HIV Treatment Failure and Drug Resistance in Western Kenyan Children

肯尼亚西部儿童的艾滋病毒治疗失败和耐药性

• 批准号: 9925893
• 负责人: Rami Kantor
• 金额: $ 72万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925893
• 关键词: 14 year old; Academic Medical Centers; Adherence; Adolescence; Adolescent; Adult; Affect; Africa South of the Sahara; African; American; Antiretroviral resistance; Birth; Blood; Blood Banks; Blood specimen; Caring; Cessation of life; Child; Childhood; Chronic Disease; Clinical; Clinical Data; Cohort Studies; Collection; Comprehensive Health Care; Data; Development; Disease Management; Dose; Drug resistance; Electronic Health Record; Enrollment; Evolution; Face; Failure; Funding; Goals; Guidelines; HIV; HIV Infections; HIV drug resistance; Hour; Immunologics; Individual; Infrastructure; Interruption; Intervention; Investigation; Kenya; Laboratories; Lead; Literature; Long-Term Care; Longitudinal Studies; Maintenance; Medical Records; Methods; Modeling; Monitor; Outcome; Participant; Patient Care; Patients; Pattern; Pediatric cohort; Pharmaceutical Preparations; Pharmacy facility; Prevalence; Public Health; Recommendation; Regimen; Research; Resistance; Resistance development; Resources; Retrospective cohort study; Risk; Sampling; Shapes; Specimen; System; Technology; Testing; Time; Treatment Failure; United States National Institutes of Health; Viral; Virus; Weight; Work; antiretroviral therapy; base; care outcomes; clinical care; clinical research site; cohort; drug development; effective therapy; electronic data; follow-up; health care availability; improved; innovation; medication nonadherence; novel; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; pediatric patients; perinatal HIV; prospective; public health relevance; resistance mutation; success; therapy development; treatment guidelines; virology

 DESCRIPTION (provided by applicant): Resistance to antiretroviral therapy (ART) poses significant barriers to effective treatment of HIV infection and optimal long-term clinical care outcomes; however, there are few longitudinal data on rates of and factors associated with viral failure and resistance development in children, particularly in sub-Saharan Africa, where over 90% of HIV-infected children live. The long-term goal of our research team is to provide new evidence to improve the clinical disease management of HIV-infected children and adolescents in resource-limited settings. The purpose of this proposal is to longitudinally investigate treatment failure, drug resistance and associated factors among a previously established, carefully characterized cohort of 685 HIV-infected children in western Kenya. This work will be conducted within a long-standing US-Kenya partnership, the Academic Model Providing Access to Healthcare (AMPATH), which currently cares for over 70,000 adult and pediatric HIV- infected individuals at 65 clinical sites in Kenya. We will utilize the excellent AMPATH infrastructure, as well as a previous NIH-funded study that established this cohort of children (Vreeman: 1K23MH087225), to provide novel and significant data on the development of failure and resistance over five years. The Specific Aims of the proposal are: Aim 1: Determine the prevalence of viral failure and examine drug resistance mutation patterns among a retrospective study cohort of 685 perinatally HIV-infected Kenyan children on 1st-line ART. Aim 2: Investigate associations between specific adherence patterns, ART drug levels and other demographic and clinical factors, with viral failure and drug resistance; Aim 3: Study long-term immunologic, virologic and drug resistance outcomes and their associations in prospectively re-enrolled study participants; and Aim 4: Enhance analyses of viral failure, drug resistance accumulation and associated demographic and clinical factors by examining the longitudinal banked samples available for a subset of the study cohort (n=327). To achieve these aims, we will use previously collected, banked blood specimens of the study cohort (collected between May 2010-October 2013), along with detailed adherence data from electronic dose monitoring and drug concentrations; re-enroll as many of the study cohort as possible for an additional blood draw; assess long-term treatment failure and drug resistance using novel resistance testing technologies; use the established AMPATH Medical Records System to obtain all clinical and pharmacy data for each child from enrollment in AMPATH to present to examine longitudinal associations with failure and resistance; and conduct prospective electronic dose monitoring of current adherence for a subset of the cohort. This research will significantly impact understanding of longitudinal failure and resistance development and which factors influence their development. This proposal is unique because we propose: (1) longitudinal investigation of failure and resistance; (2) innovative approaches to drug resistance testing; and (3) detailed investigation of adherence, drug concentration and other clinical data, to impact pediatric HIV care in resource limited settings.

 描述（由申请人提供）：抗逆转录病毒疗法（ART）的耐药性对艾滋病毒感染的有效治疗和最佳的长期临床护理结果构成了重大障碍；然而，关于儿童病毒衰竭和耐药性发展的比率和相关因素的纵向数据很少，特别是在撒哈拉以南非洲地区，那里有超过 90% 的艾滋病毒感染儿童。我们研究团队的长期目标是提供新的证据，以改善资源有限环境中艾滋病毒感染儿童和青少年的临床疾病管理。该提案的目的是纵向调查肯尼亚西部 685 名 HIV 感染儿童先前建立的、经过仔细表征的队列中的治疗失败、耐药性和相关因素。这项工作将在美国与肯尼亚的长期合作伙伴关系——提供医疗保健的学术模型 (AMPATH) 的框架内进行，该模型目前在肯尼亚的 65 个临床中心为超过 70,000 名成人和儿童 HIV 感染者提供护理。我们将利用优秀的 AMPATH 基础设施，以及之前由 NIH 资助的一项建立该儿童队列的研究（Vreeman：1K23MH087225），提供有关五年内失败和抵抗发展的新颖且重要的数据。该提案的具体目标是： 目标 1：在由 685 名接受第一线 ART 的围产期 HIV 感染肯尼亚儿童组成的回顾性研究队列中确定病毒失败的发生率并检查耐药突变模式。目标 2：研究特定依从模式、ART 药物水平以及其他人口和临床因素与病毒失败和耐药性之间的关联；目标 3：研究前瞻性重新入组研究参与者的长期免疫学、病毒学和耐药性结果及其关联；目标 4：通过检查研究队列子集 (n=327) 的纵向存储样本，加强对病毒失败、耐药性积累以及相关人口和临床因素的分析。为了实现这些目标，我们将使用之前收集、储存的研究队列血液样本（2010年5月至2013年10月期间收集），以及来自电子剂量监测和药物浓度的详细依从性数据；重新招募尽可能多的研究队列以进行额外的抽血；使用新型耐药性测试技术评估长期治疗失败和耐药性；使用已建立的 AMPATH 医疗记录系统获取每个儿童在 AMPATH 注册时的所有临床和药学数据，以检查与失败和抵抗的纵向关联；并对队列中的一个子集的当前依从性进行前瞻性电子剂量监测。这项研究将显着影响对纵向失效和阻力发展以及影响其发展的因素的理解。这个提议是独一无二的，因为我们提出：（1）失效和阻力的纵向调查； (2) 耐药性检测的创新方法； (3) 详细调查依从性、药物浓度和其他临床数据，以影响资源有限环境中的儿科艾滋病毒护理。