Resistance to therapies for infection by Plasmodium vivax

Abstract

The gravity of the threat posed by vivax malaria to public health has been poorly appreciated. The widely held misperception of Plasmodium vivax as being relatively infrequent, benign, and easily treated explains its nearly complete neglect across the range of biological and clinical research. Recent evidence suggests a far higher and more-severe disease burden imposed by increasingly drug-resistant parasites. The two frontline therapies against vivax malaria, chloroquine and primaquine, may be failing. Despite 60 years of nearly continuous use of these drugs, their respective mechanisms of activity, resistance, and toxicity remain unknown. Although standardized means of assessing therapeutic efficacy against blood and liver stages have not been developed, this review examines the provisional in vivo, ex vivo, and animal model systems for doing so. The rationale, design, and interpretation of clinical trials of therapies for vivax malaria are discussed in the context of the nuance and ambiguity imposed by the hypnozoite. Fielding new drug therapies against real-world vivax malaria may require a reworking of the strategic framework of drug development, namely, the conception, testing, and evaluation of sets of drugs designed for the cure of both blood and liver asexual stages as well as the sexual blood stages within a single therapeutic regimen.

FIG. 1.

Biological limits of the global distribution of P. vivax based on temperature, humidity, aridity, and contemporary reports of malaria risk. (Courtesy of Carlos Guerra, Malaria Atlas Project, Oxford University, United Kingdom.)

FIG. 2.

Compartments of antimalarial activity shown within the life cycle of P. vivax. At left, a mosquito ingests infectious gametocytes, which become infectious sporozoites. This sporogonic arm of the cycle may be attacked with drugs called sporontocides. Sporozoites invade the liver and become either dividing tissue schizonts or a dormant hypnozoite that later becomes another dividing tissue schizont. This arm of the cycle may be attacked with tissue schizontocides and hypnozoitocides. The tissue schizonts release merozoites into the blood, and these infect red blood cells and commence growth into trophozoites, dividing and producing mature schizonts full of merozoites that are capable of invading still more red blood cells. This arm of the cycle, which is responsible for clinical malaria, can be attacked with blood schizontocides. Some merozoites from the liver that invade red blood cells do not become asexual blood schizonts but instead differentiate into male and female sexual forms called gametocytes. The infectiousness of gametocytes to mosquitoes may be attacked with drugs called gametocytocides. P.e., pre-erythrocytic. (Courtesy of Wallace Peters and Andrea Darlow.)

FIG. 3.

Deterioration of chloroquine (CQ) efficacy between 1945 (green line) and 1995 (red line) among tropical Asian strains of P. vivax relative to natural relapse of the same strains following quinine (QN) therapy (blue line). The suppression of relapse by chloroquine in 1945 is due to lingering levels of drug in blood up to day 35, and the 1995 data suggest not only failure to suppress relapse but also failure to clear primary asexual parasitemia. Data were derived from various sources (12, 18, 47, 210, 239).

FIG. 4.

Plot of the cumulative incidence of recurrent parasitemia after chloroquine therapy of vivax malaria in western Indonesian Borneo (167) and eastern Indonesian New Guinea (11).

FIG. 5.

Distribution of confirmed resistance to chloroquine in P. vivax.

FIG. 6.

Chemical structures of chloroquine, pamaquine (plasmoquin), mepacrine (atabrine), and primaquine.