Addressing HIV drug resistance research gaps in a cohort of perinatally infected Kenyan children and adolescents

解决一群围产期感染的肯尼亚儿童和青少年的艾滋病毒耐药性研究空白

• 批准号: 10630333
• 负责人: Rami Kantor
• 金额: $ 69.3万
• 依托单位: MIRIAM HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-27 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630333
• 关键词: Address; Adherence; Adolescent; Adult; Affect; Africa South of the Sahara; Anti-Retroviral Agents; Archives; Biological Assay; Blood specimen; Cessation of life; Child; Clinical; Clinical Management; Cohort Studies; Collaborations; DNA; Developed Countries; Disease Management; Drug resistance; Enrollment; Etiology; Evaluation; Failure; Formulation; Funding; Genetic Polymorphism; Genotype; Goals; Guidelines; HIV; HIV Genome; HIV drug resistance; HIV-1; HIV-1 drug resistance; In Vitro; Investigation; Kenya; Knowledge; Length; Literature; Minority; Modeling; Monitor; Morbidity - disease rate; Mutation; Outcome; Participant; Patient Care; Perinatal; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Positioning Attribute; Predisposition; Public Health; RNA; Recommendation; Regimen; Research; Research Design; Resistance; Resource-limited setting; Resources; Sampling; Testing; Therapeutic; Treatment Failure; Treatment outcome; United States National Institutes of Health; Variant; Vulnerable Populations; Work; acquired drug resistance; antiretroviral therapy; clinically significant; cohort; design; drug resistance development; eligible participant; health care availability; improved; innovation; mortality; next generation sequencing; novel; programs; resistance mechanism; success; therapy adherence; therapy resistant; transmission process; treatment optimization

PROJECT SUMMARY HIV drug resistance may compromise the UNAIDS 90-90-90 treatment goals and is a major hurdle to sustainable antiretroviral therapy success. Though resistance testing is recommended by guidelines for patient care in developed countries, there are existing research gaps in its understanding; genotypic-phenotypic correlations in diverse HIV-1 subtypes, the relationship between minority drug resistance variants and treatment outcomes, and reasons for discordances between genotype and treatment success or failure remain unclear. These research gaps are of particular concern in resource-limited settings, where limited medications and sub-optimal monitoring are common; and in children and adolescents, a vulnerable population with the need for life-long therapy, who have higher levels of HIV-1 RNA, a wider treatment gap with fewer on therapy, lower rates of suppression, limited formulations and more non-adherence. The long-term goal of our research team is to provide new evidence to improve the clinical disease management children and adolescents living with HIV in resource-limited settings. The purpose of this proposal is to address existing drug resistance research gaps in a previously established, carefully characterized cohort of 499 children and adolescents living with HIV in Kenya. To do this, we will use our successful collaboration with the Academic Model Providing Access to Healthcare (AMPATH) in Kenya, one of the largest HIV programs in sub-Saharan Africa, and uniquely leverage existing resources from our ongoing R01 AI120792 on perinatally-infected children and adolescents at AMPATH (MPI Kantor and Vreeman). We hypothesize that comprehensive investigations of genotypic-phenotypic and resistance-treatment outcome discordances in diverse non-B subtypes will resolve some of these existing research gaps and optimize patient care in settings where it is most needed. We will address this hypothesis with the following Aims: (1) Investigate genotype-phenotype correlations; (2) Evaluate etiologies for treatment failure in the presence of a ‘susceptible genotype’; and (3) Evaluate etiologies for treatment success in the presence of a ‘resistant genotype’. To achieve these aims, we will use already available samples (collected between 2016-2018) from the existing cohort of Kenyan children and adolescents living with non-B subtypes (Aim 1); longitudinally follow the cohort for four years (Aims 2 and 3); collect blood samples bi-annually and assess adherence; identify participants that are eligible for proposed additional investigations; conduct in vitro phenotyping to examine genotypic-phenotypic correlations; and perform near full-length next generation sequencing on RNA and DNA to investigate minority resistance variants and alternative mechanisms of resistance. The proposal is innovative in the uniqueness of the cohort studied, the comprehensive proposed scientific investigations, and study design and evaluation of discordant genotype- treatment outcomes scenarios. These investigations and directly addressing the existing knowledge gaps in HIV-1 drug resistance in a particularly-vulnerable population with diverse non-B subtypes, will have a high impact on improving treatment outcomes in children, adolescents, and adults living with HIV.

项目概要 HIV 耐药性可能会损害 UNAIDS 90-90-90 治疗目标，并且是治疗的主要障碍。 尽管指南建议对患者进行耐药性检测，但可持续的抗逆转录病毒治疗取得了成功。 发达国家对基因型-表型的理解存在研究差距； 不同 HIV-1 亚型之间的相关性、少数耐药变异与 治疗结果以及基因型与治疗成功或失败之间不一致的原因仍然存在 这些研究差距在资源有限、药物有限的环境中尤其令人担忧。 监测欠佳的情况很常见；儿童和青少年是弱势群体， 需要终身治疗，HIV-1 RNA 水平较高，治疗差距较大且接受治疗的人较少， 较低的抑制率、有限的配方和更多的不依从性是我们研究的长期目标。 团队旨在为改善儿童和青少年生活的临床疾病管理提供新的证据 该提案的目的是解决现有的耐药性问题。 先前建立的、仔细描述的 499 名儿童和青少年队列中的研究空白 为此，我们将利用与学术模型提供者的成功合作。 肯尼亚的医疗保健获取 (AMPATH) 是撒哈拉以南非洲地区最大的艾滋病毒项目之一，以及 以独特的方式利用我们正在进行的针对围产期感染儿童的 R01 AI120792 的现有资源， AMPATH 的青少年（MPI Kantor 和 Vreeman）。 不同非 B 亚型的基因型-表型和耐药性-治疗结果不一致将得到解决 我们将弥补一些现有的研究空白，并在最需要的地方优化患者护理。 通过以下目标解决这一假设：(1) 研究基因型-表型；(2) 评估 存在“易感基因型”时治疗失败的病因；以及 (3) 评估“易感基因型”的病因； 在存在“耐药基因型”的情况下治疗成功 为了实现这些目标，我们将已经使用。 来自现有肯尼亚儿童和青少年队列的可用样本（2016 年至 2018 年期间收集） 与非 B 亚型一起生活（目标 1）；纵向跟踪队列四年（目标 2 和 3）； 每年两次进行抽样并评估遵守情况；确定有资格获得额外提议的参与者 研究；进行体外表型分析以检查基因型-表型相关性； 对 RNA 和 DNA 进行全长下一代测序，以研究少数耐药变异和 该提议的创新之处在于所研究的群体的独特性。 全面提出的科学研究、研究设计和不一致基因型的评估- 这些调查直接解决了现有的知识差距。 HIV-1 耐药性在具有多种非 B 亚型的特别脆弱人群中将具有很高的耐药性 对改善艾滋病毒感染儿童、青少年和成人治疗结果的影响。