A key article from the recent Malaria Journal supplement (previously discussed here) described the role of anti-malarial drugs in reducing malaria transmission (the actual title referred to eliminating malaria, going along with the issue’s theme, but the message really applies to any form of malaria control). The author of the paper is Dr. Nicholas White, an impressive malaria scientist and an authority on the treatment of malaria. Dr. White provides a comprehensive perspective of the biological, epidemiological, and pharmacological considerations needed for thinking about treatment and transmission reduction. Understandably, much of the focus is centered on gametocytes, the sexual stage of the parasite taken up by mosquitoes during blood meals, and some of the gaps in literature are noted.
Artemisnin combination therapies (ACTs) are now the first-line treatment in most countries. A benefit of ACTs is their activity against immature (but not fully developed) gametocytes. Theoretically, this will help reduce transmission by decreasing the gametocyte density and the probability a mosquito will ingest sexual stages of the parasite while feeding. However, the number of parasite carriers is more important to the spread of the disease in some areas than in others. In highly endemic settings, the size of the infectious reservoir is not a crucial determinant of transmission intensity. In low transmission settings, eliminating the carriage of gamteocytes is more important. For example, the introduction of ACTs has been associated with decreased malaria transmission in Thailand (Nosten et al. 2000, Lancet; but it is not clear whether the benefit was due to the partially gametocidal nature of ACTs or simply a switch to an efficacious drug).
Following this logic, and hoping to further reduce the number of gametocyte carriers (given the limitation of ACTs against mature forms), a few countries have opted to add primaquine to their treatment regimens. A single dose of primaquine is inexpensive and effective against all stages of gametocytes. While the logic appears sound, we unfortunately have little data regarding the safety and efficacy of doing so. Thus, a research agenda for the primaquine problem was clearly endorsed in the article:
The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection
My interest with primaquine and ACTs began in 2005 when I visited Guyana where single-dose primaquine was included with the artemether-lumefantrine combination. The colorful malaria control director Mr. Indal Rambajan told me WHO officials (it was unclear whether he was referring to country, regional, or headquarters staff) were at the time unhappy with his decision. I’ve since discussed the need for research on the addition of primaquine to ACTs with other malaria workers and am glad to see it mentioned in print, albeit briefly. The article could have benefited from a more in depth discussion on the challenges in determining how to answer the aforementioned question.
Measuring the efficacy of primaquine will not be simple because the end-point to determine needs to be malaria incidence. Several clinical trials have compared ACT alone versus ACT plus primaquine in reducing gametocytemia in patients (El-Sayed et al., Shekelage et al., 2007 PLOS One). The data from these trials is helpful, but not conclusive because their results are clinical (whether a patient has gametocytes or not) rather than population-level impact (whether malaria transmission has decreased). The two concepts are related, but not equal and the public health end-point is much harder to determine. Ideally, I think you would conduct a community intervention trial, where several villages are randomized, and measure changes in malaria incidence at baseline and over-time.
A safety risk exists because primaquine can induce hemolysis in patients with hemoglobinopathies – particularly G6PD deficiency. Testing all patients for G6PD deficiency prior to treatment is not feasible. In addition to the health risk posed to an individual patient, a high frequency of side effects or a few dramatic reactions could erode the public’s confidence in the ACT (as it will not be apparent which component of the treatment was responsible) and the control program at large. Fortunately, it appears the provision of single dose primaquine is relatively benign even in G6PD deficient individuals but we need more data.
Addressing problems such as whether the addition of primaquine to ACT is safe and effective can impact health delivery today. Such research is not easy, on the cutting edge of methodology, or well-funded and that’s too bad since we really need to know. It makes one wonder, “Why haven’t we done this? Which institutions are supposed to provide leadership in identifying and setting research priorities?” Good question.