Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate

Abstract

Background: P. falciparum gametocytes may persist after treatment with sulphadoxine-pyrimethamine (SP) plus artesunate (AS) and contribute considerably to malaria transmission. We determined the efficacy of SP+AS plus a single dose of primaquine (PQ, 0.75 mg/kg) on clearing gametocytaemia measured by molecular methods.

Methodology: The study was conducted in Mnyuzi, an area of hyperendemic malaria in north-eastern Tanzania. Children aged 3-15 years with uncomplicated P. falciparum malaria with an asexual parasite density between 500-100,000 parasites/microL were randomized to receive treatment with either SP+AS or SP+AS+PQ. P. falciparum gametocyte prevalence and density during the 42-day follow-up period were determined by real-time nucleic acid sequence-based amplification (QT-NASBA). Haemoglobin levels (Hb) were determined to address concerns about haemolysis in G6PD-deficient individuals.

Results: 108 individuals were randomized. Pfs25 QT-NASBA gametocyte prevalence was 88-91% at enrolment and decreased afterwards for both treatment arms. Gametocyte prevalence and density were significantly lower in children treated with SP+AS+PQ. On day 14 after treatment 3.9% (2/51) of the SP+AS+PQ treated children harboured gametocytes compared to 62.7% (32/51) of those treated with SP+AS (p<0.001). Hb levels were reduced in the week following treatment with SP+AS+PQ and this reduction was related to G6PD deficiency. The Hb levels of all patients recovered to pre-treatment levels or greater within one month after treatment.

Conclusions: PQ clears submicroscopic gametocytes after treatment with SP+AS and the persisting gametocytes circulated at densities that are unlikely to contribute to malaria transmission. For individuals without severe anaemia, addition of a single dose of PQ to an efficacious antimalarial drug combination is a safe approach to reduce malaria transmission following treatment.

Trial registration: Controlled-Trials.com ISRCTN61534963.

Figure 1. Profile of the study

Figure 2. Gametocyte prevalence by microscopy (A) and Pfs25 QT-NASBA (B).

Gametocyte prevalence for SP+AS (closed diamonds, solid line) and SP+AS+PQ (open triangles, broken lines) treated children. Bars indicate the 95% confidence intervals around the proportions. * indicates a statistically significant difference between the two treatment arms.

Figure 3. Haemoglobin concentration following treatment.

Concentrations are expressed relative to that at enrolment for SP+AS (closed diamonds, solid line) and SP+AS+PQ (open triangles, broken lines). Bars indicate the 95% confidence intervals around the proportions. * indicates a statistically significant difference between the two treatment arms.

Figure 4. Relative haemoglobin concentration after treatment with SP+AS+PQ for different G6PD genotypes.

Haemoglobin concentration relative to enrolment for children without the G202A mutation (G6PD genotype B; black diamonds, n = 39), heterozygotes (G6PD genotype A; white triangles, n = 9) and homozygotes or hemizygotes (G6PD genotype A-: grey diamonds, n = 4). Each individual measurement is shown; lines indicate the median value.