Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials

Summary

Background

Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa.

Methods

We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo.

Findings

The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30·3% (95% CI 19·8–39·4, p<0·0001) against clinical malaria, 21·3% (8·2–32·5, p=0·002) against the risk of anaemia, 38·1% (12·5–56·2, p=0·007) against hospital admissions associated with malaria parasitaemia, and 22·9% (10·0–34·0, p=0·001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1·05, 95% CI 0·72–1·54, p=0·79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group.

Interpretation

IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control.

Funding

Bill & Melinda Gates Foundation.

Introduction

Plasmodium falciparum malaria is a major cause of disease and death in children in sub-Saharan Africa, and improved control measures are urgently needed. Intermittent preventive treatment in infants (IPTi) is the administration of a full course of an antimalarial drug at specified timepoints, whether or not parasites are present. Previous studies have shown that continuous chemoprophylaxis in infants reduces morbidity and mortality caused by malaria. However, this approach has not been implemented in endemic countries because of the major logistical challenges involved and fears that large-scale drug use would hasten the spread of drug resistance and impair the development of naturally acquired antimalarial immunity.1, 2, 3, 4, 5 Since IPTi is associated with lower drug exposure than is chemoprophylaxis, the effect of IPTi on the spread of resistance and impairment of the development of immunity might also be lower. Furthermore, logistical challenges could be reduced by giving IPTi at the time of routine vaccinations delivered through WHO's Expanded Program on Immunization (EPI).

Sulfadoxine-pyrimethamine could be useful for IPTi because this combination is available, affordable, well tolerated, and already recommended for IPT in pregnancy.6, 7 The long half-life of sulfadoxine-pyrimethamine produces an extended prophylactic effect and enables the combination to be given as a single dose, which can be supervised. From 1999 to 2007, six randomised, placebo-controlled trials of IPTi with sulfadoxine-pyrimethamine were completed.8, 9, 10, 11, 12, 13 These trials assessed the effect of three or four doses of IPTi on malaria in early childhood. Since the study designs differed in terms of dosing schedule, primary endpoints, and duration of follow-up, we were unable to compare the trials using the published results. We therefore reanalysed the data using standardised outcome definitions and time periods to generate a meaningful pooled analysis of the safety and efficacy of IPTi given to infants at the time of routine immunisation. We also investigated whether there was a potential increase in morbidity in the period after the intervention.