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Preparing for a world with artemisinin resistance: using individual-based epidemiological modeling to minimize the long-term detrimental effects of antimalarial drug resistance

为青蒿素耐药性的世界做好准备：使用基于个体的流行病学模型最大限度地减少抗疟药物耐药性的长期有害影响

基本信息

批准号：
10667518
负责人：
Maciej F Boni
金额：
$ 38.74万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2025-07-31
项目状态：
未结题

项目摘要

Project Summary/Abstract Plasmodium falciparum is the deadliest of the five species of malaria parasites that infect humans. Annually, there are over 200 million symptomatic cases of falciparum malaria and over 400,000 deaths – the majority of which occur in African children under the age of five. The two major interventions that have had an effect on reducing malaria prevalence over the past twenty years are mosquito control and use of antimalarial drugs. The most important class of drugs in this effort has been the artemisinin derivatives, which since 2005 have been deployed as artemisinin combination therapies (ACTs) only, in order to reduce the probability of emergence and spread of artemisinin-resistant genotypes. Despite these efforts, artemisinin resistance did emerge, and we are now facing the dangerous prospect that these drug-resistant genotypes may spread to Africa, where most of the world’s malaria cases occur. In this proposal, we will introduce and evaluate a number of drug-resistance management strategies that are intended to prevent, delay, and slow down the spread of drug-resistant genotypes of P. falciparum. First, we will make a number of technical advances in our existing individual-based (agent-based) simulation that we already use to model the evolution and epidemiology of P. falciparum in human populations. We will add explicit grid- based spatial structure to make the model more realistic. Additionally, we will add a genotype-phenotype map and clinically-parameterized pharmacodynamic/pharmacokinetic sub-models to make the model’s drug- resistance component as realistic as current data allow. Second, we will evaluate strategies for how best to manage the population-level introduction of novel antimalarial therapies that will become available in the 2020s. The strategies will be aimed at minimizing the long-term risk of drug resistance to both the novel therapies and to currently used ACTs, in order to minimize the number of treatment failures in the long run. Finally, we will parameterize country scenarios for Cambodia, Zambia, and Burkina Faso to provide specific country-level advice in low, medium, and high transmission malaria settings on how best to preëmpt drug resistance or minimize its current spread. As Cambodia is the epicenter of the current wave of artemisinin resistance, the Cambodia- specific model will be used to provide advice on how to contain and eliminate currently circulating artemisinin- resistant genotypes of P. falciparum.

项目概要/摘要恶性疟原虫是感染人类的五种疟原虫中最致命的一种。每年，有超过 2 亿有症状的恶性疟疾病例，超过 40 万人死亡——其中大多数发生于五岁以下的非洲儿童。影响的两项主要干预措施过去二十年来减少疟疾流行的方法是控制蚊子和使用抗疟药物。这这一努力中最重要的一类药物是青蒿素衍生物，自 2005 年以来，仅作为青蒿素联合疗法（ACT）部署，以减少出现和发生的可能性青蒿素耐药基因型的传播。尽管做出了这些努力，青蒿素耐药性确实出现了，我们正在现在面临着这些耐药基因型可能传播到非洲的危险前景，那里的大多数世界上发生了疟疾病例。在本提案中，我们将介绍和评估一些耐药性管理策略，这些策略是旨在预防、延迟和减缓恶性疟原虫耐药基因型的传播。首先，我们将在我们现有的基于个人（基于代理）的模拟中取得了许多技术进步，我们已经用于模拟人类恶性疟原虫的进化和流行病学。我们将添加显式网格- 基于空间结构，使模型更加真实。此外，我们将添加基因型-表型图和临床参数化的药效/药代动力学子模型，使模型的药物电阻分量与当前数据允许的一样真实。其次，我们将评估如何最好地采取策略管理将在 2020 年代推出的新型抗疟疗法的人群推广。这些策略旨在最大限度地减少对新疗法和新疗法产生耐药性的长期风险。到目前使用的 ACT，以最大限度地减少长期治疗失败的次数。最后，我们将对柬埔寨、赞比亚和布基纳法索的国家情景进行参数化，以提供具体的国家级建议在低、中和高传播疟疾环境中如何最好地预防耐药性或最大限度地减少其耐药性目前的传播。由于柬埔寨是当前青蒿素耐药浪潮的中心，柬埔寨- 将使用具体模型就如何遏制和消除目前流行的青蒿素提供建议恶性疟原虫的抗性基因型。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

National-scale simulation of human movement in a spatially coupled individual-based model of malaria in Burkina Faso.

DOI：
10.1038/s41598-022-26878-5
发表时间：
2023-01-06
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda.

DOI：
10.1038/s41591-023-02551-w
发表时间：
2023-11
期刊：
NATURE MEDICINE
影响因子：
82.9
作者：
Zupko, Robert J.;Nguyen, Tran Dang;Ngabonziza, J. Claude S.;Kabera, Michee;Li, Haojun;Tran, Thu Nguyen-Anh;Tran, Kien Trung;Uwimana, Aline;Boni, Maciej F.
通讯作者：
Boni, Maciej F.

Global risk of selection and spread of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions.

恶性疟原虫富含组氨酸的蛋白 2 和 3 基因缺失的选择和传播的全球风险。

DOI：
10.1101/2023.10.21.23297352
发表时间：
2024
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Watson,OliverJ;Tran,ThuNguyen-Anh;Zupko,RobertJ;Symons,Tasmin;Thomson,Rebecca;Visser,Theodoor;Rumisha,Susan;Dzianach,PaulinaA;Hathaway,Nicholas;Kim,Isaac;Juliano,JonathanJ;Bailey,JeffreyA;Slater,Hannah;Okell,Lucy;Gething,
通讯作者：
Gething,

Preventing antimalarial drug resistance with triple artemisinin-based combination therapies.

DOI：
10.1038/s41467-023-39914-3
发表时间：
2023-07-29
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Nguyen, Tran Dang;Gao, Bo;Amaratunga, Chanaki;Dhorda, Mehul;Tran, Thu Nguyen-Anh;White, Nicholas J.;Dondorp, Arjen M.;Boni, Maciej F.;Aguas, Ricardo
通讯作者：
Aguas, Ricardo

Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum.

评估恶性疟原虫双抗和三抗基因型的出现风险。