Molecular markers in plasmodium falciparum linked to resistance to anti-malarial drugs in samples imported from Africa over an eight-year period (2002-2010): impact of the introduction of artemisinin combination therapy

Malar J. 2012 Mar 30:11:100. doi: 10.1186/1475-2875-11-100.

Abstract

Background: Drug resistance is a major problem to control Plasmodium falciparum infection in endemic countries. During last decade, African countries have changed first-line treatment to artemisinin-based combinations therapy (ACT); sulphadoxine-pyrimethamine (SP) is recommended for Intermittent Preventive Therapy (IPT). Molecular markers related to P falciparum resistance were analysed for the period of transition from SP to ACT, in isolates imported from Africa.

Methods: A first group of samples was taken in the period between June 2002 and June 2006 (n = 113); a second group in the period between November 2008 and August 2010 (n = 46). Several alleles were analysed by nested PCR-RFLP: 51, 59, 108, 164, in the pfdhfr gene; 436, 437, 540, 581, in the pfdhps gene; 86, 1246, in the pfmdr1 gene and 76, in the pfcrt gene. The prevalence of alleles in the groups was compared with the chi-squared or Fisher's exact tests.

Results: The pfdhfr N51I, C59R and S108N were over to 90% in the two groups; all samples had the I164. In the pfdhps, 437 G and 581 G, increased up to 80% and 10.9% (p = 0.024), respectively in the second group. The 540 G decreases (24% to 16.%) and the 436A disappears at the end of the follow-up (p = 0.004) in the second group. The 76I-pfcrt stayed over 95% in the two groups. Prevalence of 86Y-pfmdr1 decreased over eight years.

Conclusions: Pharmacological pressure affects the resistance strains prevalence. As for SP, the disappearance of 436A and the decrease in 540 G suggest that these mutations are not fixed. On the other hand, studies carried out after ACT introduction show there was a selection of strains carrying the SNPs N86Y, D1246Y in pfmdr1. In this work, the prevalence of pfmdr1- D1246Y is increasing, perhaps as a result of selective pressure by ACT. Continued surveillance is essential to monitor the effectiveness of treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa
  • Alleles
  • Animals
  • Antimalarials / administration & dosage
  • Antimalarials / pharmacology*
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacology
  • DNA, Protozoan / genetics
  • Drug Combinations
  • Drug Resistance*
  • Gene Frequency
  • Genotype
  • Humans
  • Malaria, Falciparum / parasitology*
  • Multidrug Resistance-Associated Proteins / genetics
  • Mutant Proteins / genetics
  • Mutation, Missense
  • Peptide Synthases / genetics
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics*
  • Plasmodium falciparum / isolation & purification
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Pyrimethamine / administration & dosage
  • Pyrimethamine / pharmacology
  • Sulfadoxine / administration & dosage
  • Sulfadoxine / pharmacology
  • Tetrahydrofolate Dehydrogenase / genetics
  • Travel*

Substances

  • Antimalarials
  • Artemisinins
  • DNA, Protozoan
  • Drug Combinations
  • Mdr1 protein, Plasmodium falciparum
  • Multidrug Resistance-Associated Proteins
  • Mutant Proteins
  • fanasil, pyrimethamine drug combination
  • Sulfadoxine
  • artemisinin
  • Tetrahydrofolate Dehydrogenase
  • Peptide Synthases
  • dihydrofolate synthetase
  • Pyrimethamine