Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries

Abstract

Primaquine is the only available antimalarial drug that kills dormant liver stages of Plasmodium vivax and Plasmodium ovale malarias and therefore prevents their relapse ('radical cure'). It is also the only generally available antimalarial that rapidly sterilises mature P. falciparum gametocytes. Radical cure requires extended courses of primaquine (usually 14 days; total dose 3.5-7 mg/kg), whereas transmissibility reduction in falciparum malaria requires a single dose (formerly 0.75 mg/kg, now a single low dose [SLD] of 0.25 mg/kg is recommended). The main adverse effect of primaquine is dose-dependent haemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy. X-linked mutations conferring varying degrees of G6PD deficiency are prevalent throughout malaria-endemic regions. Phenotypic screening tests usually detect <30% of normal G6PD activity, identifying nearly all male hemizygotes and female homozygotes and some heterozygotes. Unfortunately, G6PD deficiency screening is usually unavailable at point of care, and, as a consequence, radical cure is greatly underused. Both haemolytic risk (determined by the prevalence and severity of G6PD deficiency polymorphisms) and relapse rates vary, so there has been considerable uncertainty in both policies and practices related to G6PD deficiency testing and use of primaquine for radical cure. Review of available information on the prevalence and severity of G6PD variants together with countries' policies for the use of primaquine and G6PD deficiency testing confirms a wide range of practices. There remains lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens. Despite substantially lower haemolytic risks, implementation of SLD primaquine as a P. falciparum gametocytocide also varies. In Africa, a few countries have recently adopted SLD primaquine, yet many with areas of low seasonal transmission do not use primaquine as an antimalarial at all. Most countries that recommended the higher 0.75 mg/kg single primaquine dose for falciparum malaria (e.g., most countries in the Americas) have not changed their recommendation. Some vivax malaria-endemic countries where G6PD deficiency testing is generally unavailable have adopted the once-weekly radical cure regimen (0.75 mg/kg/week for 8 weeks), known to be safer in less severe G6PD deficiency variants. There is substantial room for improvement in radical cure policies and practices.

Fig 1. Single-dose primaquine policies in African countries.

Most countries do not include primaquine in their malaria treatment policies (shown in red). Countries that use single low dose primaquine (SLD of 0.25 mg/kg, for most countries only very recently adopted) as policy for falciparum treatment are shown in dark blue. For specific details on countries’ policies and implementation and/or upcoming modifications, refer to Table 4. The map was created using an online tool [87].

Fig 2. Radical cure primaquine policies in African countries.

Most countries do not include primaquine in their malaria treatment policies or have no policy (shown in red). Countries that have radical cure for vivax malaria (0.25 mg/kg/day for 14 days) as policy are shown in blue; dark blue: G6PD deficiency testing required prior to primaquine treatment, light blue: testing not required. Table 4 provides specific details on countries’ policies and implementation and/or upcoming modifications.

Fig 3. Single-dose primaquine policies in Asia, Oceania, and Middle East countries.

All countries except for Papua New Guinea and both Koreas (which have no falciparum malaria) have policies to use primaquine as single dose for falciparum malaria. Red indicates unobserved therapy policy, and dark blue directly observed therapy (DOT). Implementation of primaquine policies and exact dose (SLD of 0.25 mg/kg or 0.75 mg/kg) vary between countries. Table 5 provides details on countries’ policies implementation and/or upcoming modifications.

Fig 4. Radical cure primaquine policies in Asia, Oceania, and Middle East countries.

All countries have policies to use primaquine for radical cure of vivax malaria, mainly as 0.25 mg/kg/day for 14 days, with some countries using the weekly regimen (0.75 mg/kg once weekly for 8 weeks). Colours indicate requirement for G6PD deficiency testing before primaquine administration: blue—G6PD deficiency testing required, red—testing not required, with light red or blue for unobserved therapy and dark red or blue for directly observed therapy (DOT). Implementation of these policies, regimens used, and requirement for G6PD deficiency testing vary between countries. Table 5 provides details on countries’ policies, implementation, and/or upcoming modifications.

Fig 5. Single dose primaquine policies in American countries.

All countries use single dose primaquine (mostly 0.75 mg/kg) as policy for falciparum treatment (shown in blue) except for French Guiana (red), with no G6PD deficiency testing required before primaquine administration. Table 6 provides details on countries’ policies and implementation and/or upcoming modifications.

Fig 6. Radical cure primaquine policies in American countries.

None of the countries requires G6PD deficiency testing before primaquine administration except French Guiana. Colours indicate the different regimens for radical cure of vivax malaria: blue—14 days, red—7 days, with light red or blue for unobserved therapy and dark red or blue for directly observed therapy (DOT). Table 6 provides specific details on countries’ policies and implementation and/or upcoming modifications.