Description of the condition
Malaria is the most common and deadly parasitic infection. It causes an estimated 243,000,000 clinical episodes and 863,000 deaths annually, primarily among young children in sub-Saharan Africa (WHO 2009). Four main species of the malaria parasite infect humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum and P. vivax cause the majority of infections, while P. falciparum is responsible for most cases of severe and potentially fatal malaria.
In nature, malaria parasites spread by successively infecting two types of hosts: humans and female Anopheles sp. mosquitoes. All four species of malaria parasites are transmitted to humans via a mosquito bite. Malaria parasites invade hepatocytes, then multiply in the liver as liver schizonts, before being released into the blood stream, invading erythrocytes and developing into asexual blood schizonts. This cycle of erythrocyte invasion and destruction often leads to clinical disease manifested as fever, chills, and flu-like illness symptoms. Left untreated, persons may develop severe complications and die. During this erythrocytic phase, some parasites differentiate into sexual erythrocytic stages, called gametocytes. These gametocytes may be ingested by a mosquito during a blood meal, potentially perpetuating another cycle of growth and multiplication in the mosquito. Additionally, P. vivax and P. ovale can develop dormant liver stage parasites (hypnozoites), which can reactivate and cause relapsing malaria several months or years after initial infection.
Malaria is both preventable and treatable. Prevention efforts have focused on vector control strategies to reduce adult mosquito populations and human-mosquito contact, and to eradicate mosquito breeding grounds. They include the use of insecticide treated bednets, indoor residual spraying, larviciding, and environmental management. In addition, treatment strategies in endemic areas frequently combine case management, the diagnosis and treatment of malaria patients, with disease prevention by administering antimalarial drugs for prevention of clinical disease to particularly vulnerable population groups such as pregnant women, infants, and non-immune travellers to endemic areas. Success in malaria control using these existing tools has led to renewed interest in the possibility of malaria elimination in some countries or regions. While the malaria eradication agenda of the mid-twentieth century was ultimately abandoned, current calls for elimination stress the need for new technologies (insecticide delivery systems, new drugs and insecticides, and candidate vaccines) and the revitalization of older strategies (indoor residual spraying). Mass drug administration (MDA) was a component of many malaria elimination and eradication programmes in the 1950s, but is not currently recommended due to concerns about efficacy, logistical feasibility, sustainability, and the risk of accelerating drug resistance. However, evidence to guide this recommendation, particularly in light of the development of new antimalarial drugs, is lacking (WHO 2007).
Description of the intervention
Over the past 20 years, annual MDA has been a key strategy for controlling and eliminating highly prevalent neglected tropical diseases such as lymphatic filariasis, soil transmitted helminthes, onchocerciasis, schistosomiasis, and trachoma. The simultaneous administration of essential medicines to target high-prevalence neglected tropical diseases has two main functions: to treat prevalent infection and subsequently to reduce further transmission within the population (Hotez 2009). Mass antimalarial drug administration, defined as the empiric administration of a complete therapeutic course of an antimalarial regimen to an entire population or well-defined sub-population at the same time, has been used for malaria control since the early 1930s and was advocated by the World Health Organization (WHO) in the 1950s as a tool in situations where other more conventional control measures had failed (von Seidlein 2003). While not widely used, there are several examples where MDA, in combination with other malaria control measures, had some success. For instance, MDA with sulfalene-pyrimethamine combined with indoor residual spraying achieved high levels of malaria control during the Garki project in Northern Nigeria in 1969 (Molineaux 1980). In addition, the use of MDA combined with other malaria control interventions succeeded in permanently interrupting malaria transmission on the island of Aneityum in Vanuatu (Kaneko 2000). Primaquine, the only registered drug that can eliminate gametocytes, was also given in combination with chloroquine to an estimated 70% of Nicaragua's population in 1981, preventing an estimated 9200 cases of malaria (Garfield 1983). In these instances, the entire population was simultaneously treated with a therapeutic dose of an antimalarial both to reduce malaria burden and potentially to interrupt transmission.
How the intervention might work
Malaria transmission is dependent on mosquito vector dynamics, the proportion of humans with peripheral gametocytemia, and the infectiousness of circulating gametocytes to mosquitoes. MDA of antimalarials might reduce malaria burden by its direct effect on individuals who receive a treatment dose of antimalarials, as well as by reducing rates of transmission. Antimalarial MDA could reduce transmission in a number of ways. First, MDA could reduce parasitemia prevalence and potentially reduce malaria transmission via inhibition of the liver or asexual intraerythroctytic stages of the parasite, thus reducing the number of parasites that can progress to form gametocytes. Second, the antimalarial drug could have a direct effect on gametocytes. Third, the antimalarial drug could have a sporonticidal effect and inhibition of the sporogonic cycle in the mosquito. If all persons in a given population are treated by antimalarial MDA then one would expect an immediate reduction in asexual parasite prevalence in the population, and possibly a sustained reduction in the population parasite prevalence if there was a concomitant reduction in transmission.
Most antimalarial drugs target the asexual blood stage of the parasite, as this stage is responsible for the symptomatic disease. Blood schizonticidal drugs reduce asexual parasitemia and early stage gametocytes in P. falciparum by preventing the development of mature gametocytes, without having a direct effect on circulating mature gametocytes. Some antimalarial drugs, such as the artemisinins and 8-aminoquinolines (eg primaquine), have known gametocytocidal activities and have the potential to reduce transmission by reducing circulating gametocytemia. In addition, the 8-aminoquinolines also inhibit the hypnozoite stage of P. vivax and P. ovale species, thus reducing the chance of relapse (White 2008).
Why it is important to do this review
Several examples illustrate the use of MDA as a malaria control tool. Since its popularity in the 1950s and 1960s, however, it has fallen into disfavour due to concerns regarding its efficacy, logistical feasibility, sustainability as a malaria control tool, and risk of accelerating drug resistance. But with a renewed interest in malaria elimination and the development of new gametocytocidal antimalarials such as artemisinins, MDAs are once again being considered as a tool for malaria control (Feachem 2009). Given this renewed interest in conducting MDAs, it is important to review the currently available literature to assess the potential of this strategy to reduce malaria burden and transmission. In addition, a systematic review of the literature will allow us to define the gaps in our understanding of the potential benefits and risks of this strategy, such as the risk of adverse drug events in an asymptomatic population. This information could guide both future antimalarial MDA interventions and their evaluation.