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Background Until recently, due to widespread prevalence of molecular markers associated with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance in east and southern Africa, seasonal malaria chemoprevention (SMC) has not been used at scale in this region. This study assessed the protective effectiveness of monthly administration of SP + AQ (SPAQ) to children aged 3–59 months in Karamoja sub-region, Uganda, where parasite resistance is assumed to be high and malaria transmission is seasonal. Methods A two-arm quasi-experimental, open-label prospective non-randomized control trial (nRCT) was conducted in three districts. In two intervention districts, 85,000 children aged 3–59 months were targeted to receive monthly courses of SMC using SPAQ during the peak transmission season (May to September) 2021. A third district served as a control, where SMC was not implemented. Communities with comparable malaria attack rates were selected from the three districts, and households with at least one SMC-eligible child were purposively selected. A total cohort of 600 children (200 children per district) were selected and followed using passive surveillance for breakthrough confirmed malaria episodes during the five-month peak transmission season. Malaria incidence rate per person-months and number of malaria episodes among children in the two arms were compared. Kaplan–Meier failure estimates were used to compare the probability of a positive malaria test. Other factors that may influence malaria transmission and infection among children in the two arms were also assessed using multivariable cox proportional hazards regression model. Results The malaria incidence rate was 3.0 and 38.8 per 100 person-months in the intervention and control groups, respectively. In the intervention areas 90.0% (361/400) of children did not experience any malaria episodes during the study period, compared to 15% (29/200) in the control area. The incidence rate ratio was 0.078 (95% CI 0.063–0.096), which corresponds to a protective effectiveness of 92% (95% CI 90.0–94.0) among children in the intervention area. Conclusion SMC using SPAQ provided high protective effect against malaria during the peak transmission season in children aged 3–59 months in the Karamoja sub-region of Uganda.

Seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine combined with amodiaquine (SPAQ) effectively protects eligible children from malaria in areas of high and seasonal transmission. However, concerns about parasite resistance to sulfadoxine–pyrimethamine in East and Southern Africa necessitate evaluating alternative drug regimens. This study assessed the effectiveness of SPAQ and dihydroartemisinin–piperaquine for SMC in Uganda. This three-arm, open-label, non-inferiority and superiority, cluster-randomised, controlled trial was conducted in Karamoja subregion, Uganda, among children aged 3–59 months and 6–59 months for SPAQ and dihydroartemisinin–piperaquine, respectively. Of 427 villages, 380 were randomly assigned (1:1) to the SPAQ group and dihydroartemisinin–piperaquine group, and 47 were assigned to the control group (no SMC). The superiority component compared the SPAQ and dihydroartemisinin–piperaquine groups with the control group, whereas the non-inferiority component compared the dihydroartemisinin–piperaquine group with the SPAQ group. The primary endpoint was confirmed malaria incidence using rapid diagnostic tests or microscopy. Survival analyses were done on an intention-to-treat basis (in all randomised participants), with adjustments made for covariate imbalances at baseline. Additionally, molecular markers associated with resistance to sulfadoxine–pyrimethamine and amodiaquine were analysed on 750 malaria-positive blood samples from children younger than 5 years before and after five SMC cycles. This trial was registered with ClinicalTrials.gov, NCT05323721, and has been completed. During June 18–30, 2022, 3881 children were enrolled; 1755 in SPAQ, 1736 in dihydroartemisinin–piperaquine, and 390 in control villages. Of these children, 3629 were analysed. Incidence rates were 0·90 cases per 100 person-months in the SPAQ group, 0·80 cases per 100 person-months in the dihydroartemisinin–piperaquine group, and 18·26 cases per 100 person-months in the control group. SPAQ and dihydroartemisinin–piperaquine reduced malaria risk by 94% (hazard ratio [HR] 0·06 [95% CI 0·04–0·08]; p<0·001) and 96% (0·04 [0·03–0·06]; p<0·001), respectively. Based on the prespecified non-inferiority margin of 1·4, there was non-inferiority between the protective effectiveness of dihydroartemisinin–piperaquine and that of SPAQ (HR 0·90 [95% CI 0·58–1·39]). Prevalence of mutations linked to moderate (Plasmodium falciparum dihydrofolate reductase [PfDHFR] and P falciparum dihydropteroate synthetase reductase [PfDHPS]) and high (PfDHFR Ile164Leu and PfDHPS Ala581Gly) sulfadoxine–pyrimethamine resistance were more than 88% and less than 5%, respectively. Mutations associated with 4-aminoquinolone resistance (P falciparum multidrug resistance protein-1 [PfMDR1] Asp1246Tyr and PfMDR1 Asn86Tyr) were less than 1%. There was no significant increase in the prevalence of antifolate and artemisinin partial resistance-associated mutations, but a decrease was observed for key aminoquinoline resistance-associated alleles: P falciparum chloroquine resistance transporter protein Lys76Thr, P falciparum multidrug resistance protein Asn86Tyr, and PfMDR1 Asp1246Tyr (p<0·001). No serious or fatal adverse events were reported. SPAQ and dihydroartemisinin–piperaquine effectively reduced malaria in children younger than 5 years, with no safety concerns. There was no evidence of resistance selection by SMC. Although these findings support SPAQ-based SMC in Eastern and Southern Africa, ongoing resistance surveillance and efficacy monitoring are essential for sustained impact. GiveWell. For the Swahili translation of the abstract see Supplementary Materials section.

Evidence is limited on whether Integrated Community Case Management (iCCM) improves treatment coverage of the top causes of childhood mortality (acute respiratory illnesses (ARI), diarrhoea and malaria). The coverage impact of iCCM in Central Uganda was evaluated. Between July 2010 and December 2012 a pre-post quasi-experimental study in eight districts with iCCM was conducted; 3 districts without iCCM served as controls. A two-stage household cluster survey at baseline (n = 1036 and 1042) and end line (n = 3890 and 3844) was done in the intervention and comparison groups respectively. Changes in treatment coverage and timeliness were assessed using difference in differences analysis (DID). Mortality impact was modelled using the Lives Saved Tool. 5,586 Village Health Team members delivered 1,907,746 treatments to children under age five. Use of oral rehydration solution (ORS) and zinc treatment of diarrhoea increased in the intervention area, while there was a decrease in the comparison area (DID = 22.9, p = 0.001). Due to national stock-outs of amoxicillin, there was a decrease in antibiotic treatment for ARI in both areas; however, the decrease was significantly greater in the comparison area (DID = 5.18; p<0.001). There was a greater increase in Artemisinin Combination Therapy treatment for fever in the intervention areas than in the comparison area but this was not significant (DID = 1.57, p = 0.105). In the intervention area, timeliness of treatments for fever and ARI increased significantly higher in the intervention area than in the comparison area (DID = 2.12, p = 0.029 and 7.95, p<0.001, respectively). An estimated 106 lives were saved in the intervention area while 611 lives were lost in the comparison area. iCCM significantly increased treatment coverage for diarrhoea and fever, mitigated the effect of national stock outs of amoxicillin on ARI treatment, improved timeliness of treatments for fever and ARI and saved lives.

Background Malaria remains the number one cause of morbidity and mortality in Uganda. In 2009, the United States President’s Malaria Initiative (PMI) funded an indoor residual spraying (IRS) project in 10 mid-northern districts, resulting in marked reductions in malaria prevalence over 5 years, from 62.5 percent to 7.2 percent. When the project ended and IRS withdrawn, malaria prevalence increased exponentially to pre-IRS level of 63 percent in 2016 and was characterized by frequent life-threatening upsurges that were exacerbated by a weak national led malaria surveillance system with delayed and piece meal responses. Malaria Consortium, in collaboration with Nwoya district local government implemented a district led malaria surveillance and response system. This study was conducted to compare the impact of District led and national led surveillance and response systems on overall malaria burden in two sub-counties in Nwoya district, Northern Uganda. Methods The assessment was conducted between week 41 of 2018 and week 10 of 2019 in Anaka and Alero sub counties following the shift from the national to district led malaria surveillance and response system. A district multi-sectoral malaria response taskforce team, known as the District Malaria Surveillance and Response Team (DMSRT), was formed by the Nwoya District Health Team (DHT). The DMSRT was trained and equipped with new surveillance tools for early detection of and response to malaria upsurges within the district, and were mandated to develop a costed district specific malaria response plan. Results All (18) targeted health facilities provided weekly malaria reports and continuously updated the malaria normal channel graphs. There was an overall reduction in weekly new malaria cases from 12.9 in week 41 of 2018 to 6.2 cases in week 10 of 2019. Malaria positivity rates (TPR) for Alero and Anaka sub-counties reduced from 76.0 percent and 69.3 percent at week 42 of 2018 to 28 percent and 30.3 percent, respectively at week 10 of 2019. Conclusions Malaria surveillance and response, with precisely targeted multipronged activities, when led and implemented by local district health authorities is an effective, efficient, and sustainable approach to prevent malaria upsurges and associated morbidity and mortality.

Background Resistance of malaria vectors to pyrethroid insecticides has been attributed to selection pressure from long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS), and the use of chemicals in agriculture. The use of different classes of insecticides in combination or by rotation has been recommended for resistance management. The aim of this study was to understand the role of IRS with a carbamate insecticide in management of pyrethroid resistance. Methods Anopheles mosquitoes were collected from multiple sites in nine districts of Uganda (up to five sites per district). Three districts had been sprayed with bendiocarb. Phenotypic resistance was determined using standard susceptibility tests. Molecular assays were used to determine the frequency of resistance mutations. The kdr L1014S homozygote frequency in Anopheles gambiae s.s. was used as the outcome measure to test the effects of various factors using a logistic regression model. Bendiocarb coverage, annual rainfall, altitude, mosquito collection method, LLIN use, LLINs distributed in the previous 5 years, household use of agricultural pesticides, and malaria prevalence in children 2–9 years old were entered as explanatory variables. Results Tests with pyrethroid insecticides showed resistance and suspected resistance levels in all districts except Apac (a sprayed district). Bendiocarb resistance was not detected in sprayed sites, but was confirmed in one unsprayed site (Soroti). Anopheles gambiae s.s. collected from areas sprayed with bendiocarb had significantly less kdr homozygosity than those collected from unsprayed areas. Mosquitoes collected indoors as adults had significantly higher frequency of kdr homozygotes than mosquitoes collected as larvae, possibly indicating selective sampling of resistant adults, presumably due to exposure to insecticides inside houses that would disproportionately affect susceptible mosquitoes. The effect of LLIN use on kdr homozygosity was significantly modified by annual rainfall. In areas receiving high rainfall, LLIN use was associated with increased kdr homozygosity and this association weakened as rainfall decreased, indicating more frequency of exposure to pyrethroids in relatively wet areas with high vector density. Conclusion This study suggests that using a carbamate insecticide for IRS in areas with high levels of pyrethroid resistance may reduce kdr frequencies in An. gambiae s.s.

Background The World Health Organization (WHO) recommends seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SPAQ) for children aged 3 to 59 months, living in areas where malaria transmission is highly seasonal. However, due to widespread prevalence of resistance markers, SMC has not been implemented at scale in East and Southern Africa. An initial study in Uganda showed that SMC with SPAQ was feasible, acceptable, and protective against malaria in eligible children in Karamoja region. Nonetheless, exploration of alternative regimens is warranted since parasite resistance threats persist. Objective The study aims to test the effectiveness of SMC with Dihydroartemisinin-piperaquine (DP) or SPAQ (DP-SMC & SPAQ-SMC), chemoprevention efficacy as well as the safety and tolerability of DP compared to that of SPAQ among 3-59 months old children in Karamoja region, an area of Uganda where malaria transmission is highly seasonal. Methods A Type II hybrid effectiveness-implementation study design consisting of four components: 1) a cluster randomized controlled trial (cRCT) using passive surveillance to establish confirmed malaria cases in children using both SPAQ and DP; 2a) a prospective cohort study to determine the chemoprevention efficacy of SPAQ and DP (if SPAQ or DP clears sub-patent infection and provides 28 days of protection from new infection) and whether drug concentrations and/or resistance influence the ability to clear and prevent infection; 2b) a sub study examining pharmacokinetics of DP in children between 3 to <6 months; 3) a resistance markers study in children 3–59 months in the research districts plus the standard intervention districts to measure changes in resistance marker prevalence over time and finally; 4) a process evaluation. Discussion This study evaluates the effects of SPAQ-SMC versus DP-SMC on clinical malaria in vulnerable children in the context of high parasite SP resistance, whilst informing on the best implementation strategies. Conclusion This study will inform malaria policy in high-burden countries, specifically on utility of SMC outside the sahel, and contribute to progress in malaria control.

Background : The World Health Organization (WHO) recommends seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine for children aged 3 to 59 months, living in areas where malaria transmission is highly seasonal. However, due to widespread prevalence of resistance markers, SMC has not been implemented at scale in East and Southern Africa. An initial study in Uganda showed that SMC with SPAQ was feasible, acceptable, and protective against malaria in eligible children in Karamoja region. Nonetheless, exploration of alternative regimens is warranted since parasite resistance threats persist. Objective : The study aims to test the effectiveness of SMC with DP or SPAQ (DP-SMC & SPAQ-SMC), chemoprevention efficacy as well as the safety and tolerability of DP compared to that of SPAQ among 3-59 months old children in Karamoja region, an area of Uganda where malaria transmission is highly seasonal. Methods : A Type II hybrid effectiveness-implementation study design consisting of four components: 1) a cluster randomized controlled trial (cRCT) using passive surveillance to establish confirmed malaria cases in children using both SPAQ and DP; 2a) a prospective cohort study to determine the chemoprevention efficacy of SPAQ and DP (if SPAQ or DP clears sub-patent  infection and provides 28 days of protection from new infection) and whether drug concentrations and/or resistance influence the ability to clear and prevent infection; 2b) a sub study examining pharmacokinetics of DP in children between 3 to <6 months; 3) a resistance markers study in children 3–59 months in the research districts plus the standard intervention districts to measure changes in resistance marker prevalence over time and finally; 4) a process evaluation. Discussion : This study evaluates the effects of a clinical intervention on relevant outcomes whilst collecting information on implementation. Conclusion : This study will inform malaria policy in high-burden countries and contribute to progress in malaria control.

Please be advised that one of the author names is incorrectly spelled in the published article: 'Irene Kyomuhagi' should be 'Irene Kyomuhangi'.Please be advised that one of the author names is incorrectly spelled in the published article: 'Irene Kyomuhagi' should be 'Irene Kyomuhangi'.

Background Scale-up of malaria interventions seems to have contributed to a decline in the disease but other factors may also have had some role. Understanding changes in transmission and determinant factors will help to adapt control strategies accordingly. Methods Four sites in Ethiopia and Uganda were set up to monitor epidemiological changes and effectiveness of interventions over time. Here, results of a survey during the peak transmission season of 2012 are reported, which will be used as baseline for subsequent surveys and may support adaptation of control strategies. Data on malariometric and entomological variables, socio-economic status (SES) and control coverage were collected. Results Malaria prevalence varied from 1.4 % in Guba (Ethiopia) to 9.9 % in Butemba (Uganda). The most dominant species was Plasmodium vivax in Ethiopia and Plasmodium falciparum in Uganda. The majority of human-vector contact occurred indoors in Uganda, ranging from 83 % ( Anopheles funestus sensu lato) to 93 % ( Anopheles gambiae s.l.), which is an important factor for the effectiveness of insecticide-treated nets (ITNs) or indoor residual spraying (IRS). High kdr -L1014S (resistance genotype) frequency was observed in A. gambiae sensu stricto in Uganda. Too few mosquitoes were collected in Ethiopia, so it was not possible to assess vector habits and insecticide resistance levels. ITN ownership did not vary by SES and 56–98 % and 68–78 % of households owned at least one ITN in Ethiopia and Uganda, respectively. In Uganda, 7 % of nets were purchased by households, but the nets were untreated. In three of the four sites, 69–76 % of people with access to ITNs used them. IRS coverage ranged from 84 to 96 % in the three sprayed sites. Half of febrile children in Uganda and three-quarters in Ethiopia for whom treatment was sought received diagnostic tests. High levels of child undernutrition were detected in both countries carrying important implications on child development. In Uganda, 7–8 % of pregnant women took the recommended minimum three doses of intermittent preventive treatment. Conclusion Malaria epidemiology seems to be changing compared to earlier published data, and it is essential to have more data to understand how much of the changes are attributable to interventions and other factors. Regular monitoring will help to better interpret changes, identify determinants, modify strategies and improve targeting to address transmission heterogeneity.

Referral of severely ill children to hospital is key in the Integrated Management of Childhood Illness (IMCI). In rural Uganda, we documented the caretakers' ability to complete referral to hospital from 12 health facilities. Of 227 children, only 63 (28%) had completed referral after 2 weeks, at a median cost of US$8.85 (range 0.40–89.00). Failure to attend hospital resulted from lack of money (139 children, 90%), transport problems (39, 26%), and responsibilities at home (26, 17%). Children with incomplete referral continued treatment at referring health centres (87, 54%) or in the private sector (45, 28%). Our results show that cost of referral must decrease to make paediatric referral realistic. When referral is difficult, more specific IMCI referral criteria should be used and first-level health workers should be empowered to manage severely ill children.