Low-frequency HIV-1 Drug Resistance in Primary HIV-1 Infection

原发性 HIV-1 感染中的低频 HIV-1 耐药性

• 批准号: 8104191
• 负责人: Joanne Donna Stekler
• 金额: $ 43.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104191
• 关键词: Address; Anti-Retroviral Agents; Antiretroviral drug resistance; Biological Assay; Blood; Caring; Clinic; Clinical; Clinical Trials; Consensus Sequence; Data; Detection; Development; Drug resistance; Enrollment; Failure; Frequencies; Future; Genotype; Guidelines; HIV; HIV-1; Health; Infection; Intervention; Investigation; Lead; Ligation; Methods; Minority; Modeling; Mutation; Mutation Detection; Natural History; Oligonucleotides; Pattern; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pilot Projects; Plasma; Population; Population Dynamics; Population Surveillance; Prevalence; Probability; Public Health; Reaction Time; Regimen; Reporting; Research Design; Resistance; Risk; Seminal Plasma; Source; Specimen; Surveillance Program; Test Result; Testing; Time; Treatment outcome; United States; Universities; Variant; Viral; Virus; Washington; antiretroviral therapy; clinical care; clinically relevant; cohort; compliance behavior; design; drug resistant virus; experience; fitness; follow-up; genital secretion; mutant; novel; programs; resistance mutation; response; transmission process

DESCRIPTION (provided by applicant): Public health surveillance programs using consensus sequencing (genotyping) estimate that at least one in ten antiretroviral (ARV)-naive persons infected with HIV-1 in the United States acquires drug resistant HIV-1. Guidelines therefore recommend resistance testing at the time of entry into care. However, consensus sequencing cannot detect low-frequency variants at levels below 10-50% of the viral population. The oligonucleotide ligation assay (OLA) is a more-sensitive assay that can detect mutations occurring in as little as 5% of the viral quasi-species. In a pilot study conducted among subjects with primary HIV-1 infection enrolled at the University of Washington Primary Infection Clinic (PIC), consensus sequencing detected transmitted HIV-1 drug resistance in 6% of 100 subjects, and OLA detected low-frequency mutations in 28 (30%) of 94 subjects who did not have mutations identified by consensus sequencing. We propose studies that will use OLA to address questions pertaining to the transmission and subsequent consequences of HIV-1 drug resistance. In Aim #1, we will study ARV-naive PIC subjects to compare the duration of detection ("persistence") and level of detection of transmitted HIV-1 drug resistance over time in peripheral blood mononuclear cells (PBMCs), blood and seminal plasma. In Aim #2, we will study PIC subjects initiating ARV therapy and use OLA to determine whether additional mutations can be detected in PBMCs during successful treatment due to the selection of transmitted low-frequency drug resistance mutations or the development of new mutations. In Aim #3, we will use OLA to compare HIV-1 drug resistance patterns in PIC subjects and their source partners to determine whether HIV-1 drug resistance impacts "transmission fitness". These novel investigations would broaden our understanding of the natural history and clinical impact of low- frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. If more-sensitive HIV-1 drug resistance assays were to be endorsed for clinical care before there is a full understanding of the relevance of low-frequency mutations, the potential increase in the complexity of initial ARV regimens and subsequent reduction in patient adherence could paradoxically increase the prevalence of drug resistance. Finally, empiric data from partner-pairs will generate information on correlates of HIV-1 transmission that could be incorporated into future models of the population dynamics of drug resistance. These models would estimate the overall proportion of HIV-1 drug resistance that is transmitted from ARV- naive source partners with primary HIV-1 infection versus ARV-experienced source partners with established HIV-1 infection. This data could be used to design public health interventions targeted to these populations to reduce the spread of transmitted HIV-1 drug resistance. PUBLIC HEALTH RELEVANCE: These investigations would broaden our understanding of the natural history and clinical impact of low-frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. Empiric data from partner-pairs could also be used to model population dynamics of drug resistance, quantify the proportion of transmitted HIV-1 drug resistance that is from ARV-naive source partners with primary HIV-1 infection, and develop much- needed public health interventions to reduce the spread of HIV-1 drug resistance.

描述（由申请方提供）：使用共识测序（基因分型）的公共卫生监测项目估计，在美国，至少有十分之一的HIV-1感染者未接受过抗逆转录病毒（ARV）治疗，获得耐药性HIV-1。因此，指南建议在进入护理时进行耐药性测试。然而，共有序列测序无法检测病毒群体中低于10-50%水平的低频变异。寡核苷酸连接试验（奥拉）是一种灵敏度更高的试验，可检测出发生在5%病毒准种中的突变。在华盛顿大学原发性感染诊所（PIC）招募的原发性HIV-1感染受试者中进行的一项初步研究中，共有测序在100名受试者中的6%中检测到传播的HIV-1耐药性，奥拉在94名受试者中的28名（30%）中检测到低频突变，这些受试者没有通过共有测序确定的突变。我们建议研究将使用奥拉，以解决有关的传播和HIV-1耐药性的后续后果的问题。在目标#1中，我们将研究ARV初治PIC受试者，以比较外周血单核细胞（PBMC）、血液和精浆中随时间推移检测到传播的HIV-1耐药性的持续时间（“持久性”）和检测水平。在目标2中，我们将研究开始ARV治疗的PIC受试者，并使用奥拉确定在成功治疗期间是否可以在PBMC中检测到由于选择传播的低频耐药突变或新突变的发展而导致的额外突变。在目标3中，我们将使用奥拉比较PIC受试者及其来源伴侣的HIV-1耐药性模式，以确定HIV-1耐药性是否影响“传播适应性”。这些新的研究将扩大我们对低频率HIV-1耐药性的自然史和临床影响的理解，并为HIV感染者的检测和治疗提供指导。如果在充分了解低频率突变的相关性之前，将更敏感的HIV-1耐药检测方法用于临床护理，则初始ARV治疗方案复杂性的潜在增加和随后患者依从性的降低可能会矛盾地增加耐药的流行。最后，从合作伙伴对的经验数据将产生相关的HIV-1传播的信息，可以纳入未来的耐药性的人口动态模型。这些模型将估计HIV-1耐药性的总体比例，即由初次感染HIV-1的未接受过抗逆转录病毒治疗的来源伴侣传播的HIV-1耐药性与由已确定感染HIV-1的经历过抗逆转录病毒治疗的来源伴侣传播的HIV-1耐药性。这些数据可用于设计针对这些人群的公共卫生干预措施，以减少传播的HIV-1耐药性的传播。公共卫生相关性：这些调查将扩大我们对低频率HIV-1耐药性的自然历史和临床影响的了解，并为艾滋病毒感染者的检测和治疗提供指导。来自伴侣对的经验数据也可用于建立耐药性群体动态模型，量化来自初次感染HIV-1的未接受过抗逆转录病毒治疗的来源伴侣的传播HIV-1耐药性的比例，并制定急需的公共卫生干预措施，以减少HIV-1耐药性的传播。