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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Bill & Melinda Gates Foundation.
Aponte
John J
JJ
Barcelona Centre for International Health Research, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Schellenberg
David
D
Egan
Andrea
A
Breckenridge
Alasdair
A
Carneiro
Ilona
I
Critchley
Julia
J
Danquah
Ina
I
Dodoo
Alexander
A
Kobbe
Robin
R
Lell
Bertrand
B
May
Jürgen
J
Premji
Zul
Z
Sanz
Sergi
S
Sevene
Esperanza
E
Soulaymani-Becheikh
Rachida
R
Winstanley
Peter
P
Adjei
Samuel
S
Anemana
Sylvester
S
Chandramohan
Daniel
D
Issifou
Saadou
S
Mockenhaupt
Frank
F
Owusu-Agyei
Seth
S
Greenwood
Brian
B
Grobusch
Martin P
MP
Kremsner
Peter G
PG
Macete
Eusebio
E
Mshinda
Hassan
H
Newman
Robert D
RD
Slutsker
Laurence
L
Tanner
Marcel
M
Alonso
Pedro
P
Menendez
Clara
C
D000349:Africa / Q000453:epidemiology; D000740:Anemia / Q000453:epidemiology; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005500:Follow-Up Studies; D006801:Humans; D007115:Immunization Schedule; D015994:Incidence; D007223:Infant; D007226:Infant Mortality; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000517:prevention & control*; D010343:Patient Admission / Q000706:statistics & numerical data; D011739:Pyrimethamine / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D012107:Research Design; D012307:Risk Factors; D012449:Safety; D013413:Sulfadoxine / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine