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Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis
O K Doumbo1, K Kayentao, A Djimde
1Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy, and Odonto-stomatology, University of Mali, Bamako, Mali.
Insights
Pyrimethamine prophylaxis rapidly selects for mutations in Plasmodium falciparum dihydrofolate reductase (DHFR). These drug-resistant mutations emerge quickly, even from undetectable baseline infections, impacting malaria treatment strategies.
Area of Science:
- Malariology
- Molecular parasitology
- Pharmacogenetics
Background:
- Antifolate drugs like pyrimethamine are crucial for malaria prevention.
- Understanding drug resistance mechanisms is vital for effective malaria control.
- Point mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) are associated with pyrimethamine resistance.
Purpose of the Study:
- To investigate the selective pressure of pyrimethamine prophylaxis on DHFR mutations in Plasmodium falciparum.
- To determine the speed and prevalence of mutation emergence under drug pressure.
Main Methods:
- Prospective study involving 109 Malian children receiving weekly pyrimethamine prophylaxis.
- Polymerase chain reaction (PCR) analysis of P. falciparum infections to detect DHFR mutations at baseline and during prophylaxis.
- Microsatellite analysis to assess the genetic identity of infections.
Main Results:
- DHFR mutations became dramatically more frequent in breakthrough infections compared to baseline.
- Prevalence of Asn-108, Ile-51, and Arg-59 mutations increased significantly (e.g., Asn-108 from 13% to 100%).
- Eight infections developed multiple DHFR mutations within one week of starting prophylaxis, even when initially undetectable.
Conclusions:
- Pyrimethamine prophylaxis exerts strong selective pressure favoring DHFR mutations.
- These mutations arise rapidly under drug pressure, even from pre-existing, undetectable infections.
- Findings have significant implications for the design and efficacy of antifolate-based prophylaxis regimens.
Abstract:
A prospective study was conducted to measure the selective effect of pyrimethamine prophylaxis on point mutations in Plasmodium falciparum dihydrofolate reductase (DHFR). A total of 109 Malian children were given pyrimethamine weekly for 5 weeks. P. falciparum infections were analyzed by polymerase chain reaction for DHFR mutations, which were dramatically more frequent among prophylaxis-breakthrough infections than at baseline: the prevalence of Asn-108 rose from 13% to 100%, Ile-51 from 4% to 50%, and Arg-59 from 11% to 90%. Eight persistent infections lacking detectable DHFR mutations at baseline developed multiple mutations within 1 week of the patients' starting pyrimethamine prophylaxis. Microsatellite analysis found no evidence of clonal identity among baseline and breakthrough infections. Analysis of these data demonstrates that under prophylaxis conditions, pyrimethamine is strongly selective for DHFR mutations, which arise extremely rapidly under drug pressure, even when undetectable in the initial infection. These findings have implications for prophylaxis regimens with other antifolate drugs.
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