A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated plasmodium falciparum treatment in pregnancy.
A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated plasmodium falciparum treatment in pregnancy.
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DOI：
10.1371/journal.pmed.0050253
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发表时间：
2008-12-23
期刊：
影响因子：
15.8
通讯作者：
Nosten, Francois
中科院分区：
文献类型：
--
作者：
McGready, Rose;Tan, Saw Oo;Ashley, Elizabeth A.;Pimanpanarak, Mupawjay;Viladpai-Nguen, Jacher;Phaiphun, Lucy;Wuestefeld, Katja;Barends, Marion;Laochan, Natthapon;Keereecharoen, Lily;Lindegardh, Niklas;Singhasivanon, Pratap;White, Nicholas J.;Nosten, Francois
据我们所知，迄今为止，尚未进行固定剂量青蒿素联合疗法（ACT）治疗妊娠期恶性疟原虫疟疾的比较试验。由于这些药物在受疟疾影响的世界中越来越多地使用，因此需要有关妊娠期间 ACT 的安全性和有效性的证据。本研究的目的是比较蒿甲醚-本芴醇（最广泛使用的固定 ACT）与 7 天青蒿酯单药治疗在妊娠中期和晚期的疗效、耐受性和安全性。一项开放标签随机对照试验对泰国西北部边境地区在妊娠中期和晚期患有无并发症恶性疟原虫疟疾的克伦族妇女进行了一项开放标签随机对照试验，比较了直接观察的蒿甲醚-本芴醇 3 天 (AL) 或青蒿琥酯单药治疗 7 天 (AS7) 的治疗效果。主要终点是疗效，定义为在分娩时或在第 42 天评估的恶性疟原虫 PCR 调整的治愈率（如果发生晚于分娩），根据 Kaplan-Meier 生存分析估计。婴儿在出生时接受评估，并随访至出生后 1 岁。进行血液采样以表征妊娠期本芴醇的药代动力学。两种方案的耐受性都很好。意向治疗 (ITT) 人群的治愈率（95% 置信区间）为：AS7 89.2% (82.3%–96.1%) 和 AL 82.0% (74.8%–89.3%)，p = 0.054 (ITT)； AS7 89.7% (82.6%–96.8%) 和 AL 81.2% (73.6%–88.8%)，p = 0.031（每个方案人群）。 PCR确诊的复发病例中有三分之一发生在随访42天后。两组之间的出生结局和婴儿（1 岁以下）结局没有显着差异。药代动力学研究表明，低浓度的蒿甲醚和本芴醇是AL疗效不佳的主要原因。目前标准的六剂蒿甲醚-本芴醇治疗方案对于患有无并发症的恶性疟疾的克伦族孕妇具有良好的耐受性和安全性，但疗效低于 7 d 青蒿琥酯单药治疗，并且在该地理区域的普遍部署不能令人满意。疗效降低可能是由于妊娠后期药物浓度较低所致。可能需要更长或更频繁的 AL 剂量方案才能有效治疗孕妇，现在应该进行评估。妊娠期间任何抗疟药物治疗的临床试验中的寄生虫学终点应延长至分娩或第 42 天（如果较晚）。 试验注册：当前对照试验 ISRCTN86353884 Rose McGready 及其同事表明，对于患有无并发症的恶性疟疾的克伦族孕妇来说，蒿甲醚-本芴醇治疗方案具有良好的耐受性和安全性，但疗效不如青蒿酯，可能是因为妊娠后期药物浓度较低。 恶性疟原虫是一种由蚊子传播的寄生虫，会导致疟疾，每年导致近一百万人死亡。尽管大多数死亡发生在幼儿中，但怀孕期间的疟疾也是一个重要的公共卫生问题。在疟疾传播率高（稳定传播）的地区，妇女获得一定程度的免疫力。虽然与缺乏自然保护的妇女相比，症状较少，但她们的婴儿往往又小又多病，因为与疟疾相关的贫血（缺乏红细胞）和胎盘中的寄生虫限制了婴儿出生前供应的营养。相比之下，在疟疾传播率较低（传播不稳定或零星爆发）的地区，女性对恶性疟原虫的免疫力很低。如果这些妇女在怀孕期间受到感染，“简单”疟疾（发烧、发冷和贫血）可能会迅速发展为“严重”疟疾（其中重要器官受损），除非给予及时有效的治疗，否则可能对母亲和/或其未出生的孩子致命。疟疾寄生虫现在对许多较旧的抗疟药物（例如奎宁）具有抗药性。因此，自2006年起，世界卫生组织（WHO）建议妊娠中晚期的无并发症疟疾采用短程（3 d）固定剂量青蒿素联合疗法（ACT；奎宁在妊娠早期仍使用，因为目前尚不清楚ACT是否会损害胎儿发育，这主要发生在妊娠前3个月）。青蒿素衍生物是速效抗疟药，与另一种抗疟药联合使用可减少恶性疟原虫对任一药物产生耐药性的机会。最广泛使用的固定剂量 ACT 是蒿甲醚-本芴醇 (AL)，但是，尽管多项试验已经检验了这种治疗方法在非孕妇中的安全性和有效性，但人们对其在孕妇中的效果知之甚少。在这项研究中，研究人员比较了 AL 与 7 天青蒿酯单药疗法（AS7；另一种青蒿素衍生物）治疗泰国西北部妊娠期单纯性疟疾的疗效、耐受性和安全性，该地区是疟疾传播不稳定但高度耐药的地区。研究人员招募了 253 名在怀孕中期和晚期患有无并发症疟疾的女性参加他们的开放标签试验（在该试验中，患者及其医护人员知道谁正在接受哪种药物治疗）。一半的女性接受了每种治疗。该试验的主要结果是分娩时或治疗后 42 天（如果发生在分娩后）的“PCR 调整治愈率”。治愈率的评估方法是检查血涂片中是否有寄生虫，然后使用 PCR 技术来确定哪些疟疾病例是新感染（与血涂片阴性一起被归类为治疗成功），哪些是旧感染的复发（被归类为治疗失败）。 AS7 和 AL 的 PCR 调整治愈率分别为 89.7% 和 81.2%。两种治疗方法均具有良好的耐受性，几乎没有出现任何副作用，两种治疗方案的婴儿出生时和 1 岁以下的健康和发育情况相似。最后，对 AL 治疗后 7 天采集的血液样本进行的分析表明，在大约三分之一的接受测试的女性中，苯芴醇的血液浓度低于之前与治疗失败相关的浓度。尽管这些研究结果表明，对于居住在泰国西北部的孕妇来说，AL 疗法是一种耐受性良好且安全的无并发症疟疾治疗方法，但该疗法的疗效低于青蒿琥酯单一疗法。事实上，这两种治疗方法都没有达到 WHO 建议的 ACT 90% 治愈率，而且在更现实的情况下（即，不是在努力确保每个人完成治疗的试验中），治愈率可能会更低。研究结果还表明，与之前在非孕妇中观察到的疗效相比，AL 方案对孕妇的疗效降低可能是由于怀孕期间药物血液浓度较低所致。因此，可能需要更高剂量的 AL 方案（或替代 ACT）才能成功治疗妊娠期间的无并发症疟疾。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0050253。 MedlinePlus 百科全书包含有关疟疾的页面（英文和西班牙文） 世界卫生组织提供有关疟疾的信息（多种语言），其 2006 年疟疾治疗指南包括针对孕妇治疗的具体建议 美国疾病控制和预防中心提供有关疟疾和妊娠期疟疾的信息（英文和西班牙文） 可从减少疟疾伙伴关系获得有关妊娠期疟疾、基于青蒿素的联合疗法和疟疾的信息在泰国
To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy. An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL. The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later. Trial Registration: Current Controlled Trials ISRCTN86353884 Rose McGready and colleagues show that an artemether-lumefantrine regimen is well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy is inferior to artesunate, probably because of low drug concentrations in later pregnancy. Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. Although most deaths occur among young children, malaria during pregnancy is also an important public-health problem. In areas where malaria transmission is high (stable transmission), women acquire a degree of immunity. Although less symptomatic than women who lack natural protection, their babies are often small and sickly because malaria-related anemia (lack of red blood cells) and parasites in the placenta limit the nutrients supplied to the baby before birth. By contrast, in areas where malaria transmission is low (unstable transmission or sporadic outbreaks), women have little immunity to P. falciparum. If these women become infected during pregnancy, “uncomplicated” malaria (fever, chills, and anemia) can rapidly progress to “severe” malaria (in which vital organs are damaged), which can be fatal to the mother and/or her unborn child unless prompt and effective treatment is given. Malaria parasites are now resistant to many of the older antimalarial drugs (for example, quinine). So, since 2006, the World Health Organization (WHO) has recommended that uncomplicated malaria during the second and third trimester of pregnancy is treated with short course (3 d) fixed-dose artemisinin combination therapy (ACT; quinine is still used in early pregnancy because it is not known whether ACT damages fetal development, which mainly occurs during the first 3 mo of pregnancy). Artemisinin derivatives are fast-acting antimalarial agents that are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug. The most widely used fixed-dose ACT is artemether–lumefantrine (AL) but, although several trials have examined the safety and efficacy of this treatment in non-pregnant women, little is known about how well it works in pregnant women. In this study, the researchers compare the efficacy, tolerability, and safety of AL with a 7-d course of artesunate monotherapy (AS7; another artemisinin derivative) in the treatment of uncomplicated malaria in pregnancy in northwest Thailand, an area with unstable but highly drug resistant malaria transmission. The researchers enrolled 253 women with uncomplicated malaria during the second and third trimesters of pregnancy into their open-label trial (a trial in which the patients and their health-care workers know who is receiving which drug regimen). Half the women received each type of treatment. The trial's main outcome was the “PCR-adjusted cure rate” at delivery or 42 d after treatment if this occurred after delivery. This cure rate was assessed by examining blood smears for parasites and then using a technique called PCR to determine which cases of malaria were new infections (classified as treatment successes along with negative blood smears) and which were recurrences of an old infection (classified as treatment failures). The PCR-adjusted cure rates were 89.7% and 81.2% for AS7 and AL, respectively. Both treatments were well tolerated, few side effects were seen with either treatment, and infant health and development at birth and up to 1 y old were similar with both regimens. Finally, an analysis of blood samples taken 7 d after treatment with AL showed that blood levels of lumefantrine were below those previously associated with treatment failure in about a third of the women tested. Although these findings indicate that the AL regimen is a well tolerated and safe treatment for uncomplicated malaria in pregnant women living in northwest Thailand, the efficacy of this treatment was lower than that of artesunate monotherapy. In fact, neither treatment reached the 90% cure rate recommended by WHO for ACTs and it is likely that cure rates in a more realistic situation (that is, not in a trial where efforts are made to make sure everyone completes their treatment) would be even lower. The findings also suggest that the reduced efficacy of the AL regimen in pregnant women compared to the efficacy previously seen in non-pregnant women may be caused by lower drug blood levels during pregnancy. Thus, a higher-dose AL regimen (or an alternative ACT) may be needed to successfully treat uncomplicated malaria during pregnancy. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050253. The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish) Information is available from the World Health Organization on malaria (in several languages), and their 2006 Guidelines for the Treatment of Malaria includes specific recommendations for the treatment of pregnant women The US Centers for Disease Control and Prevention provide information on malaria and on malaria during pregnancy (in English and Spanish) Information is available from the Roll Back Malaria Partnership on malaria during pregnancy, on artemisinin-based combination therapies, and on malaria in Thailand
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影响因子：
--
作者：
Haataja, L;McGready, R;Dubowitz, L
通讯作者：
Dubowitz, L
影响因子：
6.7
作者：
Barnes, Karen I.;Little, Francesca;White, Nicholas J.
通讯作者：
White, Nicholas J.
影响因子：
6.4
作者：
Green, Michael D.;van Eijk, Annemieke M.;Nettey, Henry
通讯作者：
Nettey, Henry
影响因子：
5
作者：
Luxemburger, C;McGready, R;Nosten, F
通讯作者：
Nosten, F
影响因子：
5.1
作者：
DUBOWITZ, LM;DUBOWITZ, V;GOLDBERG, C
通讯作者：
GOLDBERG, C