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: 7693738
• 负责人: KATHLEEN SCHWARZ
• 金额: $ 24.21万
• 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/7693738
• 关键词: 18 year old; 21 year old; Adolescent; Adult; African American; Age; Antiviral Agents; Antiviral Therapy; 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; Patients; Placebo Control; Population; Primary carcinoma of the liver cells; Principal Investigator; Promoter Regions; Protocols documentation; Randomized; Randomized Controlled Trials; 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; Youth; entecavir; experience; improved; mutant; new technology; novel; nucleoside analog; primary outcome; promoter; response; sex

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（由申请方提供）：高HBV病毒载量与亚洲成人的疾病进展和抗病毒治疗耐药有关;然而，在其他人群中，如儿童和非亚洲成人（这两种人群均代表我们的巴尔的摩HBV感染人群），尚未阐明该作用。此外，HBV病毒复制率的病毒决定因素尚未在任何人群中完全阐明。我们的研究小组最近报道了两项发现，这可能为这些决定因素提供新的线索：1）HBV DNA的甲基化发生在非整合型和整合型HBV中，并可能下调病毒复制; 2）新的双突变型HBV 1762 T/1764 A，具有HBV核心启动子和HBV S基因的重叠序列，增加了亚洲成年人的病毒复制。与其他HCC生物标志物相比，该突变体在诊断和预测亚洲成人肝细胞癌（HCC）方面具有更高的灵敏度和特异性。我们建议在数据库和临床试验中使用这些新发现。该数据库将包含在约翰霍普金斯医疗机构接受治疗的所有HBV感染者，我们估计将包含约100名儿童和青少年和约650名成人，其中50%为非洲裔美国人，300名为HBV/HIV合并感染者; 150名为HBV/HIV/HCV三重感染者，50名患有HCC。对于数据库方案，我们将分析血清中的HBV DNA甲基化和双突变体，以检验两个假设：1）在具有甲基化血清HBV DNA的患者中，HBV DNA病毒载量将低于具有非甲基化血清HBV DNA的患者，和2）在具有HBV HCC的患者中，HBV病毒载量将更高，HBV DNA甲基化率更低，与年龄和性别匹配的HBV感染对照组相比，双突变频率增加。该临床试验将是一项在5 - 21岁免疫耐受受试者（HBsAg+，HBeAg+，HBV DNA >10（4）cpm）中进行的序贯随机对照试验，以确定通过核苷类似物（NA）降低HBV病毒载量，然后使用免疫调节剂与单独使用（NA）相比是否会改善应答。第1组接受恩替卡韦（ETV）治疗8周，随后接受聚乙二醇干扰素+ ETV治疗40周;第2组仅接受ETV治疗。缓解将定义为48周时HBeAg丢失/ HBV DNA < 200 cpm。