BOX 2

List of Committee Findings and Conclusions by Order of Appearance in the Letter Report

The committee’s findings and conclusions are based on the evidence presented to and reviewed by the committee including publicly available literature.


Efficacy of Sulfadoxine-Pyrimethamine for Use in Intermittent Preventive Treatment

  • The committee found that the six IPTi-SP studies differed in their settings, intensity and seasonality of malaria transmission, use of insecticide-treated bed net coverage, prevalence of SP resistance and age at administration of doses of SP (or of placebo). The committee viewed this heterogeneity as a positive feature of the set of trials, concluding that IPTi-SP has been evaluated in several venues within sub-Saharan Africa that have different conditions, which allows generalizability to other sites in sub-Saharan Africa that have high or moderate intensity of transmission. Analysis of results from the different sites both shows the generalizability of IPTi-SP and identifies limitations that might not be detected if the conditions were more homogeneous.

  • The committee concluded that the trials had adequate power to assess the effect of IPTi-SP on the number of episodes of clinical malaria. Assuming the analyses of the data from the individual trials are correct, the substantial amount of data on this outcome provides convincing evidence of an overall net benefit of IPTi-SP. With respect to the incidence of malaria from randomization up to 5 months after the last dose, the combined estimate of protective efficacy using a random-effects meta-analysis was 21 percent with a 95 percent CI of (11, 29; p< 0.001). The committee also concluded that an intervention with an efficacy of approximately 20 percent in diminishing the incidence of clinical malaria in infancy is a potentially useful adjunctive tool to control morbidity from malaria in areas in sub-Saharan Africa where the incidence of malaria in infants is high and where a well-functioning EPI infrastructure with reasonable immunization coverage exists (e.g., DPT3 coverage >50 percent, the GAVI cut-off for new vaccine eligibility).

  • The committee concluded that the overall estimate of efficacy of IPTi-SP compared with placebo represents a composite of events that occurs during a number of distinct time periods. For example, in the long lag from the time a dose is given at 3 or 4 months of age until the next dose at 9 months of age, a high level of protection is observed during the first 35 days after the dose of SP. Although the efficacy falls considerably over the next few months, a modest level of protection appears to persist. Exposure to infected mosquitoes in the few months just before the dose at age 9 months may result in infections that stimulate the immune system before the dose at 9 months eliminates or suppresses the circulating parasites. After the last dose of IPTi and the drop in drug blood levels roughly 5 weeks later, a period of potential rebound occurs in which more cases may occur among children who previously received SP than among children who received placebo. The cumulative efficacy during these distinct periods results in an overall net benefit from IPTi-SP.

  • The committee found that the cumulative data supporting an effect on hospitalization with malaria parasites, anemia and all-cause hospitalization were more modest and less consistent across the trials than the effect on episodes of clinical malaria. For hospitalizations of children with malaria parasites, analyses from randomization up to 5 months after the last dose of IPTi showed a net benefit in four of the six studies (estimated efficacies of 49, 37, 36 and 15 percent), with two being statistically significant. The other two sites showed an increased risk for this outcome with efficacies of −9 percent and −12 percent. The pooled estimate of protective efficacy was 21 percent with a 95 percent CI of (−2, 38). For all-cause hospitalizations, five studies had analyses from randomization through 5 months after the last dose; all showed a positive net effect with efficacies of 33, 24, 20, 11, and 2 percent; in two instances, these were statistically significant. The pooled estimate of efficacy in preventing all-cause hospitalizations was 18



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