Drug Resistance Genotypic and Phenotypic Correlates of Efavirenz and Dolutegravir based Treatment Outcomes across Non-B HIV-1 subtypes

非 B HIV-1 亚型依非韦伦和多替拉韦治疗结果的耐药性基因型和表型相关性

• 批准号: 10443774
• 负责人: Paul K Drain
• 金额: $ 121.91万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443774
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Africa; Amino Acids; Antiretroviral drug resistance; Asia; Biological Assay; CD4 Positive T Lymphocytes; Caring; Case-Control Studies; Cell Count; Child; Clinical; Codon Nucleotides; Cohort Studies; Communities; Consensus; County; Data; Databases; Developed Countries; Drug Combinations; Drug resistance; Effectiveness; Epidemic; Exhibits; Failure; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV antiretroviral; HIV-1; Health; High Prevalence; In Vitro; Income; Individual; Infection; Integrase; Lamivudine; Long Terminal Repeats; Minority; Modernization; Morbidity - disease rate; Mutation; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Phenotype; Population; Prevalence; RNA-Directed DNA Polymerase; Recombinants; Regimen; Resistance; Resistance profile; Resource-limited setting; Risk; Sample Size; Sampling; Site-Directed Mutagenesis; Southeastern Asia; Specimen; Tenofovir; Testing; Time; Treatment outcome; Variant; Viral; Viral Load result; Virus; acquired drug resistance; antiretroviral therapy; base; cohort; drug candidate; efavirenz; emtricitabine; improved; inhibitor; innovation; low and middle-income countries; mortality; next generation sequencing; non-nucleoside reverse transcriptase inhibitors; novel; novel therapeutics; programs; resistance mutation; success; transmission process

Abstract Antiretroviral therapy (ART) is critical to improving the health of people living with HIV (PLHIV), to reducing HIV transmission and to maintaining the effectiveness of the current ART programs in resource-limited settings (RLS). However, HIV antiretroviral drug resistance (HIVDR) can hamper global efforts to control the AIDS epidemic and achieve the UNAIDS 90-90-90 targets. Pre-treatment drug resistance (PDR) and on treatment- acquired drug resistance (ADR) are associated with virologic failure (VF) and increased morbidity and mortality. The correlates of PDR and ADR are not fully understood, and the level and breath of HIVDR mutations (DRM) circulating in individuals and populations, especially in RLS is lacking. Much of our understanding of HIVDR genotype-phenotype-outcome correlations have been derived from developed countries where the predominant circulating HIV strain is HIV-1 Group M subtype B. However, in communities with the highest prevalence of HIV-1 infection across the world, PLHIV are infected by non-B subtypes, such as subtypes A, C, D and circulating recombinant forms CRF01_AE and CRF02_AG. HIVDR and the correlates of viral suppression and outcome for these HIV-1 strains has been poorly studied. The success of modern ART regimens in RLS such as TDF-3TC-EFV (TLE) and the planned roll-out of dolutegravir (DTG) based regimens (TLD) could be impeded by emerging evidence of widespread HIVDR. This proposal seeks to expand our understanding of HIVDR and its correlates and consequences in low-and-middle income countries where HIV- 1 non-B subtypes circulate. To accomplish these goals, we propose the following three Specific Aims: 1. Determine the number and breadth of PDR mutations that correlate with virologic failure to TLE or TLD in adults and children infected with HIV-1 subtype A, C, D, CRF01_AE or CRF02_AG. 2. Determine known and novel DRMs at the time of VF in adults and children, including DRM frequencies across cohorts by regimen (TLE and TLD) and by HIV-1 subtype. 3. Determine the correlations between in vitro phenotypic drug resistance testing against genotypic DRMs across HIV-1 non-B subtypes (A, C, D, CRF01_AE and CRF02_AG). To address these aims we will use state-of-the-art and innovative assays to quantify the frequency of DRM in individual’s pre-ART quasispecies and use phenotypic assays to better understand DRM interactions. Our novel studies will determine (1) the risks of specific PDR DRM and minority variants across HIV-1 non-B subtypes for VF; (2) interactions between DRM that determine phenotypic resistance associated with VF; and (3) mutations selected by TLE and TLD regimens at VF. The long-term goal of this proposal is to provide data to enable the best practices for HIV-1 care across a range of resource-limited settings.

抽象的 抗逆转录病毒疗法（ART）对于改善HIV患者（PLHIV）的健康至关重要，以减少艾滋病毒 在资源有限的设置中传输并保持当前艺术计划的有效性 （RLS）。但是，HIV抗逆转录病毒耐药性（HIVDR）可能会阻碍全球控制艾滋病的努力 流行病并实现UNAID 90-90-90目标。治疗前耐药性（PDR）和治疗 - 获得的耐药性（ADR）与病毒衰竭（VF）和发病率增加有关 死亡。 PDR和ADR的相关性尚不完全了解，HIVDR的水平和呼吸 缺乏个人和人群中循环的突变（DRM），尤其是在RLS中。我们的大部分 对HIVDR基因型 - 表型结果相关性的理解是从发达的 主要的循环艾滋病毒菌株是HIV-1组M型B。但是，在社区中 随着全球HIV-1感染的最高患病率，PLHIV受到非B亚型感染，例如 作为亚型A，C，D和循环重组形式CRF01_AE和CRF02_AG。 Hivdr和相关性 这些HIV-1菌株的病毒抑制和结果的研究很差。现代艺术的成功 TDF-3TC-EFV（TLE）和计划推出DOLUTEGRAVIR（DTG）方案等RLS中的方案 （TLD）可能会受到宽度HIVDR的新兴证据的阻碍。该建议旨在扩大我们的 了解HIVDR及其在艾滋病毒的低和中间收入国家的相关性和后果 1个非B亚型循环。为了实现这些目标，我们提出以下三个具体目标： 1。确定与病毒学失败与TLE或TLD相关的PDR突变的数量和广度 成人和儿童感染了HIV-1亚型A，C，D，CRF01_AE或CRF02_AG。 2。确定成人和儿童VF时的已知和新颖DRM，包括DRM频率 通过方案（TLE和TLD）以及HIV-1亚型的跨队列。 3。确定针对基因型DRM的体外表型耐药性测试之间的相关性 跨HIV-1非B子类型（A，C，D，CRF01_AE和CRF02_AG）。 为了解决这些目标，我们将使用最先进的创新测定法来量化DRM的频率 个人的前准化学并使用表型测定法来更好地了解DRM相互作用。我们的 新的研究将确定（1）特定PDR DRM和HIV-1非B中少数族裔的风险 VF的亚型； （2）确定与VF相关的表型抗性的DRM之间的相互作用；和 （3）在VF处由TLE和TLD方案选择的突变。该建议的长期目标是提供数据 为了在一系列资源有限的设置中启用HIV-1护理的最佳实践。