Selection of drug resistant malaria parasites

该计划项目包括三个随机临床试验，以测试长期使用 儿童的化学预防抗疟疾疗法或儿童或儿童的抗逆转录病毒蛋白酶抑制剂 孕妇将减少疟疾的发病率和相关的疟疾发病率。这些干预措施 提供机会大幅减少疟疾的发病率和发病率，最重要的是 非洲儿童和孕妇中的传染病。然而，重复或慢性治疗对 传染病通常会带来选择抗药性寄生虫的风险。这是一个特别令人担忧的问题 对于疟疾，由于耐药性已经限制了治疗选择，以及基于间歇性的控制努力 治疗一直严重依赖于抗叶酸，而抗药性正在增加。因此，随着我们的临床试验 检测抗逆转录病毒和抗疟疾药物的预防效果，这是非常重要的 描述这些干预措施对选择抗药性疟疾寄生虫的影响。我们 假设间歇性或慢性使用抗疟疾和基于蛋白水解酶抑制剂的抗逆转录病毒药物 治疗方法将减少疟疾的发病率，但这些治疗方法将选择抗药性 可能变得难以控制的寄生虫。此外，我们假设不同的药物将提供 不同的选择压力。因此，对不同品种的抗性选择压力的评价 除了我们的临床试验结果外，药物还可以指导管理艾滋病毒的公共政策 非洲的感染和疟疾。项目4将利用寄生虫学和分子技术来测试我们的 假设，受益于一个专注于Tororo的临床实验室，Tororo是中国的一个中心实验室 坎帕拉拥有广泛的分子和寄生虫学能力，以及一个拥有20年 在加州大学旧金山分校研究疟疾寄生虫的经验。我们的具体目标将是：1)描述选择的特征 抗叶酸化学预防方案对疟疾耐药寄生虫的筛选 用双氢青蒿素/哌喹化学预防抗药性疟疾寄生虫，以及3) 用抗逆转录病毒蛋白水解酶抑制剂筛选耐药疟疾寄生虫的特征 抗疟疾活性。这些研究将补充我们的临床试验，以提供对 控制疟疾的新化学预防措施的成本和收益。

This program project includes three randomized clinical trials to test whether long-term use of chemopreventive antimalarial therapies in children or of antiretroviral protease inhibitors in children or pregnant women will decrease the incidence of malaria and related malarial morbidity. These interventions offer the opportunity to significantly decrease the incidence and morbidity of malaria, the most important infectious disease in children and pregnant women in Africa. However, repeated or chronic therapy for infectious diseases routinely entails a risk of selection of drug-resistant parasites. This is a particular concern for malaria, as drug resistance already limits treatment options, and control efforts based of intermittent therapy have relied heavily on antifolates, against which resistance is increasing. Thus, as our clinical trials test the preventive antimalarial efficacy of antiretroviral and antimalarial drugs, it is very important to characterize the impact of these interventions on the selection of drug-resistant malaria parasites. We hypothesize that intermittent or chronic use of antimalarial and protease inhibitor-based antiretroviral therapies will decrease the incidence of malaria, but that these therapies will select for drug resistant parasites that may become refractory to control efforts. Further, we hypothesize that different drugs will offer different selective pressures. Therefore, an appreciation of the selective pressures for resistance of different drugs can, in addition to the results of our clinical trials, guide public policy for the management of HIV infection and malaria in Africa. Project 4 will utilize parasitology and molecular techniques to test our hypotheses, benefiting from a clinical laboratory with focused expertise in Tororo, a central laboratory in Kampala with extensive molecular and parasitological capabilities, and a laboratory with 20 years of experience studying malaria parasites at UCSF. Our specific aims will be: 1) to characterize the selection of drug-resistant malaria parasites by antifolate chemopreventive regimens, 2) to characterize the selection of drug-resistant malaria parasites by chemoprevention with dihydroartemisinin/piperaquine, and 3) to characterize the selection of drug-resistant malaria parasites by antiretroviral protease inhibitors with antimalarial activity. These studies will complement our clinical trials to provide a balanced assessment of the costs and benefits of new chemopreventive measures to control malaria.