The promise and potential challenges of intermittent preventive treatment for malaria in infants (IPTi)

Abstract

Intermittent preventive treatment (IPT) administers a full therapeutic course of an anti-malarial drug at predetermined intervals, regardless of infection or disease status. It is recommended by the World Health Organization (WHO) for protecting pregnant women from the adverse effects of malaria (IPTp) and shows great potential as a strategy for reducing illness from malaria during infancy (IPTi). Administered concurrently with standard immunizations, IPTi is expected to reduce the frequency of clinical disease, but to allow blood-stage infections to occur between treatments, thus allowing parasite-specific immunity to develop. While wide deployment of IPTi is being considered, it is important to assess other potential effects. Transmission conditions, drug choice and administration schedule will likely affect the possibility of post-treatment rebound in child morbidity and mortality and the increased spread of parasite drug resistance and should be considered when implementing IPTi.

Figure 1

Concentration of anti-malarial drug in bloodstream during IPT. Drug concentration initially rises after administration of a therapeutic drug regimen. The concentration declines gradually as the drug is cleared from the bloodstream. Parasites with increasing sensitivity to the drug will be able to grow as the drug concentration declines. Parasites are divided roughly into three categories; fully sensitive, partially resistant and fully resistant. The interval between the time at which the concentration falls below the threshold for partially sensitive parasites and the time at which it falls below the threshold for sensitive parasites is a window of selection for resistant parasites. The dotted curve represents the target blood concentrations during chemoprophylaxis.

Figure 2

Effect of transmission intensity on outcome of IPTi. Qualitative depiction of the effect of transmission intensity on the age-incidence pattern of malaria morbidity and mortality. In areas of high transmission (solid line), malaria mortality is concentrated in the first two years of life. In areas of low or unstable transmission (dashed line), children may be at risk until much later in life. The arrows represent the window of greatest risk or the age interval during which roughly 75% of childhood malaria episodes are experienced.

Figure 3

Effect of transmission intensity on outcome of IPTi. Effect of biting frequency (arrows represent infectious bites) on the development of malaria-specific immunity during IPTi. The frequency of infectious bites determines whether or not an infant is exposed to malaria parasites between doses of drug during IPTi.

Figure 4

Drug treatment and immune mechanisms act synergistically to eliminate parasites. (a) A patient with some pre-existing immunity clears infection and reduces the number and transmission of the parasites that survive treatment. (b) Without pre-existing immunity, the window for proliferation and differential transmission of resistant parasites is extended. White and black circles represent sensitive and resistant parasites, respectively.

Figure 5

Effect of IPT on parasite diversity. Blood concentration of drug during two treatments of IPT is shown. All of the sensitive parasites (white circles) initially present in the host at the start of IPT are killed by the drug, leaving only resistant parasites (black circles). While the drug concentration is high, new infections are prevented and the resistant parasites proliferate without competition. When the drug concentration falls below the threshold for sensitive parasites, an infectious bite can produce an infection with sensitive parasites. A subsequent bloodmeal may take up gametocytes from both sensitive (white crescents) and resistant strains (black crescents), thereby allowing out-crossing between them. At the next treatment, the sensitive parasites are killed and the resistant parasites continue to proliferate and may acquire new genetic material at the next cycle. Black arrows at the top represent continual biting by infectious mosquitoes.