Two Articles published Online First and in an upcoming edition of The Lancet conclude that intermittent malaria treatment for African infants is both safe and effective in a variety of settings, although potential drug resistance (and therefore the choice of drug used) is a key issue in the strategy. However, in an accompanying Comment, the recent WHO decision to continue using sulfadoxine-pyrimethamine for this purpose, despite the drug's risks, is considered 'a close call'.

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 (such as when the children receive vaccinations against other diseases). Previous studies have shown continuous , rather than intermittent, administration of antimalaria drugs (prophylaxis) can reduce malaria while the drugs are given-but when they stop there is a rebound in cases as the children do not develop immunity. Use of continuous prophylaxis can also increase the risk of drug resistance developing.

In the first Article*, Dr Clara Menendez, Hospital Clínic of Barcelona - Barcelona Centre for International Health Research (Universitat de Barcelona), Spain, and colleagues pooled six randomised controlled trials (from Tanzania, Mozambique, Gabon, and three in Ghana) to assess IPTi using the drug comibination sulfadoxine-pyrimethamine. In these trials, IPTi was given to infants at the time of routine vaccinations under WHO's Expanded Program on Immunization.

A total of 7,930 infants were assessed (IPTi 3,958; placebo 3,972). The authors found that IPTi had a protective efficacy** of 30% against clinical malaria; 21% against the risk of malaria-related anaemia; 38% against hospital admissions associated with malaria; and 23% against all-cause hospital admissions. There were similar numbers of deaths in both groups (IPTi 56, placebo 53).

The authors point out that resistance to sulfadoxine-pyrimethamine has spread throughout Africa, which could limit the effectiveness of the IPTi using this drug. But they add: "Sulfadoxine-pyrimethamine is the only antimalarial drug available for IPT in both pregnancy and infancy, in view of the combination's long half-life and prophylactic effect, established safety profile, acceptability, and affordability. IPT seems to work by prophylaxis, with sulfadoxine-pyrimethamine providing protection for up to 6 weeks in infants. New long-acting antimalarial drugs are urgently needed for use in IPTi."

They conclude: "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."

In the second Article, Professor Brian Greenwood and Dr Roly Gosling, London School of Hygiene and Tropical Medicine, UK, and colleagues assessed the effectiveness of both long-acting and short-acting antimalarials in IPTi. Their study was done in a region of high-resistance to sulfadoxine-pyrimethamine combination treatment.

The randomised controlled trial took place at sites of moderate intensity transmission (MIT) (1280 infants enrolled) and low intensity transmission (LIT) (1139) of malaria in Tanzania. Infants aged 8-16 weeks were randomly assigned to sulfadoxine plus pyrimethamine, chlorproguanil plus dapsone, mefloquine, or placebo-given at the second and third immunisations for diphtheria, whooping cough, and tetanus, and for measles. Recruitment was stopped early at the LIT site because of low malaria incidence. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2-11 months of age.

The researchers found that at the MIT sites, mefloquine had a protective efficacy of 38•1% against clinical malaria in infants aged 2-11 months, but neither sulfadoxine-pyrimethamine (-6•7%,) nor chlorproguanil-dapsone (10•8%) had a (statistically significant) protective effect. No regimen had any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1731 (8%) doses given on day 1 (5.5 times more likely to vomit than with placebo). More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, respectively) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths per group).

The authors say: "IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug."

They conclude: "If IPT in infants, children, or pregnant women is to remain a key component of malaria control strategies, new long-acting and very safe antimalarial drugs are urgently needed."

In an accompanying Comment, Rose McGready, Shoklo Malaria Research Unit, Thailand, says: "WHO has clearly struggled with these issues, and currently considers that the benefits of IPT with sulfadoxine-pyrimethamine exceed the risks. But it seems a close call. WHO does recommend IPT with this combination where resistance is not high and transmission not low, but precise definitions of these terms are awaited. As ever more information is needed to support these recommendations, to define thresholds, optimise dosing, and confirm safety at scale. Looking to the future, and hoping that current downward trends in malaria are sustained, we need to evaluate the newly introduced antimalarials (piperaquine and pyronaridine look promising) as well as mefloquine to determine whether and when is the best time to give IPT."

Link to Articles and Comment

The Lancet

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