Higher gametocyte prevalence following failure of treatment of Plasmodium falciparum malaria with sulfadoxine-pyrimethamine and the combination of chloroquine plus sulfadoxine-pyrimethamine: implications for progression of anti-folate resistance

Abstract

Chloroquine (CQ) treatment of CQ-resistant Plasmodium falciparum is associated with a significantly higher prevalence of post-treatment gametocytaemia which has been linked to the preferential transmission of CQ-resistant parasites. It is not known whether treatment failure (TF) with sulfadoxine-pyrimethamine (SP) is associated with the same higher prevalence of gametocytaemia as that seen with CQ TF. Using 1997 WHO in-vivo drug efficacy protocols for malaria, we therefore compared (in a study in 1999) the frequency of gametocytaemia in those with TF to the frequency seen in those with an adequate clinical and parasitological response (ACPR) following treatment with one of 3 regimens in Papua, Indonesia: SP monotherapy (n = 87; TF 20.7%), CQ monotherapy (n = 48; TF 83.3%), and the combination of CQ plus SP (n = 34; TF 38.2%). Following SP, day 7 prevalence was significantly higher in those with TF (67%) than with ACPR (38%, P = 0.03). Following combination treatment with CQ + SP, the day 14 gametocyte prevalence was significantly higher in those with TF (100% vs 38%, P = 0.016). The higher prevalence of SP TF-associated gametocytaemia may contribute to increased transmission of antifolate-resistant strains, and further cautions against the use of SP as monotherapy. Adding SP to CQ, after significant resistance has emerged to both drugs, may not prevent enhanced transmission of dual-resistant strains and progression of anti-folate resistance.

Therapeutic Efficacies of Artesunate-Sulfadoxine-Pyrimethamine and Chloroquine-Sulfadoxine-Pyrimethamine in Vivax Malaria Pilot Studies: Relationship to Plasmodium vivax dhfr Mutations

“…Our open therapeutic efficacy studies were performed in 1999 at Genyem Health Center, Papua Province, an area where malaria with year-round transmission is meso-endemic (38,39). The pilot CQ, CQ-SP, and ART-SP efficacy studies were performed with patients with vivax malaria who had been admitted to the center from February to April 1999.…”

“…Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T3M mutation at residue 61 linked to an S3T (but not an S3N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.High rates of chloroquine (CQ) resistance and CQ treatment failure have been found in both vivax and falciparum malaria in Papua Province (formerly Irian Jaya), Indonesia (2,3,5,21,28,38), and new combination therapies are required for each species. Artemisinin-derivative combination therapies (ACT) are being used increasingly for the treatment of multidrug-resistant Plasmodium falciparum malaria (29) because of their excellent efficacy (23,31,39,41), their ability to slow or reverse the emergence of resistance (24, 30), and their ability to reduce malaria transmission (24, 30).…”

“…High rates of chloroquine (CQ) resistance and CQ treatment failure have been found in both vivax and falciparum malaria in Papua Province (formerly Irian Jaya), Indonesia (2,3,5,21,28,38), and new combination therapies are required for each species. Artemisinin-derivative combination therapies (ACT) are being used increasingly for the treatment of multidrug-resistant Plasmodium falciparum malaria (29) because of their excellent efficacy (23,31,39,41), their ability to slow or reverse the emergence of resistance (24,30), and their ability to reduce malaria transmission (24,30).…”

“…Although the CQ-SP combination was later shown to have inadequate efficacy for falciparum malaria treatment in Papua Province (8,38), it had been considered an option for the empirical management of malaria in Papua. We therefore undertook small pilot studies using modified WHO criteria to examine the efficacies of CQ and CQ-SP in vivax malaria treatment.…”

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

“…CQ treatment failure is followed by an increased gametocyte prevalence and density (4, 188, 383, 440, 448, 476) and, as a consequence, increased posttreatment malaria transmission (188,383). Similarly, posttreatment gametocytemia is also increased after treatment failure of SP alone (52,53,440,476) or in combination with CQ (476). The rapid spread of CQ and SP resistance may be due to some degree to high gametocyte carriage after treatment and treatment failure (26).These associations are explained only partly by ongoing gametocyte production by asexual parasites that survive the failing antimalarial treatment.…”