在尼日利亚作为一线抗疟药物部署十年后，儿童恶性疟原虫感染对基于青蒿素的联合治疗的反应性下降。

Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria.

机构信息

Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria.

Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria.

出版信息

Infect Dis Poverty. 2019 Aug 6;8(1):69. doi: 10.1186/s40249-019-0577-x.

BACKGROUND

The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.

METHODS

At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005.

RESULTS

Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015 (P = 0.002 and P < 0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% CI, 1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P < 0.0001 for each). Enrolment parasitaemia > 75 000 μl, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P < 0.0001).

CONCLUSIONS

These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.

TRIAL REGISTRATION

Pan African Clinical Trial Registration PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015 PACTR201510001189370 , 3 July 2015; PACTR201709002064150 , 1 March 2017; https://www.pactr.samrca.ac.za.

背景

大湄公河次区域青蒿素耐药恶性疟的出现，促使人们继续对青蒿素为基础的联合疗法（ACTs）的疗效进行全球监测。本分析旨在评估尼日利亚采用 ACTs 作为无并发症恶性疟一线治疗药物 10 年后早期治疗反应标志物的变化。

方法

在尼日利亚六个地理区域的 14 个哨点，我们评估了在 2009-2010 年和 2012-2015 年以及在 2014-2015 年和 2012-2015 年部署后 5 年、2 年的随机试验中，1341 名 5 岁以下和 360 名 16 岁以下无并发症疟疾儿童在接受青蒿琥酯-咯萘啶与青蒿琥酯-阿莫地喹治疗时的治疗反应。

结果

2009-2010 年至 2014-2015 年，治疗后第 1 天（APPD1）的无性寄生虫阳性率从 54%上升至 62%，第 2 天从 5%上升至 26%（P=0.002 和 P<0.0001）。寄生虫清除时间从 1.6 天（95%置信区间[CI]：1.55-1.64）显著增加至 1.9 天（95% CI，1.9-2.0），治疗后第 2 天的几何平均寄生虫减少比显著从 11000 下降至 4700（每个 P<0.0001）。入组时寄生虫血症>75000μl、治疗后第 1 天的血细胞比容>27%、使用青蒿琥酯-咯萘啶和入组 2014-2015 年，均可独立预测 APPD1。同时，28 天内复发感染的 Kaplan-Meier 估计风险从 8%上升至 14%（P=0.005），从 9%上升至 15%（P=0.02），分别使用青蒿琥酯-咯萘啶和青蒿琥酯-阿莫地喹。在 2 年内，无性寄生虫半减期从 1.1 小时显著增加至 1.3 小时（P<0.0001）。

结论

这些数据表明，随着时间的推移，两种 ACTs 的寄生虫学反应呈下降趋势，这可能是由于寄生虫对药物的敏感性降低或儿童对感染的免疫力下降所致。

试验注册

泛非临床试验注册 PACTR201508001188143，2015 年 7 月 3 日；PACTR201508001191898，2015 年 7 月 7 日；PACTR201508001193368，2015 年 7 月 8 日；PACTR201510001189370，2015 年 7 月 3 日；PACTR201709002064150，2017 年 3 月 1 日；https://www.pactr.samrca.ac.za。