title: Modelling the epidemiological impact of intermittent preventive treatment against malaria in infants.
abstract: BACKGROUND
  Trials of intermittent preventive treatment against malaria in infants (IPTi) using sulphadoxine-pyrimethamine (SP) have shown a positive, albeit variable, protective efficacy against clinical malaria episodes. The impact of IPTi in different epidemiological settings and over time is unknown and predictions are hampered by the lack of knowledge about how IPTi works. We investigated mechanisms proposed for the action of IPTi and made predictions of the likely impact on morbidity and mortality.
  
  
  RESULTS
  We used a comprehensive, individual-based, stochastic model of malaria epidemiology to simulate recently published trials of IPTi using SP with site-specific characteristics as inputs. This baseline model was then modified to represent hypotheses concerning the duration of action of SP, the temporal pattern of fevers caused by individual infections, potential benefits of avoiding fevers on immunity and the effect of sub-therapeutic levels of SP on parasite dynamics. The baseline model reproduced the pattern of results reasonably well. None of the models based on alternative hypotheses improved the fit between the model predictions and observed data. Predictions suggest that IPTi would have a beneficial effect across a range of transmission intensities. IPTi was predicted to avert a greater number of episodes where IPTi coverage was higher, the health system treatment coverage lower, and for drugs which were more efficacious and had longer prophylactic periods. The predicted cumulative benefits were proportionately slightly greater for severe malaria episodes and malaria-attributable mortality than for acute episodes in the settings modelled. Modest increased susceptibility was predicted between doses and following the last dose, but these were outweighed by the cumulative benefits. The impact on transmission intensity was negligible.
  
  
  CONCLUSIONS
  The pattern of trial results can be accounted for by differences between the trial sites together with known features of malaria epidemiology and the action of SP. Predictions suggest that IPTi would have a beneficial impact across a variety of epidemiological settings.
authors.affiliation: Department of Public Health and Epidemiology, Swiss Tropical Institute, Basel, Switzerland. amanda.ross@unibas.ch
authors.forename: Amanda
authors.initials: A
authors.lastname: Ross
authors.forename: Melissa
authors.initials: M
authors.lastname: Penny
authors.forename: Nicolas
authors.initials: N
authors.lastname: Maire
authors.forename: Alain
authors.initials: A
authors.lastname: Studer
authors.forename: Ilona
authors.initials: I
authors.lastname: Carneiro
authors.forename: David
authors.initials: D
authors.lastname: Schellenberg
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.forename: Marcel
authors.initials: M
authors.lastname: Tanner
authors.forename: Thomas
authors.initials: T
authors.lastname: Smith
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D004351:Drug Resistance; D006801:Humans; D007107:Immune System; D007223:Infant; D008288:Malaria / Q000453:epidemiology* / Q000517:prevention & control*; D008954:Models, Biological; D015233:Models, Statistical; D008962:Models, Theoretical; D011739:Pyrimethamine / Q000494:pharmacology; D013413:Sulfadoxine / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine