The impact of IPTi and IPTc interventions on malaria clinical burden - in silico perspectives

Abstract

Background: Clinical management of malaria is a major health issue in sub-Saharan Africa. New strategies based on intermittent preventive treatment (IPT) can tackle disease burden by simultaneously reducing frequency of infections and life-threatening illness in infants (IPTi) and children (IPTc), while allowing for immunity to build up. However, concerns as to whether immunity develops efficiently in treated individuals, and whether there is a rebound effect after treatment is halted, have made it imperative to define the effects that IPTi and IPTc exert on the clinical malaria scenario.

Methods and findings: Here, we simulate several schemes of intervention under different transmission settings, while varying immunity build up assumptions. Our model predicts that infection risk and effectiveness of acquisition of clinical immunity under prophylactic effect are associated to intervention impact during treatment and follow-up periods. These effects vary across regions of different endemicity and are highly correlated with the interplay between the timing of interventions in age and the age dependent risk of acquiring an infection. However, even when significant rebound effects are predicted to occur, the overall intervention impact is positive.

Conclusions: IPTi is predicted to have minimal impact on the acquisition of clinical immunity, since it does not interfere with the occurrence of mild infections, thus failing to reduce the underlying force of infection. On the contrary, IPTc has a significant potential to reduce transmission, specifically in areas where it is already low to moderate.

Figure 1. Model representing the dynamics of malaria transmission in a population under treatment.

The model is an extension of the model in . The compartments represent the following epidemiological classes: S = completely susceptible individuals, either newborns, or individuals that have lost protection conferred in R, or have cleared drugs from the bloodstream while in S_T; I ₁ = clinical malaria resulting from an infection in a completely susceptible individual or after drug clearance from I_1T; R = individuals that recovered from infections I₁ or I₂ or that have cleared the drugs from circulation while in R_T, and are clinically immune, developing a mild form of disease if exposed. I ₂ = mild/asymptomatic disease resulting from exposure of recovered individuals or drug clearance while in I_2T. S_T = completely susceptible individuals that were treated, have lost immunity conferred in R_T, or failed to build up their immunity after an infection. I_1T = severe disease resulting from an infection in a treated susceptible individual, or treated while in I₁. R_T = individuals that recovered from infections I_1T or I_2T and acquired clinical protection, or where treated while in R. I _2T = mild/asymptomatic disease resulting from exposure of R_T individuals or treated while in I₂. The parameters are described in Table 1. A percentage of infants (according to programme coverage) depicted as γ is discretely moved to the corresponding treated classes, at specific ages.

Figure 2. IPTi impact on clinical malaria age profiles.

Analysis of the outcome of applying prophylactics at 2, 3 and 9 months of age, for 10 years, in terms of age profile of clinical disease prevalence and intervention efficacy. Age profiles of populations under IPTi are compared with populations without intervention, in equilibrium conditions (black line). (A) Simulations assuming different combinations of values for c and σ, under intense malaria transmission. The values for these 2 parameters are equal for each curve, ranging from (green line) to (red line). The blue line represents the intermediate combination, . (B) The dashed line represents the age instantaneous intervention efficacy for the blue curve scenario in (A). The grey bars illustrate efficacy over a 3 months range. (C) Represents the same as in (A), but for a intermediate transmission setting. (D) The dashed line represents the age instantaneous intervention efficacy for the blue curve scenario in (C). The grey bars illustrate efficacy over a 3 months period.

Figure 3. Targeted interventions according to endemic level.

The IPTi intervention outcome (red line) is compared with a population without intervention in equilibrium conditions (black line), and a tailored schedule for the administration of anti-malarial drugs (blue line). These simulations are performed for a high transmission transmission setting.

Figure 4. Intervention impact on clinical malaria and overall parasite prevalence.

(A) IPTi impact on clinical malaria, assuming several values for intervention coverage, as specified in the figure legend. (B) Time dynamics of the proportion of people infected with malaria, assuming different IPTi coverage rates as in (A).

Figure 5. Impact of an IPTc strategy apllied in 5 to 18 years old children on clinical malaria age profiles, and over time.

Age profiles of populations under an IPTc intervention calibrated from data in Clarke et al. are compared with populations without intervention, represented by black lines. (A) Clinical malaria age profiles, retrieved immediately after the third dose of treatment (blue line), and 4 months after the administration of that course of drug (red line). (B) Represents the same as (A), but for a high transmission setting. (C), (D) Time dynamics of IPTc impact over all age classes in mild and intense malaria transmission areas, respectively. Intervention (starting in year 1) shapes the dynamics of both clinical (blue line) and asymptomatic/mild (red line) malaria. The dashed lines represent unperturbed equilibria.

Figure 6. Impact of an IPTc strategy applied in 2 months to 5 years old children on clinical malaria age profiles, and over time.

The same as in Figure 5 but calibrated according to Cisse et al .

Figure 7. IPTc impact in seasonal settings.

We mimic two studies conducted in regions with different seasonal transmission patterns , . (A) Clinical malaria age profiles, immediately after the administration of the third dose of treatment (blue line), and 4 months after that (red line), for the study in . The dashed lines represent the age profiles retrieved under no treatment, for each of the mentioned times points. Differences in the dashed lines refer to oscillations in transmission from one time point to the other. Intervention impact is measured as the difference between dashed and full lines of the same color (C) Time dynamics of clinical (blue line) and asymptomatic malaria (red line) in a population in which IPTc was implemented beginning in year 1 (full lines), following the schedule in , and in a population under no treatment (dashed lines). Replicating (A) and (C), whilst using the characteristics of IPTc implementation in and the seasonal transmission fluctuations in , we get (B) and (D), respectively.