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Contribuição para o estudo da resposta terapêutica in vivo às combinações baseadas em derivados da artemisinina no tratamento da Malária em Maputo
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Resumo(s)
Com o objetivo de reduzir a emergência e propagação de parasitas resistentes aos antimaláricos, a OMS recomenda o uso de terapia combinada à base de artemisinina (ACT) como tratamento de primeira linha para a malária não complicada por P. falciparum. A resistência aos ACTs foi recentemente relatada no Sudeste Asiático. Historicamente, a
região oriental da Africa sub-Sahariana tem sido um dos principais focos de disseminação da resistência aos antimaláricos. Em Moçambique, um país da Africa do Leste, a malária é um grande desafio para a saúde pública, responsável por 56% dos internamentos pediátricos e 26% das mortes intrahospitalares. O tratamento com artesunato e sulfadoxina+pyrimethamina foi implementado em 2004. Esta combinação foi substituída por artesunato+amodiaquina (ASAQ) ou arteméter+lumefantrina (AL) em 2009. Em Moçambique, a resposta terapêutica aos ACTs é pouco estudada, existindo poucos dados
sistematizados relativos aos aspetos clínicos e gravidade da doença nos pacientes hospitalizados. Os polimorfismos no gene pfmdr1 têm sido associados a alterações na susceptibilidade aos antimaláricos, incluindo os ACTs. Em 2014, foi proposto um marcador molecular correlacionando mutações no gene pfK13 ao fenótipo de susceptibilidade aos ACTs. Os nossos objetivos foram: contribuir para delinear o perfil da resposta terapêutica da malária falciparum não complicada (MnC) em pacientes tratados com ACTs em Maputo; contribuir para melhor compreensão do quadro clínico e evolução da malária grave (MG); descrever a frequência de marcadores moleculares de resistência aos antimaláricos usados em Maputo. Foram incluídos 412 pacientes com MnC (2010-2012);
284 foram tratados com AL (106 no Centro de Saúde1º de Maio e 168 no Centro de Saúde de Boane); os restantes 138 foram tratados com ASAQ em Boane. Dois pacientes (tratados com ASAQ) regressaram no D7 com sintomas e parasitémia. Os restantes tiveram resposta adequada até ao D14. Para estudo clínico e evolução da malária grave, foram selecionados
pacientes na enfermaria pediátrica do Hospital Central de Maputo, de Fevereiro a Março de 2012. Dos 129 incluídos, 30 apresentaram malária cerebral (MC) com scores de Glasgow entre 4-9. Cinco destes resultaram em óbito nas primeiras 24h após admissão. Os pacientes portadores do genótipo RNAse3 GG apresentaram score de Glasgow inferior à admissão, embora sem diferença significativa. Para analisar a tendência temporal da frequência de marcadores moleculares de resistência aos antimaláricos em Maputo, foi incluído um grupo de amostras de ADN de um estudo anterior realizado entre 2003 e 2005. Em relação aos
SNPs pfmdr1 86Y, Y184, 1246Y: a frequência dos alelos N86 e D1246 aumentou significativamente de 2003-2005 para 2010-2012; o aumento da frequência do 184F não foi significativo; exceto para NFD e NYD, a frequência de haplótipos triplos diminuiu em 2010-2012. Das 99 amostras analisadas somente 3 possuíam duas cópias pfmdr1. Em 100 amostras, não foram identificadas mutações pfK13 relacionadas com a resistência aos ACTs no Sudeste Asiático. Em 2 amostras coletadas após introdução dos ACTs foi identificado um novo polimorfismo no pfk13 (ausente em 2003-2005). Este SNP (V494I) é adjacente à mutação Y493H no pfK13, associada à resistência.
With the aim of reducing the emergence and spread of antimalarial drug resistant parasites WHO recommends the use of artemisinin-based combination therapy (ACT) as first-line treatment for P. falciparum uncomplicated malaria. ACT drug resistance has recently been reported in the Southeast Asia. Historically, East Africa has been a major focus of drug resistance spread in sub-Saharan Africa. In Mozambique, an Eastern African country, malaria is a major public-heath challenge responsible for 56% of the paediatric cases and about 26% of the hospital deaths. Here, artesunate in combination with sulphadoxine+pyrimethamie was implemented in 2004. This combination was replaced by artesunate+amodiaquine (ASAQ) or artemether+lumefantrine (AL) in 2009. In Mozambique, the treatment response to ACTs is poorly studied and documented and few systematic data on clinical aspects related to the severity of the disease in the hospitalized patients are available. SNPs in pfmdr1gene have been associated with changes in parasite susceptibility to various antimalarials, including ACTs. In 2014, molecular marker correlating ACT susceptibility phenotype with pfK13 gene mutations was proposed. Our aims were: to contribute to outline of the profile of the response to treatment of uncomplicated falciparum malaria (UnM) patients with ACTs in Maputo; to contribute to a better understanding of the clinical profile and evolution of severe malaria patients (SM); and to describe the prevalence of molecular markers of drug resistance to ACT in Maputo. A total of 412 patients with UnM (from 2010 to 2012) from Maputo area were included: 284 treated with AL (106 from Centro de Saúde 1º de Maio and 168 Centro de Saúde de Boane); the remaining 138 patients were treated with ASAQ and came from Boane. Two of the patients (treated with ASAQ) returned on D7 with symptoms and parasitemia, the remaining responded adequately up to D14. For the clinical profile and evolution of severe malaria, patients were selected on February and March 2012 on the Paediatric ward of Maputo Hospital Central. From the 129 included, 30 presented cerebral malaria (CM); 5 resulted in fatalities during the 1st 24h of admission, with CM and Glasgow score 4-9. Although, patients carrying the RNAse3 genotype GG presented lower Glasgow score on admittance, the association did not reach significance. In order to analyse the temporal trend in the antimalarial drug resistance molecular markers prevalence in Maputo, a group of DNA samples from a previous study conducted also in Maputo between 2003 and 2005 was included. Regarding pfmdr1 SNPs 86Y, Y184, 1246Y: prevalence of the alleles N86 and D1246 increased significantly from 2003-2005 to 2010-2012; although increased prevalence of 184F did not reach significance; except for NFD and NYD, all triple haplotypes decreased in prevalence in 2010-2012. Only 3/99 samples carried 2 copies of pfmdr1. Mutations in pfK13 correlating with ACT resistance in Southeast Asia were not identified in the 100 samples. A new polymorphism in pfk13 was identified in 2 of the samples collected after the introduction of ACTs (absent in 2003-2005). The newly identified SNP, V494I lays adjacent to the known pfK13 resistance-associated mutation Y493H.
With the aim of reducing the emergence and spread of antimalarial drug resistant parasites WHO recommends the use of artemisinin-based combination therapy (ACT) as first-line treatment for P. falciparum uncomplicated malaria. ACT drug resistance has recently been reported in the Southeast Asia. Historically, East Africa has been a major focus of drug resistance spread in sub-Saharan Africa. In Mozambique, an Eastern African country, malaria is a major public-heath challenge responsible for 56% of the paediatric cases and about 26% of the hospital deaths. Here, artesunate in combination with sulphadoxine+pyrimethamie was implemented in 2004. This combination was replaced by artesunate+amodiaquine (ASAQ) or artemether+lumefantrine (AL) in 2009. In Mozambique, the treatment response to ACTs is poorly studied and documented and few systematic data on clinical aspects related to the severity of the disease in the hospitalized patients are available. SNPs in pfmdr1gene have been associated with changes in parasite susceptibility to various antimalarials, including ACTs. In 2014, molecular marker correlating ACT susceptibility phenotype with pfK13 gene mutations was proposed. Our aims were: to contribute to outline of the profile of the response to treatment of uncomplicated falciparum malaria (UnM) patients with ACTs in Maputo; to contribute to a better understanding of the clinical profile and evolution of severe malaria patients (SM); and to describe the prevalence of molecular markers of drug resistance to ACT in Maputo. A total of 412 patients with UnM (from 2010 to 2012) from Maputo area were included: 284 treated with AL (106 from Centro de Saúde 1º de Maio and 168 Centro de Saúde de Boane); the remaining 138 patients were treated with ASAQ and came from Boane. Two of the patients (treated with ASAQ) returned on D7 with symptoms and parasitemia, the remaining responded adequately up to D14. For the clinical profile and evolution of severe malaria, patients were selected on February and March 2012 on the Paediatric ward of Maputo Hospital Central. From the 129 included, 30 presented cerebral malaria (CM); 5 resulted in fatalities during the 1st 24h of admission, with CM and Glasgow score 4-9. Although, patients carrying the RNAse3 genotype GG presented lower Glasgow score on admittance, the association did not reach significance. In order to analyse the temporal trend in the antimalarial drug resistance molecular markers prevalence in Maputo, a group of DNA samples from a previous study conducted also in Maputo between 2003 and 2005 was included. Regarding pfmdr1 SNPs 86Y, Y184, 1246Y: prevalence of the alleles N86 and D1246 increased significantly from 2003-2005 to 2010-2012; although increased prevalence of 184F did not reach significance; except for NFD and NYD, all triple haplotypes decreased in prevalence in 2010-2012. Only 3/99 samples carried 2 copies of pfmdr1. Mutations in pfK13 correlating with ACT resistance in Southeast Asia were not identified in the 100 samples. A new polymorphism in pfk13 was identified in 2 of the samples collected after the introduction of ACTs (absent in 2003-2005). The newly identified SNP, V494I lays adjacent to the known pfK13 resistance-associated mutation Y493H.
Descrição
Palavras-chave
Ciências biomédicas Parasitologia Malária Terapêutica Tratamento Maputo Plasmodium falciparum Marcadores moleculares de resistência
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical