Intermittent preventive treatment for malaria in Papua New Guinean infants exposed to Plasmodium falciparum and P. vivax: a randomized controlled trial.
Intermittent preventive treatment for malaria in Papua New Guinean infants exposed to Plasmodium falciparum and P. vivax: a randomized controlled trial.
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DOI：
10.1371/journal.pmed.1001195
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发表时间：
2012
期刊：
影响因子：
15.8
通讯作者：
Mueller I
中科院分区：
文献类型：
--
作者：
Senn N;Rarau P;Stanisic DI;Robinson L;Barnadas C;Manong D;Salib M;Iga J;Tarongka N;Ley S;Rosanas-Urgell A;Aponte JJ;Zimmerman PA;Beeson JG;Schofield L;Siba P;Rogerson SJ;Reeder JC;Mueller I
在巴布亚新几内亚对婴儿进行的一项三组随机试验估计了在儿童同时暴露于恶性疟疾和间日疟疾的地区，间歇性预防治疗对疟疾发作的预防效果。随机试验显示，婴儿间歇性预防性治疗（IPTi）可降低生活在恶性疟原虫（Pf）高传播地区的非洲婴儿的疟疾相关发病率。目前尚不清楚IPTi在非非洲地区或在间日疟原虫共同流行的地区是否是一种适当的预防策略。在这项研究中，1121名巴布亚新几内亚婴儿被纳入一项三组安慰剂对照随机试验，并被分配到磺胺多辛-乙胺嘧啶（SP） （25 mg/kg和1.25 mg/kg）加阿莫地喹（AQ） （10 mg/kg， 3天，n = 374）、SP加青蒿琥酯（AS） （4 mg/kg， 3天，n = 374）或安慰剂（n = 373），分别在3、6、9和12个月给予。参与者和研究小组对治疗分配都是盲法的。主要终点是对3至15月龄所有临床疟疾发作的保护功效（PE）。采用改良意向治疗法进行分析。在接受SP-AQ治疗的儿童中，临床疟疾发作（由所有物种引起）的PE（与安慰剂相比）为29% (95% CI, 10-43, p≤0.001)，而在接受SP-AS治疗的儿童中，PE为12% （95% CI， - 11至30，p = 0.12）。对Pf的药效高于对Pv。SP-AQ组Pf发生率比安慰剂组低35% (95% CI, 9-54, p = 0.012)， Pv发生率低23% （95% CI, 0-41, p = 0.048）。带有SP-AS的IPTi仅对Pf发作有保护作用（PE = 31%, 95% CI, 4-51, p = 0.027），对Pv发作无保护作用（PE = 6%, 95% CI， - 24至26，p = 0.759）。观察到的不良事件/严重不良事件数量在治疗组之间没有差异（p < 0.55）。没有严重不良事件被认为与治疗相关，两个治疗组的呕吐率都很低（1.4%-2.0%）。干预后6个月内未观察到疟疾发病率反弹。使用长半衰期药物组合的IPTi对生活在Pf和Pv高流行地区的婴儿预防疟疾和贫血有效。疟疾是一个重大的全球公共卫生问题，请参阅文章后面的编辑摘要。世界上有一半的人口面临这种寄生虫病的风险，这种疾病每年导致大约100万人（主要是撒哈拉以南非洲的幼儿）死亡。其中大多数死亡是由恶性疟原虫造成的，但间日疟原虫是最常见和分布最广泛的疟疾寄生虫，是世界上许多疟疾流行（总是存在）的热带和亚热带地区疟疾相关发病率（疾病和死亡）的主要原因。疟疾通过夜间飞行的蚊子叮咬传染给人。可以通过控制传播寄生虫的蚊子和睡在经杀虫剂处理过的蚊帐里以避免蚊子叮咬来预防疟疾。用抗疟药物及时治疗疟疾也可减少疟疾传播。此外，间歇性预防治疗（IPT）已被证明可降低疟疾流行地区孕妇和生活在恶性疟原虫高传播地区的非洲婴儿的疟疾相关发病率。间歇性预防治疗（IPT）是指在固定时间间隔对无症状个体进行完整疗程的抗疟药物治疗，而不论其感染状况如何。世界卫生组织最近建议，在非洲，在常规免疫接种的同时，应在婴儿期进行IPT（称为IPTi）。由于这一建议所依据的研究都是在撒哈拉以南非洲进行的，在恶性疟原虫为主要寄生虫而间日疟原虫不常见的人群中，目前尚不清楚IPTi在非洲以外的环境中或在恶性疟原虫和间日疟原虫都流行的地区是否会成为适当的预防策略。在这项随机安慰剂对照试验中，研究人员调查了IPTi在巴布亚新几内亚恶性疟原虫和间日疟原虫高度流行地区的婴儿中的疗效。在一项随机安慰剂对照试验中，在随机选择的个体组中比较干预和安慰剂（假）干预的效果。研究人员分配了1000多名婴儿在3、6、9和12个月大时接受磺胺多辛/乙胺嘧啶（SP）加阿莫地喹（AQ） （SP和AQ是长效抗疟药）、SP加青蒿琥酯（AS是一种短期抗疟药）或安慰剂。他们记录了3到15个月大的儿童中疟疾发作的次数。然后，通过比较接受SP-AS或SP-AQ治疗的儿童与接受安慰剂治疗的儿童的发作次数，研究人员计算了两种药物组合在研究期间的保护功效。对于SP-AQ， IPTi对所有临床疟疾发作（恶性疟原虫和间日疟原虫合并）的保护效力为29%，但与安慰剂相比，SP-AS与所有疟疾发作的统计学显著减少无关。对于单独的两种疟疾，接受SP-AQ治疗的儿童中恶性疟原虫的发病率比接受安慰剂治疗的儿童低35%，而间日疟原虫的发病率则降低23%；带有SP-AS的IPTi仅对恶性疟原虫疟疾提供保护（保护效力为31%）。重要的是，在所有治疗组中不良事件（可能的药物副作用）的数量相似，没有任何严重不良事件与治疗相关，并且在干预结束后的6个月内，与疟疾相关的发病率没有反弹。这些发现表明，在恶性疟原虫和间日疟原虫高度流行的地区，使用长效抗疟药物（SP-AQ）组合的IPTi可以有效和安全地预防疟疾。重要的是，他们还表明带有SP-AQ的IPTi可以预防恶性疟原虫和间日疟原虫疟疾。对于巴布亚新几内亚来说，这些发现表明SP-AQ是治疗IPTi的合适药物选择，特别是因为用蒿甲醚-芴酮替代SP-AQ作为国家一线疟疾治疗药物将减少对SP和AQ的耐药性选择压力。然而，尽管这些发现为IPTi的有效性和安全性提供了原理证明证据，需要进一步研究，以确定在其他疟疾流行地区用于IPTi的长效抗疟药物的最有效组合。请通过本摘要的在线版本（http://dx.doi.org/10.1371/journal.pmed.1001195）访问这些网站。世界卫生组织提供关于疟疾的资料（以几种语文提供）；《2011年世界疟疾报告》详细介绍了当前全球疟疾形势；美国疾病控制和预防中心提供关于疟疾的信息（英文和西班牙文），包括一些关于疟疾的个人故事，可从遏制疟疾伙伴关系获得关于全球控制疟疾的信息。包括一份儿童疟疾情况简报和巴布亚新几内亚疟疾情况简报成立了IPTi联盟，以评估IPTi并为公共卫生政策制定提供信息疟疾疫苗倡议有一份关于间日疟的情况简报Vivaxmalaria.com提供关于间日疟的信息MedlinePlus提供关于疟疾的其他信息的链接（英文和西班牙文）
A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria. Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv). In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention. IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv. ClinicalTrials.gov NCT00285662 Please see later in the article for the Editors' Summary Malaria is a major global public health problem. Half the world's population is at risk of this parasitic disease, which kills about one million people (mainly young children in sub-Saharan Africa) every year. Most of these deaths are caused by Plasmodium falciparum but P. vivax, the commonest and most widely distributed malaria parasite, is a major cause of malaria-related morbidity (illness and death) in many of the tropical and subtropical regions of the world where malaria is endemic (always present). Malaria is transmitted to people through the bites of night-flying mosquitoes. It can be prevented by controlling the mosquitoes that spread the parasite and by sleeping under insecticide-treated nets to avoid mosquito bites. Prompt treatment of malaria with antimalarial drugs can also reduce malaria transmission. In addition, intermittent preventative treatment (IPT)—the treatment of symptom-free individuals with full therapeutic courses of antimalarial drugs at fixed intervals regardless of their infection status—has been shown to reduce malaria-related morbidity among pregnant women in malaria-endemic areas and among African infants living in areas of high P. falciparum transmission. The World Health Organization recently recommended that, in Africa, IPT should be given during infancy (called IPTi) at the same time as routine immunizations. Because the studies on which this recommendation is based were all carried out in sub-Saharan Africa, in populations where P. falciparum is the predominant parasite and P. vivax is uncommon, it is not known whether IPTi would be an appropriate prevention strategy in non-African settings or in regions where both P. falciparum and P. vivax are endemic. In this randomized placebo-controlled trial, the researchers investigate the efficacy of IPTi in infants living in an area of Papua New Guinea where P. falciparum and P. vivax are both highly endemic. In a randomized placebo-controlled trial, the effects of an intervention and of a placebo (dummy) intervention are compared in groups of individuals chosen through the play of chance. The researchers assigned more than 1,000 infants to receive sulfadoxine/pyrimethamine (SP) plus amodiaquine (AQ) (SP and AQ are long-lasting antimalarial drugs), SP plus artesunate (AS) (AS is a short-lasting antimalarial), or placebo at 3, 6, 9, and 12 months old. They recorded the number of malaria episodes that occurred among the children between the ages of 3 and 15 months. Then, by comparing the number of episodes occurring among the children receiving SP-AS or SP-AQ with the number occurring among the children receiving placebo, the researchers calculated the protective efficacy of the two drug combinations over the study period. The protective efficacy of IPTi against all clinical malaria episodes (P. falciparum and P. vivax combined) was 29% for SP-AQ, but SP-AS was not associated with a statistically significant reduction in all malaria episodes as compared to placebo. For the two species of malaria separately, the incidence of P. falciparum malaria was 35% lower among the children receiving SP-AQ than among the children receiving placebo, whereas the incidence of P. vivax was reduced by 23%; IPTi with SP-AS provided protection only against P. falciparum malaria (protective efficacy 31%). Importantly, the number of adverse events (possible drug side effects) was similar in all the treatment arms, none of the severe adverse events were treatment-related, and there was no rebound in malaria-related morbidity for six months following the end of the intervention. These findings show that IPTi using a combination of long-lasting antimalarial drugs (SP-AQ) can effectively and safely prevent malaria in a non-African population living in a region where P. falciparum and P. vivax are both highly endemic. Importantly, they also show that IPTi with SP-AQ can prevent both P. falciparum and P. vivax malaria. For Papua New Guinea, these findings suggest that SP-AQ is an appropriate drug choice for IPTi, particularly since the replacement of SP-AQ by artemether-lumefantrine as the national first line treatment for malaria will reduce the selection pressure for resistance against SP and AQ. However, although these finding provide proof-of-principle evidence for the efficacy and safety of IPTi, further studies are needed to identify the most effective combinations of long-lasting antimalarial drugs for use in IPTi in other malaria-endemic regions. Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001195. Information is available from the World Health Organization on malaria (in several languages); the 2011 World Malaria Report provides details of the current global malaria situation; and the WHO policy recommendation on IPTi for P. falciparum malaria control in Africa is available The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria, including a fact sheet about malaria in children and information on malaria in Papua New Guinea The IPTi Consortium was established to evaluate IPTi and inform public health policy making The Malaria Vaccine Initiative has a fact sheet on P. vivax malaria Vivaxmalaria.com provides information about P. vivax MedlinePlus provides links to additional information on malaria (in English and Spanish)
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影响因子：
168.9
作者：
Gosling, Roly D.;Gesase, Samwel;Chandramohan, Daniel
通讯作者：
Chandramohan, Daniel
影响因子：
3.7
作者：
Gesase, Samwel;Gosling, Roly D.;Hashim, Ramadhan;Ord, Rosalynn;Naidoo, Inbarani;Madebe, Rashid;Mosha, Jacklin F.;Joho, Angel;Mandia, Victor;Mrema, Hedwiga;Mapunda, Ephraim;Savael, Zacharia;Mosha, Frank W.;Greenwood, Brian;Roper, Cally;Chandramohan, Daniel
通讯作者：
Chandramohan, Daniel
影响因子：
6.4
作者：
Koepfli, Cristian;Mueller, Ivo;Felger, Ingrid
通讯作者：
Felger, Ingrid
影响因子：
3.3
作者：
Lautze, Jonathan;McCartney, Matthew;Spielman, Andrew
通讯作者：
Spielman, Andrew
DOI：
10.4269/ajtmh.2006.75.588
发表时间：
2006-10-01
影响因子：
3.3
作者：
Kasehagen, Laurin J.;Mueller, Ivo;Zimmerman, Peter A.
通讯作者：
Zimmerman, Peter A.