Low infectivity of Plasmodium falciparum gametocytes to Anopheles gambiae following treatment with sulfadoxine–pyrimethamine in Mali

Abstract

Sulfadoxine–pyrimethamine (SP) treatment increases the rate of gametocyte carriage and selects SP resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), raising concerns of increased malaria transmission and spread of drug resistance. In a setting in Mali where SP was highly efficacious, we measured the prevalence of DHFR and DHPS mutations in P. falciparum infections with microscopy-detected gametocytes following SP treatment, and used direct feeding to assess infectivity to Anopheles gambiae sensu lato. Children and young adults presenting with uncomplicated malaria were treated with SP or chloroquine and followed for 28 days. Gametocyte carriage peaked at 67% 1 week after treatment with a single dose of SP. Those post-SP gametocytes carried significantly more DHFR and DHPS mutations than pre-treatment asexual parasites from the same population. Only 0.5% of 1728 mosquitoes fed on SP-treated gametocyte carriers developed oocysts, while 11% of 198 mosquitoes fed on chloroquine-treated gametocyte carriers were positive for oocysts. This study shows that in an area of high SP efficacy, although SP treatment sharply increased gametocyte carriage, the infectiousness of these gametocytes to the vector may be very low. Accurate and robust methods for measuring infectivity are needed to guide malaria control interventions that affect transmission.

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

“…Second, the QMF assay could be used for gametocyte viability assessments by conducting exflagellation assays after fractionation (45). This would enable a better assessment of the effect of antimalarial drugs on the ability of circulating gametocytes to infect mosquitoes, as it is currently not clear whether all gametocytes in the peripheral blood are viable after treatment (9,10).…”

“…As their half-lives are relatively short, this greater potency arises largely from their ability to destroy a wider range of early-stage gametocytes, presumably at their sequestration sites (4,8). However, the exact effect of antimalarial drugs on the viability of more mature P. falciparum gametocytes that continue to circulate after treatment is unclear (9,10).…”

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

“…The increase in gametocytemia after treatment is a likely result of the efflux of sequestered gametocytes rather than de novo gametocytogenesis (77). An efflux of not fully mature gametocytes may explain the finding of relatively low infectivity of gametocytes 1 week after SP treatment, despite high densities (30,466), although this could also be related to sporontocidal effects of persisting drug concentrations (229). In general, gametocytemia after treatment is a composite of (i) the ongoing production of gametocytes after initiation of treatment, possibly enhanced by drug-induced stress by slow-acting antimalarials; (ii) the release of sequestrated gametocytes; (iii) the activity of drugs against immature gametocytes, preventing their release into the circulation; and (iv) the activity of drugs against mature gametocytes, clearing the circulating gametocyte population.…”

“…6). Similarly, mutations in the dhfr and dhps genes, encoding SP resistance, were related to increased gametocyte carriage following (30,275,288) or even prior to (288) treatment and to a longer duration of gametocyte carriage than that for wild-type parasites (25). A study by Méndez and colleagues showed that malaria transmission was enhanced 10-fold for parasites with low levels of resistance compared to fully sensitive parasites, despite high SP cure rates in Colombia (274).…”

Longitudinal study on Plasmodium falciparum gametocyte carriage following artemether-lumefantrine administration in a cohort of children aged 12–47 months living in Western Kenya, a high transmission area

“…Other important risk factors for gametocyte carriage include anaemia [22], durations of the infections, recrudescent infections [23], fever [24], mixed infections [23,25] and drug treatment [26,27]. …”