Management of relapsing Plasmodium vivax malaria

Abstract

Introduction: Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections. Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria. A review was conducted with publications in English, French, Portuguese and Spanish using the search terms 'P. vivax' and 'relapse'.

Areas covered: Hypnozoites causing relapses may be activated weeks or months after initial infection. Incidence and temporal patterns of relapse varies geographically. Relapses derive from parasites either genetically similar or different from the primary infection indicating that some derive from previous infections. Malaria illness itself may activate relapse. Primaquine is the only widely available treatment for radical cure. However, it is often not given because of uncertainty over the risks of primaquine induced haemolysis when G6PD deficiency testing is unavailable. Recommended dosing of primaquine for radical cure in East Asia and Oceania is 0.5 mg base/kg/day and elsewhere is 0.25 mg base/kg/day. Alternative treatments are under investigation. Expert commentary: Geographic heterogeneity in relapse patterns and chloroquine susceptibility of P. vivax, and G6PD deficiency epidemiology mean that radical treatment should be given much more than it is today. G6PD testing should be made widely available so primaquine can be given more safely.

Keywords: 8-aminoquinoline; Plasmodium vivax; Plasmodium vivax relapse; Plasmodium vivax treatment; anti-malarial efficacy; chloroquine; glucose-6-phosphate dehydrogenase deficiency; primaquine; radical cure; review.

Figure 1.

Estimates of the global distribution of P. vivax. API = (confirmed cases during 1 year/population under surveillance) x 1000. Although P. vivax is shown as occurring across Africa, it is rare west of Uganda in Southern and Eastern Africa, and south of Mauritania and Mali in West Africa.

Figure 2.

Proposed mechanism and sequence of Plasmodium vivax relapse activation in a malaria endemic area. In the example at the time of infection the individual already has hypnozoites of two different genotypes acquired from two previous inoculations which are latent in the liver (red and white circles). Half the newly acquired infection sporozoites (blue) develop into pre-erythrocytic schizonts and half become dormant as hypnozoites (blue circles) (this is the estimated proportions for tropical ‘strains’). Illness associated with the blood stage infection activates a low fraction of the hypnozoites. In this example one of each genotypes develops into preerythrocytic schizonts. By chance the progeny of one of the preexisting latent hypnozoites reach pyrogenic densities before the progeny of the recently inoculated hypnozoite (inset: ‘competition’). The consequent illness then suppresses further multiplication of the blood stage infection so that the progeny of the other two prerythrocytic schizonts may not reach transmissible densities. The ensuing illness activates some of the remaining hypnozoites (the same fraction as were activated initially) and relapses continue until either the number of hypnozoites is exhausted or some fail to be activated. If there are some hypnozoites which fail to be activated these may be activated by a subsequent malaria infection. Figure available (open access): Nicholas J. White. Determinants of relapse periodicity in Plasmodium vivax malaria. Malar J. 2011;10(1):297. (Full color available online)

Figure 3.

Pharmacodynamic responses in tropical vivax malaria. Parasitemias (shown in pink) in vivax malaria range up to 2% which corresponds to a total body burden of up to 10¹² parasites in an adult. After treatment parasite densities decline by factors of between 10³ and 10⁴ per asexual cycle. In this example the treatment is quinine which is relatively rapidly eliminated so there is little post treatment suppression of multiplication. Approximately two weeks after the acute illness (and after one week’s intrahepatic development) the hepatic schizonts (range illustrated here is between one and ten) derived from activated hypnozoites burst to liberate merozoites. Multiplication is unrestrained and patent parasitaemias are reached approximately one week later. For a recrudescent infection (dotted line) to predominate over a relapse, asexual parasite killing must be reduced substantially. (Full color available online)

Figure 4.

Geographic distribution of chloroquine resistant P. vivax. Yellow markers-case reports, Red markers->10% recurrence by day 28 (highly suggestive of resistance), Dark orange-recurrence is confirmed with chloroquine whole blood concentrations >100nM, Light orange->5% recurrence by day 28 (potential evidence of resistance). Map provided by personal communication with Professor Ric N Price. Full data available (open access): Price, Ric N., Lorenz von Seidlein, Neena Valecha, Francois Nosten, J. Kevin Baird, and Nicholas J. White. ‘Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis.’ The Lancet Infectious Diseases 14, no. 10 (2014): 982–991.

Figure 5.

Hemolysis in G6PD deficiency during primaquine radical cure (30 mg/day in African and Mediterranean variants and 15 mg/day in Viangchan and Mahidol variants). After an initial delay of 1–2 days the average haemoglobin falls reaching a nadir 5–6 days after starting treatment, but then it rises again despite continued drug administration as young red cells with higher intraerythrocytic concentrations of G6PD enter the circulation. In the severe Mediterranean type of deficiency there is marked hemolysis and treatment must be stopped. Individual responses vary widely and so dangerous hemolysis can occur even in so called ‘mild deficiency’ genotypes. Figure available (open access): Ashley EA, Recht J, White NJ. Primaquine: the risks and the benefits. Malar J. 2014;13(1):418. (Full color available online)