Temporal evolution of sulfadoxine-pyrimethamine resistance genotypes and genetic diversity in response to a decade of increased interventions against Plasmodium falciparum in northern Ghana

被引:6
作者
Amenga-Etego, Lucas N. [1 ]
Asoala, Victor [2 ]
Agongo, Godfred [2 ]
Jacob, Christopher [3 ]
Goncalves, Sonia [3 ]
Awandare, Gordon A. [1 ]
Rockett, Kirk A. [3 ,4 ]
Kwiatkowski, Dominic [4 ,5 ]
机构
[1] Univ Ghana, West African Ctr Cell Biol Infect Pathogens, Dept Biochem Cell & Mol Biol, Legon, Accra, Ghana
[2] Navrongo Hlth Res Ctr, Ghana Hlth Serv, POB 114, Navrongo, Ghana
[3] Univ Oxford, Wellcome Ctr Human Genet, Oxford OX3 7BN, England
[4] Wellcome Sanger Inst, Wellcome Genome Campus, Hinxton, Cambs, England
[5] Univ Oxford, Big Data Inst, Oxford, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
Malaria; SP resistance; Genotypes; Haplotype; Pfdhfr; Pfdhps; Temporal; INTERMITTENT PREVENTIVE TREATMENT; ANTIFOLATE RESISTANCE; MOLECULAR MARKERS; PREGNANT-WOMEN; MALARIA; AMODIAQUINE; MUTATIONS; PARASITES; ALLELES; AFRICA;
D O I
10.1186/s12936-021-03693-3
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
BackgroundAnti-malarial drug resistance remains a key concern for the global fight against malaria. In Ghana sulfadoxine-pyrimethamine (SP) is used for intermittent preventive treatment of malaria in pregnancy and combined with amodiaquine for Seasonal Malaria Chemoprevention (SMC) during the high malaria season. Thus, surveillance of molecular markers of SP resistance is important to guide decision-making for these interventions in Ghana.MethodsA total of 4469 samples from uncomplicated malaria patients collected from 2009 to 2018 was submitted to the Wellcome Trust Sanger Institute, UK for DNA sequencing using MiSeq. Genotypes were successfully translated into haplotypes in 2694 and 846 mono infections respectively for pfdhfr and pfdhps genes and the combined pfhdfr/pfdhps genes across all years.ResultsAt the pfdhfr locus, a consistently high (>60%) prevalence of parasites carrying triple mutants (IRNI) were detected from 2009 to 2018. Two double mutant haplotypes (NRNI and ICNI) were found, with haplotype NRNI having a much higher prevalence (average 13.8%) than ICNI (average 3.2%) across all years. Six pfdhps haplotypes were detected. Of these, prevalence of five fluctuated in a downward trend over time from 2009 to 2018, except a pfdhps double mutant (AGKAA), which increased consistently from 2.5% in 2009 to 78.2% in 2018. Across both genes, pfdhfr/pfdhps combined triple (NRNI+AAKAA) mutants were only detected in 2009, 2014, 2015 and 2018, prevalence of which fluctuated between 3.5 and 5.5%. The combined quadruple (IRNI+AAKAA) genotype increased in prevalence from 19.3% in 2009 to 87.5% in 2011 before fluctuating downwards to 19.6% in 2018 with an average prevalence of 37.4% within the nine years. Prevalence of parasites carrying the quintuple (IRNI+AGKAA or SGEAA) mutant haplotypes, which are highly refractory to SP increased over time from 14.0% in 2009 to 89.0% in 2016 before decreasing to 78.9 and 76.6% in 2017 and 2018 respectively. Though quintuple mutants are rising in prevalence in both malaria seasons, together these combined genotypes vary significantly within season but not between seasons.ConclusionsDespite high prevalence of pfdhfr triple mutants and combined pfdhfr/pfdhps quadruple and quintuple mutants in this setting SP may still be efficacious. These findings are significant as they highlight the need to continuously monitor SP resistance, particularly using deep targeted sequencing to ascertain changing resistance patterns.
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