全球健康研究中心肯尼亚医学研究所Hellen C Barsosio团队研究了每日服用复方三恶唑，每月间歇性使用双氢青蒿素-哌喹对于艾滋病毒感染孕妇预防疟疾的效果与安全性。相关论文于2024年1月12日发表在《柳叶刀》杂志上。

复方三恶唑是一种用于艾滋病毒感染孕妇疟疾化学预防的叶酸拮抗剂，其每日服用疗效受到恶性疟原虫对抗叶酸药物磺胺多辛-乙胺嘧啶的交叉耐药性威胁。研究组评估了在感染艾滋病毒的孕妇中，每月在每日复方三恶唑的基础上添加双氢青蒿素-哌喹是否比每月安慰剂加每日复方三恶唑能更有效地预防疟疾感染。

研究组在肯尼亚和马拉维中磺胺多辛-乙胺嘧啶高度耐药性的地区进行了一项单独随机、双臂、安慰剂对照试验。通过计算机生成的分组随机化，将妊娠16周至28周、单胎妊娠、接受多卢特格拉韦联合抗逆转录病毒治疗（cART）的HIV感染孕妇随机分配（1:1），按地区和HIV状态分层（已知阳性与新诊断），每日复方三恶唑加每月双氢青蒿素-哌喹（三片40 mg双氢青蒿素和320 mg哌喹，每日给药3天）或每日复方三恶唑加每月安慰剂。

每日复方三恶唑由一片160毫克磺胺甲恶唑和800毫克甲氧苄啶组成。主要终点是从第一剂双氢青蒿素-哌喹或安慰剂给药后2周至分娩，通过聚合酶链式反应、显微镜、快速诊断试验或胎盘组织学（活动性感染）在外周（母体）或胎盘（母体）血液或组织中检测到的疟原虫感染发生率。二元结果采用对数二项回归，计数结果采用泊松回归。主要采用改良意向治疗分析，由所有具有主要终点数据的随机合格参与者组成。安全性分析包括所有至少服用一剂研究药物的女性。所有研究人员、实验室工作人员、数据分析人员和参与者都对治疗任务双盲。

2019年11月11日至2021年8月3日，904名女性被招募并随机分配到复方三恶唑加双氢青蒿素-哌喹组（n=448）或复方三恶唑加安慰剂组（n=456），其中895人（99%）参与了初步分析（复方三恶唑加二氢青蒿素-哌喹组，n=443；复方三恶唑加安慰剂组，n=452）。三恶唑联合双氢青蒿素-哌喹组在妊娠或分娩期间感染疟疾的累积风险低于三恶唑加安慰剂组（443名妇女中有31名[7%] VS 452名妇女中为70名[15%]，风险比为0.45，95%CI为0.30–0.67；p=0.001）。三恶唑联合双氢青蒿素-哌喹组妊娠或分娩期间任何疟疾感染的发生率为25.4/100人-年，而三恶唑联合安慰剂组为77.3/100人-年（发病率比率0.32，95%CI0.22-0.47，p<0.0001）。

每次妊娠避免一次疟疾感染所需的治疗人数为7人（95%置信区间5-10）。严重不良事件的发生率在母亲组和婴儿组之间相似（三恶唑联合双氢青蒿素-哌喹组为每100人-年17.7例[23例事件]，而三恶唑组为每100人-年17.8例[25例事件]）（每100人-年45.4例[23起事件] VS 每100人/年40.2例[21例事件]）。复方三恶唑加双氢青蒿素-哌喹组446名女性中有29名（7%）报告在治疗开始后的前4天内出现恶心，而联合三唑+安慰剂组445名女性中则有12名（3%）报告。不良妊娠结局的风险在各组之间没有差异。

研究结果表明，在高抗叶酸耐药性地区，将双氢青蒿素-哌喹每月间歇性预防性治疗添加到每日无监督的复方三恶唑的护理标准中，大大改善了使用多卢特格拉韦的cART治疗艾滋病毒感染孕妇的疟疾化学预防，应作为政策考虑。

附：英文原文

Title: Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin–piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial

Author: Hellen C Barsosio, Mwayiwawo Madanitsa, Everlyne D Ondieki, James Dodd, Eric D Onyango, Kephas Otieno, Duolao Wang, Jenny Hill, Victor Mwapasa, Kamija S Phiri, Kenneth Maleta, Miriam Taegtmeyer, Simon Kariuki, Christentze Schmiegelow, Julie R Gutman, Feiko O ter Kuile

Issue&Volume: 2024-01-12

Abstract:

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

DOI: 10.1016/S0140-6736(23)02631-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02631-4/abstract