Anti-folate drug resistance in Africa: meta-analysis of reported dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant genotype frequencies in African Plasmodium falciparum parasite populations.

Sankar Sridaran,Venkatachalam Udhayakumar,Karen M Herman,Shannon K Mcclintock,Luke M Syphard,John W Barnwell

doi:10.1186/1475-2875-9-247

Abstract

BackgroundMutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum are associated with resistance to anti-folate drugs, most notably sulphadoxine-pyrimethamine (SP). Molecular studies document the prevalence of these mutations in parasite populations across the African continent. However, there is no systematic review examining the collective epidemiological significance of these studies. This meta-analysis attempts to: 1) summarize genotype frequency data that are critical for molecular surveillance of anti-folate resistance and 2) identify the specific challenges facing the development of future molecular databases.MethodsThis review consists of 220 studies published prior to 2009 that report the frequency of select dhfr and dhps mutations in 31 African countries. Maps were created to summarize the location and prevalence of the highly resistant dhfr triple mutant (N51I, C59R, S108N) genotype and dhps double mutant (A437G and K540E) genotype in Africa. A hierarchical mixed effects logistic regression was used to examine the influence of various factors on reported mutant genotype frequency. These factors include: year and location of study, age and clinical status of sampled population, and reporting conventions for mixed genotype data.ResultsA database consisting of dhfr and dhps mutant genotype frequencies from all African studies that met selection criteria was created for this analysis. The map illustrates particularly high prevalence of both the dhfr triple and dhps double mutant genotypes along the Kenya-Tanzania border and Malawi. The regression model shows a statistically significant increase in the prevalence of both the dhfr triple and dhps double mutant genotypes in Africa.ConclusionIncreasing prevalence of the dhfr triple mutant and dhps double mutant genotypes in Africa are consistent with the loss of efficacy of SP for treatment of clinical malaria in most parts of this continent. Continued assessment of the effectiveness of SP for the treatment of clinical malaria and intermittent preventive treatment in pregnancy is needed. The creation of a centralized resistance data network, such as the one proposed by the WorldWide Antimalarial Resistance Network (WWARN), will become a valuable resource for planning timely actions to combat drug resistant malaria.

Highlights

Mutations in the dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum are associated with resistance to anti-folate drugs, most notably sulphadoxinepyrimethamine (SP)
One objective of the President’s Malaria Initiative (PMI) includes a 50% reduction in malaria mortality in 15 African countries over a five-year period by expanding the coverage of effective interventions including: insecticide-treated mosquito nets (ITNs), indoor residual spraying with insecticides, intermittent preventive treatment for pregnant women (IPTp), and artemisinin-based combination therapy (ACT) [3,4]
This observation is in line with the increase in the number of anti-malarial clinical efficacy trials reported in the literature in recent years [77] and likely reflects the growing prioritization and feasibility of surveillance as a component of malaria control strategies. 161 studies assembled in this meta-analysis collectively examined blood isolates derived from over 14,000 individuals for the dhfr triple mutant genotype and nearly 8,000 individuals for the dhps double mutant genotype

Summary

Introduction

Mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum are associated with resistance to anti-folate drugs, most notably sulphadoxinepyrimethamine (SP). There is no systematic review examining the collective epidemiological significance of these studies This meta-analysis attempts to: 1) summarize genotype frequency data that are critical for molecular surveillance of anti-folate resistance and 2) identify the specific challenges facing the development of future molecular databases. The programme confronted technical challenges including, but not limited to: anti-malarial drug resistance, insecticide resistance, lack of infrastructure to implement and sustain control measures, and a lack of community engagement and participation [1]. These obstacles collectively damaged the long-term sustainability of the eradication programme, which was abandoned in 1969 [2]. One objective of the PMI includes a 50% reduction in malaria mortality in 15 African countries over a five-year period by expanding the coverage of effective interventions including: insecticide-treated mosquito nets (ITNs), indoor residual spraying with insecticides, intermittent preventive treatment for pregnant women (IPTp), and artemisinin-based combination therapy (ACT) [3,4]

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