BACKGROUND: To reduce onward falciparum malaria transmission, the World Health Organization recommends adding
single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However,
uptake of this recommendation has been relatively slow given concerns about whether individual risks justify
potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit
profile of SLD primaquine deployment in a pre-elimination area in South Africa.
METHODS: This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to
standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of
artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations
were assayed from dried blood spot samples collected on day 7.
RESULTS: Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine
and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up
samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the
CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively;
none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped,
24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between
treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated
with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs.
31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of
adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the
no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate
was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up.
CONCLUSIONS: Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHOrecommended
SLD primaquine without G6PD testing to advance malaria elimination in South African districts with
low-intensity residual transmission.