Drug resistant Plasmodium vivax malaria

The recognition of resistance to proguanil, pyrimethamine and, later, chloroquine in some strains of Plasmodium falciparum, over 40 years ago, signalled the ability of these malarial parasites to survive anti-malarial chemotherapy by the selection of resistant mutants.Since then, clinicians and biologists have defined resistance from different perspectives, the former focusing on the host and the latter on the parasite.In the clinical tradition, such resistance in malarial organisms is defined as 'the ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to, or higher, than those usually recommended, but within the limits of tolerance of the subject'.1 The definition is usually applied to the drug susceptibility of asexual blood forms, presumably because it is this stage of the life cycle that induces the clinical symptoms of malaria.Because of the variable spectrum of in-vitro response to therapy observed in chloroquine-resistant strains of P. falciparum, the World Health Organization (WHO) proposed an arbitary system of grading.1,2 It involves the administration of a standard amount of chloroquine (25 mg base/kg over a period of 3 days) followed by observation during the next 28 days.Response is then classified as either: (i) RI: disappearance of asexual parasites by day 7 after the start of treatment with recrudescence within the 28 day observation period, providing there is no opportunity for the individual to be bitten by infected mosquitoes during the first 3 weeks of the test; (ii) RII: reduction of parasitaemia to 25% of the initial level within the first 48 h of treatment, but without subsequent clearance of the parasite; or (iii) RIII: reduction of parasitaemia by 75% or an increase in parasitaemia during the first 48 h of treatment, without subsequent clearance.This in-vivo elucidation of drug resistance has a number of disadvantages including variability in individual response to anti-malarial treatment caused by differing rates of absorption and excretion, together with the effects of acquired immunity from previous exposure.Moreover, in endemic areas where continuous malarial transmission occurs, it is often difficult to distinguish between re-infection and persistence, i.e. to distinguish RI strains from sensitive strains.These problems associated with clinical (in-vivo) determination of drug susceptibility led to the development of simple in-vitro tests which can be performed using single specimens of venous blood.3,4 Such tests essentially measure the extent to which maturation of ring forms to trophozoites is inhibited, after incubation of parasitized blood with various concentrations of anti-malarial drug for 24 h.Microtechniques for this methodology are now widely employed.While chloroquine resistance was described in P. falciparum almost 40 years ago and has now spread across the globe, the other three species of human malaria, especially the most common, Plasmodium vivax, have remained sensitive to this valuable anti-malarial agent.Chloroquine is central to both therapy and prophylaxis of vivax malaria, particularly in developing countries, by virtue of its low cost and safety; moreover, it is extremely efficacious with vivax parasites being suppressed by chloroquine concentrations in serum and plasma of 30 ng/mL and 15 ng/mL, 6 respectively.Thus, the initial descriptions of chloroquineresistant vivax malaria in 1989 from Papua New Guinea 7,8 had significant and worrying implications.Since that time, a number of reports of reduced sensitivity to chloroquine in P. vivax have followed, suggesting that this form of resistance is not uncommon in Indonesia 9,10 and Papua New Guinea 11-13 although the true extent of spread in these countries remains unknown.Sporadic reports have also occurred from Myanmar, 14 Thailand, 15 Borneo, 16 India 17,18 and Brazil.19 However, such studies are confounded by the tendency of vivax malaria to relapse from liver hypnozoites, many weeks to years after initial infection.To provide radical cure of P. vivax malaria, treatment must be prescribed to eliminate the liver stages of the parasite, otherwise intermittent relapses with clinical symptoms will continue.The interval between primary infection and relapse varies with differing strains of P. vivax-the 749