Impact of Distinct Eco-epidemiology on Malaria Drug Resistance in Ghana

独特的生态流行病学对加纳疟疾耐药性的影响

• 批准号: 8473348
• 负责人: Anita Ghansah
• 金额: $ 11.8万
• 依托单位: NOGUCHI MEMORIAL INSTITUTE / MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473348
• 关键词: Accounting; Alleles; Amodiaquine; Antigens; Antimalarials; Area; Artemisinins; Blood; Child; Chloroquine; Clinical; Collection; Combined Modality Therapy; Copy Number Polymorphism; Country; Cross-Sectional Studies; Data Analyses; District Hospitals; Dose; Drug resistance; Drug usage; Enrollment; Ensure; Epidemiologist; Epidemiology; Equilibrium; Excision; Failure; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genotype; Germ Cells; Ghana; Goals; Heterogeneity; Housing; Inbreeding; Individual; Infection; Inhibitory Concentration 50; Laboratories; Malaria; Measures; Meiosis; Methods; Monitor; Morbidity - disease rate; Mutation; Nature; Parasite resistance; Parasites; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasmodium falciparum; Population; Population Sizes; Prevalence; Process; Recrudescences; Recruitment Activity; Research; Resistance; Risk; Sampling; Schedule; Schools; Seasons; Sentinel; Site; Survey Methodology; Surveys; System; Testing; Therapeutic; Time; Treatment Failure; Visit; acquired immunity; arm; artemisinine; base; burden of illness; checkup examination; cost; drug efficacy; drug sensitivity; drug testing; fitness; follow-up; forest; improved; in vivo; inclusion criteria; killings; meetings; molecular marker; mortality; pressure; prospective; public health relevance; research clinical testing; response; sample fixation; standard of care; transmission process; vaccine candidate

DESCRIPTION (provided by applicant): Malaria remains a leading cause of morbidity and mortality worldwide, killing approximately 781,000 people in 2009. Drug therapy remains one of the major strategies of malaria control. The spread of drug resistant P. falciparum, however, remains a major threat to the goal of eradication, requiring monitoring of the efficacy of the newly deployed artemisinin based combination treatments (ACTs). Monitoring of recently removed drug pressures also remains important given 1) the possible re-expansion of susceptible P. falciparum (as a result of a fitness cost on resistance parasites) to these drugs after a period if unused and 2) their potential for redeployment in combination therapy or in increased doses. Current monitoring methods include follow up of therapeutic failures in vivo, phenotypic determination of parasite sensitivity by short-term ex vivo drug testing and studies of molecular markers associated with drug resistance are surveyed to monitor drug sensitivity to P. falciparum. The question of how resistance will spread in a country with distinct eco-epidemiological zones has not been investigated. This is important because accounting for the effects of transmission in the various eco- epidemiologist in drug efficacy monitoring can identify "hotspots" for the spread of resistance that will be used to maximize the efficiency of existing sentinel systems for efficacy monitoring. The goal of this study is to improve current methods for surveying drug sensitivity, and elucidate the importance of clonal multiplicity, a measure of transmission intensity on the surveillance of drug resistance in two major eco-epidemiological zones of Ghana. Specifically, we will measure and compare the clinical and parasitological efficacy of anti-malarial drugs in two distinct ecological zones, determine the multiplicity of infections and its association with drug resistance and characterize and compare the frequency of known drug resistance markers in two eco-epidemiological zones and their correlations with ex vivo drug response. The study will be conducted in Hohoe, in the Forest ecological zone and Ada in the Coastal Savannah zone of Ghana. A one-arm prospective evaluation of clinical and parasitological responses to treatment for uncomplicated malaria with Amodiaquine -Artemisinin (AA) or Artemisinin Lumifantrine (AL) will be conducted. A total of 200 children/year (800 over four years) with uncomplicated malaria in District hospitals of the two study sites who meet the study inclusion criteria will be enrolled during the peak of the malaria transmission season (June-October). These children will be treated on site with AA or AL following standard of care and monitored for 28 days. When we recruit the 100th child, collection will be done for that site. The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. When a child does not return to a scheduled visit, a research staff will be sent to the child's house to minimize losses to follow-up. On the basis of the results of these assessments, the children will be classified as having therapeutic failure (early, late clinical, ad late parasitological) or an adequate response (not presenting neither type of therapeutic failure). PCR analysis will be used to distinguish between a true recrudescence due to treatment failure and episodes of re-infection (msp1 and msp2 typing). Ex vivo drug testing of samples collected before treatment will be use to determine non-clinical phenotypes of drug response by measuring IC50.s. Polymorphisms in single copy P. falciparum vaccine candidate antigens (msp1, msp2 and csp) will be genotyped to assess MOI and putative molecular markers associated with drug resistance will be characterised to determine their frequency and association with drug resistance phenotypes and MOI. In addition, an annual cross-sectional survey of 100 school children per study area (200 samples from the two ecological zones and, 800 samples over a four year period) will be recruited for multiplicity of infection (MOI) assessment of the population. We will test the hypothesis that the prevalence of resistant parasites will decrease with polyclonal infections at high malaria transmission intensity (Forest ecological zone) and increase with clonal infections at low malaria transmission (Coastal Savannah ecological zone).

描述（由申请人提供）：疟疾仍然是全球发病率和死亡率的主要原因，2009年杀死了约781,000人。药物治疗仍然是疟疾控制的主要策略之一。然而，耐药性恶性疟原虫的蔓延仍然是对根除目标的主要威胁，需要监测新部署的基于阿耳马素的组合治疗（ACT）的疗效。考虑到最近去除的药物压力的监测也很重要1）在未使用的情况下，可能会重新扩展这些药物的易感性恶性疟原虫（由于抵抗寄生虫的适应性成本），如果未使用； 2）它们在组合治疗或增加剂量中的重新部署潜力。当前的监测方法包括对体内治疗性衰竭的随访，通过短期离体药物测试对寄生虫敏感性的表型确定以及对与耐药性相关的分子标记的研究进行了调查，以监测药物对恶性疟原虫的敏感性。尚未研究一个在一个具有独特生态流行病学区域的国家的抵抗力将如何传播的问题。这很重要，因为在药物疗效监测中考虑了各种生态生态学专家的传播的影响可以识别 “热点”，用于将电阻传播的传播，该电阻将最大化现有的前哨系统的效率以进行功效监测。这项研究的目的是改善当前测量药物敏感性的方法，并阐明克隆多样性的重要性，这是在加纳两个主要的生态 - epipipipidemiological区域中传播强度对耐药性监测的量度。具体而言，我们将测量和比较两个不同的生态区域中抗疟疾药物的临床和寄生学功效，确定感染的多样性及其与耐药性的相关性，并表征并比较了两个生态性人体学区域中已知耐药性标志物的频率，并与Ex Vivo药物反应相关。该研究将在加纳沿海萨凡纳地区的森林生态区和ADA的Hohoe进行。将对对单臂的临床和寄生学反应进行一臂前瞻性评估，以对氨二喹 - 阿米半氨酸蛋白（AA）或青蒿素Lumifantrine（AL）进行简单的疟疾治疗。在符合研究纳入标准的两个研究地点的地区医院中，共有200名儿童/年（四年中的800名），在疟疾传输季节的高峰期（6月至10月）的两个研究地点的疟疾将被纳入其中。这些儿童将在现场接受AA或AL遵循护理标准的现场治疗，并进行28天的监测。当我们招募第100个孩子时，将为该站点收集。随访将包括固定的检查访问时间表以及相应的临床和实验室检查。当孩子没有返回预定的访问时，研究人员将被送到孩子的房子，以最大程度地减少损失以进行跟进。根据这些评估的结果，儿童将被归类为患有治疗衰竭（早期，晚期，AD后期寄生虫学）或足够的反应（没有任何类型的治疗衰竭）。 PCR分析将用于区分由于治疗失败和重新感染的发作（MSP1和MSP2键入）而导致的真实复发。通过测量IC50.S.单拷贝疟原虫疫苗候选抗原（MSP1，MSP2和CSP）中的多态性将进行基因分型来评估MOI，并将与耐药性相关的假定分子标记物进行表征，以确定其频率并与耐药性表型和MOI相关。此外，每年对100名学童的年度横断面调查（来自两个生态区的200个样本，在四年期间，有800个样本）将被招募以进行多种感染（MOI）评估人群的评估。我们将检验以下假设：在高疟疾传播强度（森林生态区）下，抗性寄生虫的患病率将随着多克隆感染的降低，并且在低疟疾传播（沿海萨凡纳生态区）时随着克隆感染的增加而降低。