Mortality

Of the children in the six IPTi-SP trials, 104 died before their first birthdays: 55 in the SP group and 49 in the placebo group (p= 0.54 from a random-effects meta-analysis). Because of the importance of total mortality to the assessment of the safety and efficacy of interventions, the committee is presenting the complete data on mortality (Table 6). As the table shows, no statistically significant difference in mortality was observed between the IPTi-SP and the placebo groups within the first year of life in any of these clinical trials or in the combined data; however, neither any individual trial nor the combined data from the six trials had adequate power to detect plausible differences in mortality. The committee believes that a trial to assess the effect on mortality would have to be very large and therefore logistically challenging and also noted that the Consortium studies, individually and pooled, were not large enough to assess an effect of IPTi-SP in preventing mortality.

TABLE 6 Mortality in the First Year of Life for the Six IPTi-SP Trials

Study

SP n/N

Placebo n/N

Relative Risk (SP: Placebo)

95% CI

Ifakara

3/350

6/351

0.5

(0.1, 2.0)

Navrongo

23/1221

11/1225

2.1

(1.0, 4.3)

Manhiça

20/748

22/755

0.9

(0.5, 1.7)

Kumasi

3/535

3/535

1.0

(0.2, 4.9)

Lambaréné

0/504

0/507

Not estimable

Not estimable

Tamale

6/600

7/599

0.9

(0.3, 2.5)

Overall

55/3958

49/3972

1.1

(0.8, 1.6)

SOURCE: Data and estimates from IPTi Consortium 2008b,c.

Rebound Effect Following Cessation of IPTi-SP Dosing

Rebound would occur if intermittent administration of SP prevented or delayed the acquisition of a sufficient degree of naturally acquired immunity that would prevent severe and complicated malaria and death. As a consequence of the lack of acquisition of immunity in this theoretical scenario, when children who are no longer receiving intermittent SP therapy are subsequently exposed to the bites of infected mosquitoes, they would develop symptomatic malaria illness and more severe clinical malaria illness at a higher rate than would children of the same age who had not received IPTi-SP during the first year of life.

On the other hand, some researchers contend that the intermittent nature of IPTi-SP dosing may allow infants to acquire immunity despite the three spaced doses of SP administered during infancy (Schreiber et al., 2007). In order for infants to acquire immunity while on an IPTi-SP regimen, they must be exposed to several blood-stage infections during the period of IPTi-SP. Because of its intermittent nature, which consists of periods of up to 5.5 months between dosings (e.g., from the age 14 weeks to the age of 9 months), IPTi-SP would not be expected to prevent infection or asymptomatic parasitemia completely; hence, infants receiving IPTi-SP may still be able to acquire some measure of immunity.

Serum antibodies against certain surface antigens of asexual-stage erythrocytic parasites (and also against antigens of the sporozoite stage injected by anophelines) play a role in protection against symptomatic malaria. Although most malariologists believe some asexual-stage antigens (e.g., merozoite surface protein-1[MSP-1], apical membrane antigen-1[AMA-1],



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