic hepatitis B[J].J Prac Hepatol,2007,10(6):373-374.(in Chinese)王春颖,杨友国,刘成永,等.乙型肝炎病毒基因型与干扰素-α2b疗效的关系[J].实用肝脏病杂志,2007,10(6):373-374.
[27]LAU GK,PIRATVISUTH T,LUO KX,et al.Peginterferon Alfa-2a HBe Ag-Positive Chronic Hepatitis B Study Group.Peginterferon Alfa-2a,lamivudine,and the combination for HBe Ag-positive chronic hepatitis B[J].N Engl J Med,2005,352(26):2682-2695.
[28]XU ZJ,YANG H,CHEN Z,et al.Study on the relationship between hepatitis B virus genotypes and effect of alpha 1b interferon therapy[J].Chin J Gastroenterol Hepatol,2005,14(1):92-94.(in Chinese)许正锯,杨红,陈真,等.乙型肝炎病毒基因型与干扰素α1b疗效关系的研究[J].胃肠病学和肝病学杂志,2005,14(1):92-94.
[29]WU XY,ZHANG Y,ZHANG GH.Relationship between HBVgenotype and curative effect interferon and lamifudine[J].Chin J Clin Health Care,2004,7(4):278-280.(in Chinese)吴晓荫,张洋,张国虎.乙型肝炎病毒基因型与干扰素及拉米夫定疗效的关系[J].中国临床保健杂志,2004,7(4):278-280.
[30]NAKAYOSHI T,MAESHIRO T,NAKAYOSHI T,et al.Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands:a prospective study[J].J Med Virol,2003,70(3):350-354.
[31]WAI CT,CHU CJ,HUSSAIN M,et al.HBV genotype B is associated with better response to interferon therapy in HBe Ag(+)chronic hepatitis than genotype C[J].Hepatology,2002,36(6):1425-1430.
[32]KAO JH,WU NH,CHEN PJ,et al.Hepatitis B genotypes and the response to interferon therapy[J].J Hepatol,2000,33(6):998-1002.
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