Date Published: March 13, 2019
Publisher: Public Library of Science
Author(s): Jean Louis A. Ndiaye, Youssoupha Ndiaye, Mamadou S. Ba, Babacar Faye, Maguette Ndiaye, Amadou Seck, Roger Tine, Pape Moussa Thior, Sharanjeet Atwal, Khalid Beshir, Colin Sutherland, Oumar Gaye, Paul Milligan, Lorenz von Seidlein
Abstract: BackgroundSeasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011.Methods and findingsTwenty-four villages, including 2,301 children aged 3–59 months and 2,245 aged 5–9 years, were randomised to receive SMC with community case management (CCM) (SMC villages) or CCM alone (control villages). In all villages, community health workers (CHWs) were trained to treat malaria cases with artemisinin combination therapy after testing with a rapid diagnostic test (RDT). In SMC villages, CHWs administered SMC to children aged 3 months to 9 years once a month for 5 months. The study was conducted from 27 July to 31 December 2011. The primary outcome was malaria (fever or history of fever with a positive RDT). The prevalence of anaemia and parasitaemia was measured in a survey at the end of the transmission season. Molecular markers associated with resistance to SMC drugs were analysed in samples from incident malaria cases and from children with parasitaemia in the survey. SMC was well tolerated with no serious adverse reactions. There were 1,472 RDT-confirmed malaria cases in the control villages and 270 in the SMC villages. Among children under 5 years of age, the rate difference was 110.8/1,000/month (95% CI 64.7, 156.8; p < 0.001) and among children 5–9 years of age, 101.3/1,000/month (95% CI 66.7, 136.0; p < 0.001). The mean haemoglobin concentration at the end of the transmission season was higher in SMC than control villages, by 6.5 g/l (95% CI 2.0, 11; p = 0.007) among children under 5 years of age, and by 5.2 g/l (95% CI 0.4, 9.9; p = 0.035) among children 5–9 years of age. The prevalence of parasitaemia was 18% in children under 5 years of age and 25% in children 5–9 years of age in the control villages, and 5.7% and 5.8%, respectively, in these 2 age groups in the SMC villages, with prevalence differences of 12.5% (95% CI 6.8%, 18.2%; p < 0.001) in children under 5 years of age and 19.3% (95% CI 8.3%, 30.2%; p < 0.001) in children 5–9 years of age. The pfdhps-540E mutation associated with clinical resistance to sulfadoxine-pyrimethamine was found in 0.8% of samples from malaria cases but not in the final survey. Twelve children died in the control group and 14 in the SMC group, a rate difference of 0.096/1,000 child-months (95% CI 0.99, 1.18; p = 0.895). Limitations of this study include that we were not able to obtain blood smears for microscopy for all suspected malaria cases, such that we had to rely on RDTs for confirmation, which may have included false positives.ConclusionsIn this study SMC for children under 10 years of age given over 5 months was feasible, well tolerated, and effective in preventing malaria episodes, and reduced the prevalence of parasitaemia and anaemia. SMC with CCM achieved high coverage and ensured children with malaria were promptly treated with artemether-lumefantrine.Trial registrationwww.clinicaltrials.govNCT01449045.
Partial Text: Seasonal malaria chemoprevention (SMC), the administration once per month of antimalarial treatment using sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) to prevent malaria, is currently recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year . In many of parts of this region, it may be appropriate to consider extending the scope of SMC programmes by including older children [2–6] and, in areas with a longer transmission season, by providing protection for more than 4 months each year. In south-east Senegal, for example, individual patient data from Saraya Hospital extracted from registers for the year 2011 showed that 75% of cases admitted to hospital with severe malaria were children under 10 years of age, and 85% of the severe malaria cases occurred over the 5 months from July to November (Fig 1). In addition, in remote areas, it may be beneficial to combine SMC with community case management (CCM)  or to provide SMC teams with access to rapid diagnostic tests (RDTs) and artemisinin combination therapies (ACTs) so that children who are unwell can be screened quickly and treated with rapid-acting ACTs if they are shown to have malaria.
Twenty-four villages were randomised to receive SMC in addition to CCM for malaria or CCM alone (Fig 3). The 2 groups were similar with respect to baseline characteristics (Table 1); the distance to the nearest health centre ranged from 4 km to 30 km, and insecticide-treated bednet coverage was high. From July to November in 2010, the year before the trial, from district health records there were a total of 1,238 cases of malaria in children under 5 years of age in the study villages, an incidence rate of 0.12 per child per month.
In this cluster randomised trial of SMC with CCM for malaria in children aged less than 10 years delivered over 5 months in the Saraya district of south-east Senegal, we showed that SMC was associated with a reduction of more than 100 malaria cases per 1,000 children per month both in children aged less than 5 years of age and in children aged 5–9 years, compared to CCM alone, and with a reduction in the prevalence of anaemia and malaria parasitaemia at the end of the transmission season in both age groups. SMC was well tolerated over this period, which is longer than studied previously  and longer than is currently used in national SMC programmes, where SMC is provided for 3 or 4 months . A relatively small reduction in the number of cases was shown in the fifth month of treatment, but because incidence was already very high at the time of the first cycle, it is possible that if cycle 1 had started earlier, in early July, the fifth treatment might have had more impact. Delivery of SMC by resident CHWs, who were also providing CCM for malaria, achieved high coverage each month and ensured that children with symptomatic malaria were promptly treated with artemether-lumefantrine.