How antimalarial drug resistance affects post-treatment prophylaxis

Abstract

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base.

Figure 1

In this diagram a slowly eliminated drug given over three days has a single component (monoexponential) elimination phase with a half-life of 5.5 days. This corresponds with a one-compartment model. The vertical axis has a logarithmic scale. The in-vivo MIC is 1.25 μmol/L. Each doubling of MIC shortens the PTP by one half-life.

Figure 2

Worsening resistance; the antimalarial concentration-effect relationship moves to the right. In this example the shift is parallel. IC50 is the concentration giving 50% of maximum effect, and Emax is the maximum effect possible. Usually in-vitro susceptibility is assessed by growth inhibition, inhibition of uptake of ³H Hypoxanthine, or inhibition of formation of pLDH or PfHRP2.

Figure 3

Three levels of antimalarial susceptibility for a slowly eliminated antimalarial with a multiphasic elimination profile (e.g chloroquine, piperaquine) are shown reflected by the respective minimum inhibitory concentrations (MIC); sensitive (S), resistant (R) and highly resistant (HR). Post treatment prophylaxis for sensitive parasites is six weeks. In this example increasing levels of resistance progressively shorten the PTP from six to three weeks (a) and then from three to two weeks (b).

Figure 4

Post treatment prophylaxis following a slowly eliminated antimalarial such as chloroquine or piperaquine in a high transmission setting (left figure) where the EIR is 1000/year and in a low transmission setting where the EIR is 1/year. The drug concentrations are shown in red and the vertical bars represent cumulative incidence of reinfection; t₂₀ and t₅₀ are the times to reach a 20% and 50% cumulative incidence of reinfection.

Figure 5

The figure refers to the example. The drug concentrations are shown in red, the cumulative incidence of reinfection with resistant parasites is shown in blue, and the cumulative incidence of reinfection with sensitive parasites is shown in green.