Malaria incidence and efficacy of intermittent preventive treatment in infants (IPTi)

Robin Kobbe, Samuel Adjei, Christina Kreuzberg, Benno Kreuels, Benedicta Thompson, Peter A Thompson, Florian Marks, Wibke Busch, Meral Tosun, Nadine Schreiber, Ernest Opoku, Ohene Adjei, Christian G Meyer, Juergen May, Robin Kobbe, Samuel Adjei, Christina Kreuzberg, Benno Kreuels, Benedicta Thompson, Peter A Thompson, Florian Marks, Wibke Busch, Meral Tosun, Nadine Schreiber, Ernest Opoku, Ohene Adjei, Christian G Meyer, Juergen May

Abstract

Background: Intermittent preventive antimalarial treatment in infants (IPTi) is currently evaluated as a malaria control strategy. Among the factors influencing the extent of protection that is provided by IPTi are the transmission intensity, seasonality, drug resistance patterns, and the schedule of IPTi administrations. The aim of this study was to determine how far the protective efficacy of IPTi depends on spatio-temporal variations of the prevailing incidence of malaria.

Methods: One thousand seventy infants were enrolled in a registered controlled trial on the efficacy of IPTi with sulphadoxine-pyrimethamine (SP) in the Ashanti Region, Ghana, West Africa (ClinicalTrial.gov: NCT00206739). Stratification for the village of residence and the month of birth of study participants demonstrated that the malaria incidence was dependent on spatial (range of incidence rates in different villages 0.6-2.0 episodes/year) and temporal (range of incidence rates in children of different birth months 0.8-1.2 episodes/year) factors. The range of spatio-temporal variation allowed ecological analyses of the correlation between malaria incidence rates, anti-Plasmodium falciparum lysate IgG antibody levels and protective efficacies provided by IPTi.

Results: Protective efficacy of the first SP administration was positively correlated with malaria incidences in children living in a distinct village or born in a distinct month (R2 0.48, p < 0.04 and R2 0.63, p < 0.003, respectively). Corresponding trends were seen after the second and third study drug administration. Accordingly, IgG levels against parasite lysate increased with malaria incidence. This correlation was stronger in children who received IPTi, indicating an effect modification of the intervention.

Conclusion: The spatial and temporal variations of malaria incidences in a geographically and meteorologically homogeneous study area exemplify the need for close monitoring of local incidence rates in all types of intervention studies. The increase of the protective efficacy of IPTi with malaria incidences may be relevant for IPTi implementation strategies and, possibly, for other malaria control measures.

Figures

Figure 1
Figure 1
Stratified malaria incidence rates. Malaria incidence rates per PYAR in the placebo group assessed over the period of one year, beginning at the time of recruitment. A, PYAR stratified for the month of birth of the children; B, PYAR stratified for the village of residence of the children. PYAR, person year at risk.
Figure 2
Figure 2
Malaria incidence rates and protective efficacy. Correlation between the protective efficacy of each IPTi application during six months after the drug administration (blue circles and line, after IPTi-1; red diamonds and line, after IPTi-2; green triangles and line, after IPTi-3) and malaria incidence rates per PYAR for the same time periods in the placebo arm. A, stratified by month of birth (IPTi-1, R2 0.63, p < 0.003; IPTi-2, R2 0.29, p = 0.07; IPTi-3, R2 0.37, p < 0.04); B, stratified by village of residence (IPTi-1, R2 0.48, p < 0.04; IPTi-2, R2 0.33, p = 0.11; IPTi-3, R2 0.04, p = 0.60). PYAR, person year at risk.
Figure 3
Figure 3
Malaria incidence rates and anti-P. falciparum lysate IgG levels I. Panel A and B, correlation between the mean of anti-P. falciparum lysate IgG levels and malaria incidence rates in the placebo arm. A, stratified by month of birth (red diamonds and lines [linear regression, R2 0.54, p < 0.006], children from the SP arm; blue circles and lines [linear regression R2 0.05, p = 0.475], children from the placebo arm. B, stratified by village of residence (red diamonds and lines [linear regression, R2 0.90, p < 0.001], children from the SP arm; blue circles and lines [linear regression, R2 0.89, p < 0.001], children from the placebo arm). Panel C and D, correlation between malaria incidence rates and incidence rates in the placebo arm. C, stratified by month of birth (red diamonds and lines [slope 0.07, p < 0.80], children from the SP arm; blue circles and lines, children from the placebo arm as comparison [slope 1]). D, stratified by village of residence (red diamonds and lines [slope 0.67, p < 0.007], children from the SP arm; blue circles and lines, children from the placebo arm as comparison [slope 1]). PYAR, person year at risk.
Figure 4
Figure 4
Malaria incidence rates and anti-P. falciparum lysate IgG levels II. Correlation between the mean of anti-P. falciparum lysate IgG levels and malaria incidence rates of the respective study arm in each village. A, stratified by month of birth (Wald test, p = 0.118). B, stratified by village of residence (Wald test, p < 0.001). Blue circles and lines (linear regression), children from placebo arm; red diamonds and lines (linear regression), children from SP arm. PYAR, person year at risk.

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