Practical info Primaquine for preventing relapse To achieve radical cure (cure and prevention of relapse), relapses originating from liver hypnozoites must be prevented by giving primaquine. The frequency and pattern of relapses varies geographically, with relapse rates generally ranging from 8% to 80%. Temperate long-latency P. vivax strains are still prevalent in many areas. Recent evidence suggests that, in endemic areas where people are inoculated frequently with P. vivax, a significant proportion of the population harbours dormant but “activatable” hypnozoites. The exact mechanism of activation of dormant hypnozoites is unclear. There is evidence that systemic parasitic and bacterial infections, but not viral infections, can activate P. vivax hypnozoites, which explains why P. vivax commonly follows P. falciparum infections in endemic areas where both parasites are prevalent. Thus, the radical curative efficacy of primaquine must be set against the prevalent relapse frequency and the likely burden of “activatable” hypnozoites. Experimental studies on vivax malaria and the relapsing simian malaria P. cynomolgi suggest that the total dose of 8-aminoquinoline given is the main determinant of radical curative efficacy. In most therapeutic assessments, primaquine has been given for 14 days. Total doses of 3.5 mg base/kg bw (0.25 mg/kg bw per day) are required for temperate strains and 7 mg base/kg bw (0.5 mg/kg bw per day) is needed for the tropical, frequent-relapsing P. vivax prevalent in East Asia and Oceania. Primaquine causes doselimiting abdominal discomfort when taken on an empty stomach; it should always be taken with food. Use of primaquine to prevent relapse in high-transmission settings was not recommended previously, as the risk for new infections was considered to outweigh any benefits of preventing relapse. This may have been based on underestimates of the morbidity and mortality associated with multiple relapses, particularly in young children. Given the benefits of preventing relapse and in the light of changing epidemiology worldwide and more aggressive targets for malaria control and elimination, the group now recommends that primaquine be used in all settings. Primaquine formulation: If available, administer scored tablets containing 7.5 or 15 mg of primaquine. Smaller-dose tablets containing 2.5 and 5 mg base are available in some areas and facilitate accurate dosing in children. When scored tablets are not available, 5 mg tablets can be used. Therapeutic dose: 0.25–0.5 mg/kg bw per day primaquine once a day for 14 days. Use of primaquine to prevent relapse in high-transmission settings was not recommended previously, as the risk for new infections was considered to outweigh any benefits of preventing relapse. This may have been based on underestimates of the morbidity and mortality associated with multiple relapses, particularly in young children. Given the benefits of preventing relapse and in the light of changing epidemiology worldwide and more aggressive targets for malaria control and elimination, the group now recommends that primaquine be used in all settings.

Other considerations In the absence of evidence to recommend alternatives, the guideline development group considers 0.75 mg/kg bw primaquine given once weekly for 8 weeks to be the safest regimen for people with mild-to-moderate G6PD deficiency. Remarks The widely used primaquine regimen of 0.25 mg base/kg bw per day for 14 days is based on studies of long-latency Korean P. vivax. In South-East Asia and Oceania, P. vivax relapses at 3-week intervals and is more resistant to primaquine. Consequently, higher doses of primaquine have been used (0.375–0.5 mg base/kg bw per day), but there are few data from comparative trials. Primaquine is contraindicated in pregnancy and lactation < 6 months post-partum, unless the infant has been tested for G6PD deficiency. It could be given to women who have delivered and ceased breastfeeding.