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Abstract：
Seasonal malaria chemoprevention (SMC) aims to prevent malaria in children during the high malaria transmission season. The Achieving Catalytic Expansion of SMC in the Sahel (ACCESS-SMC) project sought to remove barriers to the scale-up of SMC in seven countries in 2015 and 2016. We evaluated the project, including coverage, effectiveness of the intervention, safety, feasibility, drug resistance, and cost-effectiveness.
For this observational study, we collected data on the delivery, effectiveness, safety, influence on drug resistance, costs of delivery, impact on malaria incidence and mortality, and cost-effectiveness of SMC, during its administration for 4 months each year (2015 and 2016) to children younger than 5 years, in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger, and Nigeria. SMC was administered monthly by community health workers who visited door-to-door. Drug administration was monitored via tally sheets and via household cluster-sample coverage surveys. Pharmacovigilance was based on targeted spontaneous reporting and monitoring systems were strengthened. Molecular markers of resistance to sulfadoxine-pyrimethamine and amodiaquine in the general population before and 2 years after SMC introduction was assessed from community surveys. Effectiveness of monthly SMC treatments was measured in case-control studies that compared receipt of SMC between patients with confirmed malaria and neighbourhood-matched community controls eligible to receive SMC. Impact on incidence and mortality was assessed from confirmed outpatient cases, hospital admissions, and deaths associated with malaria, as reported in national health management information systems in Burkina Faso and The Gambia, and from data from selected outpatient facilities (all countries). Provider costs of SMC were estimated from financial costs, costs of health-care staff time, and volunteer opportunity costs, and cost-effectiveness ratios were calculated as the total cost of SMC in each country divided by the predicted number of cases averted.
12 467 933 monthly SMC treatments were administered in 2015 to a target population of 3 650 455 children, and 25 117 480 were administered in 2016 to a target population of 7 551 491. In 2015, among eligible children, mean coverage per month was 76·4% (95% CI 74·0-78·8), and 54·5% children (95% CI 50·4-58·7) received all four treatments. Similar coverage was achieved in 2016 (74·8% [72·2-77·3] treated per month and 53·0% [48·5-57·4] treated four times). In 779 individual case safety reports over 2015-16, 36 serious adverse drug reactions were reported (one child with rash, two with fever, 31 with gastrointestinal disorders, one with extrapyramidal syndrome, and one with Quincke\'s oedema). No cases of severe skin reactions (Stevens-Johnson or Lyell syndrome) were reported. SMC treatment was associated with a protective effectiveness of 88·2% (95% CI 78·7-93·4) over 28 days in case-control studies (2185 cases of confirmed malaria and 4370 controls). In Burkina Faso and The Gambia, implementation of SMC was associated with reductions in the number of malaria deaths in hospital during the high transmission period, of 42·4% (95% CI 5·9 to 64·7) in Burkina Faso and 56·6% (28·9 to 73·5) in The Gambia. Over 2015-16, the estimated reduction in confirmed malaria cases at outpatient clinics during the high transmission period in the seven countries ranged from 25·5% (95% CI 6·1 to 40·9) in Nigeria to 55·2% (42·0 to 65·3) in The Gambia. Molecular markers of resistance occurred at low frequencies. In individuals aged 10-30 years without SMC, the combined mutations associated with resistance to amodiaquine (pfcrt CVIET haplotype and pfmdr1 mutations [86Tyr and 184Tyr]) had a prevalence of 0·7% (95% CI 0·4-1·2) in 2016 and 0·4% (0·1-0·8) in 2018 (prevalence ratio 0·5 [95% CI 0·2-1·2]), and the quintuple mutation associated with resistance to sulfadoxine-pyrimethamine (triple mutation in pfdhfr and pfdhps mutations [437Gly and 540Glu]) had a prevalence of 0·2% (0·1-0·5) in 2016 and 1·0% (0·6-1·6) in 2018 (prevalence ratio 4·8 [1·7-13·7]). The weighted average economic cost of administering four monthly SMC treatments was US$3·63 per child.
SMC at scale was effective in preventing morbidity and mortality from malaria. Serious adverse reactions were rarely reported. Coverage varied, with some areas consistently achieving high levels via door-to-door campaigns. Markers of resistance to sulfadoxine-pyrimethamine and amodiaquine remained uncommon, but with some selection for resistance to sulfadoxine-pyrimethamine, and the situation needs to be carefully monitored. These findings should support efforts to ensure high levels of SMC coverage in west and central Africa.
Unitaid.
For this observational study, we collected data on the delivery, effectiveness, safety, influence on drug resistance, costs of delivery, impact on malaria incidence and mortality, and cost-effectiveness of SMC, during its administration for 4 months each year (2015 and 2016) to children younger than 5 years, in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger, and Nigeria. SMC was administered monthly by community health workers who visited door-to-door. Drug administration was monitored via tally sheets and via household cluster-sample coverage surveys. Pharmacovigilance was based on targeted spontaneous reporting and monitoring systems were strengthened. Molecular markers of resistance to sulfadoxine-pyrimethamine and amodiaquine in the general population before and 2 years after SMC introduction was assessed from community surveys. Effectiveness of monthly SMC treatments was measured in case-control studies that compared receipt of SMC between patients with confirmed malaria and neighbourhood-matched community controls eligible to receive SMC. Impact on incidence and mortality was assessed from confirmed outpatient cases, hospital admissions, and deaths associated with malaria, as reported in national health management information systems in Burkina Faso and The Gambia, and from data from selected outpatient facilities (all countries). Provider costs of SMC were estimated from financial costs, costs of health-care staff time, and volunteer opportunity costs, and cost-effectiveness ratios were calculated as the total cost of SMC in each country divided by the predicted number of cases averted.
12 467 933 monthly SMC treatments were administered in 2015 to a target population of 3 650 455 children, and 25 117 480 were administered in 2016 to a target population of 7 551 491. In 2015, among eligible children, mean coverage per month was 76·4% (95% CI 74·0-78·8), and 54·5% children (95% CI 50·4-58·7) received all four treatments. Similar coverage was achieved in 2016 (74·8% [72·2-77·3] treated per month and 53·0% [48·5-57·4] treated four times). In 779 individual case safety reports over 2015-16, 36 serious adverse drug reactions were reported (one child with rash, two with fever, 31 with gastrointestinal disorders, one with extrapyramidal syndrome, and one with Quincke\'s oedema). No cases of severe skin reactions (Stevens-Johnson or Lyell syndrome) were reported. SMC treatment was associated with a protective effectiveness of 88·2% (95% CI 78·7-93·4) over 28 days in case-control studies (2185 cases of confirmed malaria and 4370 controls). In Burkina Faso and The Gambia, implementation of SMC was associated with reductions in the number of malaria deaths in hospital during the high transmission period, of 42·4% (95% CI 5·9 to 64·7) in Burkina Faso and 56·6% (28·9 to 73·5) in The Gambia. Over 2015-16, the estimated reduction in confirmed malaria cases at outpatient clinics during the high transmission period in the seven countries ranged from 25·5% (95% CI 6·1 to 40·9) in Nigeria to 55·2% (42·0 to 65·3) in The Gambia. Molecular markers of resistance occurred at low frequencies. In individuals aged 10-30 years without SMC, the combined mutations associated with resistance to amodiaquine (pfcrt CVIET haplotype and pfmdr1 mutations [86Tyr and 184Tyr]) had a prevalence of 0·7% (95% CI 0·4-1·2) in 2016 and 0·4% (0·1-0·8) in 2018 (prevalence ratio 0·5 [95% CI 0·2-1·2]), and the quintuple mutation associated with resistance to sulfadoxine-pyrimethamine (triple mutation in pfdhfr and pfdhps mutations [437Gly and 540Glu]) had a prevalence of 0·2% (0·1-0·5) in 2016 and 1·0% (0·6-1·6) in 2018 (prevalence ratio 4·8 [1·7-13·7]). The weighted average economic cost of administering four monthly SMC treatments was US$3·63 per child.
SMC at scale was effective in preventing morbidity and mortality from malaria. Serious adverse reactions were rarely reported. Coverage varied, with some areas consistently achieving high levels via door-to-door campaigns. Markers of resistance to sulfadoxine-pyrimethamine and amodiaquine remained uncommon, but with some selection for resistance to sulfadoxine-pyrimethamine, and the situation needs to be carefully monitored. These findings should support efforts to ensure high levels of SMC coverage in west and central Africa.
Unitaid.
摘要：
季节性疟疾化学预防（SMC）旨在在高疟疾传播季节预防儿童的疟疾。在萨赫勒地区实现SMC的催化扩张（ACCESS-SMC）项目旨在消除2015年和2016年在七个国家扩大SMC规模的障碍。我们评估了这个项目，包括覆盖范围，干预的有效性，安全,可行性,耐药性,和成本效益。
对于这项观察性研究，我们收集了送货的数据，有效性,安全,对耐药性的影响，交货成本，对疟疾发病率和死亡率的影响，和SMC的成本效益，在每年4个月（2015年和2016年）对5岁以下儿童的管理期间，在布基纳法索，乍得,冈比亚,几内亚,马里,尼日尔,和尼日利亚。SMC每月由上门拜访的社区卫生工作者管理。通过理货表和家庭集群样本覆盖率调查来监测药物管理。药物警戒基于有针对性的自发报告，并加强了监测系统。从社区调查中评估了在引入SMC之前和之后2年的普通人群中对磺胺多辛-乙胺嘧啶和阿莫地喹的抗性的分子标记。在病例对照研究中测量了每月SMC治疗的有效性，该研究比较了确诊疟疾患者与有资格接受SMC的邻里匹配社区对照之间SMC的接收。从确诊的门诊病例中评估对发病率和死亡率的影响，入院,以及与疟疾相关的死亡，根据布基纳法索和冈比亚国家卫生管理信息系统的报告，以及来自选定门诊设施（所有国家）的数据。SMC的提供商成本是根据财务成本估算的，医护人员的时间成本，和志愿者机会成本，成本效益比计算为每个国家的SMC总成本除以预测的避免病例数。
2015年对3650455名儿童的目标人群进行了12467933个月的SMC治疗，2016年对目标人群7551491人进行了25117480次给药.2015年，在符合条件的儿童中，每月平均覆盖率为76·4%（95%CI74·0-78·8），54·5%的儿童(95%CI50·4-58·7)接受了所有四种治疗。2016年实现了类似的覆盖率（每月治疗74·8％[72·2-77·3]和53·0％[48·5-57·4]治疗四次）。在2015-16年度的779份个体病例安全性报告中，报告了36例严重的药物不良反应（1例儿童出现皮疹，两个发烧，31患有胃肠道疾病，一个锥体外系综合征，和一个Quincke\的水肿）。没有报告严重皮肤反应（Stevens-Johnson或Lyell综合征）的病例。在病例对照研究（2185例确诊的疟疾和4370例对照）中，SMC治疗在28天内的保护效果为88·2％（95％CI78·7-93·4）。在布基纳法索和冈比亚，SMC的实施与高传播期间医院疟疾死亡人数的减少有关，布基纳法索为42·4%（95%CI5·9至64·7），冈比亚为56·6%（28·9至73·5）。在2015-16年间，七个国家在高传播期间门诊确诊的疟疾病例的估计减少范围从尼日利亚的25·5％（95％CI6·1至40·9）到冈比亚的55·2％（42·0至65·3）。抗性的分子标记发生在低频。在10-30岁没有SMC的人中，与阿莫地喹耐药相关的联合突变（pfcrtCVIET单倍型和pfmdr1突变[86Tyr和184Tyr]）在2016年的患病率为0·7％（95％CI0·4-1·2），2018年为0·4％（0·1-0·8）（患病率为0·5[95％CI0·2-1·2]），与磺胺多辛-乙胺嘧啶耐药相关的五重突变（pfdhfr和pfdhps突变的三重突变[437Gly和540Glu]）在2016年的患病率为0·2％（0·1-0·5），在2018年为1·0％（0·6-1·6）（患病率为4·8[1·7-13·7]）。每月进行四次SMC治疗的加权平均经济成本为每名儿童3·63美元。
大规模的SMC可有效预防疟疾的发病率和死亡率。严重的不良反应很少报道。覆盖范围各不相同，一些地区通过挨家挨户的运动不断达到高水平。对磺胺多辛-乙胺嘧啶和阿莫地喹的抗性标记仍然不常见，但是有一些对磺胺多辛-乙胺嘧啶的抗性选择，需要仔细监测情况。这些调查结果应支持确保西非和中非SMC覆盖率高的努力。
Unitaid。
对于这项观察性研究，我们收集了送货的数据，有效性,安全,对耐药性的影响，交货成本，对疟疾发病率和死亡率的影响，和SMC的成本效益，在每年4个月（2015年和2016年）对5岁以下儿童的管理期间，在布基纳法索，乍得,冈比亚,几内亚,马里,尼日尔,和尼日利亚。SMC每月由上门拜访的社区卫生工作者管理。通过理货表和家庭集群样本覆盖率调查来监测药物管理。药物警戒基于有针对性的自发报告，并加强了监测系统。从社区调查中评估了在引入SMC之前和之后2年的普通人群中对磺胺多辛-乙胺嘧啶和阿莫地喹的抗性的分子标记。在病例对照研究中测量了每月SMC治疗的有效性，该研究比较了确诊疟疾患者与有资格接受SMC的邻里匹配社区对照之间SMC的接收。从确诊的门诊病例中评估对发病率和死亡率的影响，入院,以及与疟疾相关的死亡，根据布基纳法索和冈比亚国家卫生管理信息系统的报告，以及来自选定门诊设施（所有国家）的数据。SMC的提供商成本是根据财务成本估算的，医护人员的时间成本，和志愿者机会成本，成本效益比计算为每个国家的SMC总成本除以预测的避免病例数。
2015年对3650455名儿童的目标人群进行了12467933个月的SMC治疗，2016年对目标人群7551491人进行了25117480次给药.2015年，在符合条件的儿童中，每月平均覆盖率为76·4%（95%CI74·0-78·8），54·5%的儿童(95%CI50·4-58·7)接受了所有四种治疗。2016年实现了类似的覆盖率（每月治疗74·8％[72·2-77·3]和53·0％[48·5-57·4]治疗四次）。在2015-16年度的779份个体病例安全性报告中，报告了36例严重的药物不良反应（1例儿童出现皮疹，两个发烧，31患有胃肠道疾病，一个锥体外系综合征，和一个Quincke\的水肿）。没有报告严重皮肤反应（Stevens-Johnson或Lyell综合征）的病例。在病例对照研究（2185例确诊的疟疾和4370例对照）中，SMC治疗在28天内的保护效果为88·2％（95％CI78·7-93·4）。在布基纳法索和冈比亚，SMC的实施与高传播期间医院疟疾死亡人数的减少有关，布基纳法索为42·4%（95%CI5·9至64·7），冈比亚为56·6%（28·9至73·5）。在2015-16年间，七个国家在高传播期间门诊确诊的疟疾病例的估计减少范围从尼日利亚的25·5％（95％CI6·1至40·9）到冈比亚的55·2％（42·0至65·3）。抗性的分子标记发生在低频。在10-30岁没有SMC的人中，与阿莫地喹耐药相关的联合突变（pfcrtCVIET单倍型和pfmdr1突变[86Tyr和184Tyr]）在2016年的患病率为0·7％（95％CI0·4-1·2），2018年为0·4％（0·1-0·8）（患病率为0·5[95％CI0·2-1·2]），与磺胺多辛-乙胺嘧啶耐药相关的五重突变（pfdhfr和pfdhps突变的三重突变[437Gly和540Glu]）在2016年的患病率为0·2％（0·1-0·5），在2018年为1·0％（0·6-1·6）（患病率为4·8[1·7-13·7]）。每月进行四次SMC治疗的加权平均经济成本为每名儿童3·63美元。
大规模的SMC可有效预防疟疾的发病率和死亡率。严重的不良反应很少报道。覆盖范围各不相同，一些地区通过挨家挨户的运动不断达到高水平。对磺胺多辛-乙胺嘧啶和阿莫地喹的抗性标记仍然不常见，但是有一些对磺胺多辛-乙胺嘧啶的抗性选择，需要仔细监测情况。这些调查结果应支持确保西非和中非SMC覆盖率高的努力。
Unitaid。
