Combination Therapy Counteracts the Enhanced Transmission of Drug-Resistant Malaria Parasites to Mosquitoes

Abstract

Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resistant parasites from treated patients to mosquito vectors has not been measured directly. In a trial comparing CQ monotherapy to the combination CQ plus artesunate (AS) in Gambian children with uncomplicated falciparum malaria, we measured transmissibility by feeding Anopheles gambiae mosquitoes with blood from 43 gametocyte-positive patients through a membrane. In the CQ-treated group, gametocytes from patients carrying parasites with the CQ resistance-associated allele pfcrt-76T prior to treatment produced infected mosquitoes with 38 times higher Plasmodium falciparum oocyst burdens than mosquitoes fed on gametocytes from patients infected with sensitive parasites (P < 0.001). Gametocytes from parasites carrying the resistance-associated allele pfmdr1-86Y produced 14-fold higher oocyst burdens than gametocytes from patients infected with sensitive parasites (P ‫؍‬ 0.011). However, parasites carrying either of these resistance-associated alleles pretreatment were not associated with higher mosquito oocyst burdens in the CQ-AS-treated group. Thus, combination therapy overcomes the transmission advantage enjoyed by drug-resistant parasites.

Immunoglobulin G Antibodies to Merozoite Surface Antigens Are Associated with Recovery from Chloroquine-ResistantPlasmodium falciparumin Gambian Children

“…These groups of patients were similar in age, anemia level (as estimated by packed cell volume), ethnicity, and asexual parasite density (Table 1), but carriage of parasites with the Pfcrt-76Thr genotype was higher among patients sampled only on day 7: 30/32 individuals (95%) compared to 31/46 (67%) among those sampled on day 7. This increase was likely due to the higher proportion of gametocytemic donors in the day 7 group, as there is a correlation between gametocytemia and drug resistance (17,26). Clinical failures occurred soon after treatment, 13/16 (81%) before day 14, and all parasitological failures were detected on day 14 (29/45) or on day 28 (16/45), with a mean detection time point of 18.9 days.…”

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

“…This may be explained partly by a longer parasite clearance time for dhfr/dhps mutant parasites allowing asexual parasites to differentiate into gametocytes (275), although other factors may also be important (25,275). In addition to this transmission advantage of mutant parasites in the human host, through a higher gametocyte prevalence or density (184,275), a selective advantage in the mosquito midgut has been suggested for Pfcrt mutants (184). In an area of low endemicity in South Africa, gametocyte carriage was highest for isolates with quintuple mutations in dhfr and dhps genes, intermediate for those with fewer mutations, and lowest for wild-type infections (25).…”

“…Even if resistant parasites are cleared successfully, they appear to have a transmission advantage over fully sensitive (wild-type) parasite strains. Mutations in the Pfcrt and Pfmdr1 genes, encoding CQ resistance, were associated with a higher gametocyte density and subsequent malaria transmission after CQ monotherapy (184,460) or SP-CQ combination treatment (183) (Fig. 6).…”

Chlorproguanil–Dapsone–Artesunate versus Chlorproguanil–Dapsone: A Randomized, Double-Blind, Phase III Trial in African Children, Adolescents, and Adults with Uncomplicated Plasmodium falciparum Malaria

“…4 Artemisinin derivatives are active against multidrug-resistant P. falciparum , 5,6 rapidly reduce asexual parasitemia, 7,8 and are gametocytocidal, potentially reducing transmission. [9][10][11][12][13] However, the short half-life of these agents precludes their use as monotherapy for uncomplicated malaria. To obtain the advantages of artemisinins, the World Health Organization (WHO) Global Malaria Program recommends artemisininbased combination therapy (ACT) for first-line treatment of P. falciparum malaria in Africa.…”