Relationship between age, molecular markers, and response to sulphadoxine–pyrimethamine treatment in Kampala, Uganda

Abstract

Sulphadoxine/pyrimethamine (SP) has become the first-line treatment of uncomplicated malaria in a number of African countries. Molecular surveillance of resistance-mediating mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) has been proposed as a means of predicting SP treatment outcomes, but optimal methods of surveillance in different populations have not been well established. To investigate the relationship between molecular markers of SP resistance, host immunity, and response to therapy, we evaluated the association between the presence of five key dhfr and dhps mutations at enrollment and clinical outcome in children and adults treated with SP for uncomplicated malaria in Kampala, Uganda. Clinical treatment failure was 11% at 14 days, increasing to 30% at 28 days, after excluding new infections. Outcomes varied markedly based on the number of dhfr and dhps mutations and on the age of treated subjects. All infections with less than two dhfr/dhps mutations were successfully treated. Treatment failure associated with any two, three, or four dhfr/dhps mutations occurred in nine of 24 (38%) children up to 5 years, but not in older patients (0/20). In the presence of all five mutations, treatment failure occurred equally in children aged 5 years or younger [7/16 (44%)] and in older patients [8/16 (50%)]. Our results showed that age, a surrogate marker of antimalarial immunity, had a major impact on the relationship between polymorphisms in SP target enzymes and treatment outcomes. The use of molecular markers of SP resistance to predict treatment failure rates should take age into account.

Mutations Associated with Sulfadoxine-Pyrimethamine and Chlorproguanil Resistance in Plasmodium falciparum Isolates from Blantyre, Malawi

“…The presence of the DHFR-164-Leu mutation is troubling because it confers cross-resistance to Lapdap. In Africa, the DHFR-164 mutation has rarely been found: previous reports of this mutation were from travelers and people treated with Lapdap, and it was also found as a rare component of samples (6,8,15). In contrast, we report the DHFR-164 mutation as a major component of samples in African women who report not taking Lapdap.…”

Surveillance of Molecular Markers of Plasmodium falciparum Resistance to Sulphadoxine-Pyrimethamine 5 Years after the Change of Malaria Treatment Policy in Ghana

“…Although triple and quadruple mutants were detected in the samples analyzed in this study, it must be emphasized that the predictive value of these markers varies geographically and involves a complex interplay between host immunity, parasites, and drug. [29][30][31] Overall, the results of this study showed a significant increase in the prevalence of mutations in the P. falciparum dhfr and dhps genes from 2003 to 2010. The combined benefits of low-cost, single-dose administration, and better tolerability as compared with ACTs currently in use in Ghana might It is unclear whether the use of SP for IPTp alone or the use of SP in the general population for the treatment of uncomplicated malaria has contributed to the drug pressure.…”

Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

“…The predictive value of the combination of these SNPs varies geographically, depending on, e.g., baseline prevalence, age, and levels of acquired immunity. [18][19][20][21][22] In Africa, the Pfdhfr triple mutant, 51I-59R-108N, together with the Pfdhps double mutant, 437G-540E forms the quintuple mutant that predicts a high risk of treatment failure after SP treatment. 23,21 Similarly, and specifically regarding IPTi, recent evidence suggests that high prevalence ( 50%) of the highly resistant Pfdhps 540E mutantessentially the quintuple Pfdhfr/Pfdhps mutant, may undermine the required protective efficacy of SP-IPTi of 20%.…”