What is the aim of this review?

Graves PM, Choi L, Gelband H, Garner P

To assess the effects of adding a single dose of primaquine (PQ) to treatment for falciparum malaria to reduce disease transmission. This Cochrane Review update includes 25 controlled trials. The date of latest search was 21 July 2017.

Key messages

A single low dose of PQ, at 0.25 mg/kg, which the World Health Organization (WHO) recommends adding to artemisinin-based combination therapy for malaria, reduces infectiousness (transmission from people to mosquitoes). In the trials, the percentage of people who infected mosquitoes three to four days after treatment was reduced from 14% to 2%, with a smaller effect at day 8, from 4% to 1%, with no evidence of harm.

What was studied in the review

PQ kills gametocytes (malaria transmission stages) of the falciparum malaria parasite. Gametocytes infect mosquitoes during a bite, thus perpetuating transmission. There is concern that PQ may cause red blood cells to burst (haemolysis) in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically-determined condition common in many malaria-endemic settings, which can lead to anaemia. Recognizing concerns about the risk of haemolysis, the WHO reduced the recommended PQ dose from 0.75 mg/kg to 0.25 mg/kg in 2012.

Ideally, this approach would be tested by randomly assigning villages to standard malaria treatment, or standard treatment plus a low dose of PQ, then measuring the effect on malaria over time but this would be difficult and expensive. So, indirect indicators are used to shed light on effectiveness, including feeding studies, in which mosquitoes are allowed to feed on people (or their blood), comparing those who were assigned PQ with those who were not. Alternatively, researchers may simply monitor the presence (prevalence), number (density), and duration (time of persistence) of gametocytes in the blood of people after different treatments, assuming that gametocytes are viable irrespective of exposure to PQ.

What the research says

The 25 included trials span several decades and include a variety of treatments and PQ doses. Related to safety assessment, some trials tested participants for G6PD activity. Other trials reported results based on their G6PD status, others did not test (or did not say whether they did), and others tested and excluded people with G6PD deficiency.

There were no ideal community-level studies that would answer the question directly.

Five feeding trials with multiple arms included three low-dose, three medium-dose, and two high-dose comparisons, showing a markedly reduced proportion of people infectious who received PQ in trials with any events. Two trials using older malaria treatments and high dose PQ had similar results.

The other trials focused on indirect measures of potential infectiousness of humans to mosquitoes. In these trials, PQ shortened the period of potential infectiousness, with a lower prevalence and density of gametocytes up to day 8 after treatment. The effect was similar at all PQ dose levels.

Few serious haemolytic events occurred in these trials, but PQ did affect non-serious haemoglobin measures, even at low doses.

What are the main results of the review?

A single low dose of PQ added to an artemisinin regimen for malaria reduces infectiousness to mosquitoes and is relatively safe for most people.

PQ at WHO-recommended dose reduces infectiousness to mosquitoes on day 3-4 and day 8 with no evidence of harm. It is unclear whether this reduction would materially reduce malaria transmission in communities.

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