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Status of Dhps and Dhfr Genes of Plasmodium Falciparum in Colombia Before Artemisinin Based Treatment Policy

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Status of Dhps and Dhfr Genes of Plasmodium Falciparum in Colombia Before Artemisinin Based Treatment Policy Status of dhps and dhfr genes of Plasmodium falciparum in Colombia before artemisinin based treatment policy ARTÍCULO ORIGINAL Status of dhps and dhfr genes of Plasmodium falciparum in Colombia before artemisinin based treatment policy Estado de los genes dhps y dhfr de Plasmodium falciparum en Colombia antes de la recomendación de tratamiento basado en artemisinina Andrés Villa1†, Jaime Carmona-Fonseca1, Agustín Benito2, Alonso Martínez3, Amanda Maestre1 Abstract Introduction: Surveillance of the genetic characteristics of dhps and dhfr can be useful to outline guidelines for application of intermittent preven- tive therapy in Northwest Colombia and to define the future use of antifolates in artemisinin-based combination therapy schemes. Objective: To evaluate the frequency of mutations in dhps and dhfr and to characterize parasite populations using msp-1, msp-2 and glurp in historic samples before artemisinin-based therapy was implemented in the country. Methods: A controlled clinical study was carried out on randomly selected Plasmodium falciparum infected volunteers of Northwest Colombia (Turbo and Zaragoza). A sample size of 25 subjects per region was calculated. Treatment efficacy to antifolates was assessed. Molecular analyses included P. falcipa- rum genotypes by msp-1, msp-2 and glurp and evaluation of the status of codons 16, 51, 59, 108 and 164 of dhfr and 436, 437, 540, 581 and 613 of dhps. Results: In total 78 subjects were recruited. A maximum number of 4 genotypes were detected by msp-1, msp-2 and glurp. Codons 16, 59 and 164 of the dhfr gene exhibited the wild-type form, while codons 51 and 108 were mutant. In the dhps gene, the mutant 437 glycine was detected in 85% on day 0, while codons 436, 540, 581 and 613 were wild-type. Conclusions: Plasmodium falciparum populations were very homogeneous in this region of Colombia, and the triple mutants of dhfr and dhps Asn108, Ile51 and Gly437 were predominant in clinical isolates. Keywords: Plasmodium falciparum, malaria, dhps, dhfr, resistance, sulphadoxine, Colombia Resumen Introducción. La vigilancia de las características genéticas de dhps y dhfr puede utilizarse para delinear guías de aplicación de terapia preventiva intermitente en el nordeste de Colombia y para definir el uso futuro de los antifolatos en esquemas terapéuticos basados en artemisinina. Objetivo. Evaluar la frecuencia de mutaciones en dhps y dhfr, y caracterizar las poblaciones parasitarias usando msp-1, msp-2 y glurp, en muestras históricas obtenidas antes de la implementación en el país de la terapia basada en artemisinina. Métodos. Se llevó a cabo un estudio clínico controlado en voluntarios infectados con Plasmodium falciparum seleccionados aleatoriamente y pro- venientes del nordeste de Colombia (Turbo y Zaragoza). Se calculó una muestra de 25 sujetos por región. Se evaluó la eficacia al tratamiento con antifolatos. Los análisis moleculares incluyeron la obtención de genotipos de msp-1, msp-2 y glurp y el estado de los codones 16, 51, 59, 108 y 164 de dhfr, y 436, 437, 5540, 581 y 613 de dhps. Resultados. Se estudiaron 78 sujetos. Se detectó un número máximo de 4 genotipos con msp-1, msp-2 y glurp. Los codones 16, 59 y 164 del gen dhfr se encontraron en su forma silvestre, mientras que los codones 51 y 108 estaban mutados. En el gen dhps, la forma mutante (glicina) en el codón 437, se detectó en 85% el día 0, mientras que los codones 436, 540, 581 y 613 se encontraron silvestres. Conclusiones. Las poblaciones de P. falciparum son muy homogéneas en esta región de Colombia y las triple mutantes de dhfr y dhps Asn108, Ile51 and Gly437, predominaron en los aislamientos clínicos. Palabras clave: Plasmodium falciparum, malaria, dhps, dhfr, resistencia, sulfadoxina, Colombia. Introduction xine/pyrimethamine (SP) have been published (1-4). A review in 2005 of 15 studies in the country During the past years, several studies in Colom- confirmed a mean frequency of treatment failu- bia on the efficacy of different drugs againstPlas - re of 14.6% (2). In the northwest region, in Ura- modium falciparum malaria, including sulphado- bá and Bajo Cauca, the reported frequency of 1 Grupo Salud y Comunidad, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia † Dirección actual: Escuela de Microbiología, Universidad de Antioquia, Medellín, Colombia Recibido: 27/10/2011; Aceptado: 08/02/2012 2 Centro Nacional de Medicina Tropical, Instituto de Salud Correspondencia: Amanda Maestre, Carrera 51 D N° 62-29, Facultad Carlos III, Madrid, Spain de Medicina, Universidad de Antioquia, Medellín, Colombia. 3 Grupo Bacterias y Cáncer, Facultad de Medicina, Universidad teléfono: (574) 219-6025; fax: (574) 219-6051 Dirección electrónica: de Antioquia, Medellín, Colombia [email protected] Infectio. 2012; 16(1): 37-44 37 Villa A, Carmona-Fonseca J, Benito A, et al treatment failure was 24% (5). However, studies med at studying the efficacy of different antima- on the molecular epidemiology of antimalarial larial regimens. resistance are still scarce in the country (4, 6-11). These studies constitute a useful tool to unders- Study area tand the events underlying treatment failure and resistance to antifolates (12). The exploration of The study was carried out between October 2002 the genetic background of clinical isolates circu- and July 2004 in two malaria endemic regions in lating in a specific region is of great relevance, Colombia: Turbo (8º5’42’’N, 76º44’123’’W) and since the efficacy and emergence of resistant Zaragoza (7º29’38’’N, 74º52’15’’W). Both regions phenotypes to new drug regimens might be have malaria transmission throughout the year affected by the baseline genetic characteristics with mean annual parasite indexes (API) (ca- (13) of the local parasite strains . ses/1000 inhabitants) during 2002-2004 of 45.3 in Turbo, and 111.6 in Zaragoza (20, 21). Currently, most intermittent preventive thera- pies (IPT) are based on the administration of an- Malaria patient enrollment and follow-up tifolates, since they are relatively safe and exhibit (14) good cost-efficacy . The study included patients attending the local malaria clinics with acute symptomatic non-seve- Resistance to antifolates has been attributed to re P. falciparum malaria. Unique infection by this mutations in the genes coding the enzymes in- species was confirmed by microscopy and by a volved in the metabolism of sulphadoxine and semi-nested PCR (22, 23). The study protocol was re- pyrimethamine: dihydrofolate reductase (dhfr) viewed and approved by the Ethics Committee of and dihydropteroate synthase (dhps), respectively. the Facultad de Medicina, Universidad de Antio- Point mutations at positions 51, 59, 108 and 164 in quia (Medellín, Colombia). Each participant gave the dhfr gene (15-17) and mutations at positions 436, a fully informed consent. The inclusion criteria 437,540, 581, and 613 in the dhps gene, have been for the original study were ≥1 years age, unique directly implicated in such resistance (18, 19). P. falciparum parasitaemia with ≥1000 asexual forms/µl and willingness to participate. Patients We conducted a study in the northwest region of were excluded if consent was withdrawn. Colombia, aimed at understanding the genetic characteristics of SP resistance in field isolates and to complement the framework in which a new ar- A sample size for each municipality was cal- temisinin-based combination therapy (ACT) is ad- culated based on the number of P. falciparum (24) ministered in the country. The study explored the malaria cases in a year: 1061 , 11% frequen- (25) frequency of mutations in the dhps and dhfr genes cy of treatment failure , a 95% confidence in- as well as the general constitution of parasite po- terval and sample error of 12%; this resulted in pulations by assessing the msp-1, msp-2 and glurp 25 subjects per region. Patients were randomly genes. Surveillance of the genetic characteristics of assigned one of various different antimalarial these genes can be useful to outline IPT guidelines regimens. Subjects selected for this report were for application in the region and to define the fu- administered a single dose of sulfadoxine/pyri- ture use of SP in an ACT scheme. methamine 25 mg/kg. All patients were treated at the local malaria clinic and the follow up pe- Materials and methods riod was at least 21 days. Treatment response was monitored according to the 1998 WHO cri- We conducted a controlled clinical study on P. teria and classification into adequate treatment falciparum infected subjects. Randomly selected response (ATR) or treatment failure (early, ETF; volunteers were part of a larger study which ai- and late, LTF) was established (26). 38 ASOCIACIÓN COLOMBIANA DE INFECTOLOGÍA Infectio. 2012; 16(1): 37-44 Status of dhps and dhfr genes of Plasmodium falciparum in Colombia before artemisinin based treatment policy Sample collection these methods is available at http://medschool. umaryland.edu/CVD/plowe.html. Whole blood for molecular analysis was taken from a peripheral vein on day 0 before treatment Laboratory maintained 3D7 and Dd2 strains of P. administration and when treatment failure was falciparum were used as controls. Products were diagnosed. Samples were collected onto What- resolved in 2-3% agarose, and fragment size was man 3MM filter paper and stored at -20°C. DNA determined under UV light after ethidium bro- was extracted with Chelex®, according to stan- mide staining. dard procedures (27) and stored at −20°C until use. Statistical analyses Plasmodium falciparum confirmation and allele genotyping The data were processed using EpiInfo 6.04. The frequency of each allele was calculated, based DNA templates were amplified to confirm the on msp-1, msp-2 and glurp genes. In addition, unique infection by P. falciparum. A semi-nested frequencies of mutations in the different codons PCR was performed at the Laboratorio de Refe- of dhps and dhfr were determined. Polyclonal rencia de Malaria, Departamento de Parasitolo- samples were included in the analysis, since in gía, Centro Nacional de Microbiología, Instituto vivo interactions of different clones might exhi- Nacional de Salud Carlos III in Madrid, according bit a trend or association.
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