Virologic and pharmacologic determinants of dolutegravir failure in East Africa

项目总结 背景：为了应对治疗前耐药率(PDR)的上升和 撒哈拉以南非洲大部分地区的病毒学失败(SSA)，一种新的负担得起的一线抗逆转录病毒疗法(ART) 替诺福韦(TFV)、拉米夫定(3TC)和多洛替格韦(TLD)方案将得到广泛实施 在整个地区。从2018年开始，TLD将成为符合以下条件的个人的首选一线方案 是新启动的ART和目前基于非核苷逆转录酶抑制剂(NNRTI)的ART 养生法。鉴于这项政策的范围，有一项至关重要的责任来评估对 TLD在这一人群中的有效性，例如先前存在的对TFV和3TC的耐药性。应聘者：我是 传染病专家和临床研究员，从事国际艾滋病毒研究1.5年 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。我也完成了 在临床研究设计和分析方面的入门教学，并在SSA学习过艾滋病毒流行病学，领导 到四个相关的出版物。我的首要职业目标是成为一名由美国国立卫生研究院资助的独立临床医生 在制定和实施优化艾滋病毒管理战略方面具有专业知识的科学家 系统性红斑狼疮治疗失败及耐药性分析培训：为了实现研究独立，我将要求 1)大型观测的高级生物统计学方法方面的有针对性的指导和额外培训 数据集，2)艾滋病毒基因组学和抗逆转录病毒耐药性的解释和分析，以及3)ART临床 药理和药理依从性监测。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，他有丰富的指导和研究经验 在乌干达进行临床研究。Bathany Hedt-Gauthier博士(生物统计学)，Daniel Kuritzkes博士(艾滋病毒药物 耐药性)和Jose Castillo-Mancilla(药物依从性监测)将担任联合导师 提供其他有重点的专业知识。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、文森特·马可尼博士、Jessica Haberer博士和Rochelle Walensky博士。研究： 在导师团队的指导下，我将评估HIV治疗失败的比率和决定因素 在东非计划通过以下具体目标实施TLD之后：1)比较 TLD与基于efavirenz的一线抗逆转录病毒疗法对东非大规模队列中病毒抑制的影响。2) 确定先前存在的耐药性对治疗失败风险的贡献 使用TLD启动ART，以及从基于NNRTI的方案切换到TLD的人。3)探索 TLD耐药与不耐药病毒学失败的药物依从性研究 使用尿TFV水平和干血斑中的TFV-二磷酸。通过这段时间的培训和研究， 我将很好地实现研究的独立性，并计划提交NIH R01申请进行研究 一种创新的基于临床的ART依从性措施，以指导SSA中TLD病毒学失败的处理。

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.