Novel Strategies to Prevent Malaria and Improve HIV Outcomes in Africa

描述(申请人提供)：艾滋病毒和疟疾是世界上最重要的两种传染病，在撒哈拉以南非洲是协同作用的。该方案项目的总体目标(P01)是评估新的战略性干预措施，以减轻疟疾负担并改善儿童和孕妇的艾滋病毒结果，儿童和孕妇是受这些疾病重叠影响最大的人群。 我们假设，与接受标准抗逆转录病毒治疗的儿童和孕妇相比，使用HIV蛋白酶抑制剂(PI)治疗将降低艾滋病毒感染儿童和孕妇的疟疾发病率和随之而来的发病率。这一假设是基于对疟疾寄生虫和艾滋病毒表达生物化学相似的蛋白酶的认识，以及对艾滋病毒PI在体外发挥强大的抗疟疾活性的观察。其次，我们假设，在未感染艾滋病毒的儿童中，化学预防治疗将对疟疾提供强有力的保护，而不会在停止干预后增加疟疾发病率。第三，我们假设间歇性或慢性抗疟疾和基于PI的抗逆转录病毒治疗将选择耐药寄生虫，并且不同的药物将提供不同的选择压力。我们的P01项目包括四项相互关联的研究，以检验这三个假设： 1：预防艾滋病毒感染儿童疟疾的蛋白水解酶抑制剂 2：用蛋白水解酶抑制剂降低感染艾滋病毒孕妇的疟疾发病率 3：对未感染艾滋病毒的婴儿和儿童进行疟疾化学预防治疗 4：通过抗疟疾和艾滋病毒治疗选择抗药性疟疾寄生虫 这些项目将招收1600名参与者，并由一个多学科、多国团队在乌干达托罗罗实施，托罗罗是疟疾高传播地。行政和数据/统计核心将支持这4个项目。这些项目将在经过验证的疟疾预防战略的背景下进行，这些战略目前是撒哈拉以南非洲大部分地区的护理标准：1)在感染艾滋病毒的儿童和孕妇中使用甲氧苄氨嘧啶-磺胺甲恶唑进行化学预防；2)使用驱虫蚊帐。我们的主要目标将是在现有知识的基础上建立新的方法，以减少撒哈拉以南非洲的艾滋病毒和疟疾负担，并推动对这两种疾病的公共卫生方法。

DESCRIPTION (provided by applicant): HIV and malaria are two of the most important infectious diseases worldwide, and are synergistic in sub-Saharan Africa. The overarching goal of this program project (P01) is to evaluate novel and strategic interventions to reduce the burden of malaria and improve HIV outcomes among children and pregnant women, the populations most affected by the overlap of these diseases. We hypothesize that treatment with HIV protease inhibitors (PIs) will lower the incidence of malaria and consequent morbidity in HIV-infected children and pregnant women compared to those treated with standard antiretroviral treatment. This hypothesis is based on the appreciation that malaria parasites and HIV express biochemically similar proteases and the observation that HIV PIs exert potent in vitro antimalarial activity. Second, we hypothesize that in HIV-uninfected children, chemopreventive therapy will offer strong protection against malaria without increased malarial morbidity after discontinuation of the intervention. Third, we hypothesize that intermittent or chronic antimalarial and PI-based antiretroviral therapy will select for drug resistant parasites, and that different drugs will offer different selective pressures. Four interlinked studies to test these three hypotheses comprise our P01 projects: 1: Protease inhibitors for the prevention of malaria in HIV-infected children 2: Protease inhibitors to reduce malaria morbidity in HIV-infected pregnant women 3: Chemopreventive therapy for malaria in HIV-uninfected infants and children 4: Selection of drug resistant malaria parasites by antimalarial and HIV therapies The projects will enroll a total of 1600 participants and be implemented by a multidisciplinary, multinational team in Tororo, Uganda, a site of high malaria transmission. Administrative and data/statistics cores will support the 4 projects. The projects will be conducted in the context of proven malaria preventive strategies that are currently the standard of care for most of sub-Saharan Africa: 1) the use of chemoprophylaxis with trimethoprim-sulfamethoxazole in HIV-infected children and pregnant women, and 2) the use of insecticide treated nets. Our primary goal will be to build on current knowledge to establish new approaches to reduce HIV and malaria burden in sub-Saharan Africa, and to advance the public health approach to both diseases.