ArticlesSeasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial
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
Section snippets
Patients and study design
An individually-randomised, double-blind, placebo-controlled trial of seasonal intermittent preventive treatment with one dose of artesunate and one dose of sulfadoxine-pyrimethamine, given on three occasions during the malaria transmission season, was undertaken in 1203 Senegalese children aged 2–59 months. Ethical approval for the study was obtained from the ethics review boards of the Senegalese Ministry of Health and London School of Hygiene & Tropical Medicine. An independent Data Safety
Results
1203 children aged between 6 weeks and 59 months were selected from the Niakhar database, 1136 of whom met the entry criteria (figure 1). 1088 were randomly assigned to the control group (546) or to the intermittent preventive treatment group (542). A high rate of compliance was achieved throughout the trial; 1075 children (99%) received the first dose, 1051 (97%) the second dose, and 1012 (93%) the third dose. Compliance was similar in the two treatment groups. The per-protocol population
Discussion
The results of this trial show that seasonal intermittent preventive treatment with sulfadoxine-pyrimethamine plus artesunate confers an impressive amount of protection against malaria in children aged 2–59 months of age in an area of seasonal malaria transmission. The protective effect remained strong even when several definitions of clinical malaria were used and was seen across all age groups. A similar, positive outcome from the use of such treatment has been reported from Kambila, Mali,31
References (38)
- et al.
Resistance to pyrimethamine/sulfadoxine in Plasmodium falciparum in 12 villages in north east Tanzania and a test of chlorproguanil/dapsone
Acta Trop
(1997) - et al.
Impact of chloroquine resistance on malaria mortality
C R Acad Sci III
(1998) Malaria disaster in Africa
Lancet
(1998)- et al.
Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants
Lancet
(1997) - et al.
Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial
Lancet
(1999) - et al.
Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial
Lancet
(2001) - et al.
Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial
Lancet
(2003) - et al.
Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial
Lancet
(2002) - et al.
Efficacy of artesunate plus pyrimethamine-sulfadoxine for uncomplicated malaria in Gambian children. A double-blind, randomized, controlled trial
Lancet
(2000) - et al.
Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial
Lancet
(2005)
Proportional mortality among under fives-regional estimates 2002
The efficacy of antimalarial monotherapies, sulphadoxine-pyrimethamine and amodiaquine in East Africa: implications for sub-regional policy
Trop Med Int Health
Analysis of the effects of malaria chemoprophylaxis in children on haematological responses, morbidity and mortality
Bull World Health Organ
Effects of heavy and repeated malarial infections on Gambian infants and children; effects of erythrocytic parasitization
BMJ
Compliance with malaria chemoprophylaxis over a five-year period among children in a rural area of The Gambia
J Trop Med Hyg
Comparison of two strategies for control of malaria within a primary health care programme in the Gambia
Lancet
The use of anti-malarial drugs to prevent malaria in the population of malaria-endemic areas
Am J Trop Med Hyg
The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi
Am J Trop Med Hyg
Cited by (182)
Malaria infection and predictor factors among Chadian nomads’ children
2024, BMC Public HealthReview Article Systematic Review and Meta-Analysis of Seasonal Malaria Chemoprevention
2024, American Journal of Tropical Medicine and Hygiene