河北正定县人群感染HBV基因型别、突变特征及家庭聚集性分析
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摘要
目的:了解河北正定地区自然人群中乙型肝炎病毒(HBV)基因型、血清型分布情况及基因型与血清型的关系;了解当地自然人群中HBV S基因α抗原决定簇氨基酸变异以及C基因A1762T/G1764A双位点变异和G1896A变异情况;初步探讨HBVα抗原决定簇氨基酸变异与实施HBV计划免疫之间的关系。了解当地HBsAg家庭聚集情况,利用分子生物学特征进一步描述当地人群感染HBV家庭聚集特点。
方法:2005年于河北正定地区以家庭为单位整群采集血清样品,采用固相放射免疫法(SPRIA)进行乙肝五项感染指标检测,选择其中表面抗原(HBsAg)阳性的血清,经过QIAamp DNA Blood Mini Kit提取HBV DNA,采用巢式PCR扩增S基因区段,C基因区段,进行序列测定。利用生物信息学软件Lasergene 6.0将其与Genebank中A-H各基因型标准序列进行对比分析,确定HBV的基因型并通过核苷酸序列推测血清型。利用软件将核苷酸序列转换为氨基酸序列,进行HBVα抗原决定簇氨基酸位点变异分析,并对HBV C基因中CP和BCP常见突变A1762T/G1764A、G1896A突变进行描述和分析。对户籍明确人群以HBsAg为指标进行负二项分布拟合优度检验分析当地HBsAg的家庭聚集情况;利用MEGA4.0.1软件对样本S基因测序结果与C基因测序结果分别进行核苷酸同源性比对分析,使用邻居连接方法(Neighbor-Joining法)中p-distance统计方法构建并绘制系统发生树,bootstrap 1000次进行验证,分析同一家庭成员核苷酸相似性。用SAS 8.0整理分析实验结果,以X~2检验及fisher确切概率法进行统计学分析,以P＜0.05为有统计学意义。
结果:本研究11478份血清样品中,共检测出HBsAg阳性血清549例,扩增出HBV S区基因序列并且成功测序434例,其中HBV B型基因11例,对应血清型为adw(90.9%)和ayw(9.1%);C型基因417例,对应的血清型为adr(95.2%),adw(3.6%),ayr(1.0%)和ayw(0.2%);D型基因6例,为ayw(66.7%)和adr(33.3%)血清型。当地流行HBV的α抗原决定簇氨基酸突变率为6.7%,HBV计划免疫后出生人群中126、143位氨基酸突变率显著高于计划免疫前出生人群。扩增出HBV C区基因序列并成功测序393例,基本核心启动子BCP A1762T/G1764A突变率40.5%;前C区G1896A的突变率为18.1%;HBeAg的表达与否与BCP双突变(P=0.0204)或前C区G1896A(P=0.0003)突变有明显相关性。收集户籍明确村民血样10011份,涉及家庭3619个,其中HBsAg阳性者533人,分布于455个家庭。河北正定地区HBsAg家庭聚集性不符合负二项分布(X~2=6.75,P＜0.05),聚集指数P=0.64;HBV C基因系统进化分析结果提示研究家庭中53.3%的HBsAg聚集家庭存在HBV家庭内传播。
结论:河北正定地区HBV基因型以C型为主,有少量B型和D型;血清型以adr型为主,同时有adw型,ayr型和ayw型;HBV不同基因型与血清型存在一定的相关性:自然人群中存在多种HBV S区α抗原决定簇突变,其中126、143位氨基酸突变可能为与疫苗相关突变;HBV A1762T/G1764A双位点变异和G1896A变异可能与HBeAg表达有关。尚不能认为当地HBsAg阳性者分布有家庭聚集性,HBV分子生物学证据进一步提示当地可能存在HBV母婴传播、夫妻间性传播及父子间水平传播等多种家庭内传播途径。
Objective: To determine the distribution of Hepatitis B virus (HBV) genotypes and serotypes in community-based Zhengding area, Hebei province and evaluate the relationship between HBV genotypes and serotypes; analyze the spectra of mutations of the a determinant of HBV, study the relationship between the mutation and the vaccination; analyze the mutations of A1762T/G1764A and G1896A in the population. To describe the households clustering of HBsAg in Zhengding area, Hebei province by HBV epidemiology and molecular evidence.
Methods: 11478 people's sera were collected by family survey and tested by SPRIA with kits in 2005 from Zhengding area, Hebei province, people's sera with positive HBsAg were collected and the S gene and C gene were amplified by PCR. After sequencing and clastwaling with the standard genotype sequences, the HBV genotype, serotype, the mutant sites of HBVαdeterminant and the A1762T/G1764A and G1896A mutations were detemined. 10011 people's sera from 3619 familys were collected and tested by SPRIA with kits. Negative-binomial distribution test were employed to fit distribution of the HBsAg. The Neighbor-Joining method was employed and the p-distance modle of MEGA 4.0 soft was selected to identify HBV transmission pairs with HBV S gene and C gene data. Statistical analyses were performed using Fisher exact test and X~2 test with SAS 8.1 software, P<0.05 was considered significant.
Result: The study acquired 434 HBV S gene sequences and 393 HBV C gene sequences from 549 HBsAg positive samples eventually. The result of the study demonstrated that the B,C,D genotype have been detected in china and C is the major genotypes. Genotype C was 417 with serotype adr (95.2%), adw (3.6%), ayr (1.0%) and ayw (0.2%) ; Genotype B was 11 with adw (90.9%) and ayw (9.1%) and Genotype D was 6 with serotype ayw (66.7%) and adr (33.3%) . The mutation rate of the HBV a dominant was 6.7% in the community-based population and 9.4% in the population who born after the HBV immunization programe was carried out in this area. The 126、143 amino acid mutant rate is significant different between the two age groups. The BCP A1762T/G1764A and G1896A mutation rates are 40.5%, 18.1%. There is relationship between the HBeAg and the A1762T/G1764A mutation (P=0.0204) and the G1896A mutation (P=0.0003). 10011 sera samples from 3619 familys with definite household register were collected, the households clustering of HBsAg in Zhengding area is not fit the Negative-binomial distribution (X~2=6.75,P<0.05) . The clusting index is 0.64; Various kinds of HBV intrafamily transmission are indentified by the epidemiology and molecular evidence.
Conclusion: The result of the study demonstrate that the B、C、D genotype and ayr、ayw、adr and adw serotype of HBV have been detected in Zhengding area,Hebei province. The C is the major genotypes and the adr is the major serotype. Genotype C with adr serotype, genotype B with adw and genotype D with ayw have the relationship. There are kinds of HBVαdeterminant mutations and 126、134 amino acid mutations are vaccine-associated mutation.A1762T/G1764A two-site mutation and G1896A mutation are the mostly common mutations in the HBV C gene region. There are virous kinds of intra-family transmission pattern in the area but the households cluster of positive serum of HBsAg does not exist.
方法:2005年于河北正定地区以家庭为单位整群采集血清样品,采用固相放射免疫法(SPRIA)进行乙肝五项感染指标检测,选择其中表面抗原(HBsAg)阳性的血清,经过QIAamp DNA Blood Mini Kit提取HBV DNA,采用巢式PCR扩增S基因区段,C基因区段,进行序列测定。利用生物信息学软件Lasergene 6.0将其与Genebank中A-H各基因型标准序列进行对比分析,确定HBV的基因型并通过核苷酸序列推测血清型。利用软件将核苷酸序列转换为氨基酸序列,进行HBVα抗原决定簇氨基酸位点变异分析,并对HBV C基因中CP和BCP常见突变A1762T/G1764A、G1896A突变进行描述和分析。对户籍明确人群以HBsAg为指标进行负二项分布拟合优度检验分析当地HBsAg的家庭聚集情况;利用MEGA4.0.1软件对样本S基因测序结果与C基因测序结果分别进行核苷酸同源性比对分析,使用邻居连接方法(Neighbor-Joining法)中p-distance统计方法构建并绘制系统发生树,bootstrap 1000次进行验证,分析同一家庭成员核苷酸相似性。用SAS 8.0整理分析实验结果,以X~2检验及fisher确切概率法进行统计学分析,以P＜0.05为有统计学意义。
结果:本研究11478份血清样品中,共检测出HBsAg阳性血清549例,扩增出HBV S区基因序列并且成功测序434例,其中HBV B型基因11例,对应血清型为adw(90.9%)和ayw(9.1%);C型基因417例,对应的血清型为adr(95.2%),adw(3.6%),ayr(1.0%)和ayw(0.2%);D型基因6例,为ayw(66.7%)和adr(33.3%)血清型。当地流行HBV的α抗原决定簇氨基酸突变率为6.7%,HBV计划免疫后出生人群中126、143位氨基酸突变率显著高于计划免疫前出生人群。扩增出HBV C区基因序列并成功测序393例,基本核心启动子BCP A1762T/G1764A突变率40.5%;前C区G1896A的突变率为18.1%;HBeAg的表达与否与BCP双突变(P=0.0204)或前C区G1896A(P=0.0003)突变有明显相关性。收集户籍明确村民血样10011份,涉及家庭3619个,其中HBsAg阳性者533人,分布于455个家庭。河北正定地区HBsAg家庭聚集性不符合负二项分布(X~2=6.75,P＜0.05),聚集指数P=0.64;HBV C基因系统进化分析结果提示研究家庭中53.3%的HBsAg聚集家庭存在HBV家庭内传播。
结论:河北正定地区HBV基因型以C型为主,有少量B型和D型;血清型以adr型为主,同时有adw型,ayr型和ayw型;HBV不同基因型与血清型存在一定的相关性:自然人群中存在多种HBV S区α抗原决定簇突变,其中126、143位氨基酸突变可能为与疫苗相关突变;HBV A1762T/G1764A双位点变异和G1896A变异可能与HBeAg表达有关。尚不能认为当地HBsAg阳性者分布有家庭聚集性,HBV分子生物学证据进一步提示当地可能存在HBV母婴传播、夫妻间性传播及父子间水平传播等多种家庭内传播途径。
Objective: To determine the distribution of Hepatitis B virus (HBV) genotypes and serotypes in community-based Zhengding area, Hebei province and evaluate the relationship between HBV genotypes and serotypes; analyze the spectra of mutations of the a determinant of HBV, study the relationship between the mutation and the vaccination; analyze the mutations of A1762T/G1764A and G1896A in the population. To describe the households clustering of HBsAg in Zhengding area, Hebei province by HBV epidemiology and molecular evidence.
Methods: 11478 people's sera were collected by family survey and tested by SPRIA with kits in 2005 from Zhengding area, Hebei province, people's sera with positive HBsAg were collected and the S gene and C gene were amplified by PCR. After sequencing and clastwaling with the standard genotype sequences, the HBV genotype, serotype, the mutant sites of HBVαdeterminant and the A1762T/G1764A and G1896A mutations were detemined. 10011 people's sera from 3619 familys were collected and tested by SPRIA with kits. Negative-binomial distribution test were employed to fit distribution of the HBsAg. The Neighbor-Joining method was employed and the p-distance modle of MEGA 4.0 soft was selected to identify HBV transmission pairs with HBV S gene and C gene data. Statistical analyses were performed using Fisher exact test and X~2 test with SAS 8.1 software, P<0.05 was considered significant.
Result: The study acquired 434 HBV S gene sequences and 393 HBV C gene sequences from 549 HBsAg positive samples eventually. The result of the study demonstrated that the B,C,D genotype have been detected in china and C is the major genotypes. Genotype C was 417 with serotype adr (95.2%), adw (3.6%), ayr (1.0%) and ayw (0.2%) ; Genotype B was 11 with adw (90.9%) and ayw (9.1%) and Genotype D was 6 with serotype ayw (66.7%) and adr (33.3%) . The mutation rate of the HBV a dominant was 6.7% in the community-based population and 9.4% in the population who born after the HBV immunization programe was carried out in this area. The 126、143 amino acid mutant rate is significant different between the two age groups. The BCP A1762T/G1764A and G1896A mutation rates are 40.5%, 18.1%. There is relationship between the HBeAg and the A1762T/G1764A mutation (P=0.0204) and the G1896A mutation (P=0.0003). 10011 sera samples from 3619 familys with definite household register were collected, the households clustering of HBsAg in Zhengding area is not fit the Negative-binomial distribution (X~2=6.75,P<0.05) . The clusting index is 0.64; Various kinds of HBV intrafamily transmission are indentified by the epidemiology and molecular evidence.
Conclusion: The result of the study demonstrate that the B、C、D genotype and ayr、ayw、adr and adw serotype of HBV have been detected in Zhengding area,Hebei province. The C is the major genotypes and the adr is the major serotype. Genotype C with adr serotype, genotype B with adw and genotype D with ayw have the relationship. There are kinds of HBVαdeterminant mutations and 126、134 amino acid mutations are vaccine-associated mutation.A1762T/G1764A two-site mutation and G1896A mutation are the mostly common mutations in the HBV C gene region. There are virous kinds of intra-family transmission pattern in the area but the households cluster of positive serum of HBsAg does not exist.
引文
1 Lavanchy D.Hepatitis B virus epidemiology,disease burden,treatment,and current and emerging prevention and control measures.J Viral Hepatol 2004;11:97-107.
2 2006.《2006年中国卫生统计年鉴》,中华人民共和国卫生部.中国协和医科大学出版社.
3 Sumi,H.,O.Yokosuka,N.Seki,et al.2003.Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease.Hepatology 37:19-26.
4 Magnius,L.O.,and H.Norder.1995.Subtypes,genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.Intervirology 38:24-34.
5 Norder,H.,A.M.Courouce,and L.O.Magnius.1992.Molecular basis of hepatitis B virus serotype variations within the four major subtypes.J Gen Virol 73(Pt 12):3141-5.
6 Norder,H.,B.Hammas,S.Lofdahl,et al.1992.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains.J Gen Virol 73(Pt 5):1201-8.
7 Okamoto,H.,F.Tsuda,H.Sakugawa,et al.1988.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 69(Pt 10):2575-83.
8 Allain,J.P.2006.Epidemiology of Hepatitis B virus and genotype.J Clin Virol 36 Suppl 1:S12-7.
9 Meeusen,R.,J.Roeykens,L.Magnus,et al.1997.Endurance performance in humans:the effect of a dopamine precursor or a specific serotonin(5-HT2A/2C)antagonist.Int J Sports Med 18:571-7.
10 Lindh,M.,A.S.Andersson,and A.Gusdal.1997.Genotypes,nt 1858 variants,and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method.J Infect Dis 175:1285-93.
11 Chu,C.M.,and Y.F.Liaw.2005.Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B:a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol 43:411-7.
12 Fujiwara,K.,Y.Tanaka,E.Paulon,et al.2005.Novel type of hepatitis B virus mutation:replacement mutation involving a hepatocyte nuclear factor 1 binding site tandem repeat in chronic hepatitis B virus genotype E.J Virol 79:14404-10.
13 Rokuhara,A.,X.Sun,E.Tanaka,et al.2005.Hepatitis B virus core and core-related antigen quantitation in Chinese patients with chronic genotype B and C hepatitis B virus infection.J Gastroenterol Hepatol 20:1726-30.
14 Wasley A,Grytdal S,Gallagher K.Surveillance for acute viral hepatitis-United States,2006.MMWR Morb Mortal Wkly Rep 2008;57:1-24.
15 Botha JF,Ritchie MJ,Dusheiko GM,Mouton HW,Kew MC.Hepatitis B virus carrier state in black children in Ovamboland:role of perinatal and horizontal infection.Lancet 1984;323:1210-12.7
16 Peter S,Sofie M.Recombination in the genesis and evolution of hepatitis B virus genotypes.Journal of virology,2005,79(24):154 67-76
17 荆庆.我国乙型肝炎表面抗原家庭内感染的某些特征.中华微生物学和免疫学杂志.增刊:41.
18 Sugauchi F,Mizokami M,Orito E,et al,Molecular evolutionary analysis of the complete nucleotide sequence of hepatitis B virus(HBV) in a case of HBV infection acquired through a needlestick accident.Clin Infect Dis 2000;31:1195-1201.
19 Khan AJ,Simard EP,Bower WA,Wurtzel HL,Khristova M,Wagner KD,Arnold KE,Nainan OV,LaMarre M,Bell BP.Ongoing transmission of hepatitisBvirus infection among inmates at a state correctional facility.Am J Public Health 2005;95:1793-1799.
20 van Houdt R,Sonder GJ,Dukers NH,Bovee LP,van den Hoek A,Coutinho RA,Bruisten SM.Impact of a targeted hepatitis B vaccination program in Amsterdam.The Netherlands Vaccine,2007;25:2698-2705.
21 Hsu,H.Y.,M.H.Chang,Y.H.Ni,et al.Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan.Gut 2004;53:1499-503.
22.Wallace,L.A.,J.E.Echevarria,J.M.Echevarria,et al.Molecular characterization of envelope antigenic variants of hepatitis B virus from Spain.J Infect Dis 1994;170:1300-3.
23 Hsu, H. Y., M. H. Chang, S. H. Liaw, et al. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 1999;30:1312-7.
24 Stuyver, L., S. De Gendt, C. Van Geyt, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol 2000; 81:67-74.
25 Norder, H., A. M. Courouce, P. Coursaget, et al. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004;47:289-309.
26 Okamoto H,Tsuda F,Sakugawa H,et al.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 1988;69(Pt10):2575-2583.
27 Norder H,Hammas B,Lofdahl S,et al.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains. J Gen Virol 1992;73(Pt5):1201-1208.
28 Progress in hepatitis B prevention through universal infant vaccination--China, 1997-2006. MMWR Morb Mortal Wkly Rep 2007;56:441-5.
29 Bowyer SM,Sim JG.,Relationships within and between genotypea of hepatitis B virus at points across the genome:footprints of recombination in certain isolates.J Gen Virol 2000.
30 Alestig E,Hannoun C,Horal P.et al.Hepatitis B virus genotypes in Mongols and Australian Aborigines.Arch Virol 2001;146:2321-2329.
31 Xu, J., Q. X. Wang, C. L. Fan, et al. Comparison of hepatitis B virus serotype and genotype among HBsAg positive hepatitis B patients in a northern and a southern city of China. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2003;17:327-9.
32 Kao JH,Chen PJ,Lai MY,et al.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology 2000;118:554-559.
33 Lindh M, Andersson A S, Gusdal A. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method. J Infect Dis, 1997;175(6): 1258-1293.
34 Hino K, Katoh Y, Vardas E, et al. The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine, 2001;19:3912-3918.
35 Carman WF. The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat, 1997;4:11-20.
36 Cooreman MP, Van Roosmalen MH, Te Morsche R, et al .Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring'α'loop escape mutations.Hepatology, 199930:1287-1292.
37 Carman WF, Van Deursen FJ, Mimms LT, et al. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia.Hepatology, 1997;26: 1658-1666.
38 Ngui, S. L., R. Hallet, and C. G. Teo. Natural and iatrogenic variation in hepatitis B virus. Rev Med Virol 1999;9:183-209.
39 Velu, V., S. Saravanan, S. Nandakumar, et al. Transmission of "a" determinant variants of hepatitis B virus in immunized babies born to HBsAg carrier mothers. Jpn J Infect Dis 2008;61:73-6.
40 Suwannakarn, K., P. Tangkijvanich, N. Thawornsuk, et al. Molecular epidemiological study of hepatitis B virus in Thailand based on the analysis of pre-S and S genes. Hepatol Res 2008;38:244-51.
41 Oon CJ, Lim GK, Zhao Y, et al. Molecular epidemiology of hepatitis B virus vaccine variants in Singapore. Vaccine, 1995;13: 699-702.
42 Lok, A. S., U. Akarca, and S. Greene. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A 1994;91:4077-81.
43 Chi-Jen Chu, Emmet B. Keeffe, Steven-Huy Han, et al. Prevalence of HBV Pre-core/Core Promoter Variants in the United States. Hepatology, 2003, Vol.38,No.3: 619-627.
44 Nakashima H, Fumsyo N, Kubo N, et al. Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection. J Gastroenterol Hepatol,2004,19(5): 541-550.
45 Chan HL, Hussain M, Lok AS.Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology, 1999, 29 (3): 976-984.
46 Lindh M, Andersson A S, Gusdal A. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method[J].J Infect Dis,1997;175(6):1258-1293
47 杨进业,沈立萍,莫兆军.乙肝疫苗长期免疫地区乙肝病毒感染家庭聚集性变化趋势的观察.应用预防医学.2007,;13.No.1.
48 李凌奋,周勇,王枝新.福建省肝炎病毒感染家庭聚集性研究.中华预防医学杂志,1997.31(6).
49 衡明莉,马林茂,陈颖丹.统计学方法在几种重要寄生虫病家庭聚集性研究中的应用,2006.33(5):273-276.
50 罗中云.HBsAg家庭聚集性的理论概率模式研究EJ3.中国卫生统计,1991;8(3):50-52.
51 陈峰,杨树勤.二项分布及医学应用一疾病的统计分布(二)EJ3.中国卫生统计.1996;13(2):10-13.
52 祝绍琪,杨树勤.主编.中国医学百科全书医学统计学,上海科学技术出版社985.21-26.
53 许隆祺,陈颖丹.主编.寄生虫病流行病学与统计学.北京:中国医药科社,2005.571-579
54 Sugauchi F,Mizokami M,Orito E,et alMolecular evolutionary analysis of the complete nucleotide sequence of hepatitis B virus(HBV) in a case of HBV infection acquired through a needlestick accident.Clin Infect Dis.2000;31:1195-1201.
55 Komatsu,H.,A.Inui,Y.Morinishi,T.Sogo,and T.Fujisawa.Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother.J.Med.Virol.2001;65:457-462.
56 Lin CL,Kao JH,Chen BF,et al..Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus.Clin Infect Dis 2005;41:1576-1581.
57 Petzold,D.R.,B.Tautz,F.Wolf,and J.Drescher.Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially.J.Med.Virol.1999;58:1-10.
58 Mizokami,M.,E.Orito,K.Ohba,K.Ikeo,J.Lau,and T.Gojobori.Constrained evolution with respect to gene overlap of hepatitis B virus.J.Mol.Evol.1997,44:83-90.
60 Hunt, C. M, J. M. McGill, M. I. Allen, and L. D. Condreay. 2003. Clinical relevance of hepatitis B viral mutations. Hepatol. 2000 31:1037-1044.
61 Szmaragd, C, G. R. Foster, A. Manica, A. Bartholomeusz, R. A. Nichols, and F. Balloux. Genome-wide characterisation of hepatitis B mutations involved in clinical outcomes. Heredity 2006.97:389-397.
62 Bracho, M. A., M. J. Gosalbes, F. Gonzalez, A. Moya, and F. Gonzalez-Candelas. Molecular epidemiology and evolution in an outbreak of fulminant hepatitis B virus. J. Clin. Microbiol. 2006. 44:1288-1294.
63 Banerjee, A., S. Banerjee, A. Chowdhury, A. Santra, S. Chowdhury, S. Roychowdhury, C. K. Panda, S. K. Bhattacharya, and R. Chakravarty. Nucleic acid sequence analysis of BCP/precore/core region of hepatitis B virus isolated from chronic carriers of the virus from Kolkata, Eastern India:low frequency of mutation in the precore region. Intervirology 2005.48:389-399.
64 Dumpis, U., E. C. Holmes, M. Mendy, A. Hill, M. Thursz, A. Hall, H.Whittle, and P. Karayiannis. 2001. Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol.35:99-104.
1.http://www.who.int/mediacentre/factsheets/fs204/en/
2.Okamoto H,Tsuda F,Sakugawa H,et al.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 1988;69(Pt10):2575-2583.
3.Norder H,Hammas B,Lofdahl S,et al.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains.J Gen Virol 1992;73(Pt5):1201-1208.
4.Progress in hepatitis B prevention through universal infant vaccination China,MMWR Morb Mortal Wkly Rep,1997-2006.56:441-5.
5.M averat C,M antegani A,Frei PC.Does hepatitis B virus(HBV)genotype influence the clinical outcome of HBV infection.Vira Hepat,1999;6:299-30.
6.范金水,庄辉,李远贵.等.我国8城市HBsAg阳性和阴性乙肝患者的病毒血清型和基因型分析.中华微生物学和免疫学杂志,1998;18:88-91
7.Michielsen PP,Van DarDre P.Viral hepatitis and pregnancy.Acta Gastroenterol Belg,1999;62:21-29.
8.Hannoun,C.,Krogsgaard,K.,Horal,P,et al.Genotype mixtures of hepatitis B virus in patients treated with interferon.Journal of Infectious Diseases,2002;15:752-759.
9.Jutavijittum,P.Jiviriyawat,Y.Yousukh,A,et al.Genotypes of Hepatitis B virus among voluntary blood donors in northern Thailand.Hepatology Research,2006;
10.Halfon,P.Bourliere,M.Pol,S.,et al.Multicenter study of Hepatitis B virus genotypes in France:Correlation with liver fibrosis and hepatitis B e antigen status.Journal of Viral Hepatology,2006;13(5):329-325.
11.Nowak,M.A.,S.Bonhoeffer,A.M.Hill,et al.1996.Varal dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA.93:4398-402.
12.Kao,J.H.,Chen,P.J.,Lai,M.Y.,and Chen,D.S.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology,2000,118:554-559.
13.Sumi,H.,Yokosuka,,O.Seki,N.Influence of Hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology, 2003;37:19-26.
14. Westland, C. Delaney, W., Yang, H. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1 .Gastroenterology, 2003; 125: 107-116.
15. Erhardt A, Reineke U, Blondin D, et al. Mutuations of the core promoter and response to interferon treatment in chronic replicative hepatitis B.Hepatology, 2000;31:716-725.
16. Kao JH, Wu NH, Chen P J , et al. Hepatitis B genotypes and the response to interferon therapy.J Hepatol, 2000, 33: 998-1002.
17. Janssen HLA,Senturk H,Zeuzem S,et al.Peginterferon alfa-2B and lamivudine combination therapy compared with peginterferon alfa-2B for chronic HBeAg-positive hepatitis B a randomized controlled trial in 307patients.Hepatology, 2003;38:1323.
18. Kao JH , Chen P J , Lai M Y, et al. Hepatitis B genotypes correlated with clinical outcomes in patients with chronic hepatitis B. Gastroenterology, 2000; 118: 554-559.
19. Yuen MF, Wong DK, Sablon E, et al. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther, 2003; 8: 531-534.
20. akashima H, Fumsyo N, Kubo N, et al. Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection. J Gastroenterol Hepatol,2004;19(5): 541-550.
21. Onto E, Mizokami M, Sakugawa H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology, 2001;33(1): 218-223.
22. Han HL, Hussain M, Lok AS.Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology, 1999; 29 (3): 976-984.
23. Tanaka Y,Hasegawa I,Kato T,et al.A case-control study for differences among hepatitis B virus infections ofgenotypes A ( subtypes Aa and Ae) and D.Hepatology,2004;40(3):747-755.
24. Takahashi K, Ohta Y, Kanai K, et al. Clinical implications of mutations C to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol, 1999;144(7): 1299-1308.
25. Kramvis A, Weitzmann L , Owiredu WK, et al. Analysis of the complete genome of subgroup N hepatitis B virus isolates from South Africa.J Gen Virol,2002;83:835-839.
26.Liaw YF,Leung NW,Chang TT et al.Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.Asia Hepatitis Lamivu dine Study Group.Gastroenterology,2000;119(1):172-180.
27.Kobayashi S,Ide T,Sata M.Detection of YMDD motif mutations in somelamivudine- untreated asymptomatic hepatitis B virus carriers.J Hepatol,2001,34(4):584-586.
28.Yeh CT,Chien RN,Chu CM,et al.Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy.Hepatology,2000;31(6):1318-1326.
29.周建良,吴诗品.拉米夫定治疗乙型肝炎病毒B、C基因型疗效比较.中华肝脏病杂志,2004;12(8):489-490.
30.Kao JH,Liu CJ,Chen DS.Hepatitis B viral genotypes and lamivudine re sistance.J Hepatol,2002;36(2):303-304
31.Xiong X,Yang H,Westland CE,et al.In vitro evaluation of hepatitis Bvirus polymerase mutations associated with famciclovir resistance.Hepatology,2000;31(1):219-224.
32.Zollner B,Petersen J,Puchhammer-Stockl E,et al.Viral features of lamivudine resistant hepatitis B genotypes A and D.Hepatology,2004;39(1):42-50.
33.Hoofnagle,J.1990.Post-transfusion hepatitis B.Transfusion 30:384-386.
34.Gross,A.,H.I.Joller-Jemelka,A.N.Wicki,and P.J.Grob.DerHepatitis-serologische Befund "Anti-HBc allein",zirkulierende virale DNS und Befund-Interpretation.Schweiz.Med.Wochenschr.1993;123:1193-1202.20.
35.Jilg,W.,E.Sieger,R.Zachoval,and H.Scha"tzl.Individuals with antibodies against hepatitis B core antigen as the only serological marker for hepatitis B infection:high percentage of carriers of hepatitis B and C virus.J.Hepatol.1995;23:14-20.
36.Carman,W.F.The clinical significance of surface antigen variants of hepatitis B virus.J.Viral Hepat.1997;4(Suppl.1):S11-S20.
37.Howard,C.R.,and L.M.C.Allison.Hepatitis B surface antigen variation and protective immunity.Intervirology,1995;38:35-40.
38.Carman,W.F.,A.R.Zanetti,P.Karayiannis,et al.Vaccine-induced escape mutant of hepatitis B virus. Lancet. 1990;336:325-329.
39. Fortuin, M., V. Karthigesu, L. Allison, C.et al. Breakthrough infections and identification of a viral variant in Gambian children immunized with hepatitis B vaccine. J. Infect.Dis. 1994;169:1374-1376.
40. Carman, W. F., Van Deursen, L. T. Mimms, D. et al. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia. Hepatology,1997;26:1658-1666.
41. .41. Howard, C. R. The structure of hepatitis B envelope and molecular variants of hepatitis B virus. J. Viral Hepat. 1995;2:165-170.
42. Carman, W. F., and L. T. Mimms. R. H. Purcell, J. L. Gerin, and G. Verne (ed.),Pre-S/S gene variants of hepatitis B virus. Viral hepatitis and liver disease. 1997;108-115.
43. Yu MW, Chang HC, Liaw YF, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. Journal of the national cancer institute,2000,92( 14): 1159-1164.
44. Hou JL, Liu ZH, Gu Fan. Epidemiology and prevention of hepatitis B virus infection. Int J Med Sci,2005,2(1):50-57.
45. Kidd-Ljunggren, K.E. Broman, H. Ekvall, and O. Gustavsson.. Nosocomial transmission of hepatitis B virus infection through multiple-dose vials. J. Hosp. Infect. 1999,43:57-62.
46. Petzold, D. R., B. Tautz, F. Wolf, and J. Drescher. Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially. J. Med. Virol. 1999,58:1-10.
47. Komatsu, H., A. Inui, Y. Morinishi, T. Sogo, and T. Fujisawa. Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother. J. Med. Virol. 2001;65:457-462.
48. Dumpis, U. E. C. Holmes, M. Mendy, A. et al.Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol. 2001,35:99-104.
49. Zampino, RS. Lobello, M. Chiaramonte, C. et al.Intra-familial transmission of hepatitis B virus in Italy: phylogenetic sequence analysis and amino-acid variation of the core gene. J. Hepatol. 2002, 36:248.
50. Petzold, D. R., B. Tautz, F. Wolf, and J. Drescher. Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially. J. Med. Virol. 1999,58:1-10.
51. Akarca, U. S., S. Greene, and A. S. Lok. 1994. Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members. Hepatology 19:1366-1370.
52. Ho, M. S., C. F. Lu, J. Kuo, Y. C. Mau, and W. H. Chao. A family cluster of an immune escape variant of hepatitis B virus infecting a mother and her two fully immunized children. Clin. Diagn. Lab. Immunol. 1995, 2:760-762.
53. Dumpis, U., E. C. Holmes, M. Mendy, et al. Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol. 2001, 35:99-104.
54. Hunt, C. M., J. M. McGill, M. I. Allen, and L. D. Condreay. 2003. Clinical relevance of hepatitis B viral mutations. Hepatol. 2000 31:1037-1044.
55. Ozasa, A., Y. Tanaka, E. Orito, M. Sugiyama, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology, 2006, 44:326-334.
56. Weinberger, K. M., T. Bauer, S. Bohm, and W. Jilg. High genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serum. J. Gen. Virol. 2000, 81:1165-1174.
57. Hino K, Katoh Y, Vardas E,et al. Carman WF The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine,2001,19:3912-3918
58. Nakanishi H, Kurosaki M, Asahina Y, et al. Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B. Intervirology 2005,48:381— 388.
59. Huy TTT, Ushijima H, Win KM, et al.High prevalence of hepatitis B virus pre-S mutant in countries where it is endemic and its relationship with genotype and chronicity. J Clin Microbiol, 2003, 41(12):5449-5455.
60. Hino K, Katoh Y, Vardas E, et al.The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine, 2001,19: 3912-3918.
61. Carman WF. The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat, 1997,4:11-20.
62. Cooreman MP, Van Roosmalen MH, Te Morsche R, et al .Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring'a'loop escape mutations. Hepatology, 1999,30:1287-1292.
63. Carman WF, Van Deursen FJ, Mimms LT, Hardie D, Coppola R, Decker R, Sanders R. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia. Hepatology, 1997, 26: 1658-1666.
64. Hsh,H.Y.,M.H.Chang,S.H.Liaw,et al. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan.Hepatology 1999,30:1312-7.
65. Oon, C. J., W. N. Chen, K. S. Goo, et al. Intra-familial evidence of horizontal transmission of hepatitis B virus surface antigen mutant G145R. J Infect, 2000,41:260-4.
66. Chen WN, Oon CJ Human hepatitis B virus mutants: significance of molecular changes. FEBS Lett .1999,453:237-242
2 2006.《2006年中国卫生统计年鉴》,中华人民共和国卫生部.中国协和医科大学出版社.
3 Sumi,H.,O.Yokosuka,N.Seki,et al.2003.Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease.Hepatology 37:19-26.
4 Magnius,L.O.,and H.Norder.1995.Subtypes,genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.Intervirology 38:24-34.
5 Norder,H.,A.M.Courouce,and L.O.Magnius.1992.Molecular basis of hepatitis B virus serotype variations within the four major subtypes.J Gen Virol 73(Pt 12):3141-5.
6 Norder,H.,B.Hammas,S.Lofdahl,et al.1992.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains.J Gen Virol 73(Pt 5):1201-8.
7 Okamoto,H.,F.Tsuda,H.Sakugawa,et al.1988.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 69(Pt 10):2575-83.
8 Allain,J.P.2006.Epidemiology of Hepatitis B virus and genotype.J Clin Virol 36 Suppl 1:S12-7.
9 Meeusen,R.,J.Roeykens,L.Magnus,et al.1997.Endurance performance in humans:the effect of a dopamine precursor or a specific serotonin(5-HT2A/2C)antagonist.Int J Sports Med 18:571-7.
10 Lindh,M.,A.S.Andersson,and A.Gusdal.1997.Genotypes,nt 1858 variants,and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method.J Infect Dis 175:1285-93.
11 Chu,C.M.,and Y.F.Liaw.2005.Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B:a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol 43:411-7.
12 Fujiwara,K.,Y.Tanaka,E.Paulon,et al.2005.Novel type of hepatitis B virus mutation:replacement mutation involving a hepatocyte nuclear factor 1 binding site tandem repeat in chronic hepatitis B virus genotype E.J Virol 79:14404-10.
13 Rokuhara,A.,X.Sun,E.Tanaka,et al.2005.Hepatitis B virus core and core-related antigen quantitation in Chinese patients with chronic genotype B and C hepatitis B virus infection.J Gastroenterol Hepatol 20:1726-30.
14 Wasley A,Grytdal S,Gallagher K.Surveillance for acute viral hepatitis-United States,2006.MMWR Morb Mortal Wkly Rep 2008;57:1-24.
15 Botha JF,Ritchie MJ,Dusheiko GM,Mouton HW,Kew MC.Hepatitis B virus carrier state in black children in Ovamboland:role of perinatal and horizontal infection.Lancet 1984;323:1210-12.7
16 Peter S,Sofie M.Recombination in the genesis and evolution of hepatitis B virus genotypes.Journal of virology,2005,79(24):154 67-76
17 荆庆.我国乙型肝炎表面抗原家庭内感染的某些特征.中华微生物学和免疫学杂志.增刊:41.
18 Sugauchi F,Mizokami M,Orito E,et al,Molecular evolutionary analysis of the complete nucleotide sequence of hepatitis B virus(HBV) in a case of HBV infection acquired through a needlestick accident.Clin Infect Dis 2000;31:1195-1201.
19 Khan AJ,Simard EP,Bower WA,Wurtzel HL,Khristova M,Wagner KD,Arnold KE,Nainan OV,LaMarre M,Bell BP.Ongoing transmission of hepatitisBvirus infection among inmates at a state correctional facility.Am J Public Health 2005;95:1793-1799.
20 van Houdt R,Sonder GJ,Dukers NH,Bovee LP,van den Hoek A,Coutinho RA,Bruisten SM.Impact of a targeted hepatitis B vaccination program in Amsterdam.The Netherlands Vaccine,2007;25:2698-2705.
21 Hsu,H.Y.,M.H.Chang,Y.H.Ni,et al.Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan.Gut 2004;53:1499-503.
22.Wallace,L.A.,J.E.Echevarria,J.M.Echevarria,et al.Molecular characterization of envelope antigenic variants of hepatitis B virus from Spain.J Infect Dis 1994;170:1300-3.
23 Hsu, H. Y., M. H. Chang, S. H. Liaw, et al. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 1999;30:1312-7.
24 Stuyver, L., S. De Gendt, C. Van Geyt, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol 2000; 81:67-74.
25 Norder, H., A. M. Courouce, P. Coursaget, et al. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004;47:289-309.
26 Okamoto H,Tsuda F,Sakugawa H,et al.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 1988;69(Pt10):2575-2583.
27 Norder H,Hammas B,Lofdahl S,et al.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains. J Gen Virol 1992;73(Pt5):1201-1208.
28 Progress in hepatitis B prevention through universal infant vaccination--China, 1997-2006. MMWR Morb Mortal Wkly Rep 2007;56:441-5.
29 Bowyer SM,Sim JG.,Relationships within and between genotypea of hepatitis B virus at points across the genome:footprints of recombination in certain isolates.J Gen Virol 2000.
30 Alestig E,Hannoun C,Horal P.et al.Hepatitis B virus genotypes in Mongols and Australian Aborigines.Arch Virol 2001;146:2321-2329.
31 Xu, J., Q. X. Wang, C. L. Fan, et al. Comparison of hepatitis B virus serotype and genotype among HBsAg positive hepatitis B patients in a northern and a southern city of China. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2003;17:327-9.
32 Kao JH,Chen PJ,Lai MY,et al.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology 2000;118:554-559.
33 Lindh M, Andersson A S, Gusdal A. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method. J Infect Dis, 1997;175(6): 1258-1293.
34 Hino K, Katoh Y, Vardas E, et al. The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine, 2001;19:3912-3918.
35 Carman WF. The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat, 1997;4:11-20.
36 Cooreman MP, Van Roosmalen MH, Te Morsche R, et al .Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring'α'loop escape mutations.Hepatology, 199930:1287-1292.
37 Carman WF, Van Deursen FJ, Mimms LT, et al. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia.Hepatology, 1997;26: 1658-1666.
38 Ngui, S. L., R. Hallet, and C. G. Teo. Natural and iatrogenic variation in hepatitis B virus. Rev Med Virol 1999;9:183-209.
39 Velu, V., S. Saravanan, S. Nandakumar, et al. Transmission of "a" determinant variants of hepatitis B virus in immunized babies born to HBsAg carrier mothers. Jpn J Infect Dis 2008;61:73-6.
40 Suwannakarn, K., P. Tangkijvanich, N. Thawornsuk, et al. Molecular epidemiological study of hepatitis B virus in Thailand based on the analysis of pre-S and S genes. Hepatol Res 2008;38:244-51.
41 Oon CJ, Lim GK, Zhao Y, et al. Molecular epidemiology of hepatitis B virus vaccine variants in Singapore. Vaccine, 1995;13: 699-702.
42 Lok, A. S., U. Akarca, and S. Greene. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A 1994;91:4077-81.
43 Chi-Jen Chu, Emmet B. Keeffe, Steven-Huy Han, et al. Prevalence of HBV Pre-core/Core Promoter Variants in the United States. Hepatology, 2003, Vol.38,No.3: 619-627.
44 Nakashima H, Fumsyo N, Kubo N, et al. Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection. J Gastroenterol Hepatol,2004,19(5): 541-550.
45 Chan HL, Hussain M, Lok AS.Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology, 1999, 29 (3): 976-984.
46 Lindh M, Andersson A S, Gusdal A. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method[J].J Infect Dis,1997;175(6):1258-1293
47 杨进业,沈立萍,莫兆军.乙肝疫苗长期免疫地区乙肝病毒感染家庭聚集性变化趋势的观察.应用预防医学.2007,;13.No.1.
48 李凌奋,周勇,王枝新.福建省肝炎病毒感染家庭聚集性研究.中华预防医学杂志,1997.31(6).
49 衡明莉,马林茂,陈颖丹.统计学方法在几种重要寄生虫病家庭聚集性研究中的应用,2006.33(5):273-276.
50 罗中云.HBsAg家庭聚集性的理论概率模式研究EJ3.中国卫生统计,1991;8(3):50-52.
51 陈峰,杨树勤.二项分布及医学应用一疾病的统计分布(二)EJ3.中国卫生统计.1996;13(2):10-13.
52 祝绍琪,杨树勤.主编.中国医学百科全书医学统计学,上海科学技术出版社985.21-26.
53 许隆祺,陈颖丹.主编.寄生虫病流行病学与统计学.北京:中国医药科社,2005.571-579
54 Sugauchi F,Mizokami M,Orito E,et alMolecular evolutionary analysis of the complete nucleotide sequence of hepatitis B virus(HBV) in a case of HBV infection acquired through a needlestick accident.Clin Infect Dis.2000;31:1195-1201.
55 Komatsu,H.,A.Inui,Y.Morinishi,T.Sogo,and T.Fujisawa.Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother.J.Med.Virol.2001;65:457-462.
56 Lin CL,Kao JH,Chen BF,et al..Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus.Clin Infect Dis 2005;41:1576-1581.
57 Petzold,D.R.,B.Tautz,F.Wolf,and J.Drescher.Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially.J.Med.Virol.1999;58:1-10.
58 Mizokami,M.,E.Orito,K.Ohba,K.Ikeo,J.Lau,and T.Gojobori.Constrained evolution with respect to gene overlap of hepatitis B virus.J.Mol.Evol.1997,44:83-90.
60 Hunt, C. M, J. M. McGill, M. I. Allen, and L. D. Condreay. 2003. Clinical relevance of hepatitis B viral mutations. Hepatol. 2000 31:1037-1044.
61 Szmaragd, C, G. R. Foster, A. Manica, A. Bartholomeusz, R. A. Nichols, and F. Balloux. Genome-wide characterisation of hepatitis B mutations involved in clinical outcomes. Heredity 2006.97:389-397.
62 Bracho, M. A., M. J. Gosalbes, F. Gonzalez, A. Moya, and F. Gonzalez-Candelas. Molecular epidemiology and evolution in an outbreak of fulminant hepatitis B virus. J. Clin. Microbiol. 2006. 44:1288-1294.
63 Banerjee, A., S. Banerjee, A. Chowdhury, A. Santra, S. Chowdhury, S. Roychowdhury, C. K. Panda, S. K. Bhattacharya, and R. Chakravarty. Nucleic acid sequence analysis of BCP/precore/core region of hepatitis B virus isolated from chronic carriers of the virus from Kolkata, Eastern India:low frequency of mutation in the precore region. Intervirology 2005.48:389-399.
64 Dumpis, U., E. C. Holmes, M. Mendy, A. Hill, M. Thursz, A. Hall, H.Whittle, and P. Karayiannis. 2001. Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol.35:99-104.
1.http://www.who.int/mediacentre/factsheets/fs204/en/
2.Okamoto H,Tsuda F,Sakugawa H,et al.Typing hepatitis B virus by homology in nucleotide sequence:comparison of surface antigen subtypes.J Gen Virol 1988;69(Pt10):2575-2583.
3.Norder H,Hammas B,Lofdahl S,et al.Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains.J Gen Virol 1992;73(Pt5):1201-1208.
4.Progress in hepatitis B prevention through universal infant vaccination China,MMWR Morb Mortal Wkly Rep,1997-2006.56:441-5.
5.M averat C,M antegani A,Frei PC.Does hepatitis B virus(HBV)genotype influence the clinical outcome of HBV infection.Vira Hepat,1999;6:299-30.
6.范金水,庄辉,李远贵.等.我国8城市HBsAg阳性和阴性乙肝患者的病毒血清型和基因型分析.中华微生物学和免疫学杂志,1998;18:88-91
7.Michielsen PP,Van DarDre P.Viral hepatitis and pregnancy.Acta Gastroenterol Belg,1999;62:21-29.
8.Hannoun,C.,Krogsgaard,K.,Horal,P,et al.Genotype mixtures of hepatitis B virus in patients treated with interferon.Journal of Infectious Diseases,2002;15:752-759.
9.Jutavijittum,P.Jiviriyawat,Y.Yousukh,A,et al.Genotypes of Hepatitis B virus among voluntary blood donors in northern Thailand.Hepatology Research,2006;
10.Halfon,P.Bourliere,M.Pol,S.,et al.Multicenter study of Hepatitis B virus genotypes in France:Correlation with liver fibrosis and hepatitis B e antigen status.Journal of Viral Hepatology,2006;13(5):329-325.
11.Nowak,M.A.,S.Bonhoeffer,A.M.Hill,et al.1996.Varal dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA.93:4398-402.
12.Kao,J.H.,Chen,P.J.,Lai,M.Y.,and Chen,D.S.Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology,2000,118:554-559.
13.Sumi,H.,Yokosuka,,O.Seki,N.Influence of Hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology, 2003;37:19-26.
14. Westland, C. Delaney, W., Yang, H. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1 .Gastroenterology, 2003; 125: 107-116.
15. Erhardt A, Reineke U, Blondin D, et al. Mutuations of the core promoter and response to interferon treatment in chronic replicative hepatitis B.Hepatology, 2000;31:716-725.
16. Kao JH, Wu NH, Chen P J , et al. Hepatitis B genotypes and the response to interferon therapy.J Hepatol, 2000, 33: 998-1002.
17. Janssen HLA,Senturk H,Zeuzem S,et al.Peginterferon alfa-2B and lamivudine combination therapy compared with peginterferon alfa-2B for chronic HBeAg-positive hepatitis B a randomized controlled trial in 307patients.Hepatology, 2003;38:1323.
18. Kao JH , Chen P J , Lai M Y, et al. Hepatitis B genotypes correlated with clinical outcomes in patients with chronic hepatitis B. Gastroenterology, 2000; 118: 554-559.
19. Yuen MF, Wong DK, Sablon E, et al. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther, 2003; 8: 531-534.
20. akashima H, Fumsyo N, Kubo N, et al. Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection. J Gastroenterol Hepatol,2004;19(5): 541-550.
21. Onto E, Mizokami M, Sakugawa H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology, 2001;33(1): 218-223.
22. Han HL, Hussain M, Lok AS.Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology, 1999; 29 (3): 976-984.
23. Tanaka Y,Hasegawa I,Kato T,et al.A case-control study for differences among hepatitis B virus infections ofgenotypes A ( subtypes Aa and Ae) and D.Hepatology,2004;40(3):747-755.
24. Takahashi K, Ohta Y, Kanai K, et al. Clinical implications of mutations C to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol, 1999;144(7): 1299-1308.
25. Kramvis A, Weitzmann L , Owiredu WK, et al. Analysis of the complete genome of subgroup N hepatitis B virus isolates from South Africa.J Gen Virol,2002;83:835-839.
26.Liaw YF,Leung NW,Chang TT et al.Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.Asia Hepatitis Lamivu dine Study Group.Gastroenterology,2000;119(1):172-180.
27.Kobayashi S,Ide T,Sata M.Detection of YMDD motif mutations in somelamivudine- untreated asymptomatic hepatitis B virus carriers.J Hepatol,2001,34(4):584-586.
28.Yeh CT,Chien RN,Chu CM,et al.Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy.Hepatology,2000;31(6):1318-1326.
29.周建良,吴诗品.拉米夫定治疗乙型肝炎病毒B、C基因型疗效比较.中华肝脏病杂志,2004;12(8):489-490.
30.Kao JH,Liu CJ,Chen DS.Hepatitis B viral genotypes and lamivudine re sistance.J Hepatol,2002;36(2):303-304
31.Xiong X,Yang H,Westland CE,et al.In vitro evaluation of hepatitis Bvirus polymerase mutations associated with famciclovir resistance.Hepatology,2000;31(1):219-224.
32.Zollner B,Petersen J,Puchhammer-Stockl E,et al.Viral features of lamivudine resistant hepatitis B genotypes A and D.Hepatology,2004;39(1):42-50.
33.Hoofnagle,J.1990.Post-transfusion hepatitis B.Transfusion 30:384-386.
34.Gross,A.,H.I.Joller-Jemelka,A.N.Wicki,and P.J.Grob.DerHepatitis-serologische Befund "Anti-HBc allein",zirkulierende virale DNS und Befund-Interpretation.Schweiz.Med.Wochenschr.1993;123:1193-1202.20.
35.Jilg,W.,E.Sieger,R.Zachoval,and H.Scha"tzl.Individuals with antibodies against hepatitis B core antigen as the only serological marker for hepatitis B infection:high percentage of carriers of hepatitis B and C virus.J.Hepatol.1995;23:14-20.
36.Carman,W.F.The clinical significance of surface antigen variants of hepatitis B virus.J.Viral Hepat.1997;4(Suppl.1):S11-S20.
37.Howard,C.R.,and L.M.C.Allison.Hepatitis B surface antigen variation and protective immunity.Intervirology,1995;38:35-40.
38.Carman,W.F.,A.R.Zanetti,P.Karayiannis,et al.Vaccine-induced escape mutant of hepatitis B virus. Lancet. 1990;336:325-329.
39. Fortuin, M., V. Karthigesu, L. Allison, C.et al. Breakthrough infections and identification of a viral variant in Gambian children immunized with hepatitis B vaccine. J. Infect.Dis. 1994;169:1374-1376.
40. Carman, W. F., Van Deursen, L. T. Mimms, D. et al. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia. Hepatology,1997;26:1658-1666.
41. .41. Howard, C. R. The structure of hepatitis B envelope and molecular variants of hepatitis B virus. J. Viral Hepat. 1995;2:165-170.
42. Carman, W. F., and L. T. Mimms. R. H. Purcell, J. L. Gerin, and G. Verne (ed.),Pre-S/S gene variants of hepatitis B virus. Viral hepatitis and liver disease. 1997;108-115.
43. Yu MW, Chang HC, Liaw YF, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. Journal of the national cancer institute,2000,92( 14): 1159-1164.
44. Hou JL, Liu ZH, Gu Fan. Epidemiology and prevention of hepatitis B virus infection. Int J Med Sci,2005,2(1):50-57.
45. Kidd-Ljunggren, K.E. Broman, H. Ekvall, and O. Gustavsson.. Nosocomial transmission of hepatitis B virus infection through multiple-dose vials. J. Hosp. Infect. 1999,43:57-62.
46. Petzold, D. R., B. Tautz, F. Wolf, and J. Drescher. Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially. J. Med. Virol. 1999,58:1-10.
47. Komatsu, H., A. Inui, Y. Morinishi, T. Sogo, and T. Fujisawa. Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother. J. Med. Virol. 2001;65:457-462.
48. Dumpis, U. E. C. Holmes, M. Mendy, A. et al.Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol. 2001,35:99-104.
49. Zampino, RS. Lobello, M. Chiaramonte, C. et al.Intra-familial transmission of hepatitis B virus in Italy: phylogenetic sequence analysis and amino-acid variation of the core gene. J. Hepatol. 2002, 36:248.
50. Petzold, D. R., B. Tautz, F. Wolf, and J. Drescher. Infection chains and evolution rates of hepatitis B virus in cardiac transplant recipients infected nosocomially. J. Med. Virol. 1999,58:1-10.
51. Akarca, U. S., S. Greene, and A. S. Lok. 1994. Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members. Hepatology 19:1366-1370.
52. Ho, M. S., C. F. Lu, J. Kuo, Y. C. Mau, and W. H. Chao. A family cluster of an immune escape variant of hepatitis B virus infecting a mother and her two fully immunized children. Clin. Diagn. Lab. Immunol. 1995, 2:760-762.
53. Dumpis, U., E. C. Holmes, M. Mendy, et al. Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J. Hepatol. 2001, 35:99-104.
54. Hunt, C. M., J. M. McGill, M. I. Allen, and L. D. Condreay. 2003. Clinical relevance of hepatitis B viral mutations. Hepatol. 2000 31:1037-1044.
55. Ozasa, A., Y. Tanaka, E. Orito, M. Sugiyama, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology, 2006, 44:326-334.
56. Weinberger, K. M., T. Bauer, S. Bohm, and W. Jilg. High genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serum. J. Gen. Virol. 2000, 81:1165-1174.
57. Hino K, Katoh Y, Vardas E,et al. Carman WF The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine,2001,19:3912-3918
58. Nakanishi H, Kurosaki M, Asahina Y, et al. Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B. Intervirology 2005,48:381— 388.
59. Huy TTT, Ushijima H, Win KM, et al.High prevalence of hepatitis B virus pre-S mutant in countries where it is endemic and its relationship with genotype and chronicity. J Clin Microbiol, 2003, 41(12):5449-5455.
60. Hino K, Katoh Y, Vardas E, et al.The effect of introduction of universal childhood hepatitis B immunization in South Africa on the prevalence of serologically negative hepatitis B virus infection and the selection of immune escape variants. Vaccine, 2001,19: 3912-3918.
61. Carman WF. The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat, 1997,4:11-20.
62. Cooreman MP, Van Roosmalen MH, Te Morsche R, et al .Characterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring'a'loop escape mutations. Hepatology, 1999,30:1287-1292.
63. Carman WF, Van Deursen FJ, Mimms LT, Hardie D, Coppola R, Decker R, Sanders R. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia. Hepatology, 1997, 26: 1658-1666.
64. Hsh,H.Y.,M.H.Chang,S.H.Liaw,et al. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan.Hepatology 1999,30:1312-7.
65. Oon, C. J., W. N. Chen, K. S. Goo, et al. Intra-familial evidence of horizontal transmission of hepatitis B virus surface antigen mutant G145R. J Infect, 2000,41:260-4.
66. Chen WN, Oon CJ Human hepatitis B virus mutants: significance of molecular changes. FEBS Lett .1999,453:237-242