Optimal chemopreventive regimens to prevent malaria and improve birth outcomes in Uganda

项目摘要/摘要 孕期疟疾在非洲仍然是一项重大挑战，那里约有5000万妇女面临疟疾的风险。 每年孕期感染恶性疟原虫。在疟疾流行地区的孕妇中 有症状的疾病并不常见，但感染疟疾寄生虫与母亲贫血有关。 以及不良分娩结果，包括流产、死产、早产、低出生体重(LBW)和婴儿 死亡率。世界卫生组织(WHO)建议使用长效杀虫网(LLIN) 和磺胺多辛-乙胺嘧啶(IPTp-SP)间歇预防性治疗预防疟疾 非洲流行地区的怀孕。然而，人们担心这些干预措施的效果会减弱。 由于媒介对拟除虫菊酯杀虫剂的抗药性的传播和对寄生虫的抗药性 沙棘属(SP.)因此，迫切需要新的战略来预防孕期疟疾和改善 出生结局。基于青蒿素的联合疗法(ACTs)现在是#年疟疾的标准治疗方法。 非洲。双氢青蒿素-哌喹(DP)是一种固定剂量的ACT，是治疗IPTp的一种有吸引力的SP替代品。dp 是非常有效的，而哌喹的长半衰期提供了至少4周的治疗后 预防措施。我们小组和其他人最近的随机对照试验表明，与IPTp相比 使用SP，带有DP的IPTp显著降低了疟疾特有结果的风险，但只有很小的影响 SP组和DP组在不良出生结局风险方面的差异。激励人们的关键问题 这就是为什么患有SP或DP的IPTp与不良生育结局的风险相似的原因 尽管DP的抗疟疾活性要好得多。可能的解释是SP，一种广谱的 抗生素，防止LBW和早产的非疟疾原因。我们的中心假设是SP 独立于其抗疟疾活性改善分娩结局，IPTp与SP+DP的组合将 提供抗疟疾和非抗疟疾福利，从而更好地预防不良生育结果 与单独使用的任何一种药物相比。为了检验这一假设，我们将进行双盲随机 在乌干达一个疟疾传播强度非常高的农村地区进行的临床试验，我们的小组已经在那里 已经建立了临床研究的基础设施。我们的具体目标将是：(1)比较 随机选择每月接受IPTp治疗的孕妇中的不良分娩结局：SP组与DP组相比， SP+DP，(2)比较IPTp方案的安全性和耐受性，孕妇随机分为 每月收到SP、DP和SP+DP的IPTp，以及(3)比较疟疾特有和非疟疾的风险 随机选择每月接受IPTp治疗的孕妇的结局分别为SP、DP和SP+DP。本研究 将第一个评估一种经过充分研究的新型药物组合的有效性和安全性，以改善 随着标准做法的改变，出生结局和我们的发现很可能具有重要的政策意义 为非洲数以百万计的孕妇服务。

PROJECT SUMMARY/ABSTRACT Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials from our group and others showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question motivating this proposal is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. Our central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis we will conduct a double-blinded randomized clinical trial in a rural area of Uganda with very high malaria transmission intensity, where our group already has an established infrastructure for clinical research. Our specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and our findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.