Epidemiology and determinants of emerging artemisinin-resistant malaria in Ethiopia

埃塞俄比亚新出现的青蒿素耐药性疟疾的流行病学和决定因素

• 批准号: 10718838
• 负责人: Jonathan Boyd Parr
• 金额: $ 72.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718838
• 关键词: Address; Affect; Africa; Anti-malarial drug resistance; Antimalarials; Artemisinins; Behavioral; Cessation of life; Clinic; Clinical; Clinical Management; Collaborations; Collection; Combined Modality Therapy; Communities; Complex; Country; Culicidae; Data; Deletion Mutation; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Drug resistance; Environment; Epidemiology; Ethiopia; Ethiopian; Falciparum Malaria; Future; Gene Deletion; Genes; Genetic; Genetic Polymorphism; HRP-2 protein; Health; Health care facility; Horns; Human; In Vitro; Incidence; Individual; Infection; Investments; Malaria; Mediating; Modeling; Monitor; Movement; Mutation; Parasite resistance; Parasites; Persons; Pharmaceutical Preparations; Plasmodium falciparum; Policies; Population; Positioning Attribute; Prevalence; Public Health; Rapid diagnostics; Regimen; Reporting; Residencies; Resistance; Resistance to infection; Risk; Risk Factors; Selection for Treatments; Statistical Models; Surveys; Testing; Time; Travel; Uncertainty; Vertebral column; accurate diagnosis; alternative treatment; arm; clinical care; clinical practice; clinical predictors; clinical risk; cost; design; diagnostic strategy; effective therapy; experimental study; fitness; human model; improved; in vivo; migration; multiple data sources; point of care; population survey; predictive modeling; predictive tools; pressure; prevent; programs; prospective; rapid diagnosis; resistance mutation; resistant Plasmodium falciparum; resistant strain; risk prediction model; therapy design; tool; transmission process; treatment strategy

PROJECT SUMMARY Plasmodium falciparum strains with resistance to first-line artemisinin-combination therapies (ACTs) threaten malaria control and elimination efforts across Africa, where 95% of the world's malaria cases and deaths occur. Artemisinin resistance is mediated by mutations in the pfkelch13 (K13) gene that have only recently impacted the region. Concerning K13 mutations have now been confirmed in Africa, including emergence and expansion of the candidate artemisinin-resistance K13 R622I mutation in the Horn of Africa (HoA). Increasing reports from the HoA by us and others also indicate that “diagnosis resistant” strains that escape detection by widely used rapid diagnostic tests due to deletions of the histidine-rich protein 2/3 (pfhrp2/3) genes are now established across the region. The dual emergence of drug and diagnostic resistance mutations threatens frontline test- and-treat strategies and may have profound impacts on malaria control. Improved understanding of the determinants of infection by R622I parasites is needed to inform clinical practice and policy decisions. In collaboration with the Ethiopian Public Health Institute, the technical arm of the Ethiopia Federal Ministry of Health, and leading academic partners, we will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia and achieve the following Aims. In Aim 1, we will elucidate risk factors for infection by artemisinin-resistant P. falciparum, including whether the presence or absence of pfhrp2/3 deletions impacts risk. We will develop a clinical risk tool to help predict who may be infected by an artemisinin- resistant parasite. Such a tool could be used for targeted implementation of antimalarial treatment options designed to overcome resistance and prevent its spread, such as triple ACT that employs two partner drugs alongside an artemisinin derivative. In Aim 2, we will determine the impact of K13 R622I on drug resistance and parasite fitness in pfhrp2/3-deleted and intact parasites. In Aim 3, we will develop a predictive model of the future spread of artemisinin resistance within and out of the HoA, focusing first on development of data/models of human and parasite migration and then integrating in vivo data from Aim 1 and in vitro data from Aim 2. Together, these Aims will improve our understanding of the epidemiology and drivers of emerging artemisinin resistance in the HoA and produce tools that can be used by malaria programs to identify, predict, and respond to emerging drug-resistant strains in Africa.

项目概要 对一线青蒿素联合疗法 (ACT) 具有抗药性的恶性疟原虫菌株威胁着 全球 95% 的疟疾病例和死亡发生在非洲。 青蒿素耐药性是由 pfkelch13 (K13) 基因突变介导的，该突变最近才影响 该地区。关于 K13 突变现已在非洲得到证实，包括出现和扩展 非洲之角 (HoA) 候选青蒿素抗性 K13 R622I 突变的研究。越来越多的报告来自 我们和其他人的 HoA 还表明，“诊断耐药”菌株逃脱了广泛使用的检测 现已建立因富含组氨酸蛋白 2/3 (pfhrp2/3) 基因缺失而产生的快速诊断测试 整个地区。药物和诊断耐药性突变的双重出现威胁着前线测试 和治疗策略，可能对疟疾控制产生深远影响。增进了对 需要了解 R622I 寄生虫感染的决定因素来为临床实践和政策决策提供信息。在 与埃塞俄比亚公共卫生研究所（埃塞俄比亚联邦卫生部的技术部门）合作 卫生部门和领先的学术合作伙伴，我们将对前往卫生机构就诊的人员进行调查 埃塞俄比亚各地的恶性疟疾并实现以下目标。在目标 1 中，我们将阐明以下风险因素： 抗青蒿素恶性疟原虫感染，包括是否存在 pfhrp2/3 删除会影响风险。我们将开发一种临床风险工具来帮助预测谁可能被青蒿素感染—— 抗性寄生虫。这种工具可用于有针对性地实施抗疟治疗方案 旨在克服耐药性并防止其传播，例如采用两种伙伴药物的三重 ACT 与青蒿素衍生物一起使用。在目标 2 中，我们将确定 K13 R622I 对耐药性的影响 以及 pfhrp2/3 删除和完整寄生虫中的寄生虫适应性。在目标 3 中，我们将开发一个预测模型 未来青蒿素耐药性在 HoA 内外的传播，首先关注数据/模型的开发 人类和寄生虫迁移，然后整合目标 1 的体内数据和目标 2 的体外数据。 这些目标将共同提高我们对新兴青蒿素的流行病学和驱动因素的理解 HoA 中的耐药性并产生可供疟疾项目识别、预测和应对的工具 非洲新出现的耐药菌株。