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

乌干达预防疟疾和改善出生结果的最佳化学预防方案

• 批准号: 10604347
• 负责人: MATTHEW G DORSEY
• 金额: $ 117.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604347
• 关键词: Advisory Committees; Africa; Aftercare; Anemia; Antibiotics; Antimalarials; Area; Artemisinins; Birth; Chemopreventive Agent; Clinical Research; Combined Modality Therapy; Disease; Dose; Double-Blind Method; Drug usage; Frequencies; Half-Life; Infant Mortality; Infection; Infection prevention; Insecticides; Low Birth Weight Infant; Malaria; Malaria prevention; Measures; Neonatal Mortality; Outcome; Parasite resistance; Parasitemia; Parasites; Pharmaceutical Preparations; Plasmodium falciparum; Policies; Pregnancy; Pregnant Women; Premature Birth; Prevalence; Prevention; Prevention strategy; Preventive treatment; Prophylactic treatment; Pyrimethamine; Randomized; Randomized, Controlled Trials; Recommendation; Regimen; Reproductive Tract Infections; Resistance; Risk; Risk Reduction; Safety; Small for Gestational Age Infant; Spontaneous abortion; Sulfadoxine; Testing; Treatment Efficacy; Uganda; Woman; World Health Organization; abortion; adverse birth outcomes; adverse event risk; clinical infrastructure; efficacy evaluation; fetal loss; gut microbiome; high risk; improved; infant death; malaria infection; malaria transmission; maternal risk; neonatal death; novel; placental malaria; policy implication; prevent; pyrethroid; randomized, clinical trials; rural area; standard care; standard of care; stillbirth; symptom treatment; vaginal microbiome; vector

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.

项目概要/摘要 妊娠期疟疾仍然是非洲的一个重大挑战，大约有 5000 万妇女面临感染风险 每年怀孕期间都会感染恶性疟原虫。生活在疟疾流行地区的孕妇 有症状的疾病并不常见，但疟原虫感染与孕产妇贫血有关 不良出生结局，包括流产、死产、早产、低出生体重 (LBW) 和婴儿 死亡。世界卫生组织 (WHO) 建议使用长效杀虫网 (LLIN) 以及用磺胺多辛-乙胺嘧啶 (IPTp-SP) 进行间歇性预防治疗，以预防疟疾 非洲流行地区的怀孕。然而，人们担心这些干预措施的功效会减弱 由于媒介对 LLIN 中使用的拟除虫菊酯杀虫剂的抗药性的传播以及寄生虫对 LLIN 的抗药性 SP。因此，迫切需要制定预防妊娠期疟疾和改善妊娠期疟疾的新策略。 出生结果。基于青蒿素的联合疗法（ACT）现已成为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 ACT，是 IPTp 中 SP 的有吸引力的替代品。 DP 高效，哌喹的半衰期长，可提供至少 4 周的治疗后效果 预防。我们小组和其他人最近的随机对照试验表明，与 IPTp 相比 与 SP、IPTp 与 DP 一起显着降低了疟疾特异性结果的风险，但影响很小 SP 组和 DP 组在不良出生结局风险方面存在差异。关键问题激励 该提议解释了为什么 IPTp 与 SP 或 DP 与不良出生结果的相似风险相关 尽管 DP 的抗疟活性要好得多。可能的解释是 SP，一种广谱 抗生素，可预防低出生体重和早产的非疟疾原因。我们的中心假设是 SP 改善出生结局，与其抗疟活性无关，并且 IPTp 与 SP+DP 的组合将 提供抗疟和非抗疟功效，从而更好地预防不良分娩结果 与单独使用任何一种药物相比。为了检验这个假设，我们将进行双盲随机试验 在疟疾传播强度非常高的乌干达农村地区进行的临床试验，我们小组已经在那里进行了 拥有完善的临床研究基础设施。我们的具体目标是 (1) 比较以下风险： 随机接受每月 IPTp（SP 与 DP 与 DP）的孕妇的不良分娩结局 SP+DP，(2) 比较随机分组的孕妇中 IPTp 方案的安全性和耐受性 每月接受 SP、DP 与 SP+DP 的 IPTp，以及 (3) 比较疟疾特异性和非疟疾的风险 随机接受每月 IPTp（SP、DP 与 SP+DP）的孕妇的结果。这项研究 将是第一个评估经过充分研究的药物的新型组合的功效和安全性，以改善 随着标准实践的改变，出生结果和我们的发现很可能产生重要的政策影响 为非洲数百万孕妇提供帮助。