Primaquine radical cure of Plasmodium vivax: a risk-benefit analysis.

Abstract

Background

Forty percent of the world’s population remain at risk of P.vivax infection, with over 14 million clinical episodes of vivax malaria each year. Primaquine-based treatment can cause haemolysis in vulnerable individuals. The risks and benefits of primaquine-based treatment remain unclear.

Objectives/Aims

We undertook a series of systematic reviews and meta-analyses to investigate the risks and benefits of primaquine-based treatment.

Method

Systematic reviews done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P.vivax clinical trials. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of antimalarial dose and primaquine use on rate of recurrence between day 7 and day 42. The haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time, with differences between treatment groups at day of nadir and day 42 estimated from this model. Results

In total, 7,250 patients from 47 studies were included in three analyses. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR]=0·82, 95%CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·006). Coadministration of primaquine reduced substantially the rate of recurrence assessed at day 42 after chloroquine (AHR=0·10, 95%CI 0·05–0·17; p<0·001), artemether-lumefantrine (AHR=0.20, 0.10–0.41, p<0.001) and at day 63 after dihydroartemisinin-piperaquine (AHR=0.08, 0.01–0.70, p=0.023). In comparison to chloroquine alone, the mean haemoglobin in 1,446 patients treated with chloroquine plus primaquine was −0.13 g/dL [−0.27,0.01] lower at day of nadir (p=0.072), but 0.49 g/dL [0.28,0.69] higher by day 42 (p<0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration − 0.72 g/dL [−0.90,−0.54] lower than patients without recurrence (p<0.001).

Implications/Outcomes for Planned Research Project

Primaquine is safe and effective in combination with chloroquine, artemether-lumefantrine or dihydroartemisinin-piperaquine.

Final Thoughts

Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation in endemic countries will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.