Role of primaquine in malaria control and elimination in French-speaking Africa

Abstract

Primaquine, an 8-aminoquinoline, is a relatively unknown and underutilized drug in French-speaking African countries. It acts against the liver stage parasites of all human malaria species, asexual blood stages of Plasmodium vivax and, to a lesser degree, Plasmodium falciparum; P. falciparum mature gametocytes, and P. vivax and Plasmodium ovale hypnozoites. Gastrointestinal disturbances are its most common side effects. The clinical utility of primaquine is limited due to its hematological side effects in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and other contraindications (pregnant woman, breastfeeding woman, infants less than 6 months old). In the light of the recent recommendations of the World Health Organization (WHO), we propose to examine how primaquine can be used in French-speaking Africa to improve malaria control and move towards malaria elimination. Two indications supported by the WHO are of relevance in Africa. First, artemisinin-based combination therapies and primaquine given as a single low dose (0.25 mg base/kg) are effective to kill asexual and sexual parasites of P. falciparum, are well-tolerated, and have very little risk even in mild to moderate G6PD-deficient patients. This strategy may be helpful to contain transmission in an area in Africa where P. falciparum malaria incidence has decreased considerably. There is an ethical concern in administering primaquine as a gametocytocide as it does not confer any direct benefit to the treated patient. However, the single low-dose primaquine is most likely associated with very low risk for adverse hematological effects, and WHO recommends its use even without prior G6PD testing. In our opinion, clinical studies including G6PD test should be conducted to assess the safety of low-dose primaquine in African patients. Second, primaquine is effective and necessary for radical treatment of P. vivax and P. ovale, but the standard 14-day treatment (0.25-0.5 mg base/kg/day) is not recommended in patients with G6PD deficiency. Prior G6PD testing is required before prescribing primaquine for radical treatment. The use of primaquine for radical treatment in patients without contraindications does not raise any major ethical problem since the probability of relapse in patients who do not receive anti-hypnozoite treatment can be relatively high and each relapse can cause or aggravate anemia, especially in children. In our opinion, patients with mild or moderate G6PD deficiency should not be treated with primaquine at present. Further clinical studies are necessary to define the role of this drug for radical treatment in G6PD-deficient African patients. Without primaquine, the eventual elimination of P. vivax and P. ovale malaria appears to be very difficult. Updated epidemiological data on G6PD, Duffy antigen, and the current distribution of and burden due to P. vivax and P. ovale are required for a rational use of primaquine in the African continent. Moreover, clinical studies on primaquine are required in Africa.