Treatment and Management of Asymptomatic Malaria
Drug therapy has often been linked to the development of gametocytaemia, as environmental pressure caused by the targeted destruction of the asexual stage parasites stimulates the production sexual stage parasites (reviewed in ). Though this may be true, there is also mounting evidence, found in studies like Bousema et al., which suggests that the production of gametocytes may be unrelated to drug therapy. In this study, Bousema et al. investigated gametocytaemia in a cohort of untreated, asymptomatic children (less than five years old). This study reported that despite a lack of treatment, a significant proportion of these children had quantifiable gametocytes. Therefore, asymptomatic individuals have the potential to develop gametocytes even in the absence of drug therapy and this pool may serve as reservoir of disease transmission.
Since the transmission of malaria parasites from humans to mosquitoes requires the presence of gametocytes, any strategy that interferes with the development or persistence of gametocytes should help to interrupt transmission. In most malaria endemic areas, the majority of parasite carriers are asymptomatic and these carriers typically do not seek medical treatment. Therefore, asymptomatic individuals carrying gametocytes remain available as a reservoir for transmission by mosquitoes, contributing to the persistence of malaria transmission within local populations.
The identification and management of asymptomatic carriers has become a new and increasingly important challenge for malaria control programs. One challenge, in particular, is to reform the development of novel anti-malarial drugs to include those that explicitly target transmissible sexual stages. At the present, the majority of anti-malarial drug treatments on the market target the asexual blood stage of P. falciparum. Treatment regimens containing artemisinin and/or its derivatives are reported to lower gametocyte carriage, and reduced infectivity among treated individuals. Artemisinin combination therapy (ACT), which is advocated as the first-line of anti-malarial treatment, and has been reported to be efficient in reducing even submicroscopic levels of gametocytes. Intermittent preventive treatment (IPT), the administration of a full course of an anti-malarial treatment to a population at risk at specified time points regardless of the infection status of individuals, has been proposed as a method of treatment for asymptomatic individuals to reduce transmission of disease. Artemether-lumefantrine, an ACT drug currently available on the market, has been suggested as a candidate for IPT treatment of asymptomatic carriers. The short half-life of lumefantrine makes it an ideal treatment strategy because of concerns for developing resistance to ACT. Pharmacokinetic determinants of resistance selection indicate that this drug has a considerably shorter "window of selection," when compared to other artemisinin companion drugs, such as mefloquine.
Apart from selection for drug resistance, there is an additional risk of the persistence of submicroscopic gametocytes even after treatment, allowing for post-treatment malaria transmission. Primaquine, a widely used drug for the treatment of P. vivax malaria, actively clears submicroscopic P. falciparum gametocytes, but the possible haemolytic effects of primaquine in relation to G6PD deficiencies must be considered before marketing this drug for the treatment of gametocytes. Reports indicate that artesunate (a derivative of artemisinin) may predominantly inhibit gametocyte development, while primaquine may accelerate its clearance. However primaquine, when given in combination with sulphadoxine-pyrimethamine and artesunate, was found to be both safe and highly efficient in clearing P. falciparum gametocytes and asexual parasites detected by microscopy as well as submicroscopic gametocytes. As part of surveillance and control strategies for malaria, the systematic diagnosis or identification and treatment of asymptomatic carriers could reduce the pool of parasites available for the infection of mosquitoes.
The transmissibility of submicroscopic parasites within asymptomatic malaria infections may help to drive the persistence of malaria within endemic regions. The use of antimalarial drug treatment (particularly ACTs), in combination with insecticide treated nets (ITNs), long-lasting insecticidal nets (LLINs), and indoor residual spraying (IRS) is perhaps the most aggressive method for reducing the malaria burden in endemic regions. A recent study by Aregawi et al. using ACT in combination with ITNs/LLINs and IRS demonstrated a 76% reduction in slide positivity for all age groups over a 4 year intensive intervention effort. Singling out the mosquito vector by undertaking comprehensive entomological and ecological studies is necessary for fully understanding malaria transmission dynamics, i.e. the identification of vector breeding and resting sites, the impact of climate change and temperature variation on vector survival and capacity, and also insecticide resistance.