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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
Open accessAbstract
BACKGROUND: Mutations 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. METHODS: This 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. RESULTS: A 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. CONCLUSION: Increasing 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.
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“Concerns that increasing SP resistance in SSA [13] may have compromised the efficacy of this chemoprophylactic control measure [14], makes WHO’s call for enhanced regular monitoring of IPTp effectiveness ever more relevant in all malaria-endemic ecosystems.”
From Intermittent preventive treatment with Sulphadoxine-Pyrimethamine (IPTp-SP) is associated with protection against sub-microscopic P. falciparum infection in pregnant women during the low transmission dry season in southwestern Cameroon: A Semi - longitudinal study (2022) · cites this paper as [13]
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Guiguemde, W. A., Shelat, A. A., Garcia-Bustos, J., Diagana, T. T., Gamo, F., & Guy, R. K. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.01.004 · Cited by 141
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Chloroquine and Sulfadoxine–Pyrimethamine Resistance in Sub-Saharan Africa—A Review
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Metadata
- Authors
- Sridaran, S., McClintock, S. K., Syphard, L. M., Herman, K. M., Barnwell, J. W., & Udhayakumar, V.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Corresponding author
- Udhayakumar, Venkatachalam
- Venue
- Malaria Journal
- Published
- 2010-08-30
- Volume
- 9
- Issue
- 1
- Pages
- 247-247
- ISSN
- 1475-2875 (ISSN-L)
- PMC
- PMC2940896
- OpenAlex
- W2165336268
- Cited by
- 124
- References
- 106
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 11 · 2015: 10 · 2014: 8 · 2013: 15 · 2012: 18
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Malaria Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Association of Public Health Laboratories
- Centers for Disease Control and Prevention
- Agency for Toxic Substances and Disease Registry
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Keywords
- Plasmodium falciparum, dihydrofolate reductase, dihydropteroate synthase, sulfadoxine-pyrimethamine, molecular surveillance, intermittent preventive treatment in pregnancy, Africa
- MeSH terms
- Africa, Antimalarials, Dihydropteroate Synthase, Drug Combinations, Drug Resistance, Gene Frequency, Genotype, Humans, Plasmodium falciparum, Pyrimethamine, Sulfadoxine, Tetrahydrofolate Dehydrogenase, Protozoan Proteins, DNA, Protozoan, Amino Acid Substitution, Mutation, Missense, Mutant Proteins
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