A new WWARN study supports safety of WHO recommended malaria treatment to advance elimination and reduce spread of artemisinin resistance

This drug has been available for more than 70 years and millions of doses have been administered over the years, but safety outcomes have not been well documented.

The WHO changed its guidelines to lower the dosage of primaquine in 2012, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. However, uptake of the recommendation has been slow due to safety concerns among those with G6PD deficiency. G6PD deficiency is an inherited enzyme deficiency that is particularly common in some malaria endemic areas that makes red blood cells more likely to break down.

Researchers performed a systematic review and an individual patient data (IPD) meta-analysis of single dose (SD) primaquine studies for Plasmodium falciparum malaria with the aim of establishing the safety of SD primaquine, improving uptake and potentially setting guidelines for the implementation of weight or age-based dosing bands. The data included 20 studies of 6,406 participants, of which over 80% had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine on haemoglobin concentrations (a measure for anaemia) in G6PD normal participants, and only a small effect on haemoglobin among the 194 G6PD-deficient African participants given a 0.25 mg/kg primaquine target dose. The authors said the results could now reassure national malaria control programmes that were considering the use of SD primaquine to advance malaria elimination or reduce the spread of artemisinin resistance.

Dr Elizabeth Allen, WWARN senior researcher based at the University of Cape Town, explained: "In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. Serious adverse haematological events after primaquine were few (0.3%) and transitory."

Dr Ingrid Chen from the University of California San Francisco, added: "Single low dose primaquine has a small to no effect on the risk of anaemia, which is common in malaria-endemic areas. However, we saw that recovery from anaemia took longer in young children and those presenting with anaemia or a high malaria parasite burden."

This research follows an earlier paper which analysed the efficacy of single-dose primaquine with artemisinin combination therapy (ACT) on P. falciparum gametocytes and transmission, which was published in the Journal of Infectious Diseases.

Dr Kasia Stepniewska, head statistician at WWARN, said: "These two studies show how combining all available individual patient data among patients given a range of single doses of primaquine can be used to optimise treatment guidelines and dosage recommendations. They confirm the WHO recommended single target dose of 0.25mg/kg."

National malaria control programs considering the use of SD primaquine can apply our findings which, when combined with results from the studies cited above, suggest that a single primaquine target dose of 0.25 mg/kg is generally safe and well tolerated when given together with an ACT. When rolling out this drug in programmatic settings, the detection of anaemia in young children, particularly those with G6PD deficiency, can be monitored for more data in this area is needed.

Read the full paper, Safety of single dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data.

Learn more about the study group

About WWARN

Since 2009, the WorldWide Antimalarial Research Network (WWARN) has generated innovative tools and reliable evidence to inform the malaria community on the factors affecting the efficacy of antimalarial medicines. In the field of poverty-related infectious diseases, data are scarce and scattered across institutions around the world. WWARN collates and standardises anonymised individual patient data (IPD) from many trials and studies conducted across the endemic regions so that they can then be harmonised and analysed as a single dataset, increasing the statistical power needed to answer key questions in malaria research.

WWARN's repository holds over 200k IPD and shares the resulting evidence widely to inform both policymakers and future researchers globally to continually advance knowledge and build capacity for evidence-based practice. Find out more at info@wwarn.org