Virologic and pharmacologic determinants of dolutegravir failure in East Africa

项目摘要 背景：为了应对治疗前耐药（PDR）率的上升和 撒哈拉以南非洲大部分地区的病毒学失败，一种新的负担得起的一线抗逆转录病毒疗法（ART） 泰诺福韦（tenofovir，TFV）、拉米夫定（lamivudine，3 TC）和度鲁特韦（dolutegravir，简称dolutegravir）的方案将被广泛实施 在整个地区。从2018年开始，顺铂将成为首选的一线治疗方案， 新开始ART和目前正在接受非核苷类逆转录酶抑制剂（NNRTI）治疗的患者 养生法鉴于这项政策的范围，评估对环境的潜在威胁是一项关键责任。 在这一人群中，如对TFV和3 TC预先存在的耐药性的有效性。候选人：我是 从事国际艾滋病毒研究的传染病专家和临床研究员， 作为一名临床研究人员在乌干达西南部生活和工作的经验。我还完成了 在临床研究设计和分析的介绍教学法，并研究了艾滋病毒流行病学在SSA，领导 4篇相关文章我的首要职业目标是成为一名独立的，NIH资助的临床医生 在制定和实施优化艾滋病毒管理战略方面具有专门知识的科学家 治疗失败和抗药性。培训：为了实现研究独立，我将要求 有针对性的指导和额外培训：1）大型观察性研究的先进生物统计方法 数据集，2）HIV基因组学和抗逆转录病毒耐药性解释和分析，以及3）ART临床 药理学和药物依从性监测。导师：我的培训和研究计划将是 由我的主要导师Mark Siedner博士监督，他拥有丰富的指导和研究经验 在乌干达进行临床研究。Bethany Hedt-Gauthier博士（生物统计学）、丹尼尔·库里茨克斯博士（艾滋病毒药物 和Jose Castillo-Mancilla（药物依从性监测）将担任共同导师， 提供更多的专业知识。我还将收到我的科学顾问委员会的年度反馈， 其中包括Mwebesa Bwana博士，Vincent Marconi，Jessica Haberer和罗谢尔Walensky。研究： 在导师团队的指导下，我将评估艾滋病毒治疗失败的比率和决定因素 在东非按计划实施可持续发展战略之后，通过以下具体目标： 在来自东非的一个大型队列中，抗逆转录病毒药物与以依法韦仑为基础的一线ART对病毒抑制的影响（二） 确定既存耐药性对治疗失败风险的贡献， 开始ART治疗的患者，以及从基于NNRTI的治疗方案转换为ART治疗的患者。3)探索 区分耐药和无耐药的耐药药物的病毒学失败的药理学措施 使用尿TFV水平和干血斑中的TFV-二磷酸盐。通过这段时间的培训和研究， 我将很好地定位，以实现研究的独立性，并计划提交NIH R 01申请学习 一种创新的基于临床的ART依从性措施，用于指导SSA中病毒学失败的管理。

PROJECT SUMMARY Background: In response to rising rates of pre-treatment drug resistance (PDR) and risk of increasing rates of virologic failure in much of sub-Saharan Africa (SSA), a new affordable first-line antiretroviral therapy (ART) regimen of tenofovir (TFV), lamivudine (3TC), and dolutegravir, known as TLD, will be implemented widely throughout the region. Beginning in 2018, TLD will be the preferred first-line regimen both for individuals who are newly initiating ART and those currently on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Given the scope of this policy, there is a critical responsibility to assess potential threats to the effectiveness of TLD in this population, such as pre-existing drug resistance to TFV and 3TC. Candidate: I am an Infectious Diseases specialist and clinical investigator engaged in international HIV research with 1.5 years of experience living and working as a clinical researcher in southwestern Uganda. I have also completed introductory didactics in clinical study design and analysis and have studied HIV epidemiology in SSA, leading to four related publications. My overarching career goal is to become an independent, NIH-funded clinician scientist with expertise in development and implementation of strategies to optimize the management of HIV treatment failure and drug resistance in SSA. Training: To achieve research independence, I will require targeted mentoring and additional training in 1) advanced biostatistical methods for large observational datasets, 2) HIV genomics and antiretroviral resistance interpretation and analysis, and 3) ART clinical pharmacology and pharmacologic adherence monitoring. Mentors: My training and research plans will be overseen by my primary mentor Dr. Mark Siedner, who has extensive mentoring and research experience conducting clinical studies in Uganda. Drs. Bethany Hedt-Gauthier (biostatistics), Daniel Kuritzkes (HIV drug resistance), and Jose Castillo-Mancilla (pharmacologic adherence monitoring) will serve as co-mentors to provide additional focused expertise. I will also receive annual feedback from my Scientific Advisory Board, which includes Drs. Mwebesa Bwana, Vincent Marconi, Jessica Haberer, and Rochelle Walensky. Research: With guidance from my team of mentors, I will evaluate the rate and determinants of HIV treatment failure following the planned implementation of TLD in East Africa through the following specific aims: 1) Compare the effect of TLD versus efavirenz-based first-line ART on viral suppression in a large cohort from East Africa. 2) Determine the contributions of pre-existing drug resistance to risk of treatment failure both for people newly initiating ART with TLD as well as for people switching to TLD from an NNRTI-based regimen. 3) Explore pharmacologic measures of adherence to distinguish virologic failure on TLD with versus without resistance using urine TFV levels and TFV-diphosphate in dried blood spots. Through this period of training and research, I will be well positioned to achieve research independence and plan to submit an NIH R01 application to study an innovative clinic-based ART adherence measure to guide management of virologic failure on TLD in SSA.