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

项目摘要 艾滋病毒耐药性可能会损害联合国艾滋病规划署的90-90-90治疗目标，是一个主要障碍， 抗逆转录病毒疗法取得成功。尽管指南建议患者进行耐药性测试， 护理在发达国家，有现有的研究差距，在其理解;基因型-表型 不同HIV-1亚型之间的相关性，少数耐药变异体之间的关系， 治疗结果，以及基因型和治疗成功或失败之间不一致的原因仍然存在 不清楚这些研究差距在资源有限的情况下尤其令人关切， 和次优监测是常见的;在儿童和青少年中， 需要终身治疗，HIV-1 RNA水平较高，治疗差距较大，治疗较少， 抑制率较低，制剂有限，不依从率较高。我们研究的长期目标是 研究小组正在为改善儿童和青少年的临床疾病管理提供新的证据 艾滋病病毒感染者在资源有限的环境中。该提案的目的是解决现有的耐药性问题 在一个先前建立的，仔细描述的499名儿童和青少年的队列中， 在肯尼亚感染艾滋病。为了做到这一点，我们将利用我们与学术模式提供者的成功合作， 肯尼亚的获得医疗保健（AMPATH）是撒哈拉以南非洲最大的艾滋病毒方案之一， 独特地利用我们正在进行的R 01 AI 120792中的现有资源，用于围产期感染儿童， AMPATH的青少年（MPI Kantor和Vreeman）。我们假设，全面调查 不同非B亚型的基因型-表型和耐药-治疗结果不一致将得到解决 这些现有的研究差距，并优化病人护理的设置，它是最需要的。我们将 解决这一假设与以下目标：（1）调查基因型-表型相关性;（2）评估 在存在“易感基因型”的情况下治疗失败的病因学;以及（3）评估 在存在“耐药基因型”的情况下治疗成功。为了实现这些目标，我们将使用 现有肯尼亚儿童和青少年队列的可用样本（2016-2018年收集） 非B亚型患者（目标1）;纵向随访队列4年（目标2和3）;采集血液 每半年抽样一次，并评估遵守情况;确定有资格获得拟议额外 研究;进行体外表型分析以检查基因型-表型相关性;并进行近 对RNA和DNA进行全长下一代测序，以研究少数耐药变异体， 替代的抵抗机制。该建议是创新的独特性的队列研究， 全面的科学调查，研究设计和评估不一致的基因型- 治疗结果情景。这些调查和直接解决现有的知识差距， 在具有多种非B亚型的特别脆弱的人群中，HIV-1耐药性将具有很高的 对改善儿童、青少年和成人艾滋病毒感染者的治疗效果的影响。

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.