Use of Pharmacoepidemiology to Understand Predictors and Impact of Low-level Viremia in Persons with HIV in West Africa

利用药物流行病学了解西非艾滋病毒感染者低水平病毒血症的预测因子和影响

• 批准号: 10749658
• 负责人: Ebiere Clara HERBERTSON
• 金额: $ 6.54万
• 依托单位: NIGERIAN INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749658
• 关键词: Acquired Immunodeficiency Syndrome; Adherence; Adult; Africa; Africa South of the Sahara; African; Anti-Retroviral Agents; Antiretroviral drug resistance; Appointment; Award; Blood; Caring; Cells; Cessation of life; Chronic; Clinical; Clinical Pharmacology; Collection; Communicable Diseases; Country; Data; Data Analyses; Databases; Development Plans; Diphosphates; Drug Exposure; Drug resistance; Dryness; Epidemic; Epidemiologist; Epidemiology; Event; Failure; Funding; Future; Goals; Guidelines; HIV; HIV-1; HIV-2; Hair; Individual; Intake; International; Intervention; K-Series Research Career Programs; Knowledge; Learning; Literature; Measurement; Measures; Mentors; Methods; Monitor; Names; Nigeria; Outcome; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacology; Pharmacy facility; Policies; Policy Maker; Predictive Value; Prevalence; Prospective cohort; Public Health; Records; Regimen; Reproductive Health; Research; Research Design; Research Personnel; Resistance; Resistance development; Resource-limited setting; Retrospective cohort; Scientist; Site; Source; Specialist; Spottings; Techniques; Tenofovir; Testing; Training; Treatment outcome; Urine; Viral; Viral Load result; Viral load measurement; Viral reservoir; Viremia; Virus Activation; Women' s Health; adolescent health; advanced analytics; antiretroviral therapy; biological sex; career; career development; clinical care; clinical prognosis; cohort; comorbidity; comparative; evidence base; experience; follow-up; improved; innovation; insight; longitudinal, prospective study; mathematical model; pharmacologic; pill; point of care; point of care testing; population health; prognostic value; scale up; skills; socioeconomics; statistics; study population; therapy outcome; translational physician; translational scientist; transmission process; treatment guidelines

PROJECT SUMMARY/ABSTRACT With this K43 Career Development Award, I will develop the skills necessary to reach my ultimate goal of becoming an independent investigator focused on the use of pharmacoepidemiology and experimental pharmacology to inform improved strategies for achieving sustained viral suppression in HIV treatment. Career Development Plan: My long-term career goal is to become an independently funded researcher with expertise in pharmacoepidemiology (epidemiology and clinical pharmacology) to inform improved strategies for achieving sustained viral suppression in HIV treatment. In the short-term during this K43 period, my goals are to Identify and characterize a retrospective cohort of PLWH in the IeDEA West Africa Database and determine the epidemiology and predictors of HIV-1, HIV-2 low-level viremia (LLV) in the cohort; and to determine the relationship between low-level viremia (LLV) and adherence to ART in a prospective cohort using 3 different adherence measures (pharmacy refill records (PRR), innovative urine-tenofovir POC test, and innovative TFV-DP in DBS). To attain these goals, I will be mentored during this K43 award period by a group of experienced career scientists: Dr. Cecile Lahiri, a clinician scientist whose focus is on HIV cure/eradication; Dr. Oliver Ezechi, a specialist in reproductive and population health whose focus is on the clinical impact of infectious diseases on women and adolescent health; Dr Antoine Jaquet, a clinician/epidemiologist with focus on the epidemiology of HIV and related chronic comorbidities; Dr. Igho Ofotokun an HIV translational clinician scientist with focus on women’s health and Dr. Castillo-Mancilla, a translational researcher focused on applied clinical pharmacology. For this K43 award, I will complete coursework and hands-on training in large data analysis and experimental pharmacology, I will also conduct research that exemplifies the undetectable = untransmissible (U=U) agenda with the goal of learning new ways of monitoring adherence to achieve effective HIV treatments that will stop transmission and eliminate HIV eventually. Merging my background in pharmacy practice in HIV care and infectious diseases, with advanced analytic skills, mathematical modelling, epidemiology, and experimental pharmacology from this K43, will give me the capacity for a career as an independent researcher. Research Plan: Emerging evidence suggests that persistent low-level viremia (LLV) in persons with HIV (PLWH) on antiretroviral therapy (ART) is a barrier to achieving the goal of zero transmission and eradication of HIV1-8, but not much is known about the impact of LLV on attaining the goal of viral suppression in West Africa; thus, this proposal aims to provide information vital to understand the impact of LLV in ART outcomes in West Africa. It will also be important to understand if differences exist between HIV-1 and HIV-2 treatment outcomes in the presence of LLV, since West Africa is one of the few regions in the world where HIV-2 is endemic. While literature is unanimous that sub-optimal adherence results in LLV, controversy surrounds the prognostic value of LLV for clinical outcomes. Some studies attribute the cause of LLV to drug resistance and reactivation of viral reservoirs, but other studies name these factors as consequences of LLV9-11. The ‘Undetectable=Untransmissible (U=U)’ concept is hinged on exploring pharmacologic, psycho- socio-economic, and other interventions to improve adherence and achieve undetectable viral load12,13. Individuals with LLV have been shown to be significantly less likely to subsequently achieve complete undetectable viral load. The upper limit of LLV (200-1000 copies/ml), has also been shown to be associated with virologic failure, development of resistance to ARVs, AIDS events and AIDS-related deaths1. Current WHO guidelines do not advise monitoring or treatment interventions even after repeated measurements of low-level viraemia. Consequently, patients are kept on failing ART regimens. Non-monitoring of LLV may result in an epidemic of resistance to currently used antiretrovirals and poor clinical prognosis in PLWH. Thus, it is vital to understand the predictors of LLV and its impact on PLWH, to inform improved clinical care of PLWH. Our proposed aims are: 1). To identify and characterize a cohort of from the IeDEA West Africa Database and determine the epidemiology and predictors of low-level viremia (LLV) in the cohort (for HIV-1 and HIV-2) and ii). Establish a prospective cohort of PLWH in Lagos, Nigeria, to estimate adherence to ART, using 3 different adherence measures (pharmacy refill records (PRR), innovative urine tenofovir POC test, and innovative TFV-DP in DBS). To accomplish this, We will assess the prevalence of LLV in a large West African database (IeDEA West Africa) and also determine the relationship between adherence with low-level viremia (LLV) in a cohort of 272 PLWH in Lagos, Nigeria and predict future LLV. This will be a 2-year follow-up prospective longitudinal study (3-monthly appointments for urine and DBS collection and 6- monthly viral load testing).

项目概要/摘要 凭借这个 K43 职业发展奖，我将培养实现我的最终目标所需的技能 成为一名专注于药物流行病学和实验应用的独立研究者 药理学为在艾滋病毒治疗中实现持续病毒抑制的改进策略提供信息。 职业发展计划：我的长期职业目标是成为一名独立资助的研究员 药物流行病学（流行病学和临床药理学）专业知识为改进策略提供信息 在 K43 期间的短期内，我的目标是在 HIV 治疗中实现持续的病毒抑制。 是为了 在 IeDEA 西非数据库中识别和描述 PLWH 队列回顾，并 确定队列中 HIV-1、HIV-2 低水平病毒血症 (LLV) 的流行病学和预测因素； 确定前瞻性队列中低水平病毒血症 (LLV) 与 ART 依从性之间的关系 使用 3 种不同的依从性措施（药房补充记录 (PRR)、创新的尿液替诺福韦 POC 测试、 为了实现这些目标，我将在 K43 颁奖期间得到一位导师的指导。 一群经验丰富的职业科学家：Cecile Lahiri 博士，一位专注于艾滋病毒研究的临床科学家 治愈/根除；Oliver Ezechi 博士，生殖和人口健康专家，重点研究 传染病对妇女和青少年健康的临床影响；Antoine Jaquet 博士， 临床医生/流行病学家，专注于艾滋病毒和相关慢性合并症的流行病学； Ofotokun 是一位专注于女性健康的艾滋病毒转化临床科学家，Castillo-Mancilla 博士是一位 专注于应用临床药理学的转化研究员 对于这个 K43 奖项，我将完成。 大数据分析和实验药理学的课程作业和实践培训，我还将进行 研究例证了不可检测=不可传播（U=U）议程，其目标是学习新的 监测依从性的方法，以实现有效的艾滋病毒治疗，从而阻止传播并消除艾滋病毒 最终将我在艾滋病毒护理和传染病方面的药学实践背景与艾滋病毒合并起来。 高级分析技能、数学建模、流行病学和实验药理学 K43，将使我有能力成为一名独立研究员。 研究计划：新出现的证据表明，患有持续性低水平病毒血症（LLV）的人 接受抗逆转录病毒治疗（ART）的艾滋病毒（PLWH）是实现零传播目标的障碍 和根除 HIV1-8，但人们对 LLV 对实现这一目标的影响知之甚少。 因此，该提案旨在提供对于理解至关重要的信息 了解 LLV 对西非 ART 结果的影响也很重要。 在 LLV 存在的情况下，HIV-1 和 HIV-2 治疗结果之间存在差异，因为 West 非洲是世界上少数几个 HIV-2 流行的地区之一，而文献对此的看法是一致的。 次优的依从性导致 LLV，围绕 LLV 的预后价值存在争议 一些研究将 LLV 的原因归因于耐药性和重新激活。 病毒储存库，但其他研究将这些因素命名为 LLV9-11 的后果。 “不可检测=不可传播（U=U）”的概念取决于探索药理学、心理- 社会经济和其他干预措施，以提高依从性并实现病毒检测不到 load12,13 已被证明患有 LLV 的人随后发生这种情况的可能性要小得多。 达到完全检测不到的病毒载量的上限（200-1000 拷贝/毫升），也已实现。 已被证明与病毒学失败、抗逆转录病毒药物耐药性的发展、艾滋病事件有关 和艾滋病相关死亡1。目前的世界卫生组织指南不建议进行监测或治疗。 即使在重复测量低水平病毒血症后也应采取干预措施。 继续失败的 ART 治疗方案 不监测 LLV 可能会导致耐药性的流行。 目前使用的抗逆转录病毒药物和 PLWH 的临床预后不良因此，了解这一点至关重要。 LLV 的预测因素及其对 PLWH 的影响，为改善 PLWH 的临床护理提供信息。 目标是：1）。 识别并描述 IeDEA 西非数据库中的一组人群 确定队列中低水平病毒血症 (LLV) 的流行病学和预测因子（针对 HIV-1 和 HIV-2) 和 ii) 在尼日利亚拉各斯建立艾滋病毒感染者的前瞻性队列，以评估其依从性。 ART，使用 3 种不同的依从性措施（药房补充记录 (PRR)、创新的尿液替诺福韦 为了实现这一目标，我们将评估 LLV 的流行率。 大型西非数据库（IeDEA 西非）也确定了依从性之间的关系 在尼日利亚拉各斯的 272 名感染者中患有低水平病毒血症 (LLV)，并预测未来的 LLV。 2 年随访前瞻性纵向研究（每 3 个月预约一次尿液和 DBS 采集，以及 6 个月预约） 每月病毒载量测试）。