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Primaquine, the only tool in our drug toolbox for preventing relapse of Plasmodium vivax or P. ovale malaria, may be the most enigmatic of the most commonly prescribed drugs today. Despite more than 50 years of continuous use by millions of people each year, we do not understand how it works. Its complex metabolism generates a dozen known metabolites, and none of these has been definitively linked either to its potent activity against hypnozoites or to its hemolytic toxicity to people having an inborn deficiency of glucose-6-phosphate dehydrogenase.
The drug is a poster child for neglect of basic and applied research bearing directly upon one of the most prevalent parasitic infections of the tropics.1 How many common infections in the developed world have only a single therapy available, and one that has been around for more than 50 years? How many of those therapies have unknown mechanisms of activity? Even worse, is there any therapy prescribed against developed world infections that we do not know if the drug is actually working?
The current efficacy of primaquine against relapses by P. vivax malaria, proven more than 50 years ago in clinical trials, is almost completely unknown. The evaluation of the therapeutic efficacy of primaquine against relapse has long been in the "too hard to do box." And it is hard. Plasmodium vivax malaria presents daunting confounders, as well as logistical and ethical obstacles against evaluating drugs preventing relapse. Molecular markers to distinguish relapse from either reinfection or recrudescence provide only ambiguities. Chloroquine as a companion blood schizonticide may not be relied upon to clear the bloodstream of parasites where resistance to it occurs, and its lingering blood levels may effectively clear chloroquine-sensitive parasites emerging from primaquine-resistant relapses. Finally, a series of early clinical trials suggested primaquine might require chloroquine or quinine to achieve its potent killing of formed hypnozoites.2
There is no validated procedure for demonstrating resistance to primaquine, but it would look something like this: primaquine administered with quinine under direct supervision of subjects who must be followed for at least 60 days in areas where reinfection is highly unlikely. Moreover, the natural relapse rate for the area would have to be known beforehand, or, ideally, evaluated in randomized fashion in people receiving only quinine therapy.3 This approach, in my hands, consistently failed to clear ethical committees in Indonesia and the work was never done. Another approach, experimental challenge of human subjects, faces perhaps less daunting ethical challenges but imposes relatively huge costs.
Epidemiology offers another approach to examining the efficacy of primaquine. Twelve years ago in the American Journal of Tropical Medicine and Hygiene, Jelinek and others4 published a study of primaquine therapy among European travelers with P. vivax malaria. Their data showed a 12-fold higher risk of relapse after standard primaquine therapy among travelers who acquired their infections in New Guinea, and thus offered perhaps the first external validation of the notion that the primaquine-tolerant Chesson strain of P. vivax from New Guinea (isolated in 1944) may actually be representative of strains occurring on that island today.
In this issue of the journal, Goller and others5 report the results of a meta-analysis of 11 randomized clinical trials and 9 observational studies of primaquine therapy against relapse by P. vivax conducted over the past 17 years. They divided the studies geographically and demonstrate substantially higher risk of primaquine failure in Thailand compared with India or Brazil, but in any location the efficacy of standard primaquine therapy (total adult dose = 210 mg base) was approximately 80%. This finding offers perhaps the most substantial justification of the recent recommendation by the U.S. Centers for Disease Control and Prevention to adopt a total adult dose of 420 mg base as standard therapy against relapse.6 Moreover, their findings also offer substantiation of the sentiment among practitioners that the commonly prescribed total adult dose of primaquine (whether 210 or 420 mg) may be inadequate for people who weigh substantially more than 60 kg.7 Their findings offer a sound basis for the recent recommendation to administer a total dose of 6 mg/kg (30 mg base/day) for as long as the patient’s weight dictates dosing.8 This analysis, although not free of potential confounding factors, provides an all too rare glimpse at the performance of the only drug we have for preventing relapse of P. vivax malaria.
Disclosure: The author wishes to disclose that he has been a paid consultant to GlaxoSmithKline on the development of tafenoquine, the next generation of primaquine for antirelapse therapy. This statement appears in the interest of full disclosure and not because the author considers this to be a conflict of interest.
Author’s address: J. Kevin Baird, ALERTAsia Foundation, Jakarta, Indonesia, E-mail: kbaird{at}alertasia.org.
This article has been cited by other articles:
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  L. H. Chen, M. E. Wilson, and P. Schlagenhauf Controversies and Misconceptions in Malaria Chemoprophylaxis for Travelers JAMA, May 23, 2007; 297(20): 2251 - 2263. [Abstract] [Full Text] [PDF]
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