Polymorphisms in thePlasmodium falciparum pfcrtandpfmdr‐1Genes and Clinical Response to Chloroquine in Kampala, Uganda

Abstract

The molecular mechanism of chloroquine resistance in Plasmodium falciparum remains uncertain. Polymorphisms in the pfcrt and pfmdr-1 genes have been associated with chloroquine resistance in vitro, although field studies are limited. In evaluations of known polymorphisms in parasites from patients with uncomplicated malaria in Kampala, Uganda, the presence of 8 pfcrt mutations and 2 pfmdr-1 mutations did not correlate with clinical response to therapy with chloroquine. Most notably, the pfcrt lysine-->threonine mutation at position 76, which recently correlated fully with chloroquine resistance in vitro, was present in 100% of 114 isolates, of which about half were from patients who recovered clinically after chloroquine therapy. These results suggest that, although key pfcrt polymorphisms may be necessary for the elaboration of resistance to chloroquine in areas with high levels of chloroquine resistance, other factors, such as host immunity, may contribute to clinical outcomes.

Association of Plasmodium Falciparum Isolates Encoding the P. Falciparum Chloroquine Resistance Transporter Gene K76t Polymorphism With Anemia and Splenomegaly, but Not With Multiple Infections

“…7 The discrepancy between clinical CQR and the prevalence of isolates carrying the pfcrt K76T allele has also been noted in several other studies. 18,19 Current models to explain this discrepancy suggest that the pfcrt K76T polymorphism is only one among other parasite factors that, in addition to host factors, ultimately determine CQ treatment failure. Djimde and others described a model to estimate the rate of clinical CQR based on the prevalence of the pfcrt K76T allele in a given population.…”

“…2,4,23 Two variables are currently discussed to explain the age distribution of CQR malaria: immune status and the drug selection pressure. 19,22,24 Adults who have acquired a premunition to malaria appear to be more capable of eliminating parasites in the presence of CQ than children do, irrespective of the susceptibility of the clone to CQ. Conversely, persistent levels of CQ increase the selection pressure on parasites and result in a higher rate of pfcrt K76T-carrying isolates.…”

Association of Plasmodium Falciparum Chloroquine Resistance Transporter Variant T76 With Age-Related Plasma Chloroquine Levels

“…27 However, all studies comparing the associations of the pfmdr Y86 variant and the pfcrt T76 variant have shown that the impact of the pfcrt gene was stronger than that of the pfmdr gene. 8,9,11,12 Although an association of a cg2 gene polymorphism with CQ resistance has been described, allelic modification experiments have excluded a significant role of this gene in CQ resistance. 28 It has been suggested that the degree of CQ resistance is further modulated by factors linked to genes other than pfcrt or pfmdr, 29 but the nature of such factors is still unclear.…”

“…4,5 Although gene polymorphisms in the P. falciparum multidrug resistance (pfmdr) gene or other mutations in the pfcrt gene may also be involved in the development of CQ resistance, pfcrt T76 is likely the main determinant of CQ resistance. 6,7 Evidence that pfcrt T76 is a key marker of CQ resistance has been demonstrated in several studies on the selection of this mutation after treatment with CQ [8][9][10][11] and by varying in vivo and in vitro responses to CQ in different parasite isolates. [12][13][14] Findings on the relationship between blood levels of CQ and the occurrence of pfcrt 76 variants have not been reported.…”

Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems

“…After the molecular mechanisms for parasite resistance to the antifolates and chloroquine were elucidated, a proliferation of field studies followed that investigated the use of molecular markers for the detection of drug resistance in Africa. [29][30][31][32][33][34] However, the challenge now is that neither molecular markers nor in-vitro assays for artemisinin resistance are well established. 35 For example, in-vitro drug sensitivity tests of samples from Cambodia produced inconsistent results with respect to identification of the in-vivo resistant phenotype, and no molecular markers have been reported in the genes (pfmdr1, pfcrt, and pfserca) thought to be associated with resistance to other antimalarials or putatively associated with artemisinin resistance.…”