Intermittent preventive treatment of infants with mefloquine reduces risk of clinical malaria in areas of moderate malaria transmission and high resistance to sulphadoxine-pyrimethamine, but safety and tolerability issues need consideration.

Resistance to the combination sulphadoxine– pyrimethamine (SP) is increasing.1–3 This is the favoured compound for intermittent preventive treatment (IPT; administration of an antimalarial at prespecifi ed intervals to prevent malaria). Gosling and colleagues report on the failure of IPT in infants (IPTi) with SP (−6.7%; 95% CI −45.9% to 22.0%) in Northern Tanzania in the same issue of a journal in which the combination is endorsed by a meta-analysis.4 In this double-blind placebo-controlled trial of IPTi in areas of low and moderate malaria intensity, infants aged 8–16 weeks were assigned to age-based doses of SP, chlorproguanil–dapsone (a short-acting antimalarial), mefl oquine (a long-acting antimalarial) or placebo administered with second and third immunisations for diphtheria, pertussis, tetanus (DPT) and polio 2 at about 2 months; DPT and polio 3 at 3 months; and measles at 9 months of age. The primary endpoint was protective effi cacy against clinical malaria in infants aged 2–11 months. Clinical malaria was defi ned as a history of fever in the previous 3 days or axillary temperature >37.5°C plus parasitaemia of any density measured passively and actively before the third IPTi dose. Cases positive by the former defi nition were treated, but those not fi tting the case defi nition (that is, asymptomatic children with a positive malaria smear) were not specifi cally mentioned. Effective IPT drugs would prevent microscopic parasitaemia. Parasitaemia can be detected before symptoms, particularly at this vulnerable age. To prevent malariarelated deaths, particularly in the context of studies, these infants should be treated. The discussion addresses excess dosing, particularly at the third immunisation, when the average dose of mefl oquine was 29.9 mg/kg (the standard treatment dose is 25 mg/kg), which unsurprisingly resulted in high rates of vomiting: 8% (141/1731), with an OR compared with placebo of 5.5 (95% CI 3.6 to 8.5). Although the study design incorporated a 3-day course of chlorproguanil– dapsone, no split-dose regimen appears to have been considered for mefl oquine, which is unfortunate, as evidence suggests it is better tolerated.5–8 The failure of the trial, particularly in the mefl oquine group, to fi nd a protective effect against moderate anaemia, malaria admissions or all-cause hospital admissions as described by some studies of IPTi with SP was thought to be due to the high level of coverage with insecticide-treated bed nets and close supervision of the children. A change in malaria transmission is also postulated, but no reason for this change is given. The authors detail the uncomplicated malaria treatment protocol, which included introduction of artemisinin combination therapy (ACT) in October 2005, 10 months after the study commenced and more than 21⁄2 years before it was completed. The introduction of ACT has resulted in signifi cant reductions in transmission rates in Asia and Africa.9 10 Pharmacokinetic studies are a necessary component of the IPTi strategy, but few data have been forthcoming.11 For none of these drugs is the pharmacokinetics well established in children, but frequency of dosing will be guided by this knowledge, and nested pharmacokinetic studies should be included in future IPT studies. This study reinforces the cautious WHO recommendations on SP for IPTi.12 SP should be considered only in areas of moderate or high transmission and when parasite resistance to SP is low. Gesase and colleagues have since defi ned the northern Tanzania site as an area of high resistance to SP.13 The WHO recommendations were based in large measure on limited data, including a metaanalysis of possibly the six most favourable trials from the IPTi Consortium, which demonstrated a 30% (95% CI 19.8% to 39.4%) overall protection against clinical malaria, a variable reduction in anaemia (<8 g/dl) of 21.3% (95% CI 8.3% to 32.5%) and a 23% reduction (95% CI 10.0% to 34.0%) in all-cause hospital admission4 and did not include the evidence of Gosling and co-authors. Protection from IPTi translates into 35-day protection after each treatment dose of SP, or an overall protective effi cacy of 20–30% in infants, which compares with more than 50% protection against clinical malaria from insecticide-treated bed nets and an 18% reduction in mortality, an effect none of the IPTi studies has matched. To date cost-effectiveness analysis of SP IPTi has been limited to cases when the reduction in malaria was highly signifi cant.14 Controversy surrounds the publication by Gosling and colleagues. The meta-analysis of six trials concluded Commentary on: Gosling RD, Gesase S, Mosha JF, et al. Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1521–32.