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

在撒哈拉以南非洲疟疾流行地区，每年有超过3000万例怀孕。妊娠期疟疾（MiP）对母亲和未出生的孩子具有毁灭性的后果。东非和南部非洲部分地区对妊娠期疟疾的控制受到威胁。孕妇感染疟疾往往没有任何外在迹象或症状，如果不加以发现和治疗，可能导致贫血，干扰胎儿发育，导致流产，或早产和出生体重过低，从而增加婴儿早期死亡的风险。因此，世界卫生组织（世卫组织）建议采用一种称为“孕期间歇预防治疗”的预防策略，即母亲在妊娠第二和第三个月开始的每次安排的产前检查中接受一剂3片磺胺嘧啶-乙胺嘧啶（SP）药物。然而，由于疟原虫种群对SP的高度耐药性，这一战略的有效性正在受到影响。最近对安全、有效和耐受性良好的替代药物的研究被证明是难以捉摸的，因为大多数新测试的候选药物的耐受性不够好，无法用于预防目的。其他评估检测和治疗策略的试验也被证明令人失望。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，这种药物已知在妊娠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（其中一项是由肯尼亚的研究小组进行的）。这些结果表明，当孕妇将DP作为IPT服用时，其耐受性良好，并且在预防疟疾方面比SP更有效。然而，这两项试验的规模还不足以评估其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确实是一种有希望的SP替代品，并建议在考虑是否在高耐药地区推荐该药物作为SP替代品之前，需要进行更大规模的验证性试验。这项多中心试验将在肯尼亚和马拉维的6家医院招募约3000名孕妇，并比较IPTp与DP的安全性、耐受性和有益效果，与目前使用磺胺嘧啶-乙胺嘧啶的策略在减少妊娠丢失、低出生体重、早产和小胎龄婴儿以及婴儿早期死亡方面的效果。该试验将包括卫生经济学的子研究，以确定该战略的效益成本，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操作可行性。潜在的应用和益处经过十年密集的多中心试验，以寻找新的妊娠期疟疾预防策略，DP已被列入候选名单，作为IPTp的SP的唯一潜在替代方案，但是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，我们处于独特的地位，可以快速解决这些差距。这项新试验的结果将为是否应该在疟原虫对疟原虫高度耐药的地区推荐使用这种药物替代疟原虫提供明确的证据。阳性结果可能导致世卫组织在经历这种疟原虫耐药水平的国家（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.