Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

マウライ国における熱帯熱マラリア感染に対する抗マラリア薬剤効果 : chloroquineよりsufladoxine/pyrimethamineへの変更7年後の経過

マラウイでは,熱帯熱マラリア患者のchloroquine治療失敗例の増加に伴い,1993年からsulfadoxine/pyrimethamine (SP)がchloroquineに代り導入された.この変更から7年後,我々はサリマ地区の無症候性熱帯熱マラリア感染学童においてin vitroおよびin vivo抗マラリア剤効果,またそれぞれpyrimethamineおよびsulfadoxine耐性と関連する原虫dihydrofolate reductase遺伝子(dhfr)およびdihydropteroate reductase遺伝子(dhps)変異について検討した.対象学童は無作為にchloroquine 3日間の標準投与群(n=50)ないしはSP一回投与群(n=40)に分けられ,治療後28日間にわたり経過が追跡された.In vivoにおけるchloroquineおよびSP感受性率はそれぞれ92%および83%であった.分離熱帯熱マラリア原虫株のin vitro薬剤感受性はSP(n=52),pyrimethamine(52),quinine(36),mefloquine(17)およびamodiaquine(14)に対して検討された.分離株の92%がpyrimethamine耐性を示したにも関わらず,85%はSP感受性であった.Quinineおよびmefloquineに対して検討したすべて,およびamodiaquineに対する93%の分離株はin vitro感受性であった.173例の熱帯熱マラリア感染において,3重変異Asn-108/Ile-51/Arg-59 dhfrおよび2重変異Gly-437/Glu-540 dhpsを持つ原虫が高頻度(78%)で認められた.これらの結果は治療薬剤変更に伴う薬剤圧の減少が原虫chloroquine感受性の回復をもたらしたことを示唆した.高度のpyrimethamineに対するin vitro耐性は高頻度にdhfr3重変異が見られたことと一致した.それにもかかわらず観察された高いSPの効果は,高度pyrimethamine耐性原虫におけるsulfadoxineおよびpyrimethamine間の相乗作用の重要性を示唆した.In Malawi chloroquine was replaced by sulfadoxine/pyrimethamine (SP) in 1993 because of increasing chloroquine treatment failures in Plasmodium falciparum (P.falciparum) patients. Seven years after this change, we studied in vitro and in vivo efficacies of different antimalarial drugs and mutations of dihydrofolate reductase (dhfr)/dihydropteroate synthase (dhps) genes in P. falciparum infections of asymptomatic school children in Salima. The included children were randomly allocated to either treatment group with a standard dose of 3-days chloroquine (n = 50) or a single dose of SP (40) and followed up for 28 days. The in vivo sensitivity rate of chloroquine and SP were 92% and 83% respectively. P.falciparum isolates were successfully evaluated for in vitro drug sensitivity to SP (n = 52), pyrimethamine (52), amodiaquine (14), quinine (36), and mefloquine (17). Although 92% of the isolates were resistant to pyrimethamine, 85% showed in vitro sensitivity to SP. All isolates assessed for quinine and mefloquine and 93% of the isolates for amodiaquine showed in vitro sensitivity. A high prevalence rate (78%) of parasites with triple Asn-108/Ile-51/Arg-59 dhfr and double Gly-437/ Glu-540 dhps mutations was found in 173 P. falciparum infections. Our results suggest that the reduced drug pressure accompanying the policy change consequently resulted in recovery of chloroquine sensitivity in parasites. The high in vitro pyrimethamine resistance was consistent with the high prevalence of the dhfr triple mutant. However, the high efficacy of SP confirmed the important role of synergism between pyrimethamine and sulfadoxine in the treatment of highly pyrimethamine-resistant parasites

マウライ国における熱帯熱マラリア感染に対する抗マラリア薬剤効果 : chloroquineよりsufladoxine/pyrimethamineへの変更7年後の経過

マラウイでは,熱帯熱マラリア患者のchloroquine治療失敗例の増加に伴い,1993年からsulfadoxine/pyrimethamine (SP)がchloroquineに代り導入された.この変更から7年後,我々はサリマ地区の無症候性熱帯熱マラリア感染学童においてin vitroおよびin vivo抗マラリア剤効果,またそれぞれpyrimethamineおよびsulfadoxine耐性と関連する原虫dihydrofolate reductase遺伝子(dhfr)およびdihydropteroate reductase遺伝子(dhps)変異について検討した.対象学童は無作為にchloroquine 3日間の標準投与群(n=50)ないしはSP一回投与群(n=40)に分けられ,治療後28日間にわたり経過が追跡された.In vivoにおけるchloroquineおよびSP感受性率はそれぞれ92%および83%であった.分離熱帯熱マラリア原虫株のin vitro薬剤感受性はSP(n=52),pyrimethamine(52),quinine(36),mefloquine(17)およびamodiaquine(14)に対して検討された.分離株の92%がpyrimethamine耐性を示したにも関わらず,85%はSP感受性であった.Quinineおよびmefloquineに対して検討したすべて,およびamodiaquineに対する93%の分離株はin vitro感受性であった.173例の熱帯熱マラリア感染において,3重変異Asn-108/Ile-51/Arg-59 dhfrおよび2重変異Gly-437/Glu-540 dhpsを持つ原虫が高頻度(78%)で認められた.これらの結果は治療薬剤変更に伴う薬剤圧の減少が原虫chloroquine感受性の回復をもたらしたことを示唆した.高度のpyrimethamineに対するin vitro耐性は高頻度にdhfr3重変異が見られたことと一致した.それにもかかわらず観察された高いSPの効果は,高度pyrimethamine耐性原虫におけるsulfadoxineおよびpyrimethamine間の相乗作用の重要性を示唆した.In Malawi chloroquine was replaced by sulfadoxine/pyrimethamine (SP) in 1993 because of increasing chloroquine treatment failures in Plasmodium falciparum (P.falciparum) patients. Seven years after this change, we studied in vitro and in vivo efficacies of different antimalarial drugs and mutations of dihydrofolate reductase (dhfr)/dihydropteroate synthase (dhps) genes in P. falciparum infections of asymptomatic school children in Salima. The included children were randomly allocated to either treatment group with a standard dose of 3-days chloroquine (n = 50) or a single dose of SP (40) and followed up for 28 days. The in vivo sensitivity rate of chloroquine and SP were 92% and 83% respectively. P.falciparum isolates were successfully evaluated for in vitro drug sensitivity to SP (n = 52), pyrimethamine (52), amodiaquine (14), quinine (36), and mefloquine (17). Although 92% of the isolates were resistant to pyrimethamine, 85% showed in vitro sensitivity to SP. All isolates assessed for quinine and mefloquine and 93% of the isolates for amodiaquine showed in vitro sensitivity. A high prevalence rate (78%) of parasites with triple Asn-108/Ile-51/Arg-59 dhfr and double Gly-437/ Glu-540 dhps mutations was found in 173 P. falciparum infections. Our results suggest that the reduced drug pressure accompanying the policy change consequently resulted in recovery of chloroquine sensitivity in parasites. The high in vitro pyrimethamine resistance was consistent with the high prevalence of the dhfr triple mutant. However, the high efficacy of SP confirmed the important role of synergism between pyrimethamine and sulfadoxine in the treatment of highly pyrimethamine-resistant parasites