The online version of this article (doi:10.1186/s12936-017-1747-6) contains supplementary material, which is available to authorized users.
To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naïve Liberian villages, 1976–78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P. falciparum resistance after 2 years of treatment are reported.
Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods.
Pfcrt 72–76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069ACT→ACG synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45–65% elsewhere, including the placebo village (P = 0.001).
Chloroquine treatment possibly resulted in the development of pfcrt 72–76 CVIET. Selection of pfmdr1 T1069ACG and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.
Millet J, Alibert S, Torrentino-Madamet M, Rogier C, Santelli-Rouvier C, Bigot P, et al. Polymorphism in Plasmodium falciparum drug transporter proteins and reversal of in vitro chloroquine resistance by a 9,10-dihydroethanoanthracene derivative. Antimicrob Agents Chemother. 2004;48:4869–72. CrossRefPubMedPubMedCentral
Basco LK, Ringwald P. Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil. Am J Trop Med Hyg. 2000;62:271–6. PubMed
Björkman A, Brohult J, Willcox M, Pehrson PO, Rombo L, Hedman P, et al. Malaria control by chlorproguanil. I. Clinical effects and susceptibility of Plasmodium falciparum in vivo after seven years of monthly chlorproguanil administration to children in a Liberian village. Ann Trop Med Parasitol. 1985;79:597–601. CrossRefPubMed
Ménard D, Andriantsoanirina V, Khim N, Ratsimbasoa A, Witkowski B, Benedet C, et al. Global analysis of Plasmodium falciparum Na+/H+ exchanger (pfnhe-1) allele polymorphism and its usefulness as a marker of in vitro resistance to quinine. Int J Parasitol Drugs Drug Resist. 2013;3:8–19. CrossRefPubMed
Summers RL, Dave A, Dolstra TJ, Bellanca S, Marchetti RV, Nash MN, et al. Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Proc Natl Acad Sci USA. 2014;111:1759–67. CrossRef
- Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naïve areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976–78
Irina T. Jovel
- BioMed Central
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