Effect of HBV DNA Methylation and the Mutant 1762T/1764A on Viral Load and HCC

HBV DNA 甲基化和突变体 1762T/1764A 对病毒载量和 HCC 的影响

• 批准号: 7579180
• 负责人: KATHLEEN SCHWARZ
• 金额: $ 9.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579180
• 关键词: Adolescent; Adult; African American; Age; Age-Years; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Asians; Baltimore; Biological Assay; Biological Markers; Caring; Characteristics; Child; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Combined Modality Therapy; Controlled Clinical Trials; CpG Islands; DNA; DNA Methylation; Databases; Development; Diagnosis; Disease Progression; Enhancers; Frequencies; Genes; Goals; Health; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Histologic; Immunomodulators; Individual; Initiator Codon; Institution; Interferons; Light; Medical; Methylation; Outcome; Patients; Placebo Control; Population; Primary carcinoma of the liver cells; Principal Investigator; Promoter Regions; Protocols documentation; Randomized; Randomized Controlled Trials; Rate; Reporting; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sensitivity and Specificity; Serum; Site; Structure; Surface; Testing; Viral; Viral Drug Resistance; Viral Load result; Week; Youth; entecavir; experience; improved; mutant; new technology; novel; nucleoside analog; promoter; response; sex; viral DNA; Adolescent; Adult; African American; Age; Age-Years; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Asians; Baltimore; Biological Assay; Biological Markers; Caring; Characteristics; Child; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Combined Modality Therapy; Controlled Clinical Trials; CpG Islands; DNA; DNA Methylation; Databases; Development; Diagnosis; Disease Progression; Enhancers; Frequencies; Genes; Goals; Health; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Histologic; Immunomodulators; Individual; Initiator Codon; Institution; Interferons; Light; Medical; Methylation; Outcome; Patients; Placebo Control; Population; Primary carcinoma of the liver cells; Principal Investigator; Promoter Regions; Protocols documentation; Randomized; Randomized Controlled Trials; Rate; Reporting; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sensitivity and Specificity; Serum; Site; Structure; Surface; Testing; Viral; Viral Drug Resistance; Viral Load result; Week; Youth; entecavir; experience; improved; mutant; new technology; novel; nucleoside analog; promoter; response; sex; viral DNA

DESCRIPTION (provided by applicant): A high HBV viral load has been implicated in both disease progression and resistance to antiviral therapy in Asian adults; however this role has not been clarified in other populations such as children and non-Asian adults (both of which typify our Baltimore population of HBV-infected individuals.) Furthermore, viral determinants of HBV viral replication rates have not been fully elucidated in any population. Our group has recently reported two findings which could shed new light on these determinants: 1) Methylation of HBV DNA occurs in non-integrated as well as integrated HBV and may down regulate viral replication and 2) The novel double mutant HBV 1762T/1764A, with overlapping sequences for the HBV core promoter and the HBV S gene, increases viral replication in Asian adults. This mutant has greater sensitivity and specificity for both diagnosing and predicting hepatocellular carcinoma (HCC) in Asian adults compared to other HCC biomarkers. We propose to use these novel findings in both a database and a clinical trial. The database will contain all HBV-infected individuals cared for in the Johns Hopkins Medical Institutions which we estimate will contain ~ 100 children and adolescents and ~650 adults of whom - 50% are African American, 300 are HBV/HIV co-infected; 150 are HBV/HIV/HCV tri-infected, and 50 have HCC. For the database protocol we will analyze sera for both HBV DNA methylation and the double mutant to test two hypotheses: 1) In patients with methylated serum HBV DNA, HBV DNA viral load will be lower compared to patients with non-methylated serum HBV DNA and 2) In patients with HBV HCC, HBV viral loads will be higher, HBV DNA methylation rates lower, and the double mutant frequency increased compared to age and sex-matched HBV-infected controls. The clinical trial will be a sequential randomized controlled trial in immunotolerant subjects 5 - 21 years (HBsAg+,HBeAG+, HBV DNA >10(4)cpm), to determine if lowering the HBV viral load by a nucleoside analogue(NA) followed by an immunomodulator will improve response compared to (NA) alone. Group 1 will receive entecavir(ETV) for 8 weeks followed by pegylated interferon + ETV for 40 weeks; Group 2 will receive ETV alone. Response will be defined by HBeAg loss/ HBV DNA < 200 cpm at 48 weeks.

描述（由申请人提供）：高HBV病毒载量与亚洲成年人的疾病进展和抗病疗法的抗性有关。但是，在其他人群（例如儿童和非亚洲成年人）中尚未阐明这一角色（这两者都代表了我们的巴尔的摩人的HBV感染者人口。我们的小组最近报道了两种发现，这些发现可能对这些决定因素有了新的启示：1）HBV DNA的甲基化发生在非集成和整合的HBV中，并可能调节病毒复制，2）新型双重突变HBV 1762T/1764a，HBV Core Core的促进者和HBV的重叠序列，Anbv afterian和HBV的Gene Anter nige in Vir in Vir signe nive nive。与其他HCC生物标志物相比，该突变体对亚洲成年人的诊断和预测肝细胞癌（HCC）具有更大的敏感性和特异性。我们建议在数据库和临床试验中使用这些新发现。该数据库将包含所有在约翰霍普金斯医疗机构中照顾的HBV感染的人，我们估计，这些人将包含约100名儿童和青少年，其中约有650名成年人-50％是非裔美国人，300名HBV/HIV共同感染； 150是HBV/HIV/HCV TRI感染，50个具有HCC。对于数据库方案，我们将分析血清的HBV DNA甲基化和双突变体以检验两个假设：1）在甲基化血清HBV DNA的患者中，HBV DNA病毒载荷将较低，而非甲基化血清HBV HBV DNA的患者在HBV HCC的患者中，HBV病毒率较高，而HBV病毒率较高，而HBV病毒率较高，而HBV病毒率较高。与年龄和性别匹配的HBV感染对照相比增加。该临床试验将是5-21岁的免疫剂受试者中的顺序随机对照试验（HBSAG+，HBEAG+，HBV DNA> 10（4）CPM），以确定降低核苷类似物（NA）的HBV病毒载荷是否会降低HBV病毒载荷，然后再进行免疫调节剂的响应，而不是（NA）与（NA）相比。第1组将在8周内接收Entecavir（ETV），然后接受pegymated Intferon + ETV 40周；第2组将单独接收ETV。响应将由HBEAG损失/ HBV DNA <200 cpm在48周定义。