Rationale:

• Primaquine is the only drug available to eliminate hypnozoites, which are latent liver forms of the parasite that can lead to relapse of malaria months or years after primary infection.
• Moderate or low-normal levels of G6PD are not absolute contraindications to primaquine use.
• Primaquine-induced hemolysis has also been associated with methemoglobin reductase deficiency.

Evidence:

• Primaquine dose is now recommended to be 0.5 mg base/kg·d for 14 days because of treatment failures at the previously recommended lower dose. For example, 43% of 60 U.S. soldiers receiving a standard dose of primaquine (15 mg base daily for 14 days) after their initial episode of P. vivax malaria subsequently relapsed (134).
• A randomized, controlled trial in India showed that a standard 14-day primaquine regimen decreased P. vivax relapses from 11.7% (no treatment) to 0% (at least 60 patients in each group) (135).
• Persons with less severe forms of G6PD deficiency may receive the standard primaquine dose, but significant decreases in hematocrit levels may still be observed. In one study involving 22 Thai male patients with P. vivax malaria and the Mahidol variant of G6PD deficiency, primaquine therapy resulted in decreases in mean hematocrit levels from 34.9 to 26.7 at day 7 (136).

Comments:

• Primaquine causes some level of methemoglobinemia in nearly all persons treated, but this is rarely clinically significant (bluish discoloration of mucous membranes may be observed).
• Many infections acquired in Southeast Asia show resistance to standard primaquine doses (137; 138; 139; 140); thus, a regimen of 0.5 mg base/kg·d for 14 days has been recommended for P. vivax infections acquired in Papua, New Guinea; Solomon Islands; Vanuatu; and parts of Indonesia (141).
• Although shorter courses of primaquine therapy would increase patient compliance, several studies have shown that 5-day courses are ineffective in preventing relapse (135; 142).
• Tafenoquine, a primaquine analogue, is currently undergoing advanced clinical testing (143). Tafenoquine is more potent than primaquine and its longer half-life allows for weekly dosing, but it still has the same contraindications as primaquine.