白细胞介素28、P21活化激酶4基因多态性与慢性乙型肝炎病人抗病毒治疗应答的关联性分析
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摘要
全世界约1/3人口曾经或正存在乙型肝炎病毒的血清学表现，3.5-4亿乙型肝炎病毒（hepatitis B virus，HBV）携带者。乙型肝炎的疾病谱和自然史多种多样，从非活动性病毒携带状态至进行性加重不等，重者发展为肝硬化（liver cirrhosis, LC）和肝细胞癌（hepatocellular carcinoma, HCC）。在亚洲，有40%的慢性乙型肝炎病人（chronic hepatitis B, CHB）死于肝硬化或肝细胞癌。
乙型肝炎的遗传易感性和对治疗的应答体现在HBV与宿主基因组之间的长期共进化作用，这种进化是以人群中DNA分子的多态性为基础的。因此，运用遗传流行病学和分子流行病学的研究方法，确定和HBV感染后抗病毒治疗应答相关的易感基因和易感位点，对乙型肝炎个体化防治具有重要意义。
白细胞介素28（IL-28）细胞因子,又称IFN-λ,分2个亚型，IL-28A和IL-28B，在抗病毒过程中起到免疫防御作用，P21活化蛋白激酶4（PAK4）位于IL-28B基因上游64kb处，属于P21活化蛋白激酶家族，Rac和Cdc42的效应蛋白。它是肌动蛋白细胞支架、神经轴突生长、细胞存活、激素信号系统和基因转录的重要调节器，PAK4特向作用于三磷酸鸟苷（GTP）形成GTP结合蛋白Cdc42Hs并且微弱作用于MAP激酶(mitogen-activatedprotein)的c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)家族，参与丝状伪足形成的调节，在肌动蛋白细胞骨架重组中起着一定作用。前期全基因组关联研究（genome-wide association study，GWAS）在美国、澳大利亚和日本分别证实分属IFN-λ家族的细胞因子IL28B附近的基因突变与丙型肝炎病毒感染后转归和治疗应答有关。IL28及其附近的PAK4基因多态性是否与中国汉族人群乙型肝炎病毒感染后抗病毒治疗应答有关目前很有争议。
本研究拟采用分子流行病学病例对照研究设计，Hapmap数据库筛选出可能会影响HBV感染后抗病毒治疗应答的单核苷酸多态性（singlenucleotide polymorphism, SNP），基质辅助激光解吸电离飞行时间质谱（Matrix Assisted Laser Desorption/ionization Time of Flight MassSpectrometry，MALDI-TOF MS）技术对目标基因位点分型，分析基因型与慢性乙型肝炎的关系，探讨IL28、PAK4的基因多态性对中国汉族慢性乙型肝炎病人抗病毒治疗应答的影响，以期为临床个体化治疗和预后提供依据。
第一部分白细胞介素28基因多态性与慢性乙型肝炎病人拉米夫定治疗应答的关系
目的：本研究选择白细胞介素28A基因（interleukin28A，IL28A，IFN-λ2）、白细胞介素28B基因（interleukin28B，IL28B，IFN-λ3）为候选基因，选取rs8099917和rs12980602两个位点分析宿主遗传因素与慢性乙型肝炎拉米夫定治疗应答的关系。
方法：354例首次应用拉米夫定治疗的慢性乙型肝炎患者作为研究对象，以调查问卷形式收集研究对象的基线资料、发病情况、检查结果，并在拉米夫定治疗1年时对病人的HBeAg血清转换情况、HBV DNA病毒载量及ALT复常情况进行跟踪随访。完全应答定义为HBe抗原转阴、HBVDNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；部分应答定义为HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；不符合上述标准者定义为非应答。
利用CNKI和Pubmed查询免疫疾病易感基因和与治疗应答相关的文献，用Hapmap在中国汉族人群选择待研究基因的单核苷酸多态性（singlenucleotide polymorphisms，SNPs）位点，Haploview软件排除呈高度连锁不平衡（linkage disequilibrium，LD）的位点。
收集外周血，采用血液基因组DNA提取试剂盒从抗凝全血提取DNA。运用基质辅助激光解吸电离飞行时间质谱（Matrix Assisted LaserDesorption/ionization Time of Flight Mass Spectrometry，MALDI-TOF MS）的实验平台对候选基因： IL28B-rs8099917（TT、 GT、 GG），IL28A-rs12980602（TT、CT、CC）进行DNA的SNPs分型。
采用SPSS16.0进行数据处理和分析，对181例拉米夫定治疗应答组和173例非应答组计量资料两两比较用独立样本的t检验，单因素计数资料比较采用卡方检验，以非条件Logistic回归校正混杂因素并计算比值比（odds ratio，OR）和95%置信区间（95%confidence intervals，95%CI），以P<0.05为有统计学意义，统计检验均为双侧。
结果：
1位点连锁不平衡
用Haploview软件证实rs8099917和rs12980602不存在连锁不平衡，选择的2个位点等位基因频率符合Hardy-Weinberg遗传平衡定律（P>0.05），不存在连锁不平衡，说明研究样本具有群体代表性。
2应答组和非应答组患者基线特征的比较
应答组中男性、吸烟和饮酒者所占的比例均低于非应答组（61.33%vs76.30%，P=0.002；29.83%vs43.35%，P=0.008；38.67%vs52.02%，P=0.012），证明性别、吸烟、饮酒是拉米夫定治疗应答的独立影响因素，男性患者、有吸烟饮酒史的患者更不容易实现治疗应答。年龄、HBV DNA和ALT水平在两组间均无统计学差异（50.86±11.03vs52.22±10.82；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。将纤维化程度分为f0-f4，与拉米夫定的治疗应答呈显著负相关，OR值为0.716(95%CI=0.432-0.986)，P=0.036，纤维化程度越高，治疗应答率越低。
3rs8099917位点与拉米夫定治疗应答的关系
对rs8099917基因位点检测结果发现，TT为其显性基因，无论在应答组还是非应答组未发现GG基因型，单因素分析应答组突变基因型GT携带率明显高于非应答组(8.8%vs2.3%)，OR值为4.097（95%CI=1.342-12.512, P=0.015）。在多因素分析中，当校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT基线水平后，IL-28B rs8099917位点的突变基因型GT仍显示与拉米夫定治疗的高应答有关，OR值为4.025(95%CI=1.316-12.354)，P=0.013。携带rs8099917GT基因型者可能预示着拉米夫定治疗的成功。
4rs12980602位点与拉米夫定治疗应答的关系
对rs12980602基因位点检测的结果与rs8099917相似，TT也是其显性基因。单因素分析应答组突变基因型CT和CC携带率明显高于非应答组（18.8%vs9.2%），OR值为2.27（95%CI=1.202-4.284）；P=0.014）。但在多因素分析中，当校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT基线水平后，IL-28B rs12980602位点的突变基因型CT和CC显示与拉米夫定治疗应答无相关性，OR值为1.765(95%CI=0.884-3.617, P=0.109)。
结论：
1用Haploview软件证实rs8099917位点和rs12980602位点不存在连锁不平衡，说明研究样本具有群体代表性。
2性别、吸烟、饮酒是拉米夫定治疗应答的独立影响因素，男性患者、
有吸烟饮酒史的患者不容易实现治疗应答。
3白细胞介素28基因的rs8099917和rs12980602两个位点基因多态性与HBeAg阳性慢性乙型肝炎病人拉米夫定治疗应答有关联，携带rs8099917位点突变基因型GT，rs12980602位点突变基因型CT和CC者可能预示着拉米夫定治疗的成功，尤其以rs8099917位点突变基因型GT为生物学标志。
4肝纤维化早期预示着对拉米夫定治疗的高应答。
第二部分白细胞介素28、P21活化激酶4基因多态性与慢性乙型肝炎病人聚乙二醇干扰素治疗应答的关系
目的：聚乙二醇干扰素治疗费用昂贵且治疗有一定的副作用，所以高应答率病人的选择对临床合理用药来说非常必要。本研究选择IL28A（IFN-λ2）、IL28B（IFN-λ3）、丝氨酸/苏氨酸蛋白激酶4基因（p21_activatedkinases4，PAK4）为候选基因，选取rs8099917、 rs12980602和rs9676717三个位点分析宿主遗传因素与慢性乙型肝炎聚乙二醇干扰素治疗应答的关系。
方法：240例首次应用聚乙二醇干扰素治疗的慢性乙型肝炎患者作为研究对象，以调查问卷形式收集研究对象的基线资料、发病情况、检查结果，并在聚乙二醇干扰素治疗6月时对病人的HBeAg血清转换情况、HBVDNA病毒载量及ALT复常情况进行跟踪随访。完全应答定义为HBe抗原转阴、HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；部分应答定义为HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；不符合上述标准者定义为非应答。
利用CNKI和Pubmed查询免疫疾病易感基因和与治疗应答相关的文献，用Hapmap在中国汉族人群选择待研究基因的单核苷酸多态性（singlenucleotide polymorphisms，SNPs）位点，Haploview软件排除呈高度连锁不平衡（linkage disequilibrium，LD）的位点。
收集外周血，采用血液基因组DNA提取试剂盒从抗凝全血提取DNA。运用基质辅助激光解吸电离飞行时间质谱（Matrix Assisted LaserDesorption/ionization Time of Flight Mass Spectrometry，MALDI-TOF MS）的实验平台对候选基因： IL28B-rs8099917（TT、 GT、 GG），IL28A-rs12980602（TT、CT、CC），PAK4-rs9676717（TT、 CT、CC）进行DNA的SNPs分型。
采用SPSS16.0进行数据处理和分析，比较92例聚乙二醇干扰素治疗应答组和148例非应答组计量资料两两比较用独立样本的t检验，单因素计数资料比较采用卡方检验，以非条件Logistic回归校正混杂因素并计算比值比（odds ratio，OR）和95%置信区间（95%confidence intervals，95%CI），以P<0.05为有统计学意义，统计检验均为双侧。
结果：
1位点连锁不平衡
用Haploview软件证实rs8099917、 rs12980602和rs9676717不存在连锁不平衡，选择的3个位点等位基因频率符合Hardy-Weinberg遗传平衡定律（P>0.05），不存在连锁不平衡，说明研究样本具有群体代表性。
2应答组和非应答组患者基线特征的比较
应答组饮酒者占36.96%，明显低于非应答组的50%（P=0.048），饮酒是聚乙二醇干扰素治疗应答的独立影响因素，有饮酒史的患者不容易实现治疗应答。年龄、男性所占比例、吸烟者所占比例、HBV DNA和ALT基线水平在两组间均无统计学差异（38.07±14.62vs37.3±12.67；67.39%vs66.22%；41.30%vs51.35%；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。
3rs8099917位点与聚乙二醇干扰素治疗应答的关系
对rs8099917基因位点检测结果表明，TT为其显性基因，应答组无GG基因型，应答组和非应答组TT、 GT和GG基因型的携带率无统计学差异(89.13%,10.87%,0.00%vs87.84%,9.46%,2.70%，P=0.838)。rs8099917位点与聚乙二醇干扰素治疗后6月的应答关联性分析结果表明，两者间没有明显的关联性，单因素分析OR值为0.881(95%CI=0.388-2.002)，P=0.838；多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，OR值为0.881(95%CI=0.388-2.002)，P=0.999。
4rs12980602位点与与聚乙二醇干扰素治疗应答的关系
对rs12980602位点检测的结果与rs8099917位点相似，TT也是其显性基因，应答组和非应答组TT、 CT和CC基因型的携带率无统计学差异(82.61%,15.22%,2.17%vs81.08%,18.92%,0.00%，P=0.186)。rs12980602位点与聚乙二醇干扰素治疗后6月的应答关联性分析结果表明，两者间没有明显的关联性，单因素分析OR值为0.902（95%CI=0.458-1.778），P=0.766；多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，OR值为0.688(95%CI=0.311-1.523)，P=0.356。
5rs9676717位点与与聚乙二醇干扰素治疗应答的关系
对rs9676717位点检测结果表明，应答组与非应答组TT、 CT和CC基因型的携带率有显著统计学差异（56.52%，32.61%，10.87%vs40.54%，52.70%，6.76%，P=0.009）。单因素分析rs9676717位点携带突变基因型CT+CC与干扰素治疗后的应答有显著的负相关性，OR值为0.524(95%CI=0.310-0.888)，P=0.016。当多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，PAK4基因的rs9676717位点的突变基因型CT+CC仍显示与干扰素治疗应答呈负相关， OR值为0.173(95%CI=0.037-0.799)；P=0.025。
结论：
1饮酒是聚乙二醇干扰素治疗应答的独立影响因素，有饮酒史的慢性乙型肝炎患者不容易实现治疗应答。
2位于IL-28的rs8099917和rs12980602位点与慢性乙型肝炎病人聚乙二醇干扰素治疗的应答率无关，而携带PAK4的突变基因型CT+CC降低干扰素治疗6月患者的应答。
第三部分IL-28B基因型与乙型肝炎病毒感染后病毒自发清除及干扰素治疗应答关系的Meta分析
目的：采用Meta分析的方法，对国内外在不同人群不同类别乙型肝炎患者中开展的研究结果进行综合评价，评价IL-28B基因rs12979860位点及rs8099917位点与HBV感染后病毒自发清除及治疗应答的相关性。方法：利用关键词“IL-28B、SNP、hepatitis B、spontaneous clearance、treatment and interferon"联合检索PUBMED、 MEDLINE、 EMBASE、Cochrane library数据库、中国万方数据库、中文科技期刊全文数据库、中国生物医学文献数据库、中国学术期刊全文数据库的中英文文献。末次检索日期是2013年3月25日。共检索到32篇文献。由两位研究人员对检索到的所有文献题目和摘要进行评估筛选，最后选出5篇关于rs12979860位点与HBV感染后自发清除的相关文献、7篇关于rs12979860位点与HBV感染后干扰素治疗应答的文献、3篇关于rs8099917位点与HBV感染后自发清除的相关文献、3篇关于rs8099917位点与HBV感染后干扰素治疗应答的文献。纳入Meta分析提取纳入文献的信息如下：第一作者、出版年、研究设计类型、受试者来自的国家和种族、乙型肝炎诊断类型、病例组和对照组的定义和数量、提取DNA和分型的方法、病毒亚型、治疗方法等。文献未提供基因型的，利用相应的基因频率计算，分别提取rs12979860位点及rs8099917位点的相关数据，对两个位点的显性模型进行了Meta分析。计算优势比（OR）及其95%CI作为效应量。首先对纳入分析的原始文献进行Q检验，分析异质性，根据异质性检验结果，选择固定效应模型或随机效应模型求其效应合并值。用漏斗图和Begg’s检验进行发表偏倚分析，以P<0.05为差异有统计学意义。所有数据用STATA11.1分析。
结果：
1rs12979860位点与乙型肝炎病毒感染后病毒自发清除的关系
共有5篇符合分析条件的关于rs12979860位点与HBV感染后自发清除的相关文献。Meta分析的异质性检验显示：各研究间不存在异质性(I2=20.0%，P=0.287)。根据异质性检验结果选择M-H固定效应模型对rs12979860位点显性模型（TC+CC vs CC）进行数据合并，结果显示，合并后的OR为1.05(95％CI：0.83-1.32，P=0.70)，证明rs12979860位点与乙型肝炎病毒感染后病毒自发清除没有关联。Begg’s偏倚分析显示无明显发表偏倚，P>0.1。
2rs12979860位点与乙型肝炎病毒感染后治疗应答的关系
有7篇符合分析条件的关于rs12979860位点与乙型肝炎病毒感染后治疗应答关系的相关文献。Meta分析的异质性检验显示：合并后的OR为1.57(95％CI：1.06-2.33，P=0.024)但各研究间存在异质性(I2=61.6%，P=0.016)。根据异质性检验结果对数据进行分层分析，按照乙型肝炎病人诊断类别分HBeAg阳性组和HBeAg阴性组进行分析。HBeAg阳性组的4篇文献仍然存在异质性(I2=77.7%，P=0.004)，采用随机效应模型分析结果如下：rs12979860位点显性模型（TC+TT vs CC）合并后的OR为0.717(95％CI：0.190-2.701，P=0.623)，证明rs12979860位点与HBeAg阳性慢性乙型肝炎病毒感染后干扰素治疗应答没有关联。HBeAg阴性组3篇文献采用固定效应模型分析结果如下：各研究间不存在异质性(I2=0.0%，P=0.710)。根据异质性检验结果对rs12979860位点显性模型（TC+TT vs CC）选择M-H固定效应模型进行数据合并，结果显示，合并后的OR为2.132(95％CI：1.15-3.95，P=0.016)，rs12979860位点与乙型肝炎病毒感染后治疗应答呈正相关，突变基因型TC+TT显著提高HBeAg阴性慢性乙型肝炎患者对干扰素治疗的应答率。无发表偏倚。
3rs8099917位点与乙型肝炎病毒感染后病毒自发清除的关系
共有3篇符合分析条件的关于rs8099917位点与HBV感染后自发清除的相关文献。Meta分析的异质性检验显示：各研究间不存在异质性(I2=0.0%，P=0.705)。根据异质性检验结果对rs8099917位点显性模型(GG+GTvs TT)选择M-H固定效应模型进行数据合并，结果显示，合并后的OR为1.084(95％CI：0.72-1.623，P=0.696)，证明rs8099917位点与乙型肝炎病毒感染后病毒自发清除没有关联。无发表偏倚。
4rs8099917位点与乙型肝炎病毒感染后治疗应答的关系
有3篇符合分析条件的关于rs8099917位点与乙型肝炎病毒感染后治疗应答关系的相关文献。对rs8099917位点显性模型(GG+GT vs TT) Meta分析的异质性检验显示：合并后的OR为0.400(95％CI：0.24-0.66，P=0.000)，证明rs8099917位点与乙型肝炎病毒感染后治疗应答呈负相关，突变基因型GG+GT显著降低慢性乙型肝炎患者对干扰素治疗的应答率。各研究间不存在异质性(I2=36.8%，P=0.206)，无发表偏倚。
结论：
1通过Meta分析证实，IL28B rs12979860位点基因型与乙型肝炎病毒感染后病毒自发清除以及HBeAg阳性慢性乙型肝炎病人干扰素治疗应答无关，与HBeAg阴性慢性乙型肝炎病人干扰素治疗应答存在一定的相关性。IL28B rs12979860位点基因型与乙型肝炎病毒感染后病毒自发清除以及HBeAg阳性慢性乙型肝炎病人干扰素治疗应答无关，与HBeAg阴性慢乙肝病人干扰素治疗应答呈正相关，以野生型等位基因C为参照，突变基因型TC+TT显著提高HBeAg阴性慢性乙型肝炎患者对干扰素治疗的应答率。
2通过Meta分析证实，IL28B rs8099917位点基因型与乙型肝炎病毒感染后病毒自发清除无关，与乙型肝炎病毒感染后治疗应答呈负相关，突变基因型GG+GT显著降低慢性乙型肝炎患者对干扰素治疗的应答率。
Approximately one third of the world population has serological evidenceof past or present infection with hepatitis B virus (HBV) and350-400millionpeople are chronic HBV surface antigen (HBsAg) carriers. The spectrum ofdisease and natural history of chronic HBV infection are diverse and variable,ranging from an inactive carrier state to progressive chronic hepatitis B (CHB),which may evolve to cirrhosis and hepatocellular carcinoma (HCC). In Asia,40%of the patients with CHB die of either complications of cirrhosis or HCC.
Persistent HBV infection and its treatment response are influenced by acomplex combination of genetic, environmental, viral components. GeneticEpidemiology supports the role of host genetic components in determining theinfection and its outcomes and treatment response of HBV.
Interleukin-28(IL-28), also known as IFN-, is a cytokine that comes intwo isoforms, IL-28A and IL-28B, and plays a role in immune defense againstviruses. P21-activated protein kinase4(PAK4), is located upstream64kb ofIL28B. It belongs to p21-activated kinases (PAKs) family of effector proteinsfor Rac and Cdc42. PAKs are important regulators of actin cytoskeletaldynamics, neurite outgrowth, cell survival, hormone signaling and genetranscription. PAK4interacts specifically with the GTP-bound form ofCdc42Hs and weakly activates the JNK family of mitogen-activated proteinkinases (MAPKs). It is a mediator of filopodia formation and may play a rolein the reorganization of the actin cytoskeleton.
In2009, three GWAS studies mainly reported some loci near IL28B genewere strongly associated with outcome and sustained virological responses inCHC patients. The three studies were carried out in American, Australian, andJapanese populations.Wether IL28and PAK4gene polymorphism are associated with CHB patients. It is not clear. We choose the tap SNPs byhapmap database and MALDI-TOF MS technic.Then we analyzed the impactof candidate genes single nucleotide polymorphisms (SNPs) includinginterleukin28A(IL28A), interleukin28B (IL28B), p21_activated kinases4(PAK4) on the infection outcomes and treatment response of HBV. Wehope that it can support clinical treatment and prognosis.
Part One Association between gene polymorphisms of IL-28andresponse to lamivudine in patients with chronic hepatitis B
Objective：To assess the association between gene polymorphisms(single nucleotide polymorphisms, SNPs) of rs8099917and rs12980602inthe IL-28A（interleukin28A，IL28A，IFN-λ2）, IL28B gene (interleukin28B，IL28B，IFN-λ3）and the response to lamivudine treatment in na ve of chronichepatitis B patients.
Methods: Three hundred and fifty-four na ve chronic hepatitis B (CHB)patients treated with lamivudine were enrolled in this study. we collected thebaseline, illness situation, checkup results of all the subjects by questionnaire.Biochemical information--seroconversion, serum HBV DNA load and ALTlevels from all subjects were collected when they came to subsequent visits at1year of lamivudine therapy.
In this study, responses were classified as MR, partial response(PR), ornon-response (NR) according to Asian-Pacific and Chinese consensusstatements. An CR included identified seroconversion, serum HBV DNAcan’t be detected or decreased2log10, and normalization of serum ALT levels.A PR included identified serum HBVDNA can’t be detected or decreased2log10,, and normal serum ALT levels. Patients who did not satisfy all of theabove-mentioned criteria were categorized as NR.
Searching candidate genes about autoimmune diseases by CNKI andPubmed. Selecting tagSNPs of candidate genes in Han Chinese by Hapmap.Removing SNPs of linkage disequilibrum (LD) by Haploview.
Genomic DNA was isolated from peripheral venous blood using aWizard Genomic DNA Puri fi cation Kit (Promega Inc., Fitchburg, WI, USA)according to the manufacturer’s instructions. Matrix-assisted laserdesorption/ionization time of flight mass spectrometry single nucleotidepolymorphism (SNP) genotyping assays were used for the detection of thereference SNPs IL-28gene on chromosome19, i.e., IL28B-rs8099917（TT、GT、GG）and IL28A-rs12980602（TT、CT、CC）. We used Haploview softwareto confirm linkage disequilibrium.
Rs8099917and rs12980602SNPs were genotyped using matrix-assistedlaser desorption/ionization time of flight mass spectrometry. SPSS version16.0software was used to analyze baseline characteristics and genotypesbetween181patients with treatment response and173without response.Group comparisons were performed using the Student’s t test, Mann-WhitneyU test,2test, or Fisher’s exact test, as appropriate. Binary logisticregression modeling was used to identify independent factors associated withlamivudine responses at the end of treatment.
Results:
1rs8099917and rs12980602were not in linkage disequilibrium.
2Compatation of baseline characteristics of response and non-responsegroup
The ratio of males, smoking and drinking in response group weresignificantly lower than that in non-responder group（61.33%vs76.30%，P=0.002；29.83%vs43.35%，P=0.008；38.67%vs52.02%，P=0.012）.Gender,smoking and drinking are independed influence factors of Lamivudinetreatment response. HBV DNA and ALT baseline level were not associatedwith response（50.86±11.03vs52.22±10.82；7.67log copies/ml vs7.69logcopies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。Fibrosis was negativecorrelation with Lamivudine treatment response. The early fibrosis stage wassignificantly associated with a higher probability of response to lamivudinetreatment (OR=0.716,95%CI=0.432-0.986; p=0.036).
3The relationship between rs8099917and Lamivudine treatment response For rs8099917, TT was the dominant genotype. There was no GG genotype atrs8099917in both the responder and non-responder groups. There was asignificant higher rate of mutation genotyoe GT in response group than that innon-response group (8.8%vs2.3%)，OR was4.097（95%CI=1.342-12.512,P=0.015）when genotypes were compared by univariate analysis. whenadjusting for baseline age, gender, smoking, drinking, and levels of HBVDNA, ALT, and HBV genotype, IL-28B genotype GT (for rs8099917)appeared to be associated with a higher probability of responding tolamivudine treatment (OR=4.025,95%CI,1.316-12.354; p=0.013). TheGT genotype may as a potential treatment mark for Chinese hepatitis Bpatients with lamivudine therapy.
4The relationship between rs12980602and Lamivudine treatment response
For rs12980602, TT was the dominant genotype as well, which wassimilar to rs8099917. Only4of181(2.2%) patients had the CC genotype atrs12980602in the responder group, and none of the173patients in thenon-responder group had the CC genotype. By univariate analysis, the rate ofgenotype CT and CC in response group was higher that in non-response group（18.8%vs9.2%），OR=2.27（95%CI=1.202-4.284）; P=0.014).
When adjusting for baseline age, gender, smoking, drinking, and levels ofHBV DNA, ALT, and HBV genotype, the relationship between rs12980602ofIL-28A and responding to treatment was not significant (OR=1.765,95%CI=0.884-3.617, p=0.109).
Conclusion:
1We used Haploview software to confirm that rs8099917andrs12980602were not in linkage disequilibrium. It is showed that the samplepopulation was good for representation.
2Gender, smoking and drinking were independent influencing factors.Male patients, the patients having history of smoking and drinking had lowresponse to Lamivudine therapy.
3Rs8099917and rs12980602of IL-28gene may associate with HBVtreatment response. The genotype GT for rs8099917may be predictive of treatment success.
5Early fibrosis stage may be predictive of treatment success.
Part Two Gene polymorphisms of interleukin-28, p21-activated proteinkinases4, and response to interferon-a based therapy in patients withchronic hepatitis B
Objective：Peg-Interferon-a treatment is expensive and associated withconsiderable adverse effects, selection of patients with the highest probabilityof response is essential for clinical practice. The objective of this study was toassess the relationship between the gene polymorphisms of interleukin-28(IL28), p21-activated protein kinase4(PAK4) and the response to interferontreatment in chronic hepatitis B patients.
Methods: Two hundred and forty interferon-naive treatmentseropositive chronic hepatitis B patients were enrolled in the presentprospective nested case-control study. We collected the baseline, illnesssituation, checkup results of all the subjects by questionnaire. Biochemicalinformation (seroconversion, serum HBV DNA load and ALT levels) fromall subjects were collected when they came to subsequent visits at6monthsof interferon treatment.
In this study, responses were classified as completely response (CR),partial response (PR), or non-response (NR) according to Asian-Pacific andChinese consensus statements. A CR included identified seroconversion,serum HBV DNA can’t be detected or decreased2log10, and normalization ofserum ALT levels. A PR included identified serum HBVDNA can’t bedetected or decreased2log10, and normal serum ALT levels. Patients who didnot satisfy all of the above-mentioned criteria were categorized as NR.
Searching candidate genes about autoimmune diseases by CNKI and Pubmed. Selecting tagSNPs of candidate genes in Han Chinese by Hapmap.Removing SNPs of linkage disequilibrum (LD) by Haploview.
Genomic DNA was isolated from peripheral venous blood using aWizard Genomic DNA Puri fi cation Kit (Promega Inc., Fitchburg, WI, USA)according to the manufacturer’s instructions. Matrix-assisted laserdesorption/ionization time of flight mass spectrometry single nucleotidepolymorphism (SNP) genotyping assays were used for the detection of thereference SNPs IL-28gene on chromosome19, i.e., IL28B-rs8099917（TT、GT、GG）, IL28A-rs12980602（TT、CT、CC）and PAK4-rs9676717（TT、CT、CC）.
Peripheral blood samples were collected, including92with favorableresponse and148without response to the interferon treatment. Rs8099917,rs12980602, and rs9676717SNP was genotyped using matrix assisted laserdesorption/ionization time of flight mass spectrometry (MALDI-TOF MS).
SPSS version16.0software was used to analyze baseline characteristicsand genotypes between92patients with treatment response and148withoutresponse. Group comparisons were performed using the Student’s t test,Mann-Whitney U test,2test, or Fisher’s exact test, as appropriate.Binarylogistic regression modeling was used to identify independent factorsassociated with interferon responses at the end of treatment.
Results:
1rs8099917, rs12980602and rs9676717were not in linkagedisequilibrium.
2Compatation of baseline characteristics of response and non-responsegroup
The ratio of drinking in response group were significantly lower thanthat in non-responder group（36.96%vs50%, P=0.048）. Drinking isindepended influence factor of interferon treatment response. Age, gender,smoking, HBV DNA and ALT baseline level were not associated withresponse（38.07±14.62vs37.3±12.67；67.39%vs66.22%；41.30%vs51.35%；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50 IU/L；P＞0.05）。
3The relationship between rs8099917and interferon treatment response
Regarding genotype at rs8099917, TT was the dominant genotype, no GGgenotype at rs8099917in responder group. There was no significant differencewhen the genotypes between the responder and non-responder group (82.61%,15.22%,2.17%vs81.08%,18.92%,0.00%，P=0.186) by univariate analysis.By multivariate analysis when adjusting for baseline age, gender, smoking,drinking, levels of HBV DNA, and ALT, the relationship between rs8099917and response was not significant (P=0.999).
4The relationship between rs12980602and interferon treatment response
Regarding genotype at rs12980602, TT was the dominant genotype too,similar to rs8099917. Only two of the92(2.17%) patients had CC genotype inthe responder group, and none of148in the non-responder group. Byunivariate analysis there was no significant difference (OR=0.902,95%CI=0.458-1.778, P=0.766). By univariate analysis, the rate of genotype CT andCC in response group was higher that in non-response group(OR=0.688,95%CI=0.311-1.523，P=0.356).
5The relationship between rs9676717and interferon treatment response
Regarding genotype at rs9676717, Only10of92or148(10.87%or6.76%) patients had CC genotype both in the responder and non-respondergroups. By univariate analysis, there was significant difference （56.52%，32.61%，10.87%vs40.54%，52.70%，6.76%，P=0.009）. By univariateanalysis, the rate of genotype CT and CC in response group was lower that innon-response group (OR=0.524,95%CI=0.310-0.888, P=0.016). Whenadjusting for baseline age, gender, smoking, drinking, and levels of HBVDNA, ALT, and HBV genotype, the relationship between rs9676717of PAK4and responding to treatment was negative corelation (OR=0.173,95%CI=0.037-0.799, P=0.025).
Conclusion:
1polymorphisms of rs8099917and rs12980602in IL-28were notassociated with the response of IFN-α treatment in positive chronic hepatitis B. Patients with favorable PAK4genotypes TT have an increased probabilityof achieving response to IFN-at the end of6months treatment.
2Drinking may influence the response of IFN-treatment in CHB.
Part Three A Meta-analysis on the association between IL-28B genotypeand spontaneous HBV clearance or interferon treatment response
Objective: To investigate the association of SNP-rs12979860,rs8099917and Spontaneous HBV clearance and interferon treatment responseamong different groups and defferent types of chronic hepatitis B byMeta-analysis.
Methods: Relevant studies were identified by a literature search ofPUBMED、MEDLINE、EMBASE、Cochrane library and WanFang databasewithout imposing study-period restrictions, using the following terms:‘hepatitis B’,‘IL28B’,‘SNP’,‘spontaneous clearance’,‘treatment’, and‘interferon’. The information contained in this report is based on articlespublished before25March2013in any language. Totally32papers wereobtained upon repeated papers excluded. Two investigators independentlyassessed the selected papers and extracted all data. At the end there are5articles about rs12979860and Spontaneous HBV clearance,7articles aboutrs12979860and interferon treatment response,3articles about rs8099917andSpontaneous HBV clearance,3articles about rs8099917and interferontreatment response.
From each study, the following information was abstracted: the firstauthor, year of publication, research design, ethnic background andgeographical distribution of participants, type of chronic hepatitis B, definitionand numbers of case group and control group, method of DNA extraction andgenotype, HBV subgroup, treatment method and so on. In this article, meta-analysis was performed on dominant and genotype models ofrs12979860and rs8099917gene locus. The pooled odd ratio (OR) with95%confidence interval (CI) was calculated to evaluate the association of twolocus with HBV infection. At first, Q-test was conducted to analyze raw dataof literature included for heterogeneity test. Subsequently, depending onheterogeneity result fixed-effects model or random-effects model will beperformed for the calculation of pooled OR with95%CI. Then funnel plot andBegg’s test were used for assessment of publication bias and P<0.05suggesteda statistical significance. All P-values were two sided. All analysis mentionedabove was fulfilled by STATA version11.1.
Results：
1Assciation between rs12979860and Spontaneous HBV clearance
There were5eligible studies reporting data on12979860andspontaneous HBV clearance. All data were pooled by Fixed effect model andshowed total OR of rs12979860dominate model (TC+CC vs CC）for overalldata was1.05(95%CI:3.18-4.69, P=0.70) and the overall heterogeneitywas not significant (I2=20.0%，P=0.287). There was no association betweenrs12979860and Spontaneous HBV clearance. Begg’s test results showed thatthere was no statistical significance in publication bias (P>0.1).
2Assciation between rs12979860and interferon treatment response
There were7eligible studies reporting data on12979860and interferontreatment response. All data were pooled by Fixed effect model and showedtotal OR of rs12979860dominate model (TC+CC vs CC）for overall data was1.57(95%CI:1.06-2.33，P=0．024) and the overall heterogeneity wassignificant ((I2=61.6%，P=0.016).
After stratified from-positive and-negative patients, regards ofrs12979860and interferon treatment response for-positive patients, all datawere pooled by Randoom effect model and showed total OR=0.717(95％CI：0.190-2.701，P=0.623), There was no association between rs12979860andinterferon treatment response with-positive HBV patients；rs12979860andinterferon treatment response for-negative patients, all data were pooled by Fixed effect model and showed total OR=2.132(95％CI：1.15-3.95，P=0.016), There was positive correlation between rs12979860and interferontreatment response with-negative HBV patients. The mutation genotypeTC+TT signigicantly promote interferon treatment response with-negativeHBV patients. Begg’s test results showed that there was no statisticalsignificance in publication bias (P>0.1).
3Assciation between rs8099917and Spontaneous HBV clearance
There were3eligible studies reporting data on rs8099917andspontaneous HBV clearance. All data were pooled by Fixed effect model andshowed total OR of rs8099917dominate model (GG+GT vs TT）for overalldata was1.084(95％CI：0.72-1.623，P=0.696), There was no associationbetween rs8099917and Spontaneous HBV clearance. And the overallheterogeneity was not significant (I2=0.0%，P=0.705). Begg’s test resultsshowed that there was no statistical significance in publication bias.
4Assciation between rs8099917and interferon treatment response
There were3eligible studies reporting data on rs8099917and interferontreatment response. All data were pooled by Fixed effect model and showedtotal OR of rs8099917dominate model (GG+GT vs TT）for overall data was0.400(95％CI：0.24-0.66，P=0.000), There was negative correlationbetween rs8099917and interferon treatment response with HBV patients. Themutation genotype GG+GT signigicantly cut down interferon treatmentresponse with HBV patients. And the overall heterogeneity was not significant((I2=36.8%，P=0.206).
Conclusion：
1IL-28B rs12979860is not associated with spontaneous HBV clearanceor interferon treatment response for-positive patients. While associated withinterferon treatment response for-negative patients. Patients with T allele ofIL28B rs12979860have a high probility of interferon treatment success. Indominant genotype model showed that the mutation genotype TC+TTsignigicantly promote interferon treatment response with-negative HBVpatients.
2IL28B rs8099917is not associated with spontaneous HBV clearance. Itis associated with interferon treatment response for-positive patients. Themutation genotype GG+GT signigicantly cut down interferon treatmentresponse with HBV patients.
乙型肝炎的遗传易感性和对治疗的应答体现在HBV与宿主基因组之间的长期共进化作用，这种进化是以人群中DNA分子的多态性为基础的。因此，运用遗传流行病学和分子流行病学的研究方法，确定和HBV感染后抗病毒治疗应答相关的易感基因和易感位点，对乙型肝炎个体化防治具有重要意义。
白细胞介素28（IL-28）细胞因子,又称IFN-λ,分2个亚型，IL-28A和IL-28B，在抗病毒过程中起到免疫防御作用，P21活化蛋白激酶4（PAK4）位于IL-28B基因上游64kb处，属于P21活化蛋白激酶家族，Rac和Cdc42的效应蛋白。它是肌动蛋白细胞支架、神经轴突生长、细胞存活、激素信号系统和基因转录的重要调节器，PAK4特向作用于三磷酸鸟苷（GTP）形成GTP结合蛋白Cdc42Hs并且微弱作用于MAP激酶(mitogen-activatedprotein)的c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)家族，参与丝状伪足形成的调节，在肌动蛋白细胞骨架重组中起着一定作用。前期全基因组关联研究（genome-wide association study，GWAS）在美国、澳大利亚和日本分别证实分属IFN-λ家族的细胞因子IL28B附近的基因突变与丙型肝炎病毒感染后转归和治疗应答有关。IL28及其附近的PAK4基因多态性是否与中国汉族人群乙型肝炎病毒感染后抗病毒治疗应答有关目前很有争议。
本研究拟采用分子流行病学病例对照研究设计，Hapmap数据库筛选出可能会影响HBV感染后抗病毒治疗应答的单核苷酸多态性（singlenucleotide polymorphism, SNP），基质辅助激光解吸电离飞行时间质谱（Matrix Assisted Laser Desorption/ionization Time of Flight MassSpectrometry，MALDI-TOF MS）技术对目标基因位点分型，分析基因型与慢性乙型肝炎的关系，探讨IL28、PAK4的基因多态性对中国汉族慢性乙型肝炎病人抗病毒治疗应答的影响，以期为临床个体化治疗和预后提供依据。
第一部分白细胞介素28基因多态性与慢性乙型肝炎病人拉米夫定治疗应答的关系
目的：本研究选择白细胞介素28A基因（interleukin28A，IL28A，IFN-λ2）、白细胞介素28B基因（interleukin28B，IL28B，IFN-λ3）为候选基因，选取rs8099917和rs12980602两个位点分析宿主遗传因素与慢性乙型肝炎拉米夫定治疗应答的关系。
方法：354例首次应用拉米夫定治疗的慢性乙型肝炎患者作为研究对象，以调查问卷形式收集研究对象的基线资料、发病情况、检查结果，并在拉米夫定治疗1年时对病人的HBeAg血清转换情况、HBV DNA病毒载量及ALT复常情况进行跟踪随访。完全应答定义为HBe抗原转阴、HBVDNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；部分应答定义为HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；不符合上述标准者定义为非应答。
利用CNKI和Pubmed查询免疫疾病易感基因和与治疗应答相关的文献，用Hapmap在中国汉族人群选择待研究基因的单核苷酸多态性（singlenucleotide polymorphisms，SNPs）位点，Haploview软件排除呈高度连锁不平衡（linkage disequilibrium，LD）的位点。
收集外周血，采用血液基因组DNA提取试剂盒从抗凝全血提取DNA。运用基质辅助激光解吸电离飞行时间质谱（Matrix Assisted LaserDesorption/ionization Time of Flight Mass Spectrometry，MALDI-TOF MS）的实验平台对候选基因： IL28B-rs8099917（TT、 GT、 GG），IL28A-rs12980602（TT、CT、CC）进行DNA的SNPs分型。
采用SPSS16.0进行数据处理和分析，对181例拉米夫定治疗应答组和173例非应答组计量资料两两比较用独立样本的t检验，单因素计数资料比较采用卡方检验，以非条件Logistic回归校正混杂因素并计算比值比（odds ratio，OR）和95%置信区间（95%confidence intervals，95%CI），以P<0.05为有统计学意义，统计检验均为双侧。
结果：
1位点连锁不平衡
用Haploview软件证实rs8099917和rs12980602不存在连锁不平衡，选择的2个位点等位基因频率符合Hardy-Weinberg遗传平衡定律（P>0.05），不存在连锁不平衡，说明研究样本具有群体代表性。
2应答组和非应答组患者基线特征的比较
应答组中男性、吸烟和饮酒者所占的比例均低于非应答组（61.33%vs76.30%，P=0.002；29.83%vs43.35%，P=0.008；38.67%vs52.02%，P=0.012），证明性别、吸烟、饮酒是拉米夫定治疗应答的独立影响因素，男性患者、有吸烟饮酒史的患者更不容易实现治疗应答。年龄、HBV DNA和ALT水平在两组间均无统计学差异（50.86±11.03vs52.22±10.82；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。将纤维化程度分为f0-f4，与拉米夫定的治疗应答呈显著负相关，OR值为0.716(95%CI=0.432-0.986)，P=0.036，纤维化程度越高，治疗应答率越低。
3rs8099917位点与拉米夫定治疗应答的关系
对rs8099917基因位点检测结果发现，TT为其显性基因，无论在应答组还是非应答组未发现GG基因型，单因素分析应答组突变基因型GT携带率明显高于非应答组(8.8%vs2.3%)，OR值为4.097（95%CI=1.342-12.512, P=0.015）。在多因素分析中，当校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT基线水平后，IL-28B rs8099917位点的突变基因型GT仍显示与拉米夫定治疗的高应答有关，OR值为4.025(95%CI=1.316-12.354)，P=0.013。携带rs8099917GT基因型者可能预示着拉米夫定治疗的成功。
4rs12980602位点与拉米夫定治疗应答的关系
对rs12980602基因位点检测的结果与rs8099917相似，TT也是其显性基因。单因素分析应答组突变基因型CT和CC携带率明显高于非应答组（18.8%vs9.2%），OR值为2.27（95%CI=1.202-4.284）；P=0.014）。但在多因素分析中，当校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT基线水平后，IL-28B rs12980602位点的突变基因型CT和CC显示与拉米夫定治疗应答无相关性，OR值为1.765(95%CI=0.884-3.617, P=0.109)。
结论：
1用Haploview软件证实rs8099917位点和rs12980602位点不存在连锁不平衡，说明研究样本具有群体代表性。
2性别、吸烟、饮酒是拉米夫定治疗应答的独立影响因素，男性患者、
有吸烟饮酒史的患者不容易实现治疗应答。
3白细胞介素28基因的rs8099917和rs12980602两个位点基因多态性与HBeAg阳性慢性乙型肝炎病人拉米夫定治疗应答有关联，携带rs8099917位点突变基因型GT，rs12980602位点突变基因型CT和CC者可能预示着拉米夫定治疗的成功，尤其以rs8099917位点突变基因型GT为生物学标志。
4肝纤维化早期预示着对拉米夫定治疗的高应答。
第二部分白细胞介素28、P21活化激酶4基因多态性与慢性乙型肝炎病人聚乙二醇干扰素治疗应答的关系
目的：聚乙二醇干扰素治疗费用昂贵且治疗有一定的副作用，所以高应答率病人的选择对临床合理用药来说非常必要。本研究选择IL28A（IFN-λ2）、IL28B（IFN-λ3）、丝氨酸/苏氨酸蛋白激酶4基因（p21_activatedkinases4，PAK4）为候选基因，选取rs8099917、 rs12980602和rs9676717三个位点分析宿主遗传因素与慢性乙型肝炎聚乙二醇干扰素治疗应答的关系。
方法：240例首次应用聚乙二醇干扰素治疗的慢性乙型肝炎患者作为研究对象，以调查问卷形式收集研究对象的基线资料、发病情况、检查结果，并在聚乙二醇干扰素治疗6月时对病人的HBeAg血清转换情况、HBVDNA病毒载量及ALT复常情况进行跟踪随访。完全应答定义为HBe抗原转阴、HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；部分应答定义为HBV DNA检测不到或低于检测下限，或较基线下降≥2log10、ALT水平下降至正常；不符合上述标准者定义为非应答。
利用CNKI和Pubmed查询免疫疾病易感基因和与治疗应答相关的文献，用Hapmap在中国汉族人群选择待研究基因的单核苷酸多态性（singlenucleotide polymorphisms，SNPs）位点，Haploview软件排除呈高度连锁不平衡（linkage disequilibrium，LD）的位点。
收集外周血，采用血液基因组DNA提取试剂盒从抗凝全血提取DNA。运用基质辅助激光解吸电离飞行时间质谱（Matrix Assisted LaserDesorption/ionization Time of Flight Mass Spectrometry，MALDI-TOF MS）的实验平台对候选基因： IL28B-rs8099917（TT、 GT、 GG），IL28A-rs12980602（TT、CT、CC），PAK4-rs9676717（TT、 CT、CC）进行DNA的SNPs分型。
采用SPSS16.0进行数据处理和分析，比较92例聚乙二醇干扰素治疗应答组和148例非应答组计量资料两两比较用独立样本的t检验，单因素计数资料比较采用卡方检验，以非条件Logistic回归校正混杂因素并计算比值比（odds ratio，OR）和95%置信区间（95%confidence intervals，95%CI），以P<0.05为有统计学意义，统计检验均为双侧。
结果：
1位点连锁不平衡
用Haploview软件证实rs8099917、 rs12980602和rs9676717不存在连锁不平衡，选择的3个位点等位基因频率符合Hardy-Weinberg遗传平衡定律（P>0.05），不存在连锁不平衡，说明研究样本具有群体代表性。
2应答组和非应答组患者基线特征的比较
应答组饮酒者占36.96%，明显低于非应答组的50%（P=0.048），饮酒是聚乙二醇干扰素治疗应答的独立影响因素，有饮酒史的患者不容易实现治疗应答。年龄、男性所占比例、吸烟者所占比例、HBV DNA和ALT基线水平在两组间均无统计学差异（38.07±14.62vs37.3±12.67；67.39%vs66.22%；41.30%vs51.35%；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。
3rs8099917位点与聚乙二醇干扰素治疗应答的关系
对rs8099917基因位点检测结果表明，TT为其显性基因，应答组无GG基因型，应答组和非应答组TT、 GT和GG基因型的携带率无统计学差异(89.13%,10.87%,0.00%vs87.84%,9.46%,2.70%，P=0.838)。rs8099917位点与聚乙二醇干扰素治疗后6月的应答关联性分析结果表明，两者间没有明显的关联性，单因素分析OR值为0.881(95%CI=0.388-2.002)，P=0.838；多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，OR值为0.881(95%CI=0.388-2.002)，P=0.999。
4rs12980602位点与与聚乙二醇干扰素治疗应答的关系
对rs12980602位点检测的结果与rs8099917位点相似，TT也是其显性基因，应答组和非应答组TT、 CT和CC基因型的携带率无统计学差异(82.61%,15.22%,2.17%vs81.08%,18.92%,0.00%，P=0.186)。rs12980602位点与聚乙二醇干扰素治疗后6月的应答关联性分析结果表明，两者间没有明显的关联性，单因素分析OR值为0.902（95%CI=0.458-1.778），P=0.766；多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，OR值为0.688(95%CI=0.311-1.523)，P=0.356。
5rs9676717位点与与聚乙二醇干扰素治疗应答的关系
对rs9676717位点检测结果表明，应答组与非应答组TT、 CT和CC基因型的携带率有显著统计学差异（56.52%，32.61%，10.87%vs40.54%，52.70%，6.76%，P=0.009）。单因素分析rs9676717位点携带突变基因型CT+CC与干扰素治疗后的应答有显著的负相关性，OR值为0.524(95%CI=0.310-0.888)，P=0.016。当多因素分析校正了年龄、性别、吸烟、饮酒、HBV DNA，ALT水平后，PAK4基因的rs9676717位点的突变基因型CT+CC仍显示与干扰素治疗应答呈负相关， OR值为0.173(95%CI=0.037-0.799)；P=0.025。
结论：
1饮酒是聚乙二醇干扰素治疗应答的独立影响因素，有饮酒史的慢性乙型肝炎患者不容易实现治疗应答。
2位于IL-28的rs8099917和rs12980602位点与慢性乙型肝炎病人聚乙二醇干扰素治疗的应答率无关，而携带PAK4的突变基因型CT+CC降低干扰素治疗6月患者的应答。
第三部分IL-28B基因型与乙型肝炎病毒感染后病毒自发清除及干扰素治疗应答关系的Meta分析
目的：采用Meta分析的方法，对国内外在不同人群不同类别乙型肝炎患者中开展的研究结果进行综合评价，评价IL-28B基因rs12979860位点及rs8099917位点与HBV感染后病毒自发清除及治疗应答的相关性。方法：利用关键词“IL-28B、SNP、hepatitis B、spontaneous clearance、treatment and interferon"联合检索PUBMED、 MEDLINE、 EMBASE、Cochrane library数据库、中国万方数据库、中文科技期刊全文数据库、中国生物医学文献数据库、中国学术期刊全文数据库的中英文文献。末次检索日期是2013年3月25日。共检索到32篇文献。由两位研究人员对检索到的所有文献题目和摘要进行评估筛选，最后选出5篇关于rs12979860位点与HBV感染后自发清除的相关文献、7篇关于rs12979860位点与HBV感染后干扰素治疗应答的文献、3篇关于rs8099917位点与HBV感染后自发清除的相关文献、3篇关于rs8099917位点与HBV感染后干扰素治疗应答的文献。纳入Meta分析提取纳入文献的信息如下：第一作者、出版年、研究设计类型、受试者来自的国家和种族、乙型肝炎诊断类型、病例组和对照组的定义和数量、提取DNA和分型的方法、病毒亚型、治疗方法等。文献未提供基因型的，利用相应的基因频率计算，分别提取rs12979860位点及rs8099917位点的相关数据，对两个位点的显性模型进行了Meta分析。计算优势比（OR）及其95%CI作为效应量。首先对纳入分析的原始文献进行Q检验，分析异质性，根据异质性检验结果，选择固定效应模型或随机效应模型求其效应合并值。用漏斗图和Begg’s检验进行发表偏倚分析，以P<0.05为差异有统计学意义。所有数据用STATA11.1分析。
结果：
1rs12979860位点与乙型肝炎病毒感染后病毒自发清除的关系
共有5篇符合分析条件的关于rs12979860位点与HBV感染后自发清除的相关文献。Meta分析的异质性检验显示：各研究间不存在异质性(I2=20.0%，P=0.287)。根据异质性检验结果选择M-H固定效应模型对rs12979860位点显性模型（TC+CC vs CC）进行数据合并，结果显示，合并后的OR为1.05(95％CI：0.83-1.32，P=0.70)，证明rs12979860位点与乙型肝炎病毒感染后病毒自发清除没有关联。Begg’s偏倚分析显示无明显发表偏倚，P>0.1。
2rs12979860位点与乙型肝炎病毒感染后治疗应答的关系
有7篇符合分析条件的关于rs12979860位点与乙型肝炎病毒感染后治疗应答关系的相关文献。Meta分析的异质性检验显示：合并后的OR为1.57(95％CI：1.06-2.33，P=0.024)但各研究间存在异质性(I2=61.6%，P=0.016)。根据异质性检验结果对数据进行分层分析，按照乙型肝炎病人诊断类别分HBeAg阳性组和HBeAg阴性组进行分析。HBeAg阳性组的4篇文献仍然存在异质性(I2=77.7%，P=0.004)，采用随机效应模型分析结果如下：rs12979860位点显性模型（TC+TT vs CC）合并后的OR为0.717(95％CI：0.190-2.701，P=0.623)，证明rs12979860位点与HBeAg阳性慢性乙型肝炎病毒感染后干扰素治疗应答没有关联。HBeAg阴性组3篇文献采用固定效应模型分析结果如下：各研究间不存在异质性(I2=0.0%，P=0.710)。根据异质性检验结果对rs12979860位点显性模型（TC+TT vs CC）选择M-H固定效应模型进行数据合并，结果显示，合并后的OR为2.132(95％CI：1.15-3.95，P=0.016)，rs12979860位点与乙型肝炎病毒感染后治疗应答呈正相关，突变基因型TC+TT显著提高HBeAg阴性慢性乙型肝炎患者对干扰素治疗的应答率。无发表偏倚。
3rs8099917位点与乙型肝炎病毒感染后病毒自发清除的关系
共有3篇符合分析条件的关于rs8099917位点与HBV感染后自发清除的相关文献。Meta分析的异质性检验显示：各研究间不存在异质性(I2=0.0%，P=0.705)。根据异质性检验结果对rs8099917位点显性模型(GG+GTvs TT)选择M-H固定效应模型进行数据合并，结果显示，合并后的OR为1.084(95％CI：0.72-1.623，P=0.696)，证明rs8099917位点与乙型肝炎病毒感染后病毒自发清除没有关联。无发表偏倚。
4rs8099917位点与乙型肝炎病毒感染后治疗应答的关系
有3篇符合分析条件的关于rs8099917位点与乙型肝炎病毒感染后治疗应答关系的相关文献。对rs8099917位点显性模型(GG+GT vs TT) Meta分析的异质性检验显示：合并后的OR为0.400(95％CI：0.24-0.66，P=0.000)，证明rs8099917位点与乙型肝炎病毒感染后治疗应答呈负相关，突变基因型GG+GT显著降低慢性乙型肝炎患者对干扰素治疗的应答率。各研究间不存在异质性(I2=36.8%，P=0.206)，无发表偏倚。
结论：
1通过Meta分析证实，IL28B rs12979860位点基因型与乙型肝炎病毒感染后病毒自发清除以及HBeAg阳性慢性乙型肝炎病人干扰素治疗应答无关，与HBeAg阴性慢性乙型肝炎病人干扰素治疗应答存在一定的相关性。IL28B rs12979860位点基因型与乙型肝炎病毒感染后病毒自发清除以及HBeAg阳性慢性乙型肝炎病人干扰素治疗应答无关，与HBeAg阴性慢乙肝病人干扰素治疗应答呈正相关，以野生型等位基因C为参照，突变基因型TC+TT显著提高HBeAg阴性慢性乙型肝炎患者对干扰素治疗的应答率。
2通过Meta分析证实，IL28B rs8099917位点基因型与乙型肝炎病毒感染后病毒自发清除无关，与乙型肝炎病毒感染后治疗应答呈负相关，突变基因型GG+GT显著降低慢性乙型肝炎患者对干扰素治疗的应答率。
Approximately one third of the world population has serological evidenceof past or present infection with hepatitis B virus (HBV) and350-400millionpeople are chronic HBV surface antigen (HBsAg) carriers. The spectrum ofdisease and natural history of chronic HBV infection are diverse and variable,ranging from an inactive carrier state to progressive chronic hepatitis B (CHB),which may evolve to cirrhosis and hepatocellular carcinoma (HCC). In Asia,40%of the patients with CHB die of either complications of cirrhosis or HCC.
Persistent HBV infection and its treatment response are influenced by acomplex combination of genetic, environmental, viral components. GeneticEpidemiology supports the role of host genetic components in determining theinfection and its outcomes and treatment response of HBV.
Interleukin-28(IL-28), also known as IFN-, is a cytokine that comes intwo isoforms, IL-28A and IL-28B, and plays a role in immune defense againstviruses. P21-activated protein kinase4(PAK4), is located upstream64kb ofIL28B. It belongs to p21-activated kinases (PAKs) family of effector proteinsfor Rac and Cdc42. PAKs are important regulators of actin cytoskeletaldynamics, neurite outgrowth, cell survival, hormone signaling and genetranscription. PAK4interacts specifically with the GTP-bound form ofCdc42Hs and weakly activates the JNK family of mitogen-activated proteinkinases (MAPKs). It is a mediator of filopodia formation and may play a rolein the reorganization of the actin cytoskeleton.
In2009, three GWAS studies mainly reported some loci near IL28B genewere strongly associated with outcome and sustained virological responses inCHC patients. The three studies were carried out in American, Australian, andJapanese populations.Wether IL28and PAK4gene polymorphism are associated with CHB patients. It is not clear. We choose the tap SNPs byhapmap database and MALDI-TOF MS technic.Then we analyzed the impactof candidate genes single nucleotide polymorphisms (SNPs) includinginterleukin28A(IL28A), interleukin28B (IL28B), p21_activated kinases4(PAK4) on the infection outcomes and treatment response of HBV. Wehope that it can support clinical treatment and prognosis.
Part One Association between gene polymorphisms of IL-28andresponse to lamivudine in patients with chronic hepatitis B
Objective：To assess the association between gene polymorphisms(single nucleotide polymorphisms, SNPs) of rs8099917and rs12980602inthe IL-28A（interleukin28A，IL28A，IFN-λ2）, IL28B gene (interleukin28B，IL28B，IFN-λ3）and the response to lamivudine treatment in na ve of chronichepatitis B patients.
Methods: Three hundred and fifty-four na ve chronic hepatitis B (CHB)patients treated with lamivudine were enrolled in this study. we collected thebaseline, illness situation, checkup results of all the subjects by questionnaire.Biochemical information--seroconversion, serum HBV DNA load and ALTlevels from all subjects were collected when they came to subsequent visits at1year of lamivudine therapy.
In this study, responses were classified as MR, partial response(PR), ornon-response (NR) according to Asian-Pacific and Chinese consensusstatements. An CR included identified seroconversion, serum HBV DNAcan’t be detected or decreased2log10, and normalization of serum ALT levels.A PR included identified serum HBVDNA can’t be detected or decreased2log10,, and normal serum ALT levels. Patients who did not satisfy all of theabove-mentioned criteria were categorized as NR.
Searching candidate genes about autoimmune diseases by CNKI andPubmed. Selecting tagSNPs of candidate genes in Han Chinese by Hapmap.Removing SNPs of linkage disequilibrum (LD) by Haploview.
Genomic DNA was isolated from peripheral venous blood using aWizard Genomic DNA Puri fi cation Kit (Promega Inc., Fitchburg, WI, USA)according to the manufacturer’s instructions. Matrix-assisted laserdesorption/ionization time of flight mass spectrometry single nucleotidepolymorphism (SNP) genotyping assays were used for the detection of thereference SNPs IL-28gene on chromosome19, i.e., IL28B-rs8099917（TT、GT、GG）and IL28A-rs12980602（TT、CT、CC）. We used Haploview softwareto confirm linkage disequilibrium.
Rs8099917and rs12980602SNPs were genotyped using matrix-assistedlaser desorption/ionization time of flight mass spectrometry. SPSS version16.0software was used to analyze baseline characteristics and genotypesbetween181patients with treatment response and173without response.Group comparisons were performed using the Student’s t test, Mann-WhitneyU test,2test, or Fisher’s exact test, as appropriate. Binary logisticregression modeling was used to identify independent factors associated withlamivudine responses at the end of treatment.
Results:
1rs8099917and rs12980602were not in linkage disequilibrium.
2Compatation of baseline characteristics of response and non-responsegroup
The ratio of males, smoking and drinking in response group weresignificantly lower than that in non-responder group（61.33%vs76.30%，P=0.002；29.83%vs43.35%，P=0.008；38.67%vs52.02%，P=0.012）.Gender,smoking and drinking are independed influence factors of Lamivudinetreatment response. HBV DNA and ALT baseline level were not associatedwith response（50.86±11.03vs52.22±10.82；7.67log copies/ml vs7.69logcopies/ml；279.50IU/L vs317.50IU/L；P＞0.05）。Fibrosis was negativecorrelation with Lamivudine treatment response. The early fibrosis stage wassignificantly associated with a higher probability of response to lamivudinetreatment (OR=0.716,95%CI=0.432-0.986; p=0.036).
3The relationship between rs8099917and Lamivudine treatment response For rs8099917, TT was the dominant genotype. There was no GG genotype atrs8099917in both the responder and non-responder groups. There was asignificant higher rate of mutation genotyoe GT in response group than that innon-response group (8.8%vs2.3%)，OR was4.097（95%CI=1.342-12.512,P=0.015）when genotypes were compared by univariate analysis. whenadjusting for baseline age, gender, smoking, drinking, and levels of HBVDNA, ALT, and HBV genotype, IL-28B genotype GT (for rs8099917)appeared to be associated with a higher probability of responding tolamivudine treatment (OR=4.025,95%CI,1.316-12.354; p=0.013). TheGT genotype may as a potential treatment mark for Chinese hepatitis Bpatients with lamivudine therapy.
4The relationship between rs12980602and Lamivudine treatment response
For rs12980602, TT was the dominant genotype as well, which wassimilar to rs8099917. Only4of181(2.2%) patients had the CC genotype atrs12980602in the responder group, and none of the173patients in thenon-responder group had the CC genotype. By univariate analysis, the rate ofgenotype CT and CC in response group was higher that in non-response group（18.8%vs9.2%），OR=2.27（95%CI=1.202-4.284）; P=0.014).
When adjusting for baseline age, gender, smoking, drinking, and levels ofHBV DNA, ALT, and HBV genotype, the relationship between rs12980602ofIL-28A and responding to treatment was not significant (OR=1.765,95%CI=0.884-3.617, p=0.109).
Conclusion:
1We used Haploview software to confirm that rs8099917andrs12980602were not in linkage disequilibrium. It is showed that the samplepopulation was good for representation.
2Gender, smoking and drinking were independent influencing factors.Male patients, the patients having history of smoking and drinking had lowresponse to Lamivudine therapy.
3Rs8099917and rs12980602of IL-28gene may associate with HBVtreatment response. The genotype GT for rs8099917may be predictive of treatment success.
5Early fibrosis stage may be predictive of treatment success.
Part Two Gene polymorphisms of interleukin-28, p21-activated proteinkinases4, and response to interferon-a based therapy in patients withchronic hepatitis B
Objective：Peg-Interferon-a treatment is expensive and associated withconsiderable adverse effects, selection of patients with the highest probabilityof response is essential for clinical practice. The objective of this study was toassess the relationship between the gene polymorphisms of interleukin-28(IL28), p21-activated protein kinase4(PAK4) and the response to interferontreatment in chronic hepatitis B patients.
Methods: Two hundred and forty interferon-naive treatmentseropositive chronic hepatitis B patients were enrolled in the presentprospective nested case-control study. We collected the baseline, illnesssituation, checkup results of all the subjects by questionnaire. Biochemicalinformation (seroconversion, serum HBV DNA load and ALT levels) fromall subjects were collected when they came to subsequent visits at6monthsof interferon treatment.
In this study, responses were classified as completely response (CR),partial response (PR), or non-response (NR) according to Asian-Pacific andChinese consensus statements. A CR included identified seroconversion,serum HBV DNA can’t be detected or decreased2log10, and normalization ofserum ALT levels. A PR included identified serum HBVDNA can’t bedetected or decreased2log10, and normal serum ALT levels. Patients who didnot satisfy all of the above-mentioned criteria were categorized as NR.
Searching candidate genes about autoimmune diseases by CNKI and Pubmed. Selecting tagSNPs of candidate genes in Han Chinese by Hapmap.Removing SNPs of linkage disequilibrum (LD) by Haploview.
Genomic DNA was isolated from peripheral venous blood using aWizard Genomic DNA Puri fi cation Kit (Promega Inc., Fitchburg, WI, USA)according to the manufacturer’s instructions. Matrix-assisted laserdesorption/ionization time of flight mass spectrometry single nucleotidepolymorphism (SNP) genotyping assays were used for the detection of thereference SNPs IL-28gene on chromosome19, i.e., IL28B-rs8099917（TT、GT、GG）, IL28A-rs12980602（TT、CT、CC）and PAK4-rs9676717（TT、CT、CC）.
Peripheral blood samples were collected, including92with favorableresponse and148without response to the interferon treatment. Rs8099917,rs12980602, and rs9676717SNP was genotyped using matrix assisted laserdesorption/ionization time of flight mass spectrometry (MALDI-TOF MS).
SPSS version16.0software was used to analyze baseline characteristicsand genotypes between92patients with treatment response and148withoutresponse. Group comparisons were performed using the Student’s t test,Mann-Whitney U test,2test, or Fisher’s exact test, as appropriate.Binarylogistic regression modeling was used to identify independent factorsassociated with interferon responses at the end of treatment.
Results:
1rs8099917, rs12980602and rs9676717were not in linkagedisequilibrium.
2Compatation of baseline characteristics of response and non-responsegroup
The ratio of drinking in response group were significantly lower thanthat in non-responder group（36.96%vs50%, P=0.048）. Drinking isindepended influence factor of interferon treatment response. Age, gender,smoking, HBV DNA and ALT baseline level were not associated withresponse（38.07±14.62vs37.3±12.67；67.39%vs66.22%；41.30%vs51.35%；7.67log copies/ml vs7.69log copies/ml；279.50IU/L vs317.50 IU/L；P＞0.05）。
3The relationship between rs8099917and interferon treatment response
Regarding genotype at rs8099917, TT was the dominant genotype, no GGgenotype at rs8099917in responder group. There was no significant differencewhen the genotypes between the responder and non-responder group (82.61%,15.22%,2.17%vs81.08%,18.92%,0.00%，P=0.186) by univariate analysis.By multivariate analysis when adjusting for baseline age, gender, smoking,drinking, levels of HBV DNA, and ALT, the relationship between rs8099917and response was not significant (P=0.999).
4The relationship between rs12980602and interferon treatment response
Regarding genotype at rs12980602, TT was the dominant genotype too,similar to rs8099917. Only two of the92(2.17%) patients had CC genotype inthe responder group, and none of148in the non-responder group. Byunivariate analysis there was no significant difference (OR=0.902,95%CI=0.458-1.778, P=0.766). By univariate analysis, the rate of genotype CT andCC in response group was higher that in non-response group(OR=0.688,95%CI=0.311-1.523，P=0.356).
5The relationship between rs9676717and interferon treatment response
Regarding genotype at rs9676717, Only10of92or148(10.87%or6.76%) patients had CC genotype both in the responder and non-respondergroups. By univariate analysis, there was significant difference （56.52%，32.61%，10.87%vs40.54%，52.70%，6.76%，P=0.009）. By univariateanalysis, the rate of genotype CT and CC in response group was lower that innon-response group (OR=0.524,95%CI=0.310-0.888, P=0.016). Whenadjusting for baseline age, gender, smoking, drinking, and levels of HBVDNA, ALT, and HBV genotype, the relationship between rs9676717of PAK4and responding to treatment was negative corelation (OR=0.173,95%CI=0.037-0.799, P=0.025).
Conclusion:
1polymorphisms of rs8099917and rs12980602in IL-28were notassociated with the response of IFN-α treatment in positive chronic hepatitis B. Patients with favorable PAK4genotypes TT have an increased probabilityof achieving response to IFN-at the end of6months treatment.
2Drinking may influence the response of IFN-treatment in CHB.
Part Three A Meta-analysis on the association between IL-28B genotypeand spontaneous HBV clearance or interferon treatment response
Objective: To investigate the association of SNP-rs12979860,rs8099917and Spontaneous HBV clearance and interferon treatment responseamong different groups and defferent types of chronic hepatitis B byMeta-analysis.
Methods: Relevant studies were identified by a literature search ofPUBMED、MEDLINE、EMBASE、Cochrane library and WanFang databasewithout imposing study-period restrictions, using the following terms:‘hepatitis B’,‘IL28B’,‘SNP’,‘spontaneous clearance’,‘treatment’, and‘interferon’. The information contained in this report is based on articlespublished before25March2013in any language. Totally32papers wereobtained upon repeated papers excluded. Two investigators independentlyassessed the selected papers and extracted all data. At the end there are5articles about rs12979860and Spontaneous HBV clearance,7articles aboutrs12979860and interferon treatment response,3articles about rs8099917andSpontaneous HBV clearance,3articles about rs8099917and interferontreatment response.
From each study, the following information was abstracted: the firstauthor, year of publication, research design, ethnic background andgeographical distribution of participants, type of chronic hepatitis B, definitionand numbers of case group and control group, method of DNA extraction andgenotype, HBV subgroup, treatment method and so on. In this article, meta-analysis was performed on dominant and genotype models ofrs12979860and rs8099917gene locus. The pooled odd ratio (OR) with95%confidence interval (CI) was calculated to evaluate the association of twolocus with HBV infection. At first, Q-test was conducted to analyze raw dataof literature included for heterogeneity test. Subsequently, depending onheterogeneity result fixed-effects model or random-effects model will beperformed for the calculation of pooled OR with95%CI. Then funnel plot andBegg’s test were used for assessment of publication bias and P<0.05suggesteda statistical significance. All P-values were two sided. All analysis mentionedabove was fulfilled by STATA version11.1.
Results：
1Assciation between rs12979860and Spontaneous HBV clearance
There were5eligible studies reporting data on12979860andspontaneous HBV clearance. All data were pooled by Fixed effect model andshowed total OR of rs12979860dominate model (TC+CC vs CC）for overalldata was1.05(95%CI:3.18-4.69, P=0.70) and the overall heterogeneitywas not significant (I2=20.0%，P=0.287). There was no association betweenrs12979860and Spontaneous HBV clearance. Begg’s test results showed thatthere was no statistical significance in publication bias (P>0.1).
2Assciation between rs12979860and interferon treatment response
There were7eligible studies reporting data on12979860and interferontreatment response. All data were pooled by Fixed effect model and showedtotal OR of rs12979860dominate model (TC+CC vs CC）for overall data was1.57(95%CI:1.06-2.33，P=0．024) and the overall heterogeneity wassignificant ((I2=61.6%，P=0.016).
After stratified from-positive and-negative patients, regards ofrs12979860and interferon treatment response for-positive patients, all datawere pooled by Randoom effect model and showed total OR=0.717(95％CI：0.190-2.701，P=0.623), There was no association between rs12979860andinterferon treatment response with-positive HBV patients；rs12979860andinterferon treatment response for-negative patients, all data were pooled by Fixed effect model and showed total OR=2.132(95％CI：1.15-3.95，P=0.016), There was positive correlation between rs12979860and interferontreatment response with-negative HBV patients. The mutation genotypeTC+TT signigicantly promote interferon treatment response with-negativeHBV patients. Begg’s test results showed that there was no statisticalsignificance in publication bias (P>0.1).
3Assciation between rs8099917and Spontaneous HBV clearance
There were3eligible studies reporting data on rs8099917andspontaneous HBV clearance. All data were pooled by Fixed effect model andshowed total OR of rs8099917dominate model (GG+GT vs TT）for overalldata was1.084(95％CI：0.72-1.623，P=0.696), There was no associationbetween rs8099917and Spontaneous HBV clearance. And the overallheterogeneity was not significant (I2=0.0%，P=0.705). Begg’s test resultsshowed that there was no statistical significance in publication bias.
4Assciation between rs8099917and interferon treatment response
There were3eligible studies reporting data on rs8099917and interferontreatment response. All data were pooled by Fixed effect model and showedtotal OR of rs8099917dominate model (GG+GT vs TT）for overall data was0.400(95％CI：0.24-0.66，P=0.000), There was negative correlationbetween rs8099917and interferon treatment response with HBV patients. Themutation genotype GG+GT signigicantly cut down interferon treatmentresponse with HBV patients. And the overall heterogeneity was not significant((I2=36.8%，P=0.206).
Conclusion：
1IL-28B rs12979860is not associated with spontaneous HBV clearanceor interferon treatment response for-positive patients. While associated withinterferon treatment response for-negative patients. Patients with T allele ofIL28B rs12979860have a high probility of interferon treatment success. Indominant genotype model showed that the mutation genotype TC+TTsignigicantly promote interferon treatment response with-negative HBVpatients.
2IL28B rs8099917is not associated with spontaneous HBV clearance. Itis associated with interferon treatment response for-positive patients. Themutation genotype GG+GT signigicantly cut down interferon treatmentresponse with HBV patients.
引文
1Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statementon the management of chronic hepatitis B: a2012update. HepatologyInternational2012;6:531-561
2Kao JH, Chen DS. Global control of hepatitis B virus infection. LancetInfect Dis2002;2:395-403
3European Association For The Study Of The Liver. EASL ClinicalPractice Guidelines: management of chronic hepatitis B. J Hepatol2009;50(2):227-242
4Liaw YF, Sung JJ, Chow WC, et al. Cirrhosis Asian LamivudineMulticentre Study Group. Lamivudine for patients with chronic hepatitis Band advanced liver disease. N Engl J Med2004;351:1521-1531
5Liaw YF. Hepatitis B virus replication and liver disease progression: theimpact of antiviral therapy. Antivir Ther2006;11:669-679
6The Chinese Liver Disease Association, Chinese Medical AssociationInfectious Disease Branch. Chinese consensus statement on themanagement of chronic hepatitis B: a2010update. Chin J Exp Clin InfectDis (Electronic Edition)2011;5:79-100
7Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysisevaluating the relative efficacy of nucleos(t)ides for treatment ofnucleos(t)ide-naive patients with chronic hepatitis B. Value Health2010;13:934-945
8Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-6
9Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat. Immunol2003;4:63-8
10Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature2009;461:399-401
11Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet2009;41:1100-1104
12Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapyfor chronic hepatitis C. Nat Genet2009;41(10):1105-1109
13Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study. Gastroenterology2009;138:1338-1345
14Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in-positive patients withchronic hepatitis B. Gastroenterology2012;142:513-520
15Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), atype III IFN, is induced by viruses and IFNs and displays potent antiviralactivity against select virus infections in vivo. J Virol2006;80:4501-4509.
16Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. JInterferon Cytokine Res2006;26:373-379
17Beom KK, Han KH, Jun YP, et al. A novel liver stiffnessmeasurement-based predictionmodel for cirrhosis in hepatitis B patients.liver int2010;30:1073-1081
18Seung UK, Ja KK, Young NP, et al. Discordance between Liver Biopsyand FibroScanH in Assessing Liver Fibrosis in Chronic Hepatitis B: RiskFactors and Influence of Necroinflammation. PLoS One2012;7:e32233
19Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine and24weeks oflamivudine/interferon combination therapy for hepatitis B eantigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol2003;38:818-826
20Jin YJ, Shim JH, Chung YH, et al. HLA-DRB1*010101allele is closelyassociated with poor virological response to lamivudine therapy in patientswith chronic hepatitis B. Digestion2011;84Suppl1:35-42
21Park YK, Lee JM, Kim do Y, et al. Association between polymorphism oftumor necrosis factor-alpha promoter and response to lamivudinetreatment in patients with chronic hepatitis B. Dig Dis Sci2010;55:2043-2048
22Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-inducible genesOAS associated with interferon-α treatment response in chronic HBVinfection. Antiviral Res2011;89:232-237
23King JK, Yeh SH, Lin MW, et al. Genetic polymorphisms in interferonpathway and response to interferon treatment in hepatitis B patients: Apilot study. Hepatology2002;36:1416-1424
24Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
25Abe H, HayesZeng YL CN, Ochi H, et al. IL28Variation affectsexpression of interferon stimulated genes and effect of peginterferon andribavirin therapy. J Hepatol2011;54:1094-1101
26Chen CM, Zhou FY, Zhou YP, et al. Relationship between singlenucleotide polymorphisms in IL28B gene and response to interferontreatment in chronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao2011;31:2012-2015
27Moreira S, Garcia RF, Gutberlet A, et al. A straightforward genotyping ofthe relevant IL28B SNPs for the prediction of hepatitis C treatmentoutcome. J Virol Methods2012;184:93-7
28Shi X, Pan Y, Wang M, et al. IL28B Genetic Variation Is Associated withSpontaneous Clearance of Hepatitis C Virus, Treatment Response, SerumIL-28B Levels in Chinese Population. PLoS One2012;7:e37054
29Poordad F, Bronowicki JP, Gordon SC, et al. Factors That PredictResponse of Patients With Hepatitis C Virus Infection to Boceprevir.Gastroenterology2012; doi:10.1053/j.gastro.2012.05.011
30Jiao XL, Gao YT, Jing L, et al, Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-7
31Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
32Li Y, Shi Y, Chen J. Association of polymorphisms in interleukin-18andinterleukin-28B with Hepatitis B recurrence after liver transplantation inChinese Han population. Int J Immunogenet2012;39:346-352
33Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Hanpopulation. Liver Int2011;31:1118-1126
1Liaw YF, Chu CM. Hepatitis B virus infection. Lancet.2009;373:582-92
2Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment,and current and emerging prevention and control measures. J Viral Hepat,2004.11:97-107
3Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer:an overview. Asian Pac J Cancer Prev,2004.5:118-25
4Zoulim F, Locarnini SA. Hepatitis B virus resistance to nucleos(t)ideanalogues. Gastroenterology2009;137:1593-1608
5Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine,and the combination for-positive chronic hepatitis B. N Engl J Med2005;352:2682-95
6Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone,lamivudine alone, and the two in combination in patients with-negativechronic hepatitis B. N Engl J Med2004;351:1206-17
7Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferonalfa-2b alone or in combination with lamivudine for-positive chronichepatitis B: a randomised trial. Lancet2005;365:123-129
8Gish, RG. Current treatment and future directions in the management ofchronic hepatitis B viral infection. Clin Liver Dis2005;9:541-565
9Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-106
10Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat Immunol2003;4:63-68
11Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature2009;461:399-401
12Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet2009;41:1100-1104
13Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapyfor chronic hepatitis C. Nat Genet2009;41:1105-1109
14Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study. Gastroenterology2009;138:1338-1345
15Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in-positive patients withchronic hepatitis B. Gastroenterology2012;142:513-520
16Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), atype III IFN, is induced by viruses and IFNs and displays potent antiviralactivity against select virus infections in vivo. J Virol2006;80:4501-4509
17Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. JInterferon Cytokine Res2006;26:373-379
18Suzuki F, Arase Y, Suzuki Y, et al. Single nucleotide polymorphism of theMxA gene promoter influences the response to interferon monotherapy inpatients with hepatitis C viral infection. J Viral Hepatol2004;11:271-276
19Ovsyannikova IG, Ryan JE, Vierkant RA, et al. Influence of host geneticvariation on rubella-specific T cell cytokine responses followingrubella vaccination. Vaccine2009;27:3359-3366
20Peng LJ, Guo JS, Zhang Z, et al. IL28B rs12979860polymorphism doesnot influence outcomes of hepatitis B virus infection. Tissue Antigens2012;79:302-305
21Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-induciblegenes OAS associated with interferon-α treatment response in chronicHBV infection. Antiviral Res2011;89:232-237
22King JK, Yeh SH, Lin MW, et al. Genetic polymorphisms in interferonpathway and response to interferon treatment in hepatitis B patients: Apilot study. Hepatology2002;36:1416-1424
23Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
24Xu HT, Xing TJ, Li H, et al. Association of T regulatory cells with naturalcourse and response to treatment with interferon-α in patients with chronichepatitis B infection. Chinese Medical Journal2012;125:1465-1468
25Abe H, HayesZeng YL CN, Ochi H, et al. IL28Variation affectsexpression of interferon stimulated genes and effect of peginterferon andribavirin therapy. J Hepatol2011;54:1094-1101
26Chen CM, Zhou FY, Zhou YP,et al. Relationship between single nucleotidepolymorphisms in IL28B gene and response to interferon treatment inchronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao (Chin)2011;31:2012-2015
27Moreira S, Garcia RF, Gutberlet A, et al. A straightforward genotyping ofthe relevant IL28B SNPs for the prediction of hepatitis C treatmentoutcome. J Virol Methods2012;184:93-97
28Shi X, Pan Y, Wang M, et al. IL28B Genetic Variation Is Associated withSpontaneous Clearance of Hepatitis C Virus, Treatment Response, SerumIL-28B Levels in Chinese Population. PLoS One2012;7: e37054
29Poordad F, Bronowicki JP, Gordon SC, et al. Factors That PredictResponse of Patients With Hepatitis C Virus Infection to Boceprevir.Gastroenterology2012;143:608-618
30Jiao XL, Gao YT, Jing L, et al. Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-1147
31Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
32Li Y, Shi Y, Chen J, et al. Association of polymorphisms in interleukin-18and interleukin-28B with Hepatitis B recurrence after liver transplantationin Chinese Han population. Int J Immunogenet2012;39:346-352.
33Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Hanpopulation. Liver Int2011;31:1118-1126
34Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. NatRev Cancer2006;6:459-471
35Ahmed T, Shea K, Masters JR, et al. A PAK4-LIMK1pathway drivesprostate cancer cell migration downstream of HGF. Cell Signalling2008;20:1320-1328
36Zhang H, Li Z, Viklund EK, et al. P21-activated kinase4interacts withintegrin αvβ5and regulates αvβ5-mediated cell migration. J Cell Biol2002;158:1287-1297
37Chen S, Auletta T, Dovirak O, et al. Copy number alterations in pancreaticcancer identify recurrent PAK4amplification. Cancer Biol Ther2008;7:1793-1802
38Kimmelman AC, Hezel AF, Aguirre AJ, et al. Genomic alterations linkRho family of GTPases to the highly invasive phenotype of pancreascancer. Proc Natl. Acad Sci2008;105:19372-19377
39Mak GW, Chan MM, Leong VY, et al. Overexpression of a novel activatorof PAK4, the CDK5kinase-associated protein CDK5RAP3,promotes hepatocellular carcinoma metastasis. Cancer Res2011;8:2949-2958
1Hou J, Liu Z, Gu F. Epidemiology and Prevention of Hepatitis B VirusInfection. Int J Med Sci,2005,2(1):50-57
2Liaw YF, Chu CM. Hepatitis B virus infection. Lancet,2009,373(9663):582-592
3Boonstra A, Woltman A M, Janssen H L. Immunology of hepatitis B andhepatitis C virus infections. Best Pract Res Clin Gastroenterol,2008.22(6):1049-61
4Tseng L H, Lin M T, Shau W Y, et al. Correlation of interleukin-10genehaplotype with hepatocellular carcinoma in Taiwan. Tissue Antigens,2006.67(2):127-33
5Kim Y J, Lee H S, Yoon J H, et al. Association of TNF-alpha promoterpolymorphisms with the clearance of hepatitis B virus infection. Hum MolGenet,2003.12(19):2541-6
6Liaw YF. Hepatitis B virus replication and liver disease progression: theimpact of antiviral therapy. Antivir Ther2006;11:669-679
7Zoulim F, Locarnini SA. Hepatitis B virus resistance to nucleos(t)ideanalogues. Gastroenterology2009;137:1593-1608
8Gish, RG. Current treatment and future directions in the management ofchronic hepatitis B viral infection. Clin Liver Dis2005;9:541-565
9Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysisevaluating the relative efficacy of nucleos(t)ides for treatment ofnucleos(t)ide-naive patients with chronic hepatitis B. Value Health2010;13:934-945
10Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapy forchronic hepatitis C. Nat Genet,2009,41(10):1105-1109
11Ge D, Fellay J, Thompson A J, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature,2009,461:399-401
12Suppiah V, Moldovan M,Ahlenstiel G,et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet,2009,41(10):1100-1104
13Rauch A, Kutalik Z, Deseombes P,et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study.Gastroenterology,2010,138(4):1338-1345
14Thomas DL,Thio CL,Martin MP, et al. Genetic variation in IL28B and tospontaneous clearance of hepatitis C virus. Nature,2009,461:798-801
15Jiao XL, Gao YT, Jing L, et al. Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-7
16Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
17Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
18Li Y, Shi Y, Chen J. Association of polymorphisms in interleukin-18andinterleukin-28B with Hepatitis B recurrence after liver transplantation inChinese Han population. Int J Immunogenet2012;39:346-352
19Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Han population.Liver Int2011;31:1118-1126
20Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-6
21Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat. Immunol2003;4:63-8
22Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat Immunol,2003,4(1):63-68
23Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviralprotection through a distinct class II cytokine receptor complex. NatImmunol,2003,4(1):69-77
24Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, et al.Meta-analysis: implications of interleukin-28B polymorphisms inspontaneous and treatment-related clearance forpatients with hepatitis C.BMC Med.2013Jan8;11:6. doi:10.1186/1741-7015-11-6
25Wu LS, Wang H, Geng XP. Two IL28B polymorphisms are associated withthe treatment response of different genotypes of hepatitis C indifferentracial populations: A meta-analysis. Exp Ther Med.2012Feb;3(2):200-206.Epub2011Nov21
26Li S, Hu P, Zhang QQ, et al. Single nucleotide polymorphisms of theIL28B and sustained virologic response of patients with chronic hepatitisCto PEG-interferon/ribavirin therapy: A meta-analysis: Meta-analysis ofIL28B. Hepat Mon.2011Mar;11(3):163-72
27Zheng MH, Li Y, Xiao DD, et al. Interleukin-28B rs12979860C/T andrs8099917T/G contribute to spontaneous clearance of hepatitis C virus inCaucasians. Gene.2013Apr15;518(2):479-82. doi:10.1016/j.gene.2012.12.067. Epub2012Dec20
28Shi KQ, Liu WY, Lin XF,et al. Interleukin-28B polymorphisms on the SVRin the treatment of na ve chronic hepatitis C with pegylated interferon-αplus ribavirin: a meta-analysis. Gene.2012Oct1;507(1):27-35. doi:10.1016/j.gene.2012.07.026. Epub2012Jul25
29Romero-Gomez M, Eslam M, Ruiz A, et al. Genes and hepatitis C:susceptibility, fibrosis progression and response to treatment. Liver Int.2011Apr;31(4):443-60. doi:10.1111/j.1478-3231.2011.02449.x. Epub2011Jan30
30Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does notdetermine outcomes of hepatitis B virus or HIV infection. J Infect Dis.2010Dec1;202(11):1749-53. doi:10.1086/657146. Epub2010Oct26
31Martín-Carbonero L, Rallón NI, Benito JM, et al. Short communication:Does interleukin-28B single nucleotide polymorphisms influence thenatural history of hepatitis B? AIDS Res Hum Retroviruses.2012Oct;28(10):1262-4. Epub2012Mar23
32Ren S, Lu J, Du X,et al. Genetic variation in IL28B is associated with thedevelopment of hepatitis B-related hepatocellular carcinoma. CancerImmunol Immunother.2012Sep;61(9):1433-9. doi:10.1007/s00262-012-1203-y. Epub2012Feb4
33Peng LJ, Guo JS, Zhang Z,et al. IL28B rs12979860polymorphism doesnot influence outcomes of hepatitis B virus infection. Tissue Antigens.2012Apr;79(4):302-5. doi:10.1111/j.1399-0039.2011.01835.x. Epub2012Jan13
34Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Han population.Liver Int.2011Sep;31(8):1118-26. doi:10.1111/j.1478-3231.2011.02507.x.Epub2011Mar30
35Holmes JA, Nguyen T, Ratnam D, et al. IL28B GENOTYPE IS NOTUSEFUL FOR PREDICTING TREATMENT OUTCOME IN ASIANCHRONIC HEPATITIS B PATIENTS TREATED WITHPEGYLATED-INTERFERON-αJ Gastroenterol Hepatol.2013Jan9. doi:10.1111/jgh.12110.[Epub ahead of print]
36Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms near IL28Band serologic response to peginterferon in-positive patients withchronichepatitis B. Gastroenterology.2012Mar;142(3):513-520.e1. doi:10.1053/j.gastro.2011.11.025. Epub2011Nov19
37de Niet A, Takkenberg RB, Benayed R, et al. Genetic variation in IL28Band treatment outcome in-positive annegative chronic hepatitis Bpatientstreated with Peg interferon alfa-2a and adefovir. Scand JGastroenterol.2012Apr;47(4):475-81. doi:10.3109/00365521.2011.648952. Epub2012Jan23.
38Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predictinterferon-related hepatitis B surface antigen seroclearance in genotype Dhepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology.
2013Mar;57(3):890-6. doi:10.1002/hep.25749. Epub2012Dec20
39Chen CM, Zhou FY, Zhou YP, et al. Relationship between single nucleotidepolymorphisms in IL28B gene and response to interferon treatmentinchronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao.2011Dec;31(12):2012-5
40焦晓磊，高英堂，景丽，等. IL-28B遗传多态性与乙型肝炎病毒感染后病毒自然清除和疾病进展关系的研究《中华流行病学杂志》2011,32(11)
41Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus forresponse to interferon-α based therapy in chronic hepatitis B patientsinChinese. Antiviral Res.2012Feb;93(2):297-300. doi:10.1016/j.antiviral.2011.12.009. Epub2011Dec19
42Tseng TC, Yu ML, Liu CJ, et al. Effect of host and viral factors on hepatitisB e antigen-positive chronic hepatitis B patients receiving pegylatedinterferon-α-2a therapy. Antivir Ther.2011;16(5):629-37
1European Association for the Study of the Liver. EASL Clinical PracticeGuidelines: management of chronic hepatitis B. J Hepatol2009;50:227-242
2Lok AS, McMahon BJ. Chronic hepatitis B: update2009. Hepatology2009;50:661-662
3Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statementon the management of chronic hepatitis B: a2012update. Hepatol Int.2012;6:531-561
4Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature.2009;46:399-401
5Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-a and ribavirin therapy. NatGenet2009;41:1100-4
6Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-a and ribavirin therapy forchronic hepatitis C. Nat Genet.2009;41:1105-9
7Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does notdetermine outcomes of hepatitis B virus or HIV infection. J Infect Dis.2010;202:1749-53
8Tseng TC, Yu ML, Liu CJ, et al. Effect of host and viral factors onhepatitis B e antigen-positive chronic hepatitis B patients receivingpegylated interferon alpha-2a therapy. Antivir Ther.2011;16:629-37
9Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in positive patients withchronic hepatitis B. Gastroenterology.2012;142:513-20
10Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res.2012;93:297-300
11Lampertico P, Vigano`M, Cheroni C, et al. Genetic variation in IL28Bpolymorphism may predict HBsAg clearance in genotype D, negativepatients treated with interferon alfa. Hepatology2010;52(suppl):442A
12Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses ofpeginterferon alfa-2a are associated with inferior hepatitis B e antigenseroconversion rates in hepatitis B virus genotypes B or C. Hepatology.2011;54:1591-9
13Brunetto MR. A new role for an old marker, HBsAg. J Hepatol2010;52:475-7
14Chan HL, Thompson A, Martinot-Peignoux M, et al. Hepatitis B surfaceantigen quantification: why and how to use it in2011dacore group report. JHepatol.2011;55:1121-31
15Liaw YF. Clinical utility of hepatitis B surface antigen quantitation inpatients with chronic hepatitis B: a review. Hepatology.2011;54: E1-9.
16Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigenand hepatitis B e antigen titers: disease phase influences correlation withviral load and intrahepatic hepatitis B virus markers. Hepatology.2010;51:1933-44
17Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: astrong predictor of sustained virological response to pegylated interferonalfa-2a in-negative patients. Hepatology.2009;49:1151-7
18Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustainedresponse to peginterferon alfa-2b for hepatitis B e antigen-positive chronichepatitis B using on-treatment hepatitis B surface antigen decline.Hepatology.2010;52:1251-7
19Piratvisuth T, Marcellin P. Further analysis is required to identify an earlystopping rule for peginterferon therapy that is valid for all-positive patients.Hepatology.2011;53:1054-5
20Piratvisuth T, Marcellin P, Popescu M, et al. Hepatitis B surface antigen:association with sustained response to peginterferon alfa-2a in hepatitis B eantigen-positive patients. Hepatol Int. Published Online First:24June2011.doi:10.1007/s12072-011-9280-0
21Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment predictionof response to peginterferon alfa-2a for-negative chronic hepatitis B usingHBsAg and HBV DNA levels. Hepatology.2010;52:454-61
22Rijckborst V, Hansen B, Ferenci P, et al. Validation of a stopping rule atweek12using HBsAg and HBV DNA for-negative patients treated withpeginterferon alfa-2a. J Hepatol. Published Online First:13January2012.doi:10.1016/j.jhep.2011.12.007
23Lampertico P, Vigano M, Di Costanzo GG, et al. A response guidedapproach to peg-interferon alfa-2a at weeks12and24improves responserates in-negative, genotype D chronic hepatitis B patients. Hepatology.2011;54:1021A
24Brunetto MR, Marcellin P, Cherubini B, et al. response to peginterferonalfa-2a in negative CHB: baseline and ontreatment kinetics of HBsAgserum levels vary according to HBV genotype. Hepatology.2011;54:1059A
25Moucari R, Martinot-Peignoux M, Mackiewicz V, et al. Influence ofgenotype on hepatitis B surface antigen kinetics in hepatitis B eantigen-negative patients treated with pegylated interferon-alpha2a.Antivir Ther.2009;14:1183-8
26Chang TT, Lai CL, Kew YS, et al. Entecavir treatment for up to5years inpatients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology.2010;51:422-30
27Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring showshepatitis B virus resistance to entecavir in nucleoside-na ve patients is rarethrough5years of therapy. Hepatology.2009;49:1503-14
28Manns M, Akarca US, Chang TT, et al. Low rates ofnucleos(t)ideassociated adverse events in the long-term experience withentecavir. J Hepatol.2010;52:S393
29Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety oftenofovir disoproxil fumarate treatment for chronic hepatitis B.Gastroenterology.2011;140:132-43
30Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovirDF (TDF) for chronic hepatitis B (CHB) infection is associated withsustained viral suppression and significant regression of histologicalfibrosis and cirrhosis. Hepatology.2011;54(Suppl1):1011A-12A. Abstract1375
31Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovirdisoproxil fumarate detected after up to144weeks of therapy in patientsmonoinfected with chronic hepatitis B virus. Hepatology.2011;53:763-73
32Liaw YF, Sheen IS, Lee CM, et al. Tenofovir Disoproxil Fumarate (TDF),Emtricitabine/TDF and Entecavir in patients with decompensated chronichepatitis B liver disease. Hepatology.2011;53:62-72
33Liaw YF, Raptopoulou-Gigi M, Cheinquer H, et al. Efficacy and safety ofentecavir versus adefovir in chronic hepatitis B patients with hepaticdecompensation: a randomized open-label study. Hepatology.2011;54:91-100
34Sogni P, Carrieri MP, Fontaine H, et al. The role of adherence invirological suppression in patients receiving anti-HBV analogues:implications for clinical management. Antivir Ther.2012;17:395-400
35Chotiyaputta W, Peterson C, Ditah FA, et al. Persistence and adherence tonucleos(t)ide analogue treatment for chronic hepatitis B. J Hepatol.2011;54:12-18
36Buti M, Morillas RM, Prieto M, et al. A viral load reduction>3log at12week of Entecavir treatment correlated with HBe seroconversion inpositive patients. Results from a real-life setting study (the ORIENTEstudy). Hepatology.2010;52(Suppl1). Abstract409
37Ridruejo E, Adrovar R, Cocozella D, et al. Effectiveness of entecavir inchronic hepatitis B NUC-na¨ve patients in routine clinical practice. Int JClin Pract.2011;65:866-70
38Carey I, Nguyen H-L, Joe D, et al. De-novo antiviral therapy withnucleos(t)ide analogues in ‘real-life’ patients with chronic hepatitis Binfection: comparison of virological responses betweenlamivudine+adefovir, entecavir vs. tenofovir therapy. Hepatology.2011;54(Suppl1):1022A. Abstract1396
39Zoutendijk R, Reijnders JG, Brown A, et al. Entecavir treatment forchronic hepatitis B: adaptation is not needed for the majority of naivepatients with a partial virological response. Hepatology.2011;54:443-51
40Lampertico P, Vigano M, Soffredini R, et al. Entecavir monotherapy fornuc-naive chronic hepatitis B patients from field practice: high efficacy andfavorable safety profile over3years. Hepatology.2011;54(Suppl1):1043A. Abstract1436
41Seto WK, Lai CL, Fung J, et al. Outcome of4-year treatment of entecavirfor treatment-na¨ve chronic hepatitis B. J Hepatol.2011;54:S301
42Yuen MF, Seto WK, Fung J, et al. Three years of continuous entecavirtherapy in treatment-na¨ve chronic hepatitis B patients: VIRALsuppression, viral resistance, and clinical safety. Am J Gastroenterol.2011;106:1264-71
43Lampertico P, Soffredini R, Vigano`M, et al.2year effectiveness andsafety of tenofovir in302NUC-naive patients with chronic hepatitis B: amulticenter European study in clinical practice. Hepatology.2011;54(Suppl1):1041A. Abstract1433
44Lok AS, Trinh H, Carosi G, et al. Entecavir (ETV) monotherapy for96weeks is comparable to combination therapy with ETV plus tenofovir(TDF) in nucleos(t)ide-na¨ve patients with chronic hepatitis B (CHB): theBE-LOW study. Hepatology.2011;54(Suppl1):471A. Abstract471A
45Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities andchallenges in Asia. J Hepatol.2009;51:403-10
46Liaw YF, Sung JJY, Chow WC, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med.2004;351:1521-31PAGE fraction trail=7Review
2Kao JH, Chen DS. Global control of hepatitis B virus infection. LancetInfect Dis2002;2:395-403
3European Association For The Study Of The Liver. EASL ClinicalPractice Guidelines: management of chronic hepatitis B. J Hepatol2009;50(2):227-242
4Liaw YF, Sung JJ, Chow WC, et al. Cirrhosis Asian LamivudineMulticentre Study Group. Lamivudine for patients with chronic hepatitis Band advanced liver disease. N Engl J Med2004;351:1521-1531
5Liaw YF. Hepatitis B virus replication and liver disease progression: theimpact of antiviral therapy. Antivir Ther2006;11:669-679
6The Chinese Liver Disease Association, Chinese Medical AssociationInfectious Disease Branch. Chinese consensus statement on themanagement of chronic hepatitis B: a2010update. Chin J Exp Clin InfectDis (Electronic Edition)2011;5:79-100
7Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysisevaluating the relative efficacy of nucleos(t)ides for treatment ofnucleos(t)ide-naive patients with chronic hepatitis B. Value Health2010;13:934-945
8Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-6
9Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat. Immunol2003;4:63-8
10Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature2009;461:399-401
11Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet2009;41:1100-1104
12Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapyfor chronic hepatitis C. Nat Genet2009;41(10):1105-1109
13Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study. Gastroenterology2009;138:1338-1345
14Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in-positive patients withchronic hepatitis B. Gastroenterology2012;142:513-520
15Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), atype III IFN, is induced by viruses and IFNs and displays potent antiviralactivity against select virus infections in vivo. J Virol2006;80:4501-4509.
16Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. JInterferon Cytokine Res2006;26:373-379
17Beom KK, Han KH, Jun YP, et al. A novel liver stiffnessmeasurement-based predictionmodel for cirrhosis in hepatitis B patients.liver int2010;30:1073-1081
18Seung UK, Ja KK, Young NP, et al. Discordance between Liver Biopsyand FibroScanH in Assessing Liver Fibrosis in Chronic Hepatitis B: RiskFactors and Influence of Necroinflammation. PLoS One2012;7:e32233
19Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine and24weeks oflamivudine/interferon combination therapy for hepatitis B eantigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol2003;38:818-826
20Jin YJ, Shim JH, Chung YH, et al. HLA-DRB1*010101allele is closelyassociated with poor virological response to lamivudine therapy in patientswith chronic hepatitis B. Digestion2011;84Suppl1:35-42
21Park YK, Lee JM, Kim do Y, et al. Association between polymorphism oftumor necrosis factor-alpha promoter and response to lamivudinetreatment in patients with chronic hepatitis B. Dig Dis Sci2010;55:2043-2048
22Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-inducible genesOAS associated with interferon-α treatment response in chronic HBVinfection. Antiviral Res2011;89:232-237
23King JK, Yeh SH, Lin MW, et al. Genetic polymorphisms in interferonpathway and response to interferon treatment in hepatitis B patients: Apilot study. Hepatology2002;36:1416-1424
24Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
25Abe H, HayesZeng YL CN, Ochi H, et al. IL28Variation affectsexpression of interferon stimulated genes and effect of peginterferon andribavirin therapy. J Hepatol2011;54:1094-1101
26Chen CM, Zhou FY, Zhou YP, et al. Relationship between singlenucleotide polymorphisms in IL28B gene and response to interferontreatment in chronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao2011;31:2012-2015
27Moreira S, Garcia RF, Gutberlet A, et al. A straightforward genotyping ofthe relevant IL28B SNPs for the prediction of hepatitis C treatmentoutcome. J Virol Methods2012;184:93-7
28Shi X, Pan Y, Wang M, et al. IL28B Genetic Variation Is Associated withSpontaneous Clearance of Hepatitis C Virus, Treatment Response, SerumIL-28B Levels in Chinese Population. PLoS One2012;7:e37054
29Poordad F, Bronowicki JP, Gordon SC, et al. Factors That PredictResponse of Patients With Hepatitis C Virus Infection to Boceprevir.Gastroenterology2012; doi:10.1053/j.gastro.2012.05.011
30Jiao XL, Gao YT, Jing L, et al, Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-7
31Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
32Li Y, Shi Y, Chen J. Association of polymorphisms in interleukin-18andinterleukin-28B with Hepatitis B recurrence after liver transplantation inChinese Han population. Int J Immunogenet2012;39:346-352
33Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Hanpopulation. Liver Int2011;31:1118-1126
1Liaw YF, Chu CM. Hepatitis B virus infection. Lancet.2009;373:582-92
2Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment,and current and emerging prevention and control measures. J Viral Hepat,2004.11:97-107
3Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer:an overview. Asian Pac J Cancer Prev,2004.5:118-25
4Zoulim F, Locarnini SA. Hepatitis B virus resistance to nucleos(t)ideanalogues. Gastroenterology2009;137:1593-1608
5Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine,and the combination for-positive chronic hepatitis B. N Engl J Med2005;352:2682-95
6Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone,lamivudine alone, and the two in combination in patients with-negativechronic hepatitis B. N Engl J Med2004;351:1206-17
7Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferonalfa-2b alone or in combination with lamivudine for-positive chronichepatitis B: a randomised trial. Lancet2005;365:123-129
8Gish, RG. Current treatment and future directions in the management ofchronic hepatitis B viral infection. Clin Liver Dis2005;9:541-565
9Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-106
10Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat Immunol2003;4:63-68
11Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature2009;461:399-401
12Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet2009;41:1100-1104
13Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapyfor chronic hepatitis C. Nat Genet2009;41:1105-1109
14Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study. Gastroenterology2009;138:1338-1345
15Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in-positive patients withchronic hepatitis B. Gastroenterology2012;142:513-520
16Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), atype III IFN, is induced by viruses and IFNs and displays potent antiviralactivity against select virus infections in vivo. J Virol2006;80:4501-4509
17Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. JInterferon Cytokine Res2006;26:373-379
18Suzuki F, Arase Y, Suzuki Y, et al. Single nucleotide polymorphism of theMxA gene promoter influences the response to interferon monotherapy inpatients with hepatitis C viral infection. J Viral Hepatol2004;11:271-276
19Ovsyannikova IG, Ryan JE, Vierkant RA, et al. Influence of host geneticvariation on rubella-specific T cell cytokine responses followingrubella vaccination. Vaccine2009;27:3359-3366
20Peng LJ, Guo JS, Zhang Z, et al. IL28B rs12979860polymorphism doesnot influence outcomes of hepatitis B virus infection. Tissue Antigens2012;79:302-305
21Ren S, Yu H, Zhang H, et al. Polymorphisms of interferon-induciblegenes OAS associated with interferon-α treatment response in chronicHBV infection. Antiviral Res2011;89:232-237
22King JK, Yeh SH, Lin MW, et al. Genetic polymorphisms in interferonpathway and response to interferon treatment in hepatitis B patients: Apilot study. Hepatology2002;36:1416-1424
23Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
24Xu HT, Xing TJ, Li H, et al. Association of T regulatory cells with naturalcourse and response to treatment with interferon-α in patients with chronichepatitis B infection. Chinese Medical Journal2012;125:1465-1468
25Abe H, HayesZeng YL CN, Ochi H, et al. IL28Variation affectsexpression of interferon stimulated genes and effect of peginterferon andribavirin therapy. J Hepatol2011;54:1094-1101
26Chen CM, Zhou FY, Zhou YP,et al. Relationship between single nucleotidepolymorphisms in IL28B gene and response to interferon treatment inchronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao (Chin)2011;31:2012-2015
27Moreira S, Garcia RF, Gutberlet A, et al. A straightforward genotyping ofthe relevant IL28B SNPs for the prediction of hepatitis C treatmentoutcome. J Virol Methods2012;184:93-97
28Shi X, Pan Y, Wang M, et al. IL28B Genetic Variation Is Associated withSpontaneous Clearance of Hepatitis C Virus, Treatment Response, SerumIL-28B Levels in Chinese Population. PLoS One2012;7: e37054
29Poordad F, Bronowicki JP, Gordon SC, et al. Factors That PredictResponse of Patients With Hepatitis C Virus Infection to Boceprevir.Gastroenterology2012;143:608-618
30Jiao XL, Gao YT, Jing L, et al. Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-1147
31Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
32Li Y, Shi Y, Chen J, et al. Association of polymorphisms in interleukin-18and interleukin-28B with Hepatitis B recurrence after liver transplantationin Chinese Han population. Int J Immunogenet2012;39:346-352.
33Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Hanpopulation. Liver Int2011;31:1118-1126
34Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. NatRev Cancer2006;6:459-471
35Ahmed T, Shea K, Masters JR, et al. A PAK4-LIMK1pathway drivesprostate cancer cell migration downstream of HGF. Cell Signalling2008;20:1320-1328
36Zhang H, Li Z, Viklund EK, et al. P21-activated kinase4interacts withintegrin αvβ5and regulates αvβ5-mediated cell migration. J Cell Biol2002;158:1287-1297
37Chen S, Auletta T, Dovirak O, et al. Copy number alterations in pancreaticcancer identify recurrent PAK4amplification. Cancer Biol Ther2008;7:1793-1802
38Kimmelman AC, Hezel AF, Aguirre AJ, et al. Genomic alterations linkRho family of GTPases to the highly invasive phenotype of pancreascancer. Proc Natl. Acad Sci2008;105:19372-19377
39Mak GW, Chan MM, Leong VY, et al. Overexpression of a novel activatorof PAK4, the CDK5kinase-associated protein CDK5RAP3,promotes hepatocellular carcinoma metastasis. Cancer Res2011;8:2949-2958
1Hou J, Liu Z, Gu F. Epidemiology and Prevention of Hepatitis B VirusInfection. Int J Med Sci,2005,2(1):50-57
2Liaw YF, Chu CM. Hepatitis B virus infection. Lancet,2009,373(9663):582-592
3Boonstra A, Woltman A M, Janssen H L. Immunology of hepatitis B andhepatitis C virus infections. Best Pract Res Clin Gastroenterol,2008.22(6):1049-61
4Tseng L H, Lin M T, Shau W Y, et al. Correlation of interleukin-10genehaplotype with hepatocellular carcinoma in Taiwan. Tissue Antigens,2006.67(2):127-33
5Kim Y J, Lee H S, Yoon J H, et al. Association of TNF-alpha promoterpolymorphisms with the clearance of hepatitis B virus infection. Hum MolGenet,2003.12(19):2541-6
6Liaw YF. Hepatitis B virus replication and liver disease progression: theimpact of antiviral therapy. Antivir Ther2006;11:669-679
7Zoulim F, Locarnini SA. Hepatitis B virus resistance to nucleos(t)ideanalogues. Gastroenterology2009;137:1593-1608
8Gish, RG. Current treatment and future directions in the management ofchronic hepatitis B viral infection. Clin Liver Dis2005;9:541-565
9Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysisevaluating the relative efficacy of nucleos(t)ides for treatment ofnucleos(t)ide-naive patients with chronic hepatitis B. Value Health2010;13:934-945
10Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-alpha and ribavirin therapy forchronic hepatitis C. Nat Genet,2009,41(10):1105-1109
11Ge D, Fellay J, Thompson A J, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature,2009,461:399-401
12Suppiah V, Moldovan M,Ahlenstiel G,et al. IL28B is associated withresponse to chronic hepatitis C interferon-alpha and ribavirin therapy. NatGenet,2009,41(10):1100-1104
13Rauch A, Kutalik Z, Deseombes P,et al. Genetic variation in IL28B isassociated with chronic hepatitis C and treatment failure: a genome-wideassociation study.Gastroenterology,2010,138(4):1338-1345
14Thomas DL,Thio CL,Martin MP, et al. Genetic variation in IL28B and tospontaneous clearance of hepatitis C virus. Nature,2009,461:798-801
15Jiao XL, Gao YT, Jing L, et al. Studies on the relationship betweenpolymorphism of IL-28B rs8099917and the outcome of HBV infection.Zhonghua Liu Xing Bing Xue Za Zhi2011;32:1143-7
16Tai-Chung Tseng, Ming-Lung Yu, Chun-Jen Liu. Effect of host and viralfactors on hepatitis B e antigen-positive chronic hepatitis B patientsreceiving pegylated interferon-a-2a therapy. Antiviral Therapy2011;16:629-637
17Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res2012;93:297-300
18Li Y, Shi Y, Chen J. Association of polymorphisms in interleukin-18andinterleukin-28B with Hepatitis B recurrence after liver transplantation inChinese Han population. Int J Immunogenet2012;39:346-352
19Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Han population.Liver Int2011;31:1118-1126
20Kempuraj D, Donelan J, Frydas S, et al. Interleukin-28and29(IL-28andIL-29): new cytokines with anti-viral activities. Int J ImmunopatholPharmacol2004;17:103-6
21Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat. Immunol2003;4:63-8
22Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29and their class IIcytokine receptor IL-28R. Nat Immunol,2003,4(1):63-68
23Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviralprotection through a distinct class II cytokine receptor complex. NatImmunol,2003,4(1):69-77
24Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, et al.Meta-analysis: implications of interleukin-28B polymorphisms inspontaneous and treatment-related clearance forpatients with hepatitis C.BMC Med.2013Jan8;11:6. doi:10.1186/1741-7015-11-6
25Wu LS, Wang H, Geng XP. Two IL28B polymorphisms are associated withthe treatment response of different genotypes of hepatitis C indifferentracial populations: A meta-analysis. Exp Ther Med.2012Feb;3(2):200-206.Epub2011Nov21
26Li S, Hu P, Zhang QQ, et al. Single nucleotide polymorphisms of theIL28B and sustained virologic response of patients with chronic hepatitisCto PEG-interferon/ribavirin therapy: A meta-analysis: Meta-analysis ofIL28B. Hepat Mon.2011Mar;11(3):163-72
27Zheng MH, Li Y, Xiao DD, et al. Interleukin-28B rs12979860C/T andrs8099917T/G contribute to spontaneous clearance of hepatitis C virus inCaucasians. Gene.2013Apr15;518(2):479-82. doi:10.1016/j.gene.2012.12.067. Epub2012Dec20
28Shi KQ, Liu WY, Lin XF,et al. Interleukin-28B polymorphisms on the SVRin the treatment of na ve chronic hepatitis C with pegylated interferon-αplus ribavirin: a meta-analysis. Gene.2012Oct1;507(1):27-35. doi:10.1016/j.gene.2012.07.026. Epub2012Jul25
29Romero-Gomez M, Eslam M, Ruiz A, et al. Genes and hepatitis C:susceptibility, fibrosis progression and response to treatment. Liver Int.2011Apr;31(4):443-60. doi:10.1111/j.1478-3231.2011.02449.x. Epub2011Jan30
30Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does notdetermine outcomes of hepatitis B virus or HIV infection. J Infect Dis.2010Dec1;202(11):1749-53. doi:10.1086/657146. Epub2010Oct26
31Martín-Carbonero L, Rallón NI, Benito JM, et al. Short communication:Does interleukin-28B single nucleotide polymorphisms influence thenatural history of hepatitis B? AIDS Res Hum Retroviruses.2012Oct;28(10):1262-4. Epub2012Mar23
32Ren S, Lu J, Du X,et al. Genetic variation in IL28B is associated with thedevelopment of hepatitis B-related hepatocellular carcinoma. CancerImmunol Immunother.2012Sep;61(9):1433-9. doi:10.1007/s00262-012-1203-y. Epub2012Feb4
33Peng LJ, Guo JS, Zhang Z,et al. IL28B rs12979860polymorphism doesnot influence outcomes of hepatitis B virus infection. Tissue Antigens.2012Apr;79(4):302-5. doi:10.1111/j.1399-0039.2011.01835.x. Epub2012Jan13
34Li W, Jiang Y, Jin Q, et al. Expression and gene polymorphisms ofinterleukin28B and hepatitis B virus infection in a Chinese Han population.Liver Int.2011Sep;31(8):1118-26. doi:10.1111/j.1478-3231.2011.02507.x.Epub2011Mar30
35Holmes JA, Nguyen T, Ratnam D, et al. IL28B GENOTYPE IS NOTUSEFUL FOR PREDICTING TREATMENT OUTCOME IN ASIANCHRONIC HEPATITIS B PATIENTS TREATED WITHPEGYLATED-INTERFERON-αJ Gastroenterol Hepatol.2013Jan9. doi:10.1111/jgh.12110.[Epub ahead of print]
36Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms near IL28Band serologic response to peginterferon in-positive patients withchronichepatitis B. Gastroenterology.2012Mar;142(3):513-520.e1. doi:10.1053/j.gastro.2011.11.025. Epub2011Nov19
37de Niet A, Takkenberg RB, Benayed R, et al. Genetic variation in IL28Band treatment outcome in-positive annegative chronic hepatitis Bpatientstreated with Peg interferon alfa-2a and adefovir. Scand JGastroenterol.2012Apr;47(4):475-81. doi:10.3109/00365521.2011.648952. Epub2012Jan23.
38Lampertico P, Viganò M, Cheroni C, et al. IL28B polymorphisms predictinterferon-related hepatitis B surface antigen seroclearance in genotype Dhepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology.
2013Mar;57(3):890-6. doi:10.1002/hep.25749. Epub2012Dec20
39Chen CM, Zhou FY, Zhou YP, et al. Relationship between single nucleotidepolymorphisms in IL28B gene and response to interferon treatmentinchronic hepatitis B patients. Nan Fang Yi Ke Da Xue Xue Bao.2011Dec;31(12):2012-5
40焦晓磊，高英堂，景丽，等. IL-28B遗传多态性与乙型肝炎病毒感染后病毒自然清除和疾病进展关系的研究《中华流行病学杂志》2011,32(11)
41Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus forresponse to interferon-α based therapy in chronic hepatitis B patientsinChinese. Antiviral Res.2012Feb;93(2):297-300. doi:10.1016/j.antiviral.2011.12.009. Epub2011Dec19
42Tseng TC, Yu ML, Liu CJ, et al. Effect of host and viral factors on hepatitisB e antigen-positive chronic hepatitis B patients receiving pegylatedinterferon-α-2a therapy. Antivir Ther.2011;16(5):629-37
1European Association for the Study of the Liver. EASL Clinical PracticeGuidelines: management of chronic hepatitis B. J Hepatol2009;50:227-242
2Lok AS, McMahon BJ. Chronic hepatitis B: update2009. Hepatology2009;50:661-662
3Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statementon the management of chronic hepatitis B: a2012update. Hepatol Int.2012;6:531-561
4Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predictshepatitis C treatment-induced viral clearance. Nature.2009;46:399-401
5Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated withresponse to chronic hepatitis C interferon-a and ribavirin therapy. NatGenet2009;41:1100-4
6Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association ofIL28B with response to pegylated interferon-a and ribavirin therapy forchronic hepatitis C. Nat Genet.2009;41:1105-9
7Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does notdetermine outcomes of hepatitis B virus or HIV infection. J Infect Dis.2010;202:1749-53
8Tseng TC, Yu ML, Liu CJ, et al. Effect of host and viral factors onhepatitis B e antigen-positive chronic hepatitis B patients receivingpegylated interferon alpha-2a therapy. Antivir Ther.2011;16:629-37
9Sonneveld MJ, Wong VW, Woltman AM, et al. Polymorphisms nearIL28B and serologic response to peginterferon in positive patients withchronic hepatitis B. Gastroenterology.2012;142:513-20
10Wu X, Xin Z, Zhu X, et al. Evaluation of susceptibility locus for responseto interferon-alpha based therapy in chronic hepatitis B patients in Chinese.Antiviral Res.2012;93:297-300
11Lampertico P, Vigano`M, Cheroni C, et al. Genetic variation in IL28Bpolymorphism may predict HBsAg clearance in genotype D, negativepatients treated with interferon alfa. Hepatology2010;52(suppl):442A
12Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses ofpeginterferon alfa-2a are associated with inferior hepatitis B e antigenseroconversion rates in hepatitis B virus genotypes B or C. Hepatology.2011;54:1591-9
13Brunetto MR. A new role for an old marker, HBsAg. J Hepatol2010;52:475-7
14Chan HL, Thompson A, Martinot-Peignoux M, et al. Hepatitis B surfaceantigen quantification: why and how to use it in2011dacore group report. JHepatol.2011;55:1121-31
15Liaw YF. Clinical utility of hepatitis B surface antigen quantitation inpatients with chronic hepatitis B: a review. Hepatology.2011;54: E1-9.
16Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigenand hepatitis B e antigen titers: disease phase influences correlation withviral load and intrahepatic hepatitis B virus markers. Hepatology.2010;51:1933-44
17Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: astrong predictor of sustained virological response to pegylated interferonalfa-2a in-negative patients. Hepatology.2009;49:1151-7
18Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustainedresponse to peginterferon alfa-2b for hepatitis B e antigen-positive chronichepatitis B using on-treatment hepatitis B surface antigen decline.Hepatology.2010;52:1251-7
19Piratvisuth T, Marcellin P. Further analysis is required to identify an earlystopping rule for peginterferon therapy that is valid for all-positive patients.Hepatology.2011;53:1054-5
20Piratvisuth T, Marcellin P, Popescu M, et al. Hepatitis B surface antigen:association with sustained response to peginterferon alfa-2a in hepatitis B eantigen-positive patients. Hepatol Int. Published Online First:24June2011.doi:10.1007/s12072-011-9280-0
21Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment predictionof response to peginterferon alfa-2a for-negative chronic hepatitis B usingHBsAg and HBV DNA levels. Hepatology.2010;52:454-61
22Rijckborst V, Hansen B, Ferenci P, et al. Validation of a stopping rule atweek12using HBsAg and HBV DNA for-negative patients treated withpeginterferon alfa-2a. J Hepatol. Published Online First:13January2012.doi:10.1016/j.jhep.2011.12.007
23Lampertico P, Vigano M, Di Costanzo GG, et al. A response guidedapproach to peg-interferon alfa-2a at weeks12and24improves responserates in-negative, genotype D chronic hepatitis B patients. Hepatology.2011;54:1021A
24Brunetto MR, Marcellin P, Cherubini B, et al. response to peginterferonalfa-2a in negative CHB: baseline and ontreatment kinetics of HBsAgserum levels vary according to HBV genotype. Hepatology.2011;54:1059A
25Moucari R, Martinot-Peignoux M, Mackiewicz V, et al. Influence ofgenotype on hepatitis B surface antigen kinetics in hepatitis B eantigen-negative patients treated with pegylated interferon-alpha2a.Antivir Ther.2009;14:1183-8
26Chang TT, Lai CL, Kew YS, et al. Entecavir treatment for up to5years inpatients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology.2010;51:422-30
27Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring showshepatitis B virus resistance to entecavir in nucleoside-na ve patients is rarethrough5years of therapy. Hepatology.2009;49:1503-14
28Manns M, Akarca US, Chang TT, et al. Low rates ofnucleos(t)ideassociated adverse events in the long-term experience withentecavir. J Hepatol.2010;52:S393
29Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety oftenofovir disoproxil fumarate treatment for chronic hepatitis B.Gastroenterology.2011;140:132-43
30Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovirDF (TDF) for chronic hepatitis B (CHB) infection is associated withsustained viral suppression and significant regression of histologicalfibrosis and cirrhosis. Hepatology.2011;54(Suppl1):1011A-12A. Abstract1375
31Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovirdisoproxil fumarate detected after up to144weeks of therapy in patientsmonoinfected with chronic hepatitis B virus. Hepatology.2011;53:763-73
32Liaw YF, Sheen IS, Lee CM, et al. Tenofovir Disoproxil Fumarate (TDF),Emtricitabine/TDF and Entecavir in patients with decompensated chronichepatitis B liver disease. Hepatology.2011;53:62-72
33Liaw YF, Raptopoulou-Gigi M, Cheinquer H, et al. Efficacy and safety ofentecavir versus adefovir in chronic hepatitis B patients with hepaticdecompensation: a randomized open-label study. Hepatology.2011;54:91-100
34Sogni P, Carrieri MP, Fontaine H, et al. The role of adherence invirological suppression in patients receiving anti-HBV analogues:implications for clinical management. Antivir Ther.2012;17:395-400
35Chotiyaputta W, Peterson C, Ditah FA, et al. Persistence and adherence tonucleos(t)ide analogue treatment for chronic hepatitis B. J Hepatol.2011;54:12-18
36Buti M, Morillas RM, Prieto M, et al. A viral load reduction>3log at12week of Entecavir treatment correlated with HBe seroconversion inpositive patients. Results from a real-life setting study (the ORIENTEstudy). Hepatology.2010;52(Suppl1). Abstract409
37Ridruejo E, Adrovar R, Cocozella D, et al. Effectiveness of entecavir inchronic hepatitis B NUC-na¨ve patients in routine clinical practice. Int JClin Pract.2011;65:866-70
38Carey I, Nguyen H-L, Joe D, et al. De-novo antiviral therapy withnucleos(t)ide analogues in ‘real-life’ patients with chronic hepatitis Binfection: comparison of virological responses betweenlamivudine+adefovir, entecavir vs. tenofovir therapy. Hepatology.2011;54(Suppl1):1022A. Abstract1396
39Zoutendijk R, Reijnders JG, Brown A, et al. Entecavir treatment forchronic hepatitis B: adaptation is not needed for the majority of naivepatients with a partial virological response. Hepatology.2011;54:443-51
40Lampertico P, Vigano M, Soffredini R, et al. Entecavir monotherapy fornuc-naive chronic hepatitis B patients from field practice: high efficacy andfavorable safety profile over3years. Hepatology.2011;54(Suppl1):1043A. Abstract1436
41Seto WK, Lai CL, Fung J, et al. Outcome of4-year treatment of entecavirfor treatment-na¨ve chronic hepatitis B. J Hepatol.2011;54:S301
42Yuen MF, Seto WK, Fung J, et al. Three years of continuous entecavirtherapy in treatment-na¨ve chronic hepatitis B patients: VIRALsuppression, viral resistance, and clinical safety. Am J Gastroenterol.2011;106:1264-71
43Lampertico P, Soffredini R, Vigano`M, et al.2year effectiveness andsafety of tenofovir in302NUC-naive patients with chronic hepatitis B: amulticenter European study in clinical practice. Hepatology.2011;54(Suppl1):1041A. Abstract1433
44Lok AS, Trinh H, Carosi G, et al. Entecavir (ETV) monotherapy for96weeks is comparable to combination therapy with ETV plus tenofovir(TDF) in nucleos(t)ide-na¨ve patients with chronic hepatitis B (CHB): theBE-LOW study. Hepatology.2011;54(Suppl1):471A. Abstract471A
45Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities andchallenges in Asia. J Hepatol.2009;51:403-10
46Liaw YF, Sung JJY, Chow WC, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med.2004;351:1521-31PAGE fraction trail=7Review