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

基本信息

批准号：
8723809
负责人：
KATHLEEN SCHWARZ
金额：
$ 26.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723809
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 Disease Resistance Enhancers Frequencies Genes Goals HIV Health Hepatitis B Hepatitis B Surface Antigens Hepatitis B Virus Hepatitis B e Antigens Hepatitis C virus 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

项目摘要

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毒治疗耐药性有关；然而，这种作用在其他人群中尚未得到阐明，例如儿童和非亚洲成年人（这两种人群都是巴尔的摩 HBV 感染者人群的典型代表。）此外，在任何人群中，HBV 病毒复制率的病毒决定因素尚未得到充分阐明。我们的小组最近报告了两项研究结果，可能为这些决定因素提供新的线索：1) HBV DNA 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) 新型双突变型 HBV 1762T/1764A， HBV 核心启动子和 HBV S 基因的重叠序列可增加亚洲成人中的病毒复制。与其他 HCC 生物标志物相比，该突变体对于诊断和预测亚洲成人肝细胞癌 (HCC) 具有更高的敏感性和特异性。我们建议在数据库和临床试验中使用这些新发现。该数据库将包含约翰·霍普金斯医疗机构护理的所有 HBV 感染者，我们估计将包含约 100 名儿童和青少年以及约 650 名成年人，其中 50% 是非裔美国人，300 人是 HBV/HIV 双重感染者； 150 人患有 HBV/HIV/HCV 三重感染，50 人患有 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，以测试两个假设：1) 在血清 HBV DNA 甲基化的患者中，与血清 HBV DNA 非甲基化的患者相比，HBV DNA 病毒载量较低，并且2）与年龄和性别匹配的HBV感染对照相比，HBV HCC患者的HBV病毒载量较高，HBV DNA甲基化率较低，双突变频率增加。该临床试验将是一项序贯随机对照试验，在 5 - 21 岁的免疫耐受受试者（HBsAg+、HBeAG+、HBV DNA >10(4)cpm）中进行，以确定是否可以通过核苷类似物 (NA) 降低 HBV 病毒载量，然后再使用与单独使用（NA）相比，免疫调节剂将改善反应。第1组将接受恩替卡韦（ETV）治疗8周，然后接受聚乙二醇化干扰素+ETV治疗40周；第 2 组将单独接收 ETV。反应的定义是 48 周时 HBeAg 消失/HBV DNA < 200 cpm。