Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.
School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi; Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi.
Lancet. 2024 Jan 27;403(10424):365-378. doi: 10.1016/S0140-6736(23)02631-4. Epub 2024 Jan 12.
The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV.
We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713.
From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups.
Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy.
European and Developing Countries Clinical Trials Partnership 2; UK Joint Global Health Trials Scheme (UK Foreign, Commonwealth and Development Office; Medical Research Council; National Institute for Health Research; Wellcome); and Swedish International Development Cooperation Agency.
在感染艾滋病毒的孕妇中，使用磺胺多辛-乙胺嘧啶的叶酸拮抗剂进行疟疾化学预防，其疗效受到恶性疟原虫对叶酸拮抗剂青蒿素-哌喹的交叉耐药性的威胁。我们评估了在肯尼亚和马拉维的磺胺多辛-乙胺嘧啶高等级耐药地区，每日复方磺胺甲噁唑联合每月青蒿琥酯-哌喹是否比每日复方磺胺甲噁唑联合每月安慰剂更能有效预防疟疾感染。
我们在感染艾滋病毒的孕妇中进行了一项个体随机、双盲、安慰剂对照试验，这些孕妇正在接受基于多替拉韦的联合抗逆转录病毒疗法（cART），怀孕 16 周到 28 周，随机分为（1:1）按计算机生成的区块随机化，分层按地点和 HIV 状况（已知阳性与新诊断），每日复方磺胺甲噁唑联合每月青蒿琥酯-哌喹（每日 3 天给予 40mg 青蒿琥酯和 320mg 哌喹 3 片）或每日复方磺胺甲噁唑联合每月安慰剂。每日复方磺胺甲噁唑由一片 160mg 磺胺甲噁唑和 800mg 甲氧苄啶组成。主要终点是在接受青蒿琥酯-哌喹或安慰剂首剂后 2 周至分娩期间，通过 PCR、显微镜检查、快速诊断试验或胎盘组织学（活性感染）检测到的外周（母体）或胎盘（母体）血液或组织中的疟原虫感染发生率。二项结局采用对数二项式回归，计数结局采用泊松回归。主要分析为改良意向治疗，包括所有主要终点数据的随机合格参与者。安全性分析包括所有至少接受一剂研究药物的女性。所有研究者、实验室工作人员、数据分析人员和参与者均对治疗分配进行了盲法。该试验在 ClinicalTrials.gov 注册，NCT04158713。
从 2019 年 11 月 11 日至 2021 年 8 月 3 日，招募了 904 名女性并随机分配至复方磺胺甲噁唑联合青蒿琥酯-哌喹（n=448）或复方磺胺甲噁唑联合安慰剂（n=456），其中 895 名（99%）女性参与了主要分析（复方磺胺甲噁唑联合青蒿琥酯-哌喹，n=443；复方磺胺甲噁唑联合安慰剂，n=452）。在怀孕期间或分娩期间任何疟疾感染的累积风险在复方磺胺甲噁唑联合青蒿琥酯-哌喹组中低于复方磺胺甲噁唑联合安慰剂组（443 名女性中有 31 名[7%]与 452 名女性中有 70 名[15%]，风险比 0.45，95%CI 0.30-0.67；p=0.0001）。在怀孕期间或分娩期间任何疟疾感染的发生率在复方磺胺甲噁唑联合青蒿琥酯-哌喹组中为每 100 人年 25.4 例，在复方磺胺甲噁唑联合安慰剂组中为每 100 人年 77.3 例（发生率比 0.32，95%CI 0.22-0.47，p<0.0001）。每预防一次疟疾感染需要治疗的人数为 7（95%CI 5-10）。母亲（复方磺胺甲噁唑联合青蒿琥酯-哌喹组每 100 人年 17.7 例[23 例]，复方磺胺甲噁唑组每 100 人年 17.8 例[25 例]）和婴儿（复方磺胺甲噁唑联合青蒿琥酯-哌喹组每 100 人年 45.4 例[23 例]，复方磺胺甲噁唑组每 100 人年 40.2 例[21 例]）两组之间严重不良事件的发生率相似。在治疗开始后 4 天内，446 名复方磺胺甲噁唑联合青蒿琥酯-哌喹组的女性中有 29 名（7%）报告有恶心，而 445 名复方磺胺甲噁唑联合安慰剂组的女性中有 12 名（3%）报告有恶心。两组之间不良妊娠结局的风险没有差异。
在磺胺多辛-乙胺嘧啶高耐药地区，在基于多替拉韦的联合抗逆转录病毒疗法的标准治疗基础上，每月加用青蒿琥酯-哌喹的间歇性预防治疗，大大改善了感染艾滋病毒的孕妇的疟疾化学预防，应考虑将其纳入政策。
欧洲和发展中国家临床试验伙伴关系 2；英国联合全球卫生试验计划（英国外交、联邦及发展事务部；医学研究理事会；国家卫生研究院；瑞典国际开发合作署）。
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