Abstract
BackgroundIn Papua New Guinea (PNG), combination therapy with amodiaquine (AQ) or chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000.MethodsWe assessed in vivo treatment failure rates with AQ+SP in two different areas in PNG and twenty-four molecular drug resistance markers of Plasmodium falciparum were characterized in pre-treatment samples. The aim of the study was to investigate the association between infecting genotype and treatment response in order to identify useful predictors of treatment failure with AQ+SP.ResultsIn 2004, Day-28 treatment failure rates for AQ+SP were 29% in the Karimui and 19% in the South Wosera area, respectively. The strongest independent predictors for treatment failure with AQ+SP were pfmdr1 N86Y (OR = 7.87, p < 0.01) and pfdhps A437G (OR = 3.44, p < 0.01). Mutations found in CQ/AQ related markers pfcrt K76T, A220S, N326D, and I356L did not help to increase the predictive value, the most likely reason being that these mutations reached almost fixed levels. Though mutations in SP related markers pfdhfr S108N and C59R were not associated with treatment failure, they increased the predictive value of pfdhps A437G. The difference in treatment failure rate in the two sites was reflected in the corresponding genetic profile of the parasite populations, with significant differences seen in the allele frequencies of mutant pfmdr1 N86Y, pfmdr1 Y184F, pfcrt A220S, and pfdhps A437G.ConclusionThe study provides evidence for high levels of resistance to the combination regimen of AQ+SP in PNG and indicates which of the many molecular markers analysed are useful for the monitoring of parasite resistance to combinations with AQ+SP.
Highlights
In Papua New Guinea (PNG), combination therapy with amodiaquine (AQ) or chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000
Whereas several studies have shown the key role of pfcrt K76T in conferring in vivo resistance to CQ [3,4], the relationship between phenotypic resistance and other pfcrt polymorphisms (i.e., C72S/R, M74I/T, N75E/D/K/I, K76T/I/N, I77T, H97Q/L, A144F/T, L148I, L160Y, I194T, A220S, Q271E, N326S/D, I356V/T/L and R371T/I), which have been shown to be associated with CQ resistance in vitro, has been little studied in the field
Single-base changes in pfmdr1 N86Y, Y184F, S1034C, N1042D and D1246Y have been documented in CQ resistant laboratory strains, but a straightforward association of these polymorphisms with in vivo CQ resistance has been questioned by several authors [5,6]
Summary
In Papua New Guinea (PNG), combination therapy with amodiaquine (AQ) or chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000. The effectiveness of the most widely used first-line antimalarials chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has been heavily compromised by the emergence and spread of Plasmodium falciparum resistance to these drugs. In order to improve treatment efficacy and to delay the development and spread of drug resistance, there is strong advocacy for combination therapy [1]. Apart from studies assessing in vivo drug efficacy and in vitro drug sensitivity, molecular markers have been proposed as a means to monitor drug resistant malaria [2]. Single-base changes in pfmdr N86Y, Y184F, S1034C, N1042D and D1246Y have been documented in CQ resistant laboratory strains, but a straightforward association of these polymorphisms with in vivo CQ resistance has been questioned by several authors [5,6]
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