The enigma of the hypnozoite
P. cynomolgi malaria liver forms
While Plasmodium falciparum is the most deadly species of malaria parasite, Plasmodium vivax has proven the most elusive to cure. The P. vivax parasite has an uncanny ability to remain dormant in the liver of its host in a form known as the hypnozoite. This liver-stage form can reactivate any time between 3 weeks and several years – leaving its victims vulnerable to relapse into the feverish symptoms of malaria at any time and without warning.
These repeated attacks are rarely fatal; nonetheless, P. vivax poses a considerable public health problem – accounting for between 80 to 300 million clinical cases every year.1 Although P. vivax transmission has been reported to occur in Africa, it is widely endemic in South and Southeast Asia, and Central and South America where, in 2009, 2.85 billion people were at risk.2
The only approved medicine able to eliminate hypnozoites and thus provide a radical cure for P. vivax is primaquine – an 8-aminoquinoline deployed against P. vivax malaria in the Korean War by the US Army.3 Primaquine, however, has two significant weak points: First, it must be taken daily for 14 days to be effective. Compliance to such a regimen is often unachievable in reality, as patients do not suffer with symptoms for most of this time. Second, in patients who are deficient in the enzyme glucose 6-phospate 1-dehydrogenase (G6PD), primaquine can cause the blood cells to breakdown leading to anaemia. This means that patients already anaemic due to the malaria infection will suffer further – potentially with fatal consequences. Unfortunately, G6PD-deficiency is not a rare occurrence; it can be present in more than 25% of the population in some disease-endemic countries.4
MMV is actively looking for new molecules that will provide a radical cure for P. vivax malaria and therefore put an end to the relapse. A next-generation 8-aminoquinoline, tafenoquine, originally also developed by the US Army (the Walter Reed Army Institute of Research), is our lead contender and is currently in clinical development with MMV partner GlaxoSmithKline. Studies show tafenoquine could be taken as a 1-day treatment course for liver-stage malaria – a significant improvement on primaquine’s 14-day course. As a member of the same chemical family as primaquine, however, the safety of tafenoquine in G6PD-deficient patients must be assessed. Trials are underway to do just that, with a view to entering pivotal clinical trials in 2011. Nonetheless, the need remains for new classes of anti-relapse drugs without the safety concern in G6PD-deficient patients.
Historically, research to discover such new classes of medicines has been hampered by the lack of a suitable model to mimic the hypnozoite, on which we could test new compounds. Recently, in collaboration with MMV and other partners, scientists at the Dutch primate centre have identified liver forms of the monkey parasite P. cynomolgi, believed to be hypnozoites. This breakthrough discovery has provided us with a model in which we can now test a variety of compounds – bringing us a step closer to the next radical cure of vivax malaria and understanding the enigma of the hypnozoite.
1 Mueller I. Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. Lancet Infect Dis. 9(9):555-66 (2009).
2 Guerra CA et al. The International Limits and Population at Risk of Plasmodium vivax Transmission in 2009. PLoS Negl Trop Dis. 4(8):e774 (2010).
3 Wells TN et al. Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trends Parasitol. 26(3):145-51 (2010)
4 Nkhoma ET et al. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: A
systematic review and meta-analysis. Blood Cells Mol Dis. 42(3):267-78. (2009).
