Temporal trends of molecular markers associated with artemether-lumefantrine tolerance/resistance in Bagamoyo district, Tanzania

Malaria Journal

Research

Max Petzold¹  José P Gil²  Billy Ngasala³  Zul Premji³  Erik Larsson⁴  Anders Björkman⁴  Maja Malmberg⁴  Angelica Hjalmarsson⁴  Pedro E Ferreira⁵  Irina Jovel⁶  Andreas Mårtensson⁷ 

[1] Centre for Applied Biostatistics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Centre of Molecular and Structural Biomedicine, Institute of Biotechnology and Bioengineering, University of Algarve, Faro, Portugal;Drug resistance Unit, Division of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;Department of Biological Sciences, The Harpur College of Arts and Sciences, Binghamton University, Binghamton, NY, USA;Department of Parasitology, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania;Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden;Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden;Centre of Molecular and Structural Biomedicine, Institute of Biotechnology and Bioengineering, University of Algarve, Faro, Portugal;Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden;Departamento de Parasitología, Escuela de Microbiología, Facultad de Ciencias Universidad Nacional Autónoma de Honduras (UNAH), Tegucigalpa, Honduras;Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden;Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden;

关键词: Plasmodium falciparum;    Malaria;    pfmdr1;    pfcrt;    Artemether-lumefantrine;    Lumefantrine;    Drug resistance;    Tanzania;   

DOI  :  10.1186/1475-2875-12-103

 received in 2012-11-18, accepted in 2013-03-09,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundDevelopment and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) constitutes a major threat to recent global malaria control achievements. Surveillance of molecular markers could act as an early warning system of ACT-resistance before clinical treatment failures are apparent. The aim of this study was to analyse temporal trends of established genotypes associated with artemether-lumefantrine tolerance/resistance before and after its deployment as first-line treatment for uncomplicated malaria in Tanzania 2006.MethodsSingle nucleotide polymorphisms in the P. falciparum multidrug resistance gene 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine transporter gene (pfcrt) K76T were analysed from dried blood spots collected during six consecutive studies from children with uncomplicated P. falciparum malaria in Fukayosi village, Bagamoyo District, Tanzania, between 2004–2011.ResultsThere was a statistically significant yearly increase of pfmdr1 N86, 184F, D1246 and pfcrt K76 between 2006–2011 from 14% to 61% (yearly OR = 1.38 [95% CI 1.25-1.52] p < 0.0001), 14% to 35% (OR = 1.17 [95% CI 1.07-1.30] p = 0.001), 54% to 85% (OR = 1.21 [95% CI 1.03-1.42] p = 0.016) and 49% to 85% (OR = 1.33 [95% CI 1.17-1.51] p < 0.0001), respectively. Unlike for the pfmdr1 SNP, a significant increase of pfcrt K76 was observed already between 2004–2006, from 26% to 49% (OR = 1.68 [95% CI 1.17-2.40] p = 0.005). From 2006 to 2011 the pfmdr1 NFD haplotype increased from 10% to 37% (OR = 1.25 [95% CI 1.12-1.39] p < 0.0001), whereas the YYY haplotype decreased from 31% to 6% (OR = 0.73 [95% CI 0.56-0.98] p = 0.018). All 390 successfully analysed samples had one copy of the pfmdr1 gene.ConclusionThe temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy in Tanzania and emphasizes the importance of molecular surveillance as a complement to standard in vivo trials.

【 授权许可】

CC BY   
© Malmberg et al.; licensee BioMed Central Ltd. 2013