Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial

Summary

Background

In the Sahel and sub-Sahelian regions of Africa, malaria transmission is highly seasonal. During a short period of high malaria transmission, mortality and morbidity are high in children under age 5 years. We assessed the efficacy of seasonal intermittent preventive treatment—a full dose of antimalarial treatment given at defined times without previous testing for malaria infection.

Methods

We did a randomised, placebo-controlled, double-blind trial of the effect of intermittent preventive treatment on morbidity from malaria in three health-care centres in Niakhar, a rural area of Senegal. 1136 children aged 2–59 months received either one dose of artesunate plus one dose of sulfadoxine-pyrimethamine or two placebos on three occasions during the malaria transmission season. The primary outcome was a first or single episode of clinical malaria detected through active or passive case detection. Primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00132561.

Findings

During 13 weeks of follow-up, the intervention led to an 86% (95% CI 80–90) reduction in the occurrence of clinical episodes of malaria. With passive case detection, protective efficacy against malaria was 86% (77–92), and when detected actively was 86% (78–91). The incidence of malaria in children on active drugs was 308 episodes per 1000 person-years at risk, whereas in those on placebo it was 2250 episodes per 1000 person-years at risk. 13 children were not included in the intention-to-treat analysis, which was restricted to children who received a first dose of antimalarial or placebo. There was an increase in vomiting in children who received the active drugs, but generally the intervention was well tolerated.

Interpretation

Intermittent preventive treatment could be highly effective for prevention of malaria in children under 5 years of age living in areas of seasonal malaria infection.

Introduction

According to the World Health Organization, 90% of deaths from malaria are in Africa and mostly in children under 5 years of age.¹ Efforts to control this disease in Africa have been hindered by the spread of resistance to chloroquine and, more recently, to sulfadoxine-pyrimethamine.2, 3 In Senegal, the yearly mortality rate from malaria in children has increased substantially since the beginning of the 1990s.⁴ This rise, associated with the emergence of chloroquine resistance, has been recorded in three regions of the country with different rates of malaria endemicity.⁵ The loss of effective and affordable drugs for the treatment of malaria has focused attention not only on the need for new antimalarial drugs,⁶ but also on the need for new ways to prevent infection, especially in children under 5 years.

Several studies have shown that African children can be protected effectively from the consequences of malaria by chemoprophylaxis, with use of anti-malarial drugs on a regular basis, sometimes in a subtherapeutic dose.7, 8, 9, 10, 11 In The Gambia, a pyrimethamine-dapsone combination taken fortnightly during the malaria transmission season reduced overall mortality in children by about 35%.¹¹ However, this approach to malaria control is difficult to sustain and there have been concerns that it would contribute to the spread of drug resistance.¹²

Intermittent preventive treatment differs from chemoprophylaxis because members of an at risk population are given a full therapeutic dose of treatment at set times, whether or not they are known to be infected. By contrast with chemoprophylaxis, drug concentrations might fall below parasite inhibitory concentrations between drug administrations. Such preventive treatment was first shown to be an effective approach for the control of malaria in pregnant women. In Malawi, this treatment method with sulfadoxine pyrimethamine reduced placental malaria by 72%.¹³ Subsequent studies have shown the beneficial effect of such treatment on severe anaemia in pregnant women and on the incidence of low birthweight.14, 15

A similar approach has been adapted to the prevention of malaria in infants in two studies in areas of Tanzania where disease transmission is perennial.16, 17 The frequencies of clinical episodes of malaria and anaemia were reduced by about two-thirds. Intermittent treatment has also been investigated in older children, with some success.18, 19, 20

In the Sahel and sub-Sahelian regions of Africa, which have a population of around 200 million, malaria transmission is highly seasonal and a high proportion of malaria deaths and admissions to hospital with severe malaria are in children older than 1 year.21, 22 In such situations, a successful programme of intermittent preventive treatment restricted to infants is likely to have only a modest effect on the overall burden of mortality and morbidity from malaria, and protection of older children is required. We have, therefore, studied the potential role of such treatment for the control of malaria in older children in a rural community.

The study was done in Niakhar, a rural district in central Senegal,²³ where the mortality rate for children under 5 years of age is 40 deaths per 1000 children per year. Malaria accounts for about a quarter of deaths in those aged 1–5 years.24, 25 Malaria transmission is highly seasonal (from August to October) with an average entomological inoculation rate of ten infective bites per person per year;²⁶ a substantial proportion of children are parasitaemic at the end of the malaria transmission season.²⁷