乙肝相关肝病HBV-DNA载量与细胞免疫功能的研究
|
摘要
目的:研究T淋巴细胞亚群在乙肝相关疾病患者外周血中的变化及其临床意义,并探讨乙肝相关疾病血中乙肝病毒脱氧核糖核酸(HBV-DNA)载量与T细胞免疫的关系。
方法:应用流式细胞仪检测乙肝病毒携带者(ASC)21例、慢性乙型肝炎(CHB)26例、乙肝肝硬化(LC)患者30例、原发性肝癌(PHC)31例及20例健康人的外周血T淋巴细胞亚群,采用荧光定量聚合酶链反应(FQ-PCR)检测上述108例乙肝相关疾病患者血清的HBVDNA的含量,并进行统计分析。
结果:与对照组相比较,ASC、CHB组及LC组的CD3~+(P＜0.05)、CD4~+(P＜0.05)、CD4~+/CD8~+显著性下降(P＜0.01);PHC组CD4~+、CD4~+/CD8~+比值有显著性上升(P＜0.01),CD8+无统计学差异。对照组、HBV-DNA阳性组和HBV-DNA阴性组三组比较,CD3~+、CD4~+、CD8~+、CD4~+/CD8~+项指标均有显著性差异(P＜0.01)。HBV-DNA载量与CD3~+、CD4~+、CD4~+/CD8~+均有负相关关系,HBV-DNA的载量与CD8~+有正相关关系。
结论:乙肝相关疾病患者细胞免疫功能紊乱,外周血T淋巴细胞亚群发生改变与HBV-DNA载量有关系。
Objective:To study the level of T-lymphocyte subsets and its significance in the peripheral blood of patients with hepatitis B virus-related diseases,and to investigate the correlation between T-lymphocyte subsets and HBV-DNA loads.
Methods:The level of T-lymphocyte subsets were detected by flow cytometry, when HBV-DNA loads were detected by FQ-PCR in 108 cases of peripheral blood,including 21 cases of ASC,26 of CHB,30 of LC,31 of PHC and 20 of healthy people.
Results:The level of CD3~+,CD4~+,CD4~+/CD8~+ inASC,CHB,LC,PHC groups were significantly lower than that in control group(P＜0.05,P＜0.05, P＜0.01,respectively),when the level of CD8~+ in ASC,CHB,LC,PHC groups and the level of CD4~+、CD4~+/CD8~+ in PHC group were significantly higher than that in control group,without any significant difference between the level of CD8~+ in PHC and control groups.The level of CD3~+,CD4~+,CD8~+,CD4~+/CD8~+were all significantly different between HBV-DNA positive and negative groups. HBV-DNA loads had negative relationship with CD3~+,CD4~+,CD4~+/CD8~+ and had positive relationship with CD8~+.
Conclusions:The cell-mediated immunity in patient with hepatitis B virus-related diseases was disordered,and the HBV-DNA loads are involved in the progress of these diseases.
方法:应用流式细胞仪检测乙肝病毒携带者(ASC)21例、慢性乙型肝炎(CHB)26例、乙肝肝硬化(LC)患者30例、原发性肝癌(PHC)31例及20例健康人的外周血T淋巴细胞亚群,采用荧光定量聚合酶链反应(FQ-PCR)检测上述108例乙肝相关疾病患者血清的HBVDNA的含量,并进行统计分析。
结果:与对照组相比较,ASC、CHB组及LC组的CD3~+(P＜0.05)、CD4~+(P＜0.05)、CD4~+/CD8~+显著性下降(P＜0.01);PHC组CD4~+、CD4~+/CD8~+比值有显著性上升(P＜0.01),CD8+无统计学差异。对照组、HBV-DNA阳性组和HBV-DNA阴性组三组比较,CD3~+、CD4~+、CD8~+、CD4~+/CD8~+项指标均有显著性差异(P＜0.01)。HBV-DNA载量与CD3~+、CD4~+、CD4~+/CD8~+均有负相关关系,HBV-DNA的载量与CD8~+有正相关关系。
结论:乙肝相关疾病患者细胞免疫功能紊乱,外周血T淋巴细胞亚群发生改变与HBV-DNA载量有关系。
Objective:To study the level of T-lymphocyte subsets and its significance in the peripheral blood of patients with hepatitis B virus-related diseases,and to investigate the correlation between T-lymphocyte subsets and HBV-DNA loads.
Methods:The level of T-lymphocyte subsets were detected by flow cytometry, when HBV-DNA loads were detected by FQ-PCR in 108 cases of peripheral blood,including 21 cases of ASC,26 of CHB,30 of LC,31 of PHC and 20 of healthy people.
Results:The level of CD3~+,CD4~+,CD4~+/CD8~+ inASC,CHB,LC,PHC groups were significantly lower than that in control group(P＜0.05,P＜0.05, P＜0.01,respectively),when the level of CD8~+ in ASC,CHB,LC,PHC groups and the level of CD4~+、CD4~+/CD8~+ in PHC group were significantly higher than that in control group,without any significant difference between the level of CD8~+ in PHC and control groups.The level of CD3~+,CD4~+,CD8~+,CD4~+/CD8~+were all significantly different between HBV-DNA positive and negative groups. HBV-DNA loads had negative relationship with CD3~+,CD4~+,CD4~+/CD8~+ and had positive relationship with CD8~+.
Conclusions:The cell-mediated immunity in patient with hepatitis B virus-related diseases was disordered,and the HBV-DNA loads are involved in the progress of these diseases.
引文
1.Alatrakchi N,KozielMJ.Antiviral T—cell responses and therapy in chronic hepatitis B.J Hepatol,2003,39(4):631-634.
2.Lavanchy D.Hepatitis B virus epidemiology,disease burden,Treatment,and current and emerging prevention and controlMeasures.J Viral Hepat,2004,11(2):97-107.
3.Kao JH,Chen DS.Global control of hepatitis B virus infection.Lancet Infect Dis,2002,2(7):395-403.
4.Koziel MJ.The immunopathogenesis of HBV infection.Antivir Ther,1998,3(Suppl 3):13-24.
5.Chisari FV.Cytotoxic T cells and viral hepatitis.J Clin Invest,Apr 1997,99:1472-1477.
6.Jung MC,Pape GR.Immunology of hepatitis B infection.LancetInfectDis,2002,2(1):43-50.
7.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.现代消化及介入诊疗,2006,11(4):245-255.
8.中国抗癌协会肝癌专业委员会.原发性肝癌的临床诊断与分期标准.中华肝脏病杂志,2004,9(9):67-68.
9.Wei J,Wang YQ,Lu ZM,et al.Detection of anti-preS1 antibodies for recovery of hepatitis B patients by immunoassay.World J Gastroenterol,2002,8(2):276-281.
10.Liu DX.A new hypothesis of pathogenetic mechanism of viral hepatitis B and C.Med Hypotheses,Mar 2001,56(3):405-408.
11.王静艳,穆桂玲,刘沛,等.乙型重型肝炎基因变异与免疫异常的关系.中华传染病杂志,2001,19(2):73-76.
12.Guidotti LG,Ishikawa T,Hobbs MV,etal.Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.Immunity,1996,4(1):25-36.
13.高金华,李丽君.IL-6和T细胞亚群与慢性乙型肝炎的关系.交通医学,2001,15(4):378-388.
14.李玉中,胡宏,王敏,等.肝病患者血中T淋巴细胞亚群及NK细胞数量的变化.大连医科大学学,2001,23(1):56-58.
15.李鸿宾,江晓萍,黄浏培,等.测定慢性乙型肝炎患者外周血T淋巴细胞亚群的临床意义.安徽医药,2006,10(8):588-589.
16.Choon MI,Ton SH,Cheong SK,etal.The Cellular immune status of HBsAg positive carriers in Malaysia.Asian Pac J Allergy Immuol,1996,14(1):19-24.
17.Yang PM,Pu IJ,Lai MY,et al.Immunohischemical studies on Intranepaticlymphocyte in filtrates in chronic type B hepatitis,with special emphasis on the activation status of lympphocytes.AmJ Gastnenterol,1998,83:948-951.
18.Brian DL,Jeff A.Altered helper T lymphocyte function associated with Chronic Hepatitis B Virus infection and its Role in Response Therapeutic Vaccination in Human.Immunol,1999,162:3088-3093.
19.张保国,孙君江,田韧,等.HBV感染肝病的细胞免疫功能观察.南京医科大学学报,1999,19(1):33-35.
20.范淳,刘林.慢性乙肝患者杀伤性免疫细胞功能的研究.免疫学杂志,1996,12(1):43-47.
21.郝晓,催东来,姚希贤,等.乙肝病毒复制与细胞免疫功能的研究.中国中西医结合脾胃杂志,1998,6(2):85-86.
22.Peters M,Vierling J,Gershwin ME,etal.Immunology and the liver.Hepatology,1991,13(5):977-994.
1. Zuckerman AJ. More than one third of world's population has been infected with hepatitis B virus.Br Med J,1999;318:1213
2. Maddrey WC.Hepatitis B:An important public health issue .J Med Virol,2000;61(3):362-366.
3. Tiollais P,Pourcelc G,Dejean A. The hepatitis B Virus.Nature.1985;317(6037):489-498.
4. Le Bovier GL.Subtypes of Australia antigen and hepatitis B virus.JAMA,1972,22:928-930.
5. Coruouce-Pauty AM.New hepatitis B surface antigen subtypes inside the ad category.Vox Sang,1978,35:304-308.
6. Okamoto H, Imail M,Shimozaki M, et al. Nucleotide sequence of a cloned hepatitis B virus genome,subtyp ary: comparison with genome of the other three subtypes. J Gen Virol 1986,67:2305-2314.
7. Okamoto H, Tsuda F, Sakugawa H, et al .Typing hepatitis B virus by homolohty in nucleotide sequence; comparison of surface antigen subtype. J Gen Virol, 1988,69:2575-2583.
8. Stuyer L. A new genotype of hepatitis B virus;complete genome and phylogenetic relatedness. J Gen Virol, 2000, 81:67-74.
9. Lindh M,Andersson AS, Gusdal A.Genotypes ntl858 variants and geographic origin of hepatitis B virus large scale analysis using a new genotyping method. J Infect Dis, 1997,175(6): 1285-1293.
10. Lindh M, Gonzalez JE, Norkrans G, et al. Genotypes of hepatitis B virus by restriction pattern analysis of a pre-S amplicon. J Virol Methods, 1998, 72(2); 163-174.
11. Mizokami M, Nakano T, Orito E, et al. Hepatitis B virus genotype assignment using restriction fragment length polymorphism patterns. FEBS Letters, 1999,450(1-2): 66-71.
12. Suda S, Okamoto H, Iwanari H, et al. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product.J Virol Methods,1999,80(1):97-112.
13.Chu CJ,Hussain M,Lok AS.Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology,2002,122(7):1756-1762.
14.Naito H.Hayashi S,Abe K.Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers.J Clin Microbiol,2001,39:362-364.
15.王虹,王省良,万成松,等.采用微板核酸杂交-ELISA技术进行HBV DNA基因分型的研究.中华微生物和免疫学杂志,2001,21(2):234-236.
16.张天宝.基因芯片及其在医学研究中的意义.第二军医大学学报,2000,21(1):91-94.
17.杨光,崔金环.基因芯片技术在乙型肝炎病毒基因分型检测中的应用探讨.国外医学病毒学分册,2003,10(2):50-52.
18.Norder H,Hammas B Lee SD,et al.Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary stucture of surface antigen.J Gen Virol,1993,74(7):1341-1348.
19.Tuyver L,de Gendt S,Van Geyt C,et al.A new genotype of hepatitis B virus:complete genome and phylogenetic relatedness.J Gen Virol,2000,81(1):67-74.
20.Rauz-Ruiz P,Norder H,Robertson BH,et al.Genotype H:a new Amerin dian genotype of hepatitis B virus revealed in Central America.J Gen Virol,2002,83(8):2059-2073.
21.Lindh M.Go of a pre-S anplicon.J Virol Methods,1998,72(2):163-174.
22.Wenson PD,van Geyt C,Alexander ER,et al.Hepatitis B virus genotypes and HbsAg subtypes in refugees and injection drug users in the United States determined by LiPA and monoclonal EIA.J Med Virol,2001,64(3):305-311.
23.Blitz L,Pujol FH,Swenson PD,et al.Antigenic diversity of hepatitis B virus strains of genotype F in Amerindans and other population groups from Vene2 zuela.J Clin Microbilo,1998,36(3):648-651.
24.Kao JH,Chen PJ,Lai MY,et al.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic Hepatitis B.Gastroenterolgy,2000,118(3):554-594.
25.范金水,庄辉,李远贵,等.我国八城市HbsAg阳性和阴性乙肝患者的病毒血清型和基因型分析.中国微生物和免疫学杂志,1998,18:88-92.
26.阎丽.宁夏地区乙型肝炎病毒型分布及D基因型的测定鉴定.解放军医学杂志,2000,25(2):4-7.
27.夏国良,贾志远.乙型肝炎病毒基因型和血清亚型在我国部分地区的分布及其特点.中华流行病学杂志,2001,22(5):348-351.
28.Grandjacques C,Pradat P,Stuyver L,et al.Rapid detection of genotypes andmutations in the pre-core promoter and the pre-core region of hepatitis B virus genome:correlation with virus persistence and disease severity.J Hepatol,2000,33(3):430-439.
29.Mayerat C,Mantegani A,Frei PC.Does hepatitis B virus genotype influence the clinical outcome of HBV infection? J Viral Hepatitis,1999,6(4):299-304.
30.Chan HL,Tsang SW,ML Wong,et al.Genotype B hepatitis B virus is associated with severe icteric flare-up of chronic hepatitis B virus infection in Hong Kong.Am J Gastroenterol,2002,97(10):2629-2633.
31.苏冬娜,吴品诗,石之磷,等.HBV基因分型的检测和意义.临床荟萃,2002,22(4):303-305.
32.Ding X,Mizokami M,Yao G,et al.Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai,China.Intervirology,2001,44(1):43-47.
33.Orito E,Ichida T,Sakugawa H,et al.Geographic distribution of hepatitis B virus genotype in patients with chronic HBV infection in Japan,Hepatology,2001,34(3);590-594.
34.Kao JH,Liu CJ,Chen DS,et al.Hepatitis B virus genotypes and hepatocellular carcinoma in Japan:Reply Gastroenterology,2001,120:1564-1565.
35.Kao JH,Chen PJ,Lai MY,et al.Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C.J Clin Microbiol,2002,40:22-25.
36.Kao JH,Chen PJ,MY Lai MY,et al.Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus.Hepatology,Oct 2001,34(4 Pt 1):817-823.
37.Hannoun C,Krogsgaard K,Horal P,et al.Genotype mixtures of hepatitis B virus in patients treated with interferon.J Infect Dis,2002,186(6):752-759.
38.Hou J,Schilling R,Janssen HLA,et al.B virus genotype a confer a higher response rate to inteferon treatment.J Hepatol,2001,34(Suppl 1):15-20.
39.Kao JH,Wu NH,Chen PJ,et al.Hepatitis B genotypes and the response tointerferon therapy.J Hepatol,2000,33:998-1002.
40.谢南,朱小诚.190例HBV基因型与拉米夫定疗效的研究.实用临床医学,2003,4(4):5-8.
41.Akuta N,Suzuki F,Kobayashi M,et al.The influence of hepatitis Bvirus genotype on the development of lamivudine resistance during long.term treatment.Hepatol,2003,38(3):315-321.
42.Zollner B,Petersen J,Schafer P,etal.Subtype-dependent response of hepatitis B virus during the early phase of lamivudine treatment.Clin Infect Dis,2002,34(9):1273-1277.
43.Westland C,Delaney 4th W,Yang H,etal.Hepatitis B virus genotypes and viro logic response in 694patients in phase Ⅲ studies of adefovir dipivoxil.Gastroentero logy,2003,125(1):107-116.
44.US Food and Drug Administration:Drug Approval Package Enteeavir.July 12,2005.
45.Colonllo R,Rose RE,Levine SM,et al.Enteeavir(ECV)resistance is not observed in nueleoside-naive subiects and is observed infrequently by week 48 in lamivudine-refractory subjects with chronic HBV infectionJ hepatol, 2005,42(Suppl 2):173-178.
46. Tsubota A, Arase Y, Ren F, et al.Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw.J Med Virol, 2001; 65(2): 257-265.
47. Devarbhavi HC, Cohen AJ, Patel R, et al. Preliminary results: outcome of liver transplantation for hepatitis B virus varies by hepatitis B virus genotype. Liver Transpl, 2002, 8(6): 550-555.
2.Lavanchy D.Hepatitis B virus epidemiology,disease burden,Treatment,and current and emerging prevention and controlMeasures.J Viral Hepat,2004,11(2):97-107.
3.Kao JH,Chen DS.Global control of hepatitis B virus infection.Lancet Infect Dis,2002,2(7):395-403.
4.Koziel MJ.The immunopathogenesis of HBV infection.Antivir Ther,1998,3(Suppl 3):13-24.
5.Chisari FV.Cytotoxic T cells and viral hepatitis.J Clin Invest,Apr 1997,99:1472-1477.
6.Jung MC,Pape GR.Immunology of hepatitis B infection.LancetInfectDis,2002,2(1):43-50.
7.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.现代消化及介入诊疗,2006,11(4):245-255.
8.中国抗癌协会肝癌专业委员会.原发性肝癌的临床诊断与分期标准.中华肝脏病杂志,2004,9(9):67-68.
9.Wei J,Wang YQ,Lu ZM,et al.Detection of anti-preS1 antibodies for recovery of hepatitis B patients by immunoassay.World J Gastroenterol,2002,8(2):276-281.
10.Liu DX.A new hypothesis of pathogenetic mechanism of viral hepatitis B and C.Med Hypotheses,Mar 2001,56(3):405-408.
11.王静艳,穆桂玲,刘沛,等.乙型重型肝炎基因变异与免疫异常的关系.中华传染病杂志,2001,19(2):73-76.
12.Guidotti LG,Ishikawa T,Hobbs MV,etal.Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.Immunity,1996,4(1):25-36.
13.高金华,李丽君.IL-6和T细胞亚群与慢性乙型肝炎的关系.交通医学,2001,15(4):378-388.
14.李玉中,胡宏,王敏,等.肝病患者血中T淋巴细胞亚群及NK细胞数量的变化.大连医科大学学,2001,23(1):56-58.
15.李鸿宾,江晓萍,黄浏培,等.测定慢性乙型肝炎患者外周血T淋巴细胞亚群的临床意义.安徽医药,2006,10(8):588-589.
16.Choon MI,Ton SH,Cheong SK,etal.The Cellular immune status of HBsAg positive carriers in Malaysia.Asian Pac J Allergy Immuol,1996,14(1):19-24.
17.Yang PM,Pu IJ,Lai MY,et al.Immunohischemical studies on Intranepaticlymphocyte in filtrates in chronic type B hepatitis,with special emphasis on the activation status of lympphocytes.AmJ Gastnenterol,1998,83:948-951.
18.Brian DL,Jeff A.Altered helper T lymphocyte function associated with Chronic Hepatitis B Virus infection and its Role in Response Therapeutic Vaccination in Human.Immunol,1999,162:3088-3093.
19.张保国,孙君江,田韧,等.HBV感染肝病的细胞免疫功能观察.南京医科大学学报,1999,19(1):33-35.
20.范淳,刘林.慢性乙肝患者杀伤性免疫细胞功能的研究.免疫学杂志,1996,12(1):43-47.
21.郝晓,催东来,姚希贤,等.乙肝病毒复制与细胞免疫功能的研究.中国中西医结合脾胃杂志,1998,6(2):85-86.
22.Peters M,Vierling J,Gershwin ME,etal.Immunology and the liver.Hepatology,1991,13(5):977-994.
1. Zuckerman AJ. More than one third of world's population has been infected with hepatitis B virus.Br Med J,1999;318:1213
2. Maddrey WC.Hepatitis B:An important public health issue .J Med Virol,2000;61(3):362-366.
3. Tiollais P,Pourcelc G,Dejean A. The hepatitis B Virus.Nature.1985;317(6037):489-498.
4. Le Bovier GL.Subtypes of Australia antigen and hepatitis B virus.JAMA,1972,22:928-930.
5. Coruouce-Pauty AM.New hepatitis B surface antigen subtypes inside the ad category.Vox Sang,1978,35:304-308.
6. Okamoto H, Imail M,Shimozaki M, et al. Nucleotide sequence of a cloned hepatitis B virus genome,subtyp ary: comparison with genome of the other three subtypes. J Gen Virol 1986,67:2305-2314.
7. Okamoto H, Tsuda F, Sakugawa H, et al .Typing hepatitis B virus by homolohty in nucleotide sequence; comparison of surface antigen subtype. J Gen Virol, 1988,69:2575-2583.
8. Stuyer L. A new genotype of hepatitis B virus;complete genome and phylogenetic relatedness. J Gen Virol, 2000, 81:67-74.
9. Lindh M,Andersson AS, Gusdal A.Genotypes ntl858 variants and geographic origin of hepatitis B virus large scale analysis using a new genotyping method. J Infect Dis, 1997,175(6): 1285-1293.
10. Lindh M, Gonzalez JE, Norkrans G, et al. Genotypes of hepatitis B virus by restriction pattern analysis of a pre-S amplicon. J Virol Methods, 1998, 72(2); 163-174.
11. Mizokami M, Nakano T, Orito E, et al. Hepatitis B virus genotype assignment using restriction fragment length polymorphism patterns. FEBS Letters, 1999,450(1-2): 66-71.
12. Suda S, Okamoto H, Iwanari H, et al. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product.J Virol Methods,1999,80(1):97-112.
13.Chu CJ,Hussain M,Lok AS.Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology,2002,122(7):1756-1762.
14.Naito H.Hayashi S,Abe K.Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers.J Clin Microbiol,2001,39:362-364.
15.王虹,王省良,万成松,等.采用微板核酸杂交-ELISA技术进行HBV DNA基因分型的研究.中华微生物和免疫学杂志,2001,21(2):234-236.
16.张天宝.基因芯片及其在医学研究中的意义.第二军医大学学报,2000,21(1):91-94.
17.杨光,崔金环.基因芯片技术在乙型肝炎病毒基因分型检测中的应用探讨.国外医学病毒学分册,2003,10(2):50-52.
18.Norder H,Hammas B Lee SD,et al.Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary stucture of surface antigen.J Gen Virol,1993,74(7):1341-1348.
19.Tuyver L,de Gendt S,Van Geyt C,et al.A new genotype of hepatitis B virus:complete genome and phylogenetic relatedness.J Gen Virol,2000,81(1):67-74.
20.Rauz-Ruiz P,Norder H,Robertson BH,et al.Genotype H:a new Amerin dian genotype of hepatitis B virus revealed in Central America.J Gen Virol,2002,83(8):2059-2073.
21.Lindh M.Go of a pre-S anplicon.J Virol Methods,1998,72(2):163-174.
22.Wenson PD,van Geyt C,Alexander ER,et al.Hepatitis B virus genotypes and HbsAg subtypes in refugees and injection drug users in the United States determined by LiPA and monoclonal EIA.J Med Virol,2001,64(3):305-311.
23.Blitz L,Pujol FH,Swenson PD,et al.Antigenic diversity of hepatitis B virus strains of genotype F in Amerindans and other population groups from Vene2 zuela.J Clin Microbilo,1998,36(3):648-651.
24.Kao JH,Chen PJ,Lai MY,et al.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic Hepatitis B.Gastroenterolgy,2000,118(3):554-594.
25.范金水,庄辉,李远贵,等.我国八城市HbsAg阳性和阴性乙肝患者的病毒血清型和基因型分析.中国微生物和免疫学杂志,1998,18:88-92.
26.阎丽.宁夏地区乙型肝炎病毒型分布及D基因型的测定鉴定.解放军医学杂志,2000,25(2):4-7.
27.夏国良,贾志远.乙型肝炎病毒基因型和血清亚型在我国部分地区的分布及其特点.中华流行病学杂志,2001,22(5):348-351.
28.Grandjacques C,Pradat P,Stuyver L,et al.Rapid detection of genotypes andmutations in the pre-core promoter and the pre-core region of hepatitis B virus genome:correlation with virus persistence and disease severity.J Hepatol,2000,33(3):430-439.
29.Mayerat C,Mantegani A,Frei PC.Does hepatitis B virus genotype influence the clinical outcome of HBV infection? J Viral Hepatitis,1999,6(4):299-304.
30.Chan HL,Tsang SW,ML Wong,et al.Genotype B hepatitis B virus is associated with severe icteric flare-up of chronic hepatitis B virus infection in Hong Kong.Am J Gastroenterol,2002,97(10):2629-2633.
31.苏冬娜,吴品诗,石之磷,等.HBV基因分型的检测和意义.临床荟萃,2002,22(4):303-305.
32.Ding X,Mizokami M,Yao G,et al.Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai,China.Intervirology,2001,44(1):43-47.
33.Orito E,Ichida T,Sakugawa H,et al.Geographic distribution of hepatitis B virus genotype in patients with chronic HBV infection in Japan,Hepatology,2001,34(3);590-594.
34.Kao JH,Liu CJ,Chen DS,et al.Hepatitis B virus genotypes and hepatocellular carcinoma in Japan:Reply Gastroenterology,2001,120:1564-1565.
35.Kao JH,Chen PJ,Lai MY,et al.Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C.J Clin Microbiol,2002,40:22-25.
36.Kao JH,Chen PJ,MY Lai MY,et al.Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus.Hepatology,Oct 2001,34(4 Pt 1):817-823.
37.Hannoun C,Krogsgaard K,Horal P,et al.Genotype mixtures of hepatitis B virus in patients treated with interferon.J Infect Dis,2002,186(6):752-759.
38.Hou J,Schilling R,Janssen HLA,et al.B virus genotype a confer a higher response rate to inteferon treatment.J Hepatol,2001,34(Suppl 1):15-20.
39.Kao JH,Wu NH,Chen PJ,et al.Hepatitis B genotypes and the response tointerferon therapy.J Hepatol,2000,33:998-1002.
40.谢南,朱小诚.190例HBV基因型与拉米夫定疗效的研究.实用临床医学,2003,4(4):5-8.
41.Akuta N,Suzuki F,Kobayashi M,et al.The influence of hepatitis Bvirus genotype on the development of lamivudine resistance during long.term treatment.Hepatol,2003,38(3):315-321.
42.Zollner B,Petersen J,Schafer P,etal.Subtype-dependent response of hepatitis B virus during the early phase of lamivudine treatment.Clin Infect Dis,2002,34(9):1273-1277.
43.Westland C,Delaney 4th W,Yang H,etal.Hepatitis B virus genotypes and viro logic response in 694patients in phase Ⅲ studies of adefovir dipivoxil.Gastroentero logy,2003,125(1):107-116.
44.US Food and Drug Administration:Drug Approval Package Enteeavir.July 12,2005.
45.Colonllo R,Rose RE,Levine SM,et al.Enteeavir(ECV)resistance is not observed in nueleoside-naive subiects and is observed infrequently by week 48 in lamivudine-refractory subjects with chronic HBV infectionJ hepatol, 2005,42(Suppl 2):173-178.
46. Tsubota A, Arase Y, Ren F, et al.Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw.J Med Virol, 2001; 65(2): 257-265.
47. Devarbhavi HC, Cohen AJ, Patel R, et al. Preliminary results: outcome of liver transplantation for hepatitis B virus varies by hepatitis B virus genotype. Liver Transpl, 2002, 8(6): 550-555.