True prevalence of pre-existing reverse transcriptase inhibitor resistance in tre

先前存在的逆转录酶抑制剂耐药性的真实流行率

• 批准号: 7336262
• 负责人: Rafael Eduardo Campo
• 金额: $ 24.46万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336262
• 关键词: Advocate; Alleles; Anti-Retroviral Agents; Antiretroviral resistance; Biological Assay; Blood; Caring; Class; Clinic Visits; Clinical; Clinical Trials; Detection; Diagnosis; Drug resistance; Enrollment; Frequencies; Genotype; Guidelines; HIV-1; High Prevalence; Individual; Infection; Lead; Literature; Measures; Methodology; Methods; Mutation; NNRTI-resistance; Nucleosides; Numbers; Patients; Pharmaceutical Preparations; Population; Prevalence; Public Health; Rate; Relative (related person); Research Proposals; Resistance; Reverse Transcriptase Inhibitors; Sampling; Sequence Analysis; Specimen; Standards of Weights and Measures; Structure; Study Subject; Techniques; Technology; Testing; Time; Treatment outcome; United States; Variant; Viral; Viral Load result; Week; antiretroviral therapy; base; cost; day; experience; non-nucleoside reverse transcriptase inhibitors; novel; pressure; response; transmission process

DESCRIPTION (provided by applicant): Antiretroviral resistance in antiretroviral therapy (ART) na¿ve HIV-infected individuals is a growing problem. As many as 18% of treatment-na¿ve patients in the United States are infected with HIV-1 with resistance to at least one antiretroviral drug class. Resistance testing prior to initiating ART is recommended by widely followed treatment guidelines; however, the population-based genotypic resistance testing (PBGRT) in clinical use can detect resistant viral variants only if they constitute at least 20% of the circulating viral population. This brings up the distinct and worrisome possibility, supported by recent preliminary findings, that undetected resistance that pre-dates the initiation of ART can compromise the eventual efficacy of ART. The hypothesis behind this proposal is that the prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside reverse transcriptase inhibitor (NRTI) resistant-HIV in treatment na¿ve individuals is higher than what is detected by PBGRT as it is currently used. This study will demonstrate that it is possible to increase the rate of detection of pre-existing antiretroviral resistance in individuals who are initiating ART. This will be accomplished through the use of PBGRT before and 7 days after starting NNRTI-NRTI ART. It is expected that by day 7, replication of wild-type, drug susceptible HIV-1 variants will have been suppressed by therapy whereas drug-resistant variants, under the selective pressure of therapy, will have a competitive advantage over drug-susceptible ones and will have increased both in absolute number and as a proportion of the circulating pool of HIV-1 variants. This "enrichment" of the resistant variants will allow for their successful detection through the same PBGRT that failed to detect them prior to initiating ART. These findings will be confirmed by performing more sensitive resistance assays at the same time points: a clonal analysis and the recently developed parallel allele-specific sequencing (PASS) assay. A limited assessment of the association between the presence of NNRTI-NRTI resistance and the short-term (3-month) response to NNRTI- NRTI therapy will also be performed. The latter will provide a general sense of the virological response to ART of subjects with unrecognized resistance compared to the response of subjects without resistance. Identification of a higher prevalence of antiretroviral resistance among treatment-na¿ve patients than what is currently recognized is an important public health issue. It brings into question the efficacy of current resistance detection strategies and raises the possibility that new methodologies or techniques are needed. Most importantly, unrecognized resistance might impair the efficacy of antiretroviral therapy, and its timely identification could lead to better treatment outcomes.

描述（由申请人提供）：对艾滋病毒感染者来说，抗逆转录病毒治疗（ART）的抗逆转录病毒耐药性是一个日益严重的问题。在美国，多达18%的接受治疗的患者感染了HIV-1，并且对至少一种抗逆转录病毒药物具有耐药性。广泛遵循的治疗指南建议在开始抗逆转录病毒治疗之前进行耐药性检测；然而，临床使用的基于人群的基因型耐药检测（PBGRT）只能检测到耐药病毒变体，前提是它们至少占循环病毒种群的20%。最近的初步研究结果支持了这一明显而令人担忧的可能性，即在开始抗逆转录病毒治疗之前未被发现的耐药性可能损害抗逆转录病毒治疗的最终疗效。这一建议背后的假设是，非核苷类逆转录酶抑制剂（NNRTI）和核苷类逆转录酶抑制剂（NRTI）在治疗中的耐药hiv个体的患病率高于目前使用的PBGRT检测到的患病率。这项研究将证明，在开始抗逆转录病毒治疗的个体中，有可能提高预先存在的抗逆转录病毒耐药性的检出率。这将通过在开始NNRTI-NRTI抗逆转录病毒治疗之前和之后7天使用PBGRT来实现。预计到第7天，药物敏感的野生型HIV-1变异的复制将受到治疗的抑制，而耐药变异在治疗的选择性压力下，将比药物敏感的变异具有竞争优势，并且在绝对数量和循环库中HIV-1变异的比例上都将增加。这种耐药变异的“富集”将允许通过在启动抗逆转录病毒治疗之前未能检测到它们的相同PBGRT成功检测它们。这些发现将通过在同一时间点进行更敏感的耐药试验来证实：克隆分析和最近开发的平行等位基因特异性测序（PASS）测定。还将对NNRTI-NRTI耐药与NNRTI-NRTI治疗的短期（3个月）反应之间的关系进行有限的评估。后者将提供与无耐药性受试者的反应相比，具有未识别耐药性受试者对抗逆转录病毒治疗的病毒学反应的一般感觉。在没有接受治疗的患者中发现比目前认识到的更高的抗逆转录病毒耐药性是一个重要的公共卫生问题。它对当前耐药性检测策略的有效性提出了质疑，并提出了需要新方法或新技术的可能性。最重要的是，未被发现的耐药性可能会损害抗逆转录病毒治疗的疗效，及时发现耐药性可能会带来更好的治疗结果。