Radical Cure: The Case for Anti-Relapse Therapy Against All Malarias

Douglas et al [1] describe patency with Plasmodium vivax in the 63 days after treatment of malaria caused by Plasmodium falciparum in . 10,000 subjects in Thailand over a 14-year period who received 25 different therapies. Therapy for acute malaria aims at the asexual stages of the organism infecting blood. Among the many blood schizontocidal drugs that achieve this therapeutic effect, none eliminate dormant stages in the liver, which are known as hypnozoites. Regardless of the species being treated, if hypnozoites are present, relapse may occur in the absence of treatment with primaquine, which is the only registered hypnozoitocide. The patients evaluated by Douglas et al [1] did not receive hypnozoitocidal therapy for the simple reason that it is not indicated for falciparum malaria. Parasitemia with P. vivax occurred in 20%–51% of these patients, with that rate correlated to the rapidity of excretion of drugs administered against P. falciparum. Malaria manifests as many infections of distinct biological character, with susceptibility to distinct classes of drugs, and distinct clinical or epidemiological consequences [2]. Anopheline mosquitoes transmit all of the 5 species of the genus Plasmodium known to naturally infect humans. Each passes through a series of liver and blood stages of asexual development that massively expand the numbers of individual parasites. In a biological sense, that expansion aims solely at positioning male and female sexual forms (called gametocytes) where they can access the gut of feeding anopheline mosquitoes—the only site where these parasites execute the sexual recombination essential to their propagation. Humans simply represent a means for the plasmodia to traffic among their mosquito definitive hosts. Two species of plasmodia infecting humans hedge the probability that biting anophelines will be present to capitalize the relatively risky venture into blood. Among the infectious sporozoites of P. vivax and Plasmodium ovale introduced by biting anophelines, an unknown and variable fraction arrest development after invading human hepatocytes [3]. These clinically silent hypnozoites later commence development and emerge into the bloodstream to cause another round of malaria, which is termed a relapse. The probability, interval, and frequency of relapse in the absence of primaquine treatment vary geographically in a manner suggesting linkage to a high probability of a relative abundance of anophelines [4]. Only 30% of individuals with infection due to P. vivax from the temperate Korean peninsula, for example, experience relapse after 8 months and only once; whereas almost all individuals with infections due to P. vivax from the perpetually warm and wet climate of New Guinea experience relapse within 4 weeks and experience relapse >5 times. These climate-specific relapse behaviors persist among strains transferred to another hemisphere, and they thus appear to be genetically programmed [3, 4]. In Thailand, 60% of patients treated for acute vivax malaria with rapidly excreted blood schizontocides experienced relapse within 28 days after patency [5]. When slowly excreted blood schizontocides (eg, chloroquine or mefloquine) were applied, no relapses appeared by day 28, because drug lingering in blood killed the asexual blood stages emanating from activated hypnozoites. When drug levels slip below minimally effective concentrations, relapses may occur [6]. Received 13 December 2010; accepted 17 December 2010. Correspondence: J. Kevin Baird, PhD, Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No.69, Jakarta 10430 Indonesia (kbaird@eocru.org). Clinical Infectious Diseases 2011;52(5):621–623 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. 2011. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/ by-nc/2.5/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1058-4838/2011/525-0001$37.00 DOI: 10.1093/cid/ciq258