本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(23)02631-4

摘要内容如下：

背景

恶性疟原虫（Plasmodium falciparum）对抗叶酸剂磺胺多辛-乙胺嘧啶（sulfadoxine-pyrimethamine）的交叉耐药性威胁着每日服用复方新诺明（一种用于感染艾滋病毒的孕妇进行疟疾化学预防的抗叶酸剂）的疗效。我们评估了在感染HIV的孕妇中，在每日服用复方新诺明的基础上每月服用双氢青蒿素-哌喹是否比每月服用安慰剂加每日服用复方新诺明更能有效预防疟疾感染。

方法

我们在肯尼亚和马拉维的磺胺多辛-乙胺嘧啶高度耐药地区进行了一项个体随机、两组、安慰剂对照试验。接受以dolutegravir为基础的联合抗逆转录病毒治疗（CART）的单胎妊娠在妊娠16周至28周之间的HIV感染孕妇，通过计算机生成的区组随机化，按部位和HIV状态（已知阳性与新诊断）分层，被随机分配（1:1）至每日复方新诺明加每月双氢青蒿素-哌喹（每日给予三片40 mg双氢青蒿素和320 mg哌喹，共3天）或每日复方新诺明加每月安慰剂。每日复方新诺明由一片160毫克磺胺甲恶唑和800毫克甲氧苄啶组成。主要终点是从首次服用双氢青蒿素哌喹或安慰剂后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检查（活动性感染），在外周（母体）或胎盘（母体）血液或组织中检测到疟原虫感染的发生率。对数二项回归用于二元结果，泊松回归用于计数结果。主要分析采用改良意向治疗，包括所有具有主要终点数据的随机合格参与者。安全性分析包括所有接受至少一剂研究药物的妇女。所有研究人员、实验室工作人员、数据分析人员和参与者都不知道治疗分配。该试验已在ClinicalTrials.gov（NCT04158713）上注册。

调查结果

从2019年11月11日至2021年8月3日，共招募了904名妇女，并将其随机分配至复方新诺明+双氢青蒿素哌喹组（n=448）或复方新诺明+安慰剂组（n=456），其中895人（99%）参与了主要分析（复方新诺明+双氢青蒿素哌喹，n=443；复方新诺明+安慰剂，n=452）。与复方新诺明+安慰剂组相比，复方新诺明+双氢青蒿素哌喹组妊娠或分娩期间任何疟疾感染的累积风险较低[443名妇女中的31名[7%]vs 452名妇女中的70名[15%]，风险比0.45，95%CI 0.30~0.67；P=0.0001）。妊娠或分娩期间任何疟疾感染的发生率在复方新诺明+双氢青蒿素哌喹组为25.4/100人-年，而在复方新诺明+安慰剂组为77.3/100人-年（发生率比0.32，95%CI 0.22~0.47，P<0.0001）。需要治疗以避免每次怀孕感染疟疾的人数为7人（95%CI 5-10）。母亲（复方新诺明+双氢青蒿素哌喹组17.7例/100人-年[23例事件]vs复方新诺明组17.8例/100人-年[25例事件]）和婴儿（45.4例/100人-年[23例事件]vs 40.2例/100人-年[21例事件]）的严重不良事件发生率相似。复方新诺明+双氢青蒿素-哌喹组的446名妇女中有29名（7%）在治疗开始后的前4天内出现恶心，而复方新诺明+安慰剂组的445名妇女中有12名（3%）出现恶心。不良妊娠结局的风险在两组之间没有差异。

解释

在抗叶酸剂高度耐药的地区，在每日使用无监督复方新诺明的标准护理基础上，增加每月使用双氢青蒿素-哌喹的间歇性预防治疗，可显著改善接受以dolutegravir为基础的CART的艾滋病毒感染孕妇的疟疾化学预防，应考虑将其纳入政策。

英文原文如下：

Abstracts

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.

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