Use of clonal genotyping to predict resistance development in ART-naive IDU

使用克隆基因分型预测未接受 ART 的 IDU 的耐药性发展

• 批准号: 7805532
• 负责人: Richard B. Markham
• 金额: $ 57.97万
• 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: 2008-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805532
• 关键词: Affect; Age; Anti-Retroviral Agents; CD4 Lymphocyte Count; Caring; Cells; Clinical; Cost Savings; Data; Data Analyses; Detection; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Disease Progression; Drug usage; Drug user; Employee Strikes; Event; Face; Failure; Frequencies; Genotype; HIV-1; Haplotypes; Health; Health Care Costs; Highly Active Antiretroviral Therapy; Illicit Drugs; Incidence; Individual; Injecting drug user; Injection of therapeutic agent; Laboratory Study; Light; Medical; Methods; Minority; Mutation; Mutation Detection; NNRTI-resistance; Nucleosides; Patients; Pattern; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Population; Process; Protease Inhibitor; RNA; Recording of previous events; Regimen; Relapse; Reporting; Research Design; Research Personnel; Resistance; Resistance development; Resistance profile; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk; Sampling; Sequence Analysis; Site; Social Impacts; Techniques; Technology; Testing; Time; Variant; Viral; Virion; Virus; Visit; Woman; antiretroviral therapy; base; case control; clinical research site; clinically relevant; cohort; cost; design; experience; high risk; interest; medical schools; new technology; non-compliance; non-nucleoside reverse transcriptase inhibitors; novel; pol Gene Products; pol genes; pressure; resistance mutation; response; standard of care; therapy development

DESCRIPTION (provided by applicant): Failure of antiretroviral therapy (ART) has been a particular problem among HIV-1 infected illicit drug users. This failure has primarily been attributed to poor compliance with antiretroviral drug regimens. Studies from this laboratory have indicated that a higher viral mutation frequency that we have documented in injection drug users (IDU) and the resulting higher frequency of primary resistance mutations in pol might contribute to the poor response in this group. Genotypic resistance analysis using population sequencing has proved useful in guiding selection of antiretroviral therapy in individuals who have developed viral relapse after initial treatment. Our preliminary data analyzing up to 10 viral clones from protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) naive IDU have indicated that a strikingly and significantly high proportion of IDU subject-visits (28%) carry PI resistance mutations compared to the much lower proportion (8%) found in non-IDU. Almost none of these resistance mutations were detected using standard population genotyping techniques. Similar high levels of primary resistance have been found in a cohort of non-injection illicit drug users followed by investigators at Vanderbilt Medical School. This proposal hypothesizes that use of sensitive sequencing techniques prior to initiation of HAART will be predictive of rapid development of resistance, therefore enabling the development of personalized and more effective initial HAART regimens. Specifically in cohorts from the Johns Hopkins and Vanderbilt Schools of Medicine of 150 HAART-naive drug users who rapidly failed HAART and 150 comparable subjects for whom therapy was successful we will 1) Determine whether identification of resistance mutations by standard clonal analysis using the Sanger sequencing method to study the pol region from 20 HIV-1 clones from a single visit predicts risk of subsequent therapy failure better than population genotyping from that same visit 2) evaluate whether identification of resistance mutations by high throughput clonal analysis of relatively short sequences from the RT and protease regions (454 sequencing) predicts risk of subsequent therapy failure better than: i) standard population genotyping and ii) analysis of 20 clones (sequenced using the Sanger method) in which both NRTI and NNRTI or PI resistance mutations can be identified on the same viral clone and 3) Evaluate, using 454 sequencing technology, the frequency of clonal resistance needed for clones with PI or NNRTI resistance to predict increased risk of rapid development of therapy failure. The results of this study could provide a new standard of care for initiation of HAART and could greatly reduce the financial and social impact of HAART failure. This study is designed to evaluate new technologies that will render anti-HIV-1 drug therapy more effective. This new technology will permit better characterization of the viral strains that are infecting an individual so that the therapy can be specifically targeted to those viruses.

描述（由申请人提供）：在HIV-1感染的非法吸毒者中，抗逆转录病毒疗法（ART）的失败一直是一个特殊的问题。这种失败主要归因于抗逆转录病毒药物方案的依从性不佳。该实验室的研究表明，我们在注射吸毒者（IDU）中记录的较高的病毒突变频率以及POL中较高的原发性突变频率可能导致该组的反应不佳。事实证明，使用种群测序的基因型耐药性分析可用于指导在初次治疗后患有病毒复发的个体中抗逆转录病毒治疗的选择。我们从蛋白酶抑制剂（PI）和非核苷逆转录酶抑制剂（NNRTI）NAIVE IDU中分析多达10个病毒克隆的初步数据表明，与在不合格中（8％）相比，IDU受试者Visits（28％）的IDU受试者（28％）的显着高比例（28％）。使用标准种群基因分型技术检测到几乎没有检测到这些抗性突变。在范德比尔特医学院的调查人员之后，在一群非注射非法吸毒者中发现了类似的主要抵抗力。该建议假设在开始HAART之前使用敏感的测序技术将可以预测抗药性的快速发展，从而能够开发个性化和更有效的初始HAART方案。特别是在约翰·霍普金斯（Johns Hopkins）和范德比尔特（Vanderbilt evaluate whether identification of resistance mutations by high throughput clonal analysis of relatively short sequences from the RT and protease regions (454 sequencing) predicts risk of subsequent therapy failure better than: i) standard population genotyping and ii) analysis of 20 clones (sequenced using the Sanger method) in which both NRTI and NNRTI or PI resistance mutations can be identified on the same viral clone and 3) Evaluate, using 454测序技术，具有PI或NNRTI耐药性的克隆所需的克隆电阻频率，以预测治疗衰竭快速发展的风险增加。这项研究的结果可以为HAART的启动提供新的护理标准，并可以大大减少HAART失败的财务和社会影响。这项研究旨在评估将使抗HIV-1药物治疗更有效的新技术。这项新技术将允许更好地表征感染个体的病毒菌株，以便可以将治疗专门针对这些病毒。