Effects of Daily Cotrimoxazole on Malaria in HIV Exposed, Uninfected Infants

描述（由申请人提供）：世界卫生组织建议所有暴露于艾滋病毒的婴儿在4 - 6周龄之间开始复方新诺明预防治疗（CPT），并继续CPT直至停止母乳喂养和明确排除艾滋病毒感染后至少6周。随着非洲越来越广泛地提供婴儿艾滋病毒早期诊断服务，以及采用更有效的药物疗法预防母婴传播艾滋病毒，并将其延长到母乳喂养期，接触艾滋病毒但未感染的婴儿人数正在增加。虽然向感染艾滋病毒的婴儿普遍提供CPT的理由很充分，但对向接触艾滋病毒的未感染婴儿普遍提供CPT的影响知之甚少。由于复方新诺明是一种抗疟剂，因此必须了解每日CPT对接触艾滋病毒但未感染的婴儿预防疟疾的影响，以及在疟疾发作时使用CPT是否导致寄生虫密度下降。母乳喂养、抗逆转录病毒和营养（BAN）研究（ClinicalTrials.gov编号，NCT 00164736）为本研究提供了最佳研究人群。2004年至2006年期间，共有259名艾滋病毒暴露、未感染的婴儿符合资格标准，由于遵守马拉维国家准则，没有接受CPT。从2006年开始，马拉维修订了其持续性预防治疗政策，使626名在BAN登记的接触艾滋病毒、未感染的婴儿从4至6周龄开始接受持续性预防治疗，这些婴儿符合资格标准。该项目的目标是：1）确定CPT对疟疾发病率的影响; 2）确定CPT对平均寄生虫血症水平的影响。对于目标1，疟疾将被定义为临床疟疾（临床症状与记录的显微镜检查阳性寄生虫血症）和血斑PCR阳性的组合，以确定在12、24和36周龄时采集的无症状寄生虫血症。对于目标2，我们将联合收割机现有的显微镜下寄生虫血症数据与通过新的定量真实的时间PCR测定从血斑确定的寄生虫血症相结合。使用广义估计方程的二项回归和线性回归模型将分别用于估计CPT状态的疟疾风险比和CPT状态的疟疾寄生虫血症的平均差异。这项研究将使我们能够比较疟疾的发病率（目标1）和疟疾寄生虫血症（目标2）的平均差异，在前36周的生活在艾滋病毒暴露，未感染的婴儿，没有和没有接受每日复方新诺明开始在6周龄。随着预防母婴传播和儿科艾滋病毒状况的不断变化，必须严格和科学地评估向艾滋病毒暴露婴儿普遍提供复方新诺明预防性治疗的益处。这项研究将增加CPT在HIV暴露的未感染婴儿中的有限证据，并将对马拉维的国家健康儿童，疟疾和HIV计划产生直接影响。

DESCRIPTION (provided by applicant): The World Health Organization recommends that all HIV-exposed infants begin co-trimoxazole preventive therapy (CPT) between four and six weeks of age, and continue CPT until at least six weeks after cessation of breastfeeding and definitive exclusion of HIV infection. As early infant HIV diagnosis services are becoming more widely available in Africa, and as more efficacious drug regimens for the prevention of mother-to-child HIV transmission (PMTCT) are being adopted and extended through the breastfeeding period, the population of HIV-exposed, uninfected infants is growing. While the case for universal provision of CPT to HIV-infected infants is strong, little is known about the impact of universal provision of CPT to HIV-exposed, uninfected infants. As co-trimoxazole is an antimalarial agent, it will be imperative to know the impact of daily CPT on the prevention of malaria among HIV-exposed but uninfected infants, and whether its use leads to decreased parasite density when malaria episodes do occur. The Breastfeeding, Antiretroviral and Nutrition (BAN) study (ClinicalTrials.gov number, NCT00164736) provides an optimal study population for this research. A total of 259 HIV-exposed, uninfected infants enrolled between 2004 and 2006 met eligibility criteria and did not receive CPT due to compliance with the Malawian national guidelines. Beginning in 2006 Malawi revised their CPT policy resulting in 626 HIV-exposed, uninfected infants enrolled in BAN being initiated on CPT starting at 4 to 6 weeks of age who met eligibility criteria. The goal of this project is to 1) determine the effect of CPT on malaria incidence and 2) determine the effect of CPT on mean parasitemia levels. For Aim 1, malaria will be defined as the combination of clinical malaria (clinical symptoms with documented microscopy positive parasitemia) and PCR positivity on blood spots to determine asymptomatic parasitemias taken at 12, 24, and 36 weeks of age. For Aim 2, we will combine existing microscopic parasitemia data with parasitemias determined by a novel quantitative real time PCR assay from the blood spots. A binomial regression and linear regression model using generalized estimating equations will be used to estimate a risk ratio for malaria by CPT status, and mean difference in malaria parasitemia by CPT status respectively. This research will allow us to compare incidence of malaria (Aim 1) and mean difference in malaria parasitemia (Aim 2) during the first 36 weeks of life among HIV-exposed, uninfected infants that did and did not receive daily co-trimoxazole beginning at 6 weeks of age. As the PMTCT and pediatric HIV landscape continues to change, it is imperative to critically and scientifically assess the benefit of universal provision of co-trimoxazole preventive therapy to HIV-exposed infants. This research will add to the limited body of evidence on CPT in HIV-exposed uninfected infants, and will have direct implications for Malawi's national well-child, malaria, and HIV programs.