An antimalarial drug that does nothing to help patients’ symptoms may yet be the key to stopping malaria. Dr Chi Eziefula, a Wellcome Trust Clinical Fellow, explains the potential significance of her research recently published in the Lancet Infectious Diseases.
A single dose of primaquine can stop the falciparum malaria parasite being transmitted from humans to mosquitoes. The drug has no effect on the parasite stage that causes illness and death in humans, so has no role in treating malaria, but it clears the transmission stage of the parasite from the bloodstream and, since the parasite is then unable to leave the body, it cannot spread to mosquitoes and from them to other people. For decades, therefore, primaquine has been recommended by the World Health Organization (WHO) to be given in combination with standard antimalarial treatment, with the aim of eliminating this deadly parasite.
However, only a small number of countries include primaquine in their national malaria treatment policy. Primaquine has been available since the 1940s, it is low-cost, and it is the only drug widely available that effectively blocks malaria transmission. Why then, given the WHO recommendations, is it not used everywhere to block global malaria transmission?
The reason is that, in some people, primaquine causes destruction of red cells in the bloodstream, resulting in anaemia, which in some cases can be severe and damage the kidneys. This only happens in people with a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD). This deficiency is the result of a gene defect which is common in areas with a high burden of malaria, and there is a lack of simple, affordable tests to diagnose it. Therefore, rather than risk harming people who might have an undiagnosed G6PD deficiency, primaquine is rarely used.
The dose of primaquine recommended by the WHO was based on data published by Alf Alving in 1960 from an experiment in just one individual. His experiment suggested that the effect of primaquine in G6PD deficiency may be dose-related. Fascinated by the distinct lack of dose-finding studies on this potentially useful drug, my colleagues and I investigated whether lower doses of primaquine would still stop malaria parasite transmission. Our hope was that we might find a lower dose that could be safely given to people with G6PD deficiency.
Our trial was designed to test whether lower doses of primaquine were as good at clearing the transmission stage of the parasite as the standard WHO dose of 0.75mg/kg in children in Uganda. We tested these lower doses in children with malaria and found that a dose of 0.4mg/kg of primaquine was no worse than the standard 0.75mg/kg dose. As a safety precaution, only children with normal G6PD levels were included in this trial, and we found that all doses were safe for them; in particular, there was no significant difference in levels of anaemia in the different dose treatment arms.
This raises hope that low-dose primaquine might be deployable more widely to block malaria transmission. However, reflecting on these findings, we are several steps away from the prospect of using primaquine universally in malaria-endemic areas. We need to know now whether lower doses of primaquine are safe in people with G6PD deficiency, bearing in mind that the degree of G6PD deficiency varies greatly geographically. We also need to know how best to use primaquine to block malaria at the population level. For example, what proportion of the infected population needs to be treated, and how often, to reduce the parasite burden, and what are the ethical issues involved in giving a drug at large scale to achieve this?
It is estimated that 3.3 billion people are at risk of malaria infection globally. Annually 660 000 people die of malaria and 90% of these deaths are in Africa in children aged less than 5 years. Encouragingly, these figures represent a substantial improvement over the last decade. Sustained malaria control efforts have meant that several countries are on the brink of malaria elimination. To make elimination a reality we need to focus on tools that specifically target malaria transmission. This is even more urgent now in the context of the threat of drug-resistant malaria that is emerging in Southeast Asia.
Eziefula AC et al (2013). Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial. The Lancet Infectious Diseases PMID: 24239324
Image credits: Chi Eziefula / Andrea Conroy (Uganda); The Wellcome Trust courtesy of RA Shooter, Wellcome Images (gametocyte).