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

Robin Kobbe 2 Samuel Adjei 1 2 Christina Kreuzberg 2 Benno Kreuels 2 Benedicta Thompson 0 Peter A Thompson 0 Florian Marks 2 4 Wibke Busch 2 Meral Tosun 2 Nadine Schreiber 2 Ernest Opoku 0 Ohene Adjei 0 Christian G Meyer 3 Juergen May 2 0 Kumasi Centre for Collaborative Research in Tropical Medicine , Kumasi , Ghana 1 Ministry of Health/Ghana Health Service District Health Directorate , Agona, Ashanti Region , Ghana 2 Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine , Bernhard-Nocht-Strae 74, D-20359 Hamburg , Germany 3 Dept. Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine , Hamburg , Germany 4 International Vaccine Institute , Seoul , South Korea 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 sulphadoxinepyrimethamine (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. - Background Effective antimalarial control strategies for young children in Africa must urgently be improved, as this group is at highest risk of morbidity and mortality due to Plasmodium falciparum malaria [1,2]. In most parts of sub-Saharan Africa, individual control measures concentrate on the reduction of parasite transmission through insecticidetreated bed nets and treatment of acute malaria episodes [3], the latter often being inappropriate due to increasing parasite drug resistance [4,5]. In addition to established control measures [6], novel approaches comprise preerythrocytic stage vaccines and the concept of "intermittent preventive treatment in infants" (IPTi) [7,8]. IPTi essentially exerts therapeutic and prophylactic effects of antimalarial drugs administered at intervals short enough to prevent disease, but long enough to allow for the development of protective immunity [9]. However, the exact mechanisms of protection are still not clear. It has been assumed that an optimal drug application schedule depends on the half-life of the antimalarial drugs used, the extent of current parasite drug-resistance, the transmission intensity, and the incidence of malaria episodes [10]. The IPTi application schedule that was originally evaluated in Tanzania was based on weight-adapted singledose sulphadoxine-pyrimethamine (SP) and was pragmatically linked to the expanded programme on immunization (EPI) recommended by WHO, with vaccinations at months 2, 3 and 9 [8]. In that study, IPTi was 59% effective in reducing malaria episodes in an area with an incidence rate (IR) of 0.43 per person-year. In subsequent trials performed in Northern Ghana and Mozambique, protective efficacies were 24.8% (IR 1.02) and 22.2% (IR 0.55), respectively [11,12]. So far, studies modelling the impact of the malaria incidence on the protection that is provided by IPTi are not available. The linear regression model presented here makes use of data of a recent controlled trial on SP-based IPTi performed in Ghana. The overall protective efficacy in this trial was 20.3% (IR 1.20) and decreased with the age of study participants [13]. The study presented here aims to determine the influence of spatio-temporally different malaria incidences on the efficacy of IPTi with SP in an ecological analysis. Methods Study area The trial was conducted from January 2003 to September 2005 in the Ashanti Region, Ghana, West Africa, in nine neighboring villages of the rural Afigya Sekyere district. The district occupies an area of 714 km2 in the forest belt. Geographically, the study area is homogeneous [14]. All distances between villages are < 15 km with altitude levels between 300 and 500 metres above the sea level. Temperature varies between 20.4C and 33.5C while monthly rainfall ranges from 15 mm (January) to 214 mm (June) with similar fluctuation in all villages. The area is holoendemic for P. falciparum malaria with perennial transmission and seasonal peaks (high transmission from May to October) [15]. Malaria vectors are mosquitoes of the Anopheles gambiae complex and Anopheles funestus. The peak entomological inoculation rate (EIR) of P. falciparum is > 100 infectious bites per individual in October. While chloroquine was the first-line drug for treatment of uncomplicated malaria in Ghana at the beginnning of the study, the Ghana Health Services has recommended a three-day regimen of amodiaquine-artesunate since March 2003. Plasmodium falciparum resistance against chloroquine and SP in the study area is high [16]. Study design One-thousand seventy infants at the age of three months (tolerance of four weeks accepted) with permanent residence in one of the villages under survey were recruited throughout the year 2003 [13]. In average 89 infants (range 59110) were enrolled monthly and randomized to receive either a single-dose of 250 mg sulphadoxine and 12.5 mg pyrimethamine or placebo (verum drug and placebo provided by Roche, Basel, Switzerland). IPTitreatment doses were given at the age of 3, 9 and 15 months (IPTi-1, IPTi-2, IPTi-3, respectively (...truncated)