Characteristics ofPlasmodium falciparum dhfrHaplotypes That Confer Pyrimethamine Resistance, Kilifi, Kenya, 1987–2006

Abstract

Resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP) emerged in Plasmodium falciparum from Asia in the 1960s and subsequently spread to Africa. It is not known whether alleles that confer SP resistance also arose independently in Africa. We defined the coding region and microsatellite haplotypes of dhfr alleles in P. falciparum collected in Kilifi, Kenya, during 1987--2006, which spans the period when SP was first introduced. Isolates that carried a double-mutant or triple-mutant dhfr allele were detected at a low frequency, even during 1987--1988. Each of 2 double mutants carried a unique haplotype, and both were related to wild-type haplotypes from the same population. The number of isolates that carried a triple-mutant dhfr allele increased rapidly after introduction of SP and shared the haplotype of the triple mutant derived form Asia. We observed no triple-mutant alleles with haplotypes related to those of the Africa-derived wild-type and double-mutant alleles.

Antimalarial Drug Sensitivity Profile of Western Kenya Plasmodium falciparum Field Isolates Determined by a SYBR Green I in vitro Assay and Molecular Analysis

“…Anti-folate drugs were omitted because P. falciparum resistance in Kenya is established. 15,18,19 Reference P. falciparum clones assayed periodically for internal control against all six drugs included D6, considered CQ-sensitive and MQ-resistant (CQ-S; MQ-R) and W2, considered CQ-resistant and MQ-sensitive (CQ-R; MQ-S), as well as AR-sensitive. 5 Quinine sulfate hydrate generally parallels CQ for D6 and W2 IC 50 trends.…”

Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance

“…As seen with chloroquine resistance, the pyrimethamine-resistant dhfr allele (encoding the CIRNI enzyme) that is currently predominant in many endemic regions in Africa (8,12,60,62) arose initially in Southeast Asia. The earliest detection of this allele in Africa occurred in 1988 in Kenya (63). Most recently, we have shown that several pyrimethamine-sensitive dhfr alleles (encoding NCSI, ICSI, NRSI, and IRSI enzymes at positions 51, 59, 108, and 164) that were prevalent in Africa before the 1990s were rapidly displaced by the IRNI-encoding allele following the introduction of pyrimethamine/sulfadoxine as a first-line therapy in …”

Multiple Origins of Plasmodium falciparum Dihydropteroate Synthetase Mutant Alleles Associated with Sulfadoxine Resistance in India

“…This leads to hitchhiking of the markers flanking the gene and an increase in linkage disequilibrium. Genetic hitchhiking across the dhfr alleles had previously been reported from several countries (7,12,14,16,21,22,24,28,29), in contrast to fewer reports on dhps alleles (4,25,28,33). Earlier, we have reported that antimalarial drug resistance is widespread in the Indian P. falciparum population (1)(2)(3)20).…”

“…In Southeast Asia, dhfr alleles with a single mutation have multiple independent origins (21,22), whereas alleles with 2 or more mutations have a single common origin (12,21,22). The Southeast Asian triple mutant dhfr allele AIRNI later spread to Africa, where this is in abundance (7,14,24,28,29). However, there is evidence of indigenous origins of triple mutant dhfr allele AIRNI in several African countries like Kenya, Ghana, and Cameroon (18,19).…”