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

项目总结/摘要 有了这个K43职业发展奖，我将发展必要的技能，以达到我的最终目标， 成为一名独立的研究者，专注于使用药物流行病学和实验 药理学，为实现HIV治疗中持续的病毒抑制提供改进的策略。 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人员， 药物流行病学（流行病学和临床药理学）方面的专业知识，为改进策略提供信息 在HIV治疗中实现持续的病毒抑制。在K43期间，我的目标是 要 在西非数据库中识别和描述一个回顾性的PLWH队列， 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;以及 在前瞻性队列中确定低水平病毒血症（LLV）与ART依从性之间的关系 使用3种不同的依从性测量（药房再填充记录（PRR），创新的尿-替诺福韦POC测试， 和DBS中的创新TFV-DP）。为了实现这些目标，我将在K43奖期间接受一位 一组经验丰富的职业科学家：Cecile Lahiri博士，一位专注于艾滋病毒的临床科学家 奥利弗Ezechi博士，生殖和人口健康专家，其重点是 传染病对妇女和青少年健康的临床影响; 临床医生/流行病学家，专注于HIV流行病学和相关慢性合并症; Igho博士 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 翻译研究员专注于应用临床药理学。为了这个K43奖，我将完成 在大数据分析和实验药理学的课程和实践培训，我还将进行 研究，证实不可检测=不可传播（U=U）议程的目标是学习新的 监测坚持的方法，以实现有效的艾滋病毒治疗，将阻止传播和消除 艾滋病最终结合我在艾滋病护理和传染病方面的药学实践背景， 先进的分析技能，数学建模，流行病学和实验药理学，从这个 K43，将给我作为一个独立的研究人员的职业生涯的能力。 研究计划：新出现的证据表明，持续低水平病毒血症（LLV）的人， 接受抗逆转录病毒治疗的艾滋病毒感染者是实现零传播目标的障碍 和根除艾滋病毒1 -8，但对LLV对实现 西非的病毒抑制;因此，这项建议旨在提供重要信息，以了解 减毒活疫苗对西非抗逆转录病毒治疗结果的影响。同样重要的是要了解， HIV-1和HIV-2治疗结果之间存在差异，因为西 非洲是世界上艾滋病毒2型流行的少数地区之一。虽然文学是一致的 次优的粘附导致LLV，围绕LLV的预后价值的争议， 临床结果。一些研究将LLV的原因归因于耐药性和LLV的重新激活。 病毒储库，但其他研究将这些因素命名为LLV 9 -11的后果。的 “不可检测=不可传播（U=U）”的概念取决于探索药理学，心理学， 社会经济和其他干预措施，以提高依从性并实现不可检测的病毒 装载12，13。患有LLV的个体被证明不太可能随后 达到完全检测不到的病毒载量。LLV的上限（200-1000拷贝/ml）也 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 与艾滋病有关的死亡1.目前世卫组织的指南不建议监测或治疗 即使在反复测量低水平病毒血症后，因此，患者 继续接受失败的抗逆转录病毒疗法不监测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的临床预后差。因此，了解 LLV的预测因素及其对PLWH的影响，以改善PLWH的临床护理。我们提出的 目标是：1）。 从西非数据库中确定并描述一个队列， 确定队列中低水平病毒血症（LLV）的流行病学和预测因素（HIV-1和 HIV-2）和ii）。在尼日利亚的拉各斯建立一个PLWH前瞻性队列，以估计对 ART，使用3种不同的依从性指标（药房续药记录（PRR），创新尿替诺福韦 POC测试和DBS中的创新TFV-DP）。为了实现这一目标，我们将评估LLV的患病率， 大型西非数据库（IeDEA西非），并确定遵守之间的关系 在尼日利亚的拉各斯的272名PLWH的队列中检测低水平病毒血症（LLV），并预测未来的LLV。这将是一 2-一项为期一年的前瞻性纵向随访研究（3个月一次的尿液和DBS采集预约和6个月一次的DBS采集预约）， 每月病毒载量检测）。

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).