Single dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission in Cambodia: An open-label randomized trial

Background Single low dose primaquine(SLD PQ, 0.25mg/kg) is recommended in combination with artemisinin-based combination therapy (ACT) as a gametocytocide to prevent Plasmodium falciparum transmission in areas threatened by artemisininresistance. To date, no randomized controlled trials have measured primaquine’s effect on infectiousness to Anopheline mosquitoes in Southeast Asia. Methods Cambodian adults with uncomplicated falciparum malaria were randomized to receive a single 45mg dose of primaquine(equivalent to three SLD PQ) or no primaquineafter the third dose of dihydroartemisin- piperaquine( DHP) therapy. A membrane-feeding assay measured infectiousness to Anopheles diruson days 0, 3, 7, and 14 of blood-stage therapy. Gametocytemia was evaluated by microscopy and reverse-transcriptase PCR. Results Prior to trial halt for poor DHPtreatment efficacy, 101 participants were randomized and 50 received primaquine. Overall microscopic gametocyteprevalence was low (9%), but gametocytemic subjects given primaquinewere gametocyte-free by day 14, and significantly less likely to harbor gametocytesby day 7 compared to those treated with DHP-alone, who remained gametocytemic for a median of two weeks. Only one infectious subject was randomized to the primaquinegroup, precluding assessment of transmission-blocking efficacy. However, he showed a two-fold reduction in oocyst density of infected mosquitoes less than 24 hours after primaquinedosing. In the DHP-alone group, four subjects remained infectious through day 14, infecting roughly the same number of mosquitoes pre and post-treatment. Overall, microscopic gametocytemia was an excellent predictor of infectiousness, and performed better than submicroscopic gametocytemia post-treatment, with none of 474 mosquitoes infected post-treatment arising from submicroscopic gametocytes. Conclusions In a setting of established ACT resistance, a single dose of 45mg primaquineadded to DHPrapidly and significantly reduced gametocytemia, while DHP-alone failed to reduce gametocytemia and prevent malaria transmission to mosquitoes. Continued efforts to make single dose primaquinewidely available are needed to help achieve malaria elimination.