Research Article: Effectiveness of Seasonal Malaria Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-Randomised Trial

Date Published: November 22, 2016

Publisher: Public Library of Science

Author(s): Badara Cissé, El Hadj Ba, Cheikh Sokhna, Jean Louis NDiaye, Jules F. Gomis, Yankhoba Dial, Catherine Pitt, Mouhamed NDiaye, Matthew Cairns, Ernest Faye, Magatte NDiaye, Aminata Lo, Roger Tine, Sylvain Faye, Babacar Faye, Ousmane Sy, Lansana Konate, Ekoue Kouevijdin, Clare Flach, Ousmane Faye, Jean-Francois Trape, Colin Sutherland, Fatou Ba Fall, Pape M. Thior, Oumar K. Faye, Brian Greenwood, Oumar Gaye, Paul Milligan, Abdisalan Mohamed Noor

Abstract: BackgroundSeasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age.Methods and FindingsSMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3–59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68–1.2, p = 0.496). A reduction of 60% (95% CI 54%–64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%–72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%–33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%–35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%–68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%–85%) p = 0.002 in 2008, 84% (95% CI 58%–94%, p < 0.001) in 2009, and 30% (95% CI -130%–79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint.ConclusionsSMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission.Trial NCT00712374

Partial Text: In 2012, WHO recommended that children under five years of age living in areas of highly seasonal malaria transmission in the Sahel and sub-Sahel should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) for up to four months of the year to prevent malaria [1]. It has been estimated that about 25 million children under five years of age resident in 15 countries live in areas suitable for SMC, defined as areas where 60% of annual cases fall in four consecutive months of the year. About 20 million of these children live in areas where estimates of the parasite rate (PfPr2-10) were consistent with an incidence of malaria in excess of 0.1 cases per child per year, areas where SMC is likely to be most cost effective [2,3]. Following regional meetings of malaria control programme managers to develop SMC implementation plans and the publication of an implementation guide detailing methods of delivery, monitoring, and evaluation of SMC [4,5], National Malaria Control Programmes have been quick to adopt this policy. SMC schemes have started in eleven countries (Burkina Faso, Cameroon, Chad, The Gambia, Ghana, Guinea, Mali, Niger, Nigeria, Senegal, and Togo). Seven of these countries are expanding access to SMC through a UNITAID-funded programme (ACCESS-SMC, [6]).

A census undertaken in May 2008 identified approximately 600,000 persons who were normally resident in the study area, living in 1,247 villages. Coverage with long-lasting insecticide treated nets (LLIN) in children was similar in all zones, ranging from 45% to 59% in the first year of the study and increasing to 67% to 77% by the third year (Table 1). SMC implementation started in September 2008 in Zone 1, treating about 14,000 children aged 3–59 months each month (mid-September, mid-October, and mid-November). About 90,000 children under ten years of age were treated in 2009, and about 160,000 were treated in 2010.

This trial showed that SMC delivered to children under ten years of age by district health teams on a large scale was highly effective in reducing the malaria burden in young and older children by at least 60%, that the intervention was well tolerated and well accepted by communities, and that high coverage could be achieved at moderate cost. There was a substantial reduction in the incidence of malaria and in the prevalence of parasitaemia, and, importantly, our results were consistent with an indirect benefit in age groups too old to receive SMC themselves.



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