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Pesquisa de mutações pontuais em genes de Plasmodium falciparum associadas à resistência aos antimaláricos em Timor-Leste
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Em 2016 a malária foi considerada endémica em 91 países e apesar do decréscimo, estima-se que em 2015 terão ocorrido cerca de 212 milhões de novos casos de malária a nível mundial. Face à propagação da resistência do Plasmodium falciparum à maioria dos medicamentos antimaláricos disponíveis, a Organização Mundial de Saúde (OMS) recomenda a utilização de terapêuticas combinadas à base de artemisinina (ACT) como tratamento da malária não complicada. Em Timor-Leste os ACTs foram implementados em 2007, sendo o artemeter-lumefantrina (AL) usado como tratamento de primeira linha da malária desde então. A resistência à artemisinina e seus derivados foi confirmada no Sudeste Asiático, por isso o risco de aparecimento e propagação de resistência à artemisinina e seus derivados tem levado a esforços no sentido de serem realizados estudos de resistência em todas as regiões endémicas para a malária.
Nesse sentido, neste estudo pretendeu-se determinar a frequência de polimorfismos, nos genes pfk13 e pfmdr1, associados à resposta aos ACTs em isolados de P. falciparum provenientes de Timor-Leste. Dois grupos foram estudados, sendo que as amostras do grupo A foram recolhidas entre 2003 e 2005 e as do grupo B entre 2012 e 2013, correspondentes aos períodos antes e depois da introdução dos ACTs em Timor-Leste, respetivamente. O gene pfk13 e polimorfismos no codão 86 do gene pfmdr1 foram analisados através de amplificação de DNA pela técnica de Polymerase Chain Reaction (PCR) e sequenciação.
Em relação ao gene pfk13 não se obteve nenhum polimorfismo nas sequências de ambos os grupos em estudo. Relativamente ao estudo de polimorfismos no codão 86 do gene pfmdr1, verificou-se um aumento significativo da prevalência do alelo selvagem (wild-type) N86 (35,8% para 50%) e uma diminuição do polimorfismo N86Y (64,2% para 34,6%), de 2003-2005 para 2012-2013. Foi descrito pela primeira em Timor-Leste, o polimorfismo N86F, tendo-se verificado uma prevalência de 15,4% (em 4 amostras) no período após a introdução dos ACTs.
Apesar de não se observarem polimorfismos no gene pfk13 e de não se encontrarem descritos casos de falência terapêutica em Timor-Leste, estudos contínuos através do uso de marcadores moleculares que permitam a determinação de resistência aos antimaláricos são muito importantes de modo a detetar precocemente o aparecimento e evitar o alastramento de parasitas P. falciparum resistentes/tolerantes aos ACTs
Abstract In 2016 malaria was considered endemic in 91 countries and despite this decrease, updated estimates indicate that 212 million malaria new cases occurred globally in 2015. The spread of resistance Plasmodium falciparum to several antimalarial drugs available, lead the World Health Organization (WHO) to recommends the use of artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. In East-Timor the ACTs were implemented in 2007, being artemether-lumefantrine (AL) used has the first-line treatment for malaria since then. The resistance to artemisinin and derivatives was confirmed in Southeast Asia, therefore the risk of emerge and spread of resistance to artemisinin and derivatives has leading to efforts in the implementation of studies to control the resistance in all endemic regions to malaria. The aim of this study is to determine the frequency of polymorphisms, in pfk13 and pfmdr1 genes, associated to the answer to the ACT in isolate of Plasmodium falciparum from East-Timor. Two groups were studied, the samples from the group A were collected between 2003 and 2005 and the group B were between 2012 and 2013, corresponding to the time before and after the introduction of ACTs in East-Timor, respectively. The pfk13 gene and the polymorphism in the 86 codon of pfmdr1 gene were analyzed by the amplification of DNA using a PCR (Polymerase Chain Reaction) method and sequencing. No polymorphisms were detected in the sequencing of pfk13 gene in both groups in study. Relatively to the polymorphism in the codon 86 of pfmdr1 gene, we verified a significant increase of the prevalence of the wild-type N86 (35,8% to 50%) and a decrease of the polymorphism N86Y (64,2% to 34,6%), between 2003-2005 and 2012-2013. It was described for the first time in East Timor, the N86F polymorphism, which verified an increase of the prevalence to 15,4% (in 4 samples) in the period after the introduction of ACTs. Despite no evidence of polymorphism in the pfk13 gene and no failure of treatment for malaria in East-Timor, continued surveillance using molecular markers are very important to monitor de emergence and avoid the spread of parasites P. falciparum resistance/tolerance to ACTs.
Abstract In 2016 malaria was considered endemic in 91 countries and despite this decrease, updated estimates indicate that 212 million malaria new cases occurred globally in 2015. The spread of resistance Plasmodium falciparum to several antimalarial drugs available, lead the World Health Organization (WHO) to recommends the use of artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. In East-Timor the ACTs were implemented in 2007, being artemether-lumefantrine (AL) used has the first-line treatment for malaria since then. The resistance to artemisinin and derivatives was confirmed in Southeast Asia, therefore the risk of emerge and spread of resistance to artemisinin and derivatives has leading to efforts in the implementation of studies to control the resistance in all endemic regions to malaria. The aim of this study is to determine the frequency of polymorphisms, in pfk13 and pfmdr1 genes, associated to the answer to the ACT in isolate of Plasmodium falciparum from East-Timor. Two groups were studied, the samples from the group A were collected between 2003 and 2005 and the group B were between 2012 and 2013, corresponding to the time before and after the introduction of ACTs in East-Timor, respectively. The pfk13 gene and the polymorphism in the 86 codon of pfmdr1 gene were analyzed by the amplification of DNA using a PCR (Polymerase Chain Reaction) method and sequencing. No polymorphisms were detected in the sequencing of pfk13 gene in both groups in study. Relatively to the polymorphism in the codon 86 of pfmdr1 gene, we verified a significant increase of the prevalence of the wild-type N86 (35,8% to 50%) and a decrease of the polymorphism N86Y (64,2% to 34,6%), between 2003-2005 and 2012-2013. It was described for the first time in East Timor, the N86F polymorphism, which verified an increase of the prevalence to 15,4% (in 4 samples) in the period after the introduction of ACTs. Despite no evidence of polymorphism in the pfk13 gene and no failure of treatment for malaria in East-Timor, continued surveillance using molecular markers are very important to monitor de emergence and avoid the spread of parasites P. falciparum resistance/tolerance to ACTs.
Descrição
Palavras-chave
Malária Timor-Leste ACT Pfk13 Pfmdr1
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical