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（由申请人提供）：使用共识测序（基因分型）的公共卫生监视计划估计，在美国，至少有十分之一的抗逆转录病毒（ARV）的人在美国感染了HIV-1的人，从而获得了抗药性HIV-HIV-HIV-1。因此，指南建议在进入护理时进行抵抗测试。但是，共识测序无法检测到低于病毒种群10-50％的低频变体。寡核苷酸连接测定法（OLA）是一种更敏感的测定法，可以检测到仅在5％的病毒准物种中发生的突变。在一项试点研究中，在华盛顿大学初级感染诊所（PIC）招募的原发性HIV-1感染的受试者中，在100名受试者中有6％的6％的耐HIV-1耐药性在28（30％）中检测到的低频率突变的94名未通过共识测试的突变中的28（30％）中的低频率突变。我们提出的研究将使用OLA解决与HIV-1耐药性的传播和后续后果有关的问题。在AIM＃1中，我们将研究ARV-NOIVE PIC受试者，以比较外周血单核细胞（PBMC），血液和精神分裂性的检测持续时间（“持久性”）和传播HIV-1耐药性的检测水平。在AIM＃2中，我们将研究启动ARV治疗的PIC受试者，并使用OLA来确定由于选择了传播的低频耐药性突变或新突变的发展，因此在成功治疗过程中是否可以在PBMC中检测到其他突变。在AIM＃3中，我们将使用OLA比较PIC受试者及其来源伙伴中的HIV-1耐药性模式，以确定HIV-1耐药性是否影响“传播适应性”。这些新颖的研究将扩大我们对低频HIV-1耐药性的自然史和临床影响的理解，并为对HIV感染者的测试和治疗提供了指南。如果在对低频突变的相关性充分了解之前，应认可更敏感的HIV-1药物耐药性测定法，那么初始ARV方案的复杂性和随后患者依从性的降低可能会增加毒性耐药性的患病率可能会增加。最后，来自伴侣对的经验数据将生成有关HIV-1传播相关性的信息，这些信息可以纳入耐药性人群动态的未来模型。这些模型将估计由原发性HIV-1感染的ARV-nive Source合作伙伴与已建立HIV-1感染的ARV经验的源合作伙伴传播的HIV-1耐药性的总比例。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HIV-1耐药性的自然史和临床影响的理解，并为对HIV感染者的测试和治疗提供了指南。来自伴侣对的经验数据也可用于模拟耐药性的种群动力学，量化来自原发性HIV-1感染的ARV-NOIVE源合作伙伴的传播HIV-1耐药性的比例，并开发了急需的公共卫生干预措施以降低HIV-1耐药性的传播。