Selection of drug resistant malaria parasites

该计划项目包括三项随机临床试验，以测试长期使用 在儿童中使用抗逆转录病毒蛋白酶抑制剂， 孕妇将减少疟疾发病率和相关疟疾发病率。这些干预措施 提供机会，大幅度降低疟疾的发病率和发病率， 非洲儿童和孕妇的传染病。然而，反复或长期治疗 感染性疾病通常具有选择抗药性寄生虫的风险。这是一个特别令人关注的问题 对于疟疾，由于抗药性已经限制了治疗选择， 治疗严重依赖于抗叶酸剂，抗叶酸剂的耐药性正在增加。因此，我们的临床试验 为了测试抗逆转录病毒和抗疟疾药物的预防性抗疟效果， 描述这些干预措施对抗药性疟疾寄生虫选择的影响。我们 假设间歇性或长期使用抗疟药和基于蛋白酶催化剂抗逆转录病毒药物 治疗将降低疟疾的发病率，但这些治疗将选择耐药的 寄生虫可能变得难以控制的努力。此外，我们假设不同的药物将提供 不同的选择压力。因此，对不同抗性的选择性压力的评价 除了我们的临床试验结果外，药物还可以指导艾滋病毒管理的公共政策 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，受益于托罗罗的临床实验室，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历我们的具体目标将是：1）描述选择 抗叶酸剂化学预防方案的耐药疟疾寄生虫，2）表征选择 用双氢青蒿素/哌喹进行化学预防， 描述抗逆转录病毒蛋白酶抑制剂对抗药性疟疾寄生虫的选择， 抗疟疾活性。这些研究将补充我们的临床试验，以提供平衡的评估， 控制疟疾的新化学预防措施的成本和效益。

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.