Virologic and pharmacologic determinants of dolutegravir failure in East Africa

东非多替拉韦失败的病毒学和药理学决定因素

• 批准号: 10321907
• 负责人: Suzanne McCluskey
• 金额: $ 20.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321907
• 关键词: Adherence; Affect; Africa; Africa South of the Sahara; Antiretroviral resistance; Biological Assay; Biometry; Biostatistical Methods; Blood; Clinic; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Research; Clinical Trials; Communicable Diseases; Computerized Medical Record; Country; Data; Data Set; Development; Diphosphates; Dose; Drug resistance; Effectiveness; Ensure; Epidemiology; Europe; Failure; Feedback; Fumarates; Funding; Genomics; Genotype; Goals; Guidelines; HIV; HIV drug resistance; HIV-1; Individual; Integrase; International; Lamivudine; Lead; Measures; Mediating; Mentors; Methods; Monitor; Mutation; Nested Case-Control Study; Outcome; Participant; Pathway interactions; Persons; Pharmacology; Plasma; Policies; Policy Maker; Population; Positioning Attribute; Publications; RNA; Regimen; Reporting; Research; Research Design; Research Personnel; Resistance; Risk; Rural; Scientist; Specialist; Specimen; Spottings; Tenofovir; Testing; Training; Treatment Failure; Uganda; United States National Institutes of Health; Urine; Veins; Viral; Viral Load result; World Health Organization; antiretroviral therapy; base; career; cohort; cost; efavirenz; effectiveness evaluation; electronic data; experience; inhibitor; innovation; medication compliance; non-nucleoside reverse transcriptase inhibitors; novel; public health relevance; response; routine care; skills; therapy adherence; treatment guidelines; treatment risk

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.

项目概要 背景：为了应对治疗前耐药性 (PDR) 率上升和耐药率上升的风险 撒哈拉以南非洲大部分地区（SSA）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） 替诺福韦（TFV）、拉米夫定（3TC）和多替拉韦（TLD）方案将得到广泛实施 整个地区。从 2018 年开始，TLD 将成为以下人群的首选一线治疗方案： 新开始 ART 的患者和目前正在接受基于非核苷逆转录酶抑制剂 (NNRTI) 的患者 治疗方案。鉴于本政策的范围，评估对本政策的潜在威胁至关重要。 TLD 在该人群中的有效性，例如预先存在的对 TFV 和 3TC 的耐药性。候选人：我是 从事国际HIV研究1.5年的传染病专家和临床研究员 在乌干达西南部担任临床研究员的生活和工作经验。我也完成了 临床研究设计和分析的入门教学法，并研究了 SSA 的艾滋病毒流行病学，领先 四份相关出版物。我的首要职业目标是成为一名独立的、由 NIH 资助的临床医生 具有制定和实施优化艾滋病毒管理战略的专业知识的科学家 SSA 的治疗失败和耐药性。培训：为了实现研究独立性，我需要 1）针对大型观测的先进生物统计方法的有针对性的指导和额外培训 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 药理学和药理依从性监测。导师：我的训练和研究计划将是 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。博士。 Bethany Hedt-Gauthier（生物统计学）、Daniel Kuritzkes（艾滋病毒药物） 耐药性）和 Jose Castillo-Mancilla（药物依从性监测）将作为共同导师 提供额外的重点专业知识。我还将收到我的科学顾问委员会的年度反馈， 其中包括博士。姆韦贝萨·布瓦纳、文森特·马可尼、杰西卡·哈贝勒和罗谢尔·瓦伦斯基。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 按照计划在东非实施 TLD，实现以下具体目标： 1) 比较 在来自东非的大型队列中，TLD 与基于依非韦伦的一线 ART 对病毒抑制的影响。 2） 确定新患者先前存在的耐药性对治疗失败风险的影响 使用 TLD 启动 ART 以及从基于 NNRTI 的治疗方案转为 TLD 的患者。 3）探索 区分 TLD 病毒学失败的依从性药理学措施（有耐药性和无耐药性） 使用尿液 TFV 水平和干血斑中的 TFV-二磷酸盐。通过这段时间的训练和研究， 我将有能力实现研究独立并计划提交 NIH R01 申请来学习 一种基于临床的创新 ART 依从性措施，用于指导 SSA 中 TLD 病毒学失败的管理。