Predictors of relapse
Several different factors determine whether vivax or ovale malarias will relapse. The hypnozoite burden, geographic origin (i.e. “strain”), and degree of immunity are all important determinants. Liver stage immunity may affect hepatic schizont development and blood stage immunity suppresses the relapse parasitaemia to an extent that it is asymptomatic, subpatent, or both (13, 14). Although there is no evidence of acquired 8-aminoquinoline resistance in hypnozoites, parasites do differ in intrinsic susceptibility. For example, the long latencyP. vivax “strains” prevalent in temperate regions are more susceptible to 8-aminoquinolines than tropical frequent relapse strains, and P. vivax parasites in SE Asia and Oceania appear to be less susceptible (i.e. require a larger primaquine dosage) than other tropical “strains” (15).
From a therapeutic perspective exposure to the biologically active metabolites of the 8-aminoquinoline is the critical factor determining relapse prevention (radical cure) efficacy (16, 17). This exposure results from the total dose absorbed, and the degree of biotransformation. Patients with cytochrome P450 2D6 polymorphisms conferring reduced function have reduced production of primaquine’s bioactive metabolite(s) and correspondingly reduced radical curative efficacy (18,19). The oxidative activity of the 8-aminoquinoline treatment is also reflected in the intraerythrocytic concentrations of methaemoglobin. The association of methaemoglobinaemia with radical curative efficacy of 8-aminoquinolines is discussed.