RESUMO
BACKGROUND: Seasonal malaria chemoprevention (SMC) has shown high protective efficacy against clinical malaria and severe malaria in a series of clinical trials. We evaluated the effectiveness of SMC treatments against clinical malaria when delivered at scale through national malaria control programmes in 2015 and 2016. METHODS AND FINDINGS: Case-control studies were carried out in Mali and The Gambia in 2015, and in Burkina Faso, Chad, Mali, Nigeria, and The Gambia in 2016. Children aged 3-59 months presenting at selected health facilities with microscopically confirmed clinical malaria were recruited as cases. Two controls per case were recruited concurrently (on or shortly after the day the case was detected) from the neighbourhood in which the case lived. The primary exposure was the time since the most recent course of SMC treatment, determined from SMC recipient cards, caregiver recall, and administrative records. Conditional logistic regression was used to estimate the odds ratio (OR) associated with receipt of SMC within the previous 28 days, and SMC 29 to 42 days ago, compared with no SMC in the past 42 days. These ORs, which are equivalent to incidence rate ratios, were used to calculate the percentage reduction in clinical malaria incidence in the corresponding time periods. Results from individual countries were pooled in a random-effects meta-analysis. In total, 2,126 cases and 4,252 controls were included in the analysis. Across the 7 studies, the mean age ranged from 1.7 to 2.4 years and from 2.1 to 2.8 years among controls and cases, respectively; 42.2%-50.9% and 38.9%-46.9% of controls and cases, respectively, were male. In all 7 individual case-control studies, a high degree of personal protection from SMC against clinical malaria was observed, ranging from 73% in Mali in 2016 to 98% in Mali in 2015. The overall OR for SMC within 28 days was 0.12 (95% CI: 0.06, 0.21; p < 0.001), indicating a protective effectiveness of 88% (95% CI: 79%, 94%). Effectiveness against clinical malaria for SMC 29-42 days ago was 61% (95% CI: 47%, 72%). Similar results were obtained when the analysis was restricted to cases with parasite density in excess of 5,000 parasites per microlitre: Protective effectiveness 90% (95% CI: 79%, 96%; P<0.001), and 59% (95% CI: 34%, 74%; P<0.001) for SMC 0-28 days and 29-42 days ago, respectively. Potential limitations include the possibility of residual confounding due to an association between exposure to malaria and access to SMC, or differences in access to SMC between patients attending a clinic and community controls; however, neighbourhood matching of cases and controls, and covariate adjustment, attempted to control for these aspects, and the observed decline in protection over time, consistent with expected trends, argues against a major bias from these sources. CONCLUSIONS: SMC administered as part of routine national malaria control activities provided a very high level of personal protection against clinical malaria over 28 days post-treatment, similar to the efficacy observed in clinical trials. The case-control design used in this study can be used at intervals to ensure SMC treatments remain effective.
Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Controle de Doenças Transmissíveis , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Pirimetamina/uso terapêutico , Estações do Ano , Sulfadoxina/uso terapêutico , África Ocidental/epidemiologia , Fatores Etários , Amodiaquina/efeitos adversos , Antimaláricos/efeitos adversos , Estudos de Casos e Controles , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Incidência , Lactente , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Masculino , Carga Parasitária , Plasmodium falciparum/crescimento & desenvolvimento , Avaliação de Programas e Projetos de Saúde , Pirimetamina/efeitos adversos , Medição de Risco , Fatores de Risco , Sulfadoxina/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Seasonal malaria chemoprevention is used in 13 countries in the Sahel region of Africa to prevent malaria in children younger than 5 years. Resistance of Plasmodium falciparum to seasonal malaria chemoprevention drugs across the region is a potential threat to this intervention. METHODS: Between December, 2015, and March, 2016, and between December, 2017, and March, 2018, immediately following the 2015 and 2017 malaria transmission seasons, community surveys were done among children younger than 5 years and individuals aged 10-30 years in districts implementing seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine in Burkina Faso, Chad, Guinea, Mali, Nigeria, Niger and The Gambia. Dried blood samples were collected and tested for P falciparum DNA by PCR. Resistance-associated haplotypes of the P falciparum genes crt, mdr1, dhfr, and dhps were identified by quantitative PCR and sequencing of isolates from the collected samples, and survey-weighted prevalence and prevalence ratio between the first and second surveys were estimated for each variant. FINDINGS: 5130 (17·5%) of 29 274 samples from 2016 and 2176 (7·6%) of 28 546 samples from 2018 were positive for P falciparum on quantitative PCR. Among children younger than 5 years, parasite carriage decreased from 2844 of 14 345 samples (19·8% [95% CI 19·2-20·5]) in 2016 to 801 of 14 019 samples (5·7% [5·3-6·1]) in 2018 (prevalence ratio 0·27 [95% CI 0·24-0·31], p<0·0001). Genotyping found no consistent evidence of increasing prevalence of amodiaquine resistance-associated variants of crt and mdr1 between 2016 and 2018. The dhfr haplotype IRN (consisting of 51Ile-59Arg-108Asn) was common at both survey timepoints, but the dhps haplotype ISGEAA (431Ile-436Ser-437Gly-540Glu-581Ala-613Ala), crucial for resistance to sulfadoxine-pyrimethamine, was always rare. Parasites carrying amodiaquine resistance-associated variants of both crt and mdr1 together with dhfr IRN and dhps ISGEAA occurred in 0·05% of isolates. The emerging dhps haplotype VAGKGS (431Val-436Ala-437Gly-540Lys-581Gly-613Ser) was present in four countries. INTERPRETATION: In seven African countries, evidence of a significant reduction in parasite carriage among children receiving seasonal malaria chemoprevention was found 2 years after intervention scale-up. Combined resistance-associated haplotypes remained rare, and seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine is expected to retain effectiveness. The threat of future erosion of effectiveness due to dhps variant haplotypes requires further monitoring. FUNDING: Unitaid.
Assuntos
Antimaláricos , Malária Falciparum , Malária , Criança , Humanos , Plasmodium falciparum , Amodiaquina/uso terapêutico , Haplótipos , Antimaláricos/uso terapêutico , Estações do Ano , Prevalência , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Combinação de Medicamentos , Quimioprevenção , Nigéria , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/uso terapêutico , Genômica , Resistência a Medicamentos/genéticaRESUMO
BACKGROUND: The intermittent administration of seasonal malaria chemoprevention (SMC) is recommended to prevent malaria among children aged 3-59 months in areas of the Sahel subregion in Africa. However, the cost-effectiveness and cost savings of SMC have not previously been evaluated in large-scale studies. METHODS: We did a cost-effectiveness and cost-savings analysis of a large-scale, multi-country SMC campaign with sulfadoxine-pyrimethamine plus amodiaquine for children younger than 5 years in seven countries in the Sahel subregion (Burkina Faso, Chad, Guinea, Mali, Niger, Nigeria, and The Gambia) in 2016. The financial and economic costs were analysed from the programmatic perspective and are reported in 2016 US$ for each country. The estimated numbers of averted malaria cases, deaths, and disability-adjusted life-years (DALYs) were based on numbers of SMC treatments administered and modelled malaria transmission. Cost savings were calculated from a programmatic perspective corresponding to the diagnostic and treatment costs for malaria cases averted. FINDINGS: The total cost of SMC for all seven countries was $22·8 million, and the weighted average economic cost of administering four monthly SMC cycles was $3·63 per child (ranging from $2·71 in Niger to $8·20 in The Gambia). Based on 80% modelled effectiveness of SMC, the incremental economic cost per malaria case averted ranged from $2·91 in Niger to $30·73 in The Gambia; the cost per severe case averted ranged from $119·63 in Niger to $506·00 in The Gambia; the cost per death averted ranged from $533·56 in Niger to $2256·92 in The Gambia; and the cost per DALY averted (discounted by 3%) ranged from $18·66 in Niger to $78·91 in The Gambia. The estimated total economic cost savings to the health systems in all seven countries were US$66·0 million and the total net economic cost savings were US$43·2 million. INTERPRETATION: SMC is a low-cost and highly cost-effective intervention that contributes to substantial cost savings by reducing malaria diagnostic and treatment costs among children. FUNDING: Unitaid.