Intermittent preventive treatment for malaria in Papua New Guinean infants exposed to Plasmodium falciparum and P. vivax: a randomized controlled trial

Nicolas Senn, Patricia Rarau, Danielle I Stanisic, Leanne Robinson, Céline Barnadas, Doris Manong, Mary Salib, Jonah Iga, Nandao Tarongka, Serej Ley, Anna Rosanas-Urgell, John J Aponte, Peter A Zimmerman, James G Beeson, Louis Schofield, Peter Siba, Stephen J Rogerson, John C Reeder, Ivo Mueller, Nicolas Senn, Patricia Rarau, Danielle I Stanisic, Leanne Robinson, Céline Barnadas, Doris Manong, Mary Salib, Jonah Iga, Nandao Tarongka, Serej Ley, Anna Rosanas-Urgell, John J Aponte, Peter A Zimmerman, James G Beeson, Louis Schofield, Peter Siba, Stephen J Rogerson, John C Reeder, Ivo Mueller

Abstract

Background: Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).

Methods and findings: In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10-43, p ≤ 0.001) in children receiving SP-AQ and 12% (95% CI, -11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9-54, p = 0.012) and Pv incidence was 23% (95% CI, 0-41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4-51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, -24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p > 0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%-2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.

Conclusions: IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Trial registration: ClinicalTrials.gov NCT00285662.

Conflict of interest statement

SJR is a member of the PLoS Medicine Editorial Board. The authors have declared that no competing interests exist.

Figures

Figure 1. Trial profile.
Figure 1. Trial profile.
incomplete FU, incomplete follow-up (i.e., the study was terminated before the participant completed the 21-mo follow-up time period); LTF, lost to follow-up.
Figure 2. Summary of IPTi preventive efficacy…
Figure 2. Summary of IPTi preventive efficacy against malaria at 15 mo of age adjusted for sex, place of residence, season of enrollment, and average insecticide-treated net use.
Figure 3. Prevalence of P. falciparum and…
Figure 3. Prevalence of P. falciparum and P. vivax infections during follow-up by treatment group (light microscopy) and overall (PCR).
* p<0.05.

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