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

Seif Shekalaghe, Chris Drakeley, Roly Gosling, Arnold Ndaro, Monique van Meegeren, Anders Enevold, Michael Alifrangis, Frank Mosha, Robert Sauerwein, Teun Bousema, Seif Shekalaghe, Chris Drakeley, Roly Gosling, Arnold Ndaro, Monique van Meegeren, Anders Enevold, Michael Alifrangis, Frank Mosha, Robert Sauerwein, Teun Bousema

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Profile of the study
Figure 1. Profile of the study
Figure 2. Gametocyte prevalence by microscopy (A)…
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.
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…
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.

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