The Institute of Medicine (IOM) convened a committee with the following charge: (1) to review clinical trial methods and data analyses used in the studies conducted by the Intermittent Preventive Treatment in Infants (IPTi) Consortium (the Consortium); (2) to formulate consensus conclusions as to the advisability of further investment in IPTi using sulfadoxine-pyrimethamine (SP), on the basis of the results of six efficacy studies conducted over the last decade (or, if the evidence is sufficient, to consider investment with alternative drugs more recently studied); and (3) to consider drug safety (of prophylactic antimalarial drug use in infants in general and of treatment with SP in particular) and drug resistance; dosage regimens; potential collateral effects on other childhood healthcare programs (e.g., immunization); cost-effectiveness; and program management. As time and resources did not allow independent audits of trial conduct, data management, or analysis, the charge to the committee required it to assume, for the studies presented, that data collection and management were consistent with quality practices and that the analyses presented were correctly performed. The exception to this was the committee’s undertaking to conduct limited analyses to confirm some of the results of unpublished data from the Consortium.
The purpose of the IOM review is to provide guidance to the Bill and Melinda Gates Foundation on a number of scientific, clinical, and programmatic issues related to IPTi, including whether the efficacy data from these studies support continued investment in IPTi-SP as a potentially useful tool to reduce morbidity from malaria in infants in some regions of sub-Saharan Africa. The Consortium (a group of autonomous institutions involved with malaria research in Africa, Europe, and the United States) is funded by the Bill and Melinda Gates Foundation.
The committee reviewed the published results of six IPTi-SP Consortium field trials as well as unpublished pooled analyses by the Statistical Working Group (SWG) of the Consortium. Based on these analyses, the committee found substantial evidence indicating that IPTi-SP significantly diminished the incidence of clinical malaria in infants living in areas of high and moderate intensity of transmission. Reported data showed that IPTi-SP diminished the incidence of clinical malaria episodes by approximately 20–30 percent in infants who received IPTi-SP rather than a placebo and who were followed from the time of their first dose until a point 5 months and 5 weeks after receipt of their last dose.1 Data for the same period showed suggestive trends but not substantive evidence that IPTi-SP reduces the incidence of hospitalizations of patients with malaria parasites, anemia, and all-cause hospitalizations. The committee found that the extent of rebound is small compared to the overall benefit of IPTi-SP.
A 20-30 percent reduction in incidence of clinical malaria in these epidemiologic settings is comparable to the levels of efficacy observed for the use of impregnated bed nets (Lengeler, 2004), which have translated to important improvements in child survival when bed nets were implemented en masse (Schellenberg et al., 2001). The committee therefore concludes that an intervention with results of this magnitude is worthy of further investment as part of a public health strategy to decrease morbidity from malaria infections in infants.
The 5-month follow-up period began 5 weeks after receipt of the last dose in order to allow time for the protective effect to wear off. Inclusion of the follow-up period is necessary to look for a rebound effect—that is, an increase in morbidity or mortality after treatment ends compared to a control group that had not received continuous chemoprophylaxis or intermittent therapy.