Intermittent Preventive Treatment with DHA-piperaquine for malaria in pregnancy in areas with high sulphadoxine-pyrimethamine resistance in Africa

研究背景在撒哈拉以南非洲的疟疾流行地区，每年有3000多万人怀孕。妊娠期疟疾（MiP）对母亲和未出生的孩子造成毁灭性的后果。在东非和南部非洲部分地区，对妊娠期疟疾的控制受到威胁。孕妇感染疟疾时往往没有任何外在的迹象或症状，如果不及时发现和治疗，可能会造成贫血，干扰胎儿发育，导致流产，或早产和出生体重不足，这反过来又增加了婴儿早期死亡的风险。因此，世界卫生组织（世卫组织）建议采取一种名为“妊娠期间歇性预防治疗”的预防策略，即母亲在妊娠第二和第三个三个月开始的每次计划产前检查中接受单剂量的3片名为磺胺嘧啶-乙胺嘧啶（SP）的药物。然而，这一战略的有效性正在受到损害，由于高水平的耐药性SP疟疾寄生虫population.The最近寻找安全，有效和耐受性良好的替代药物已被证明是难以捉摸的，因为大多数新的候选人测试耐受性不足以用于预防目的。其他评估测试和治疗策略的试验也令人失望。现在，所有的希望都寄托在一种名为双氢青蒿素-哌喹（DP）的抗疟疾药物上，众所周知，这种药物在怀孕第二和第三个月是安全的，并且对治疗临床疟疾非常有效。知名期刊《柳叶刀》和《新英格兰医学杂志》最近发表了2015年完成的两项探索性试验的结果（其中一项由肯尼亚的研究小组完成）。这些结果表明，DP作为IPT被孕妇服用时，耐受性良好，并且在预防疟疾方面比SP有效得多。然而，这两项试验的规模还不足以评估对妊娠结局和新生儿健康的影响。世卫组织于2015年7月审查了证据，得出结论认为DP确实是SP的有希望的替代品，并建议在考虑是否推荐这种药物作为高耐药性地区SP的替代品之前，需要进行更大规模的确证性试验。这项多中心试验将在肯尼亚和马拉维的六家医院招募约3，000名孕妇，并比较IPTp与DP的安全性，耐受性和有益效果，以减少妊娠丢失，低出生体重，早产和小于胎龄婴儿以及早期婴儿死亡。试验将包括关于卫生经济学的次级研究，以确定该战略的成本与其效益的关系、孕妇和保健提供者对干预措施的可接受性，特别注意遵守3天方案，以及在常规卫生系统中实施干预措施的业务可行性。潜在的应用和益处经过十年的密集多中心试验，以寻找妊娠期疟疾的新预防策略，DP已被列入候选名单，作为唯一潜在的替代SP用于IPTp，但需要证据证明其对婴儿结局的益处。作为一个经验丰富的网络，专门从事妊娠期疟疾预防试验，我们处于一个独特的地位，以加快解决这些差距。这项新试验的结果将为是否应推荐这种药物在寄生虫对SP具有高水平耐药性的地区取代SP提供明确的证据。积极的结果可能导致世卫组织在经历这些水平的寄生虫耐药性的国家，包括东非和南部非洲的大多数国家，直接改变政策。使这些地区面临疟疾风险的妇女受益，从而使怀孕和新生儿更健康。

Context of the researchEach year over 30 million pregnancies occur in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The control of malaria in pregnancy in parts of East and southern Africa is under threat. Pregnant women are often infected with malaria without showing any outward signs or symptoms which, if left undetected and untreated, can cause anaemia and interfere with the development of the foetus leading to loss of the pregnancy, or premature birth and low birth weight, which in turn increases the risk of early infant death. The World Health Organisation (WHO) therefore recommends a preventive strategy called 'intermittent preventive treatment in pregnancy' (IPTp) in which mothers receive a single dose of 3 tablets of medication called sulphadoxine-pyrimethamine (SP) at each scheduled antenatal visit starting in the 2nd and 3rd trimester. However, the effectiveness of this strategy is being compromised due to high levels of resistance to SP in the malaria parasite population.The recent search for safe, effective and well-tolerated alternatives drugs has proven elusive because most of the new candidates tested were not tolerated well enough to be used for preventive purposes. Other trials evaluating test and treat strategies have also proven disappointing. All hopes are now pinned on an antimalarial called dihydroartemisinin-piperaquine (DP), which is known to be safe in the 2nd and 3rd trimester of pregnancy and highly effective for treatment of clinical malaria. The high profile journals Lancet and the New England Journal of Medicine recently published the results of two exploratory trials, completed in 2015 (including one by this research team in Kenya). These showed that DP, when taken as IPT by pregnant women, was well tolerated and much more effective than SP in preventing malaria. However these two trials were not big enough to be able to evaluate the impact on the pregnancy outcome and the health of the newborn. WHO reviewed the evidence in July 2015 and concluded that DP is indeed a promising alternative to SP and recommended that a larger, confirmatory, trial is needed, before it can consider whether to recommend this drug as an alternative to SP in areas of high resistance. Study aims and objectivesThis multi-centre trial will enrol about 3,000 pregnant women in six hospitals in Kenya and Malawi and compare the safety, tolerance and beneficial effects of IPTp with DP to the current strategy with sulphadoxine-pyrimethamine in reducing pregnancy loss, low birthweight, preterm birth and small-for-gestational-age babies, and early infant deaths. The trial will include sub-studies on health economics to determine the cost of the strategy in relation to its benefits, the acceptability of the intervention among pregnant women and health providers, paying particular attention to adherence to the 3-day regimen, and the operational feasibility of implementing the intervention in the routine health system. Potential applications and benefitsAfter a decade of intensive multi-centre trials to find new prevention strategies for malaria in pregnancy, DP has been shortlisted as the only potential alternative to SP for IPTp, but evidence of its benefits on infant outcomes is needed. As an experienced network, specialised in malaria prevention trials in pregnancy, we are in a unique position to address these gaps in an expedited manner. The findings of this new trial will provide the definitive evidence for whether or not this drug should be recommended to replace SP in areas with high levels of resistance by the parasite to SP. A positive result may lead to a direct policy change by the WHO in countries experiencing these levels of parasite resistance, including most countries in East and southern Africa, benefiting women at risk of malaria in these regions resulting in healthier pregnancies and healthier newborns.