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Background In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761

The scale-up of malaria control efforts has led to marked reductions in malaria burden over the past twenty years, but progress has slowed. Implementation of indoor residual spraying (IRS) of insecticide, a proven vector control intervention, has been limited and difficult to sustain partly because questions remain on its added impact over widely accepted interventions such as bed nets. Using data from 14 enhanced surveillance health facilities in Uganda, a country with high bet net coverage yet high malaria burden, we estimate the impact of starting and stopping IRS. We show that stopping IRS resulted in a 5-fold increase in malaria incidence within 10 months, but reinstating IRS led to an over 5-fold decrease within 8 months. In areas where IRS was initiated and sustained, malaria incidence dropped by 85% after year 4. IRS could play a critical role in achieving global malaria targets, particularly in areas where progress has stalled.

Background Malaria is a major cause of morbidity and mortality globally, especially in sub-Saharan Africa. Widespread resistance to pyrethroids threatens the gains achieved by vector control. To counter resistance to pyrethroids, third-generation indoor residual spraying (3GIRS) products have been developed. This study details the results of a multi-country cost and cost-effectiveness analysis of indoor residual spraying (IRS) programmes using Actellic®300CS, a 3GIRS product with pirimiphos-methyl, in sub-Saharan Africa in 2017 added to standard malaria control interventions including insecticide-treated bed nets versus standard malaria control interventions alone. Methods An economic evaluation of 3GIRS using Actellic®300CS in a broad range of sub-Saharan African settings was conducted using a variety of primary data collection and evidence synthesis methods. Four IRS programmes in Ghana, Mali, Uganda, and Zambia were included in the effectiveness analysis. Cost data come from six IRS programmes: one in each of the four countries where effect was measured plus Mozambique and a separate programme conducted by AngloGold Ashanti Malaria Control in Ghana. Financial and economic costs were quantified and valued. The main indicator for the cost was cost per person targeted. Country-specific case incidence rate ratios (IRRs), estimated by comparing IRS study districts to adjacent non-IRS study districts or facilities, were used to calculate cases averted in each study area. A deterministic analysis and sensitivity analysis were conducted in each of the four countries for which effectiveness evaluations were available. Probabilistic sensitivity analysis was used to generate plausibility bounds around the incremental cost-effectiveness ratio estimates for adding IRS to other standard interventions in each study setting as well as jointly utilizing data on effect and cost across all settings. Results Overall, IRRs from each country indicated that adding IRS with Actellic®300CS to the local standard intervention package was protective compared to the standard intervention package alone (IRR 0.67, [95% CI 0.50–0.91]). Results indicate that Actellic®300CS is expected to be a cost-effective (> 60% probability of being cost-effective in all settings) or highly cost-effective intervention across a range of transmission settings in sub-Saharan Africa. Discussion Variations in the incremental costs and cost-effectiveness likely result from several sources including: variation in the sprayed wall surfaces and house size relative to household population, the underlying malaria burden in the communities sprayed, the effectiveness of 3GIRS in different settings, and insecticide price. Programmes should be aware that current recommendations to rotate can mean variation and uncertainty in budgets; programmes should consider this in their insecticide-resistance management strategies. Conclusions The optimal combination of 3GIRS delivery with other malaria control interventions will be highly context specific. 3GIRS using Actellic®300CS is expected to deliver acceptable value for money in a broad range of sub-Saharan African malaria transmission settings.

Background: Integrated community case management (iCCM) for malaria, pneumonia and diarrhea continues to be a recommended strategy to address child mortality in areas where access to health facilities is limited. Objective: To identify models of, and gaps in, institutionalization of benchmark components of iCCM into national health systems of low-and-middle-income countries, in order to draw lessons for future iCCM implementation and sustainability. Methods: A scoping review of relevant searchable policy documents and publications available in English literature was undertaken. Data were selected, collated and characterized by three reviewers using the Arksey and O’Malley framework. Results: Overall 19 countries were reviewed. Despite the existence of discrete policies, most iCCM programs relied heavily on implementing partners and donor financing. Parallel implementing partner-run systems were often used to procure and supply iCCM medicines. These modes of implementation occasionally violated some health system strengthening principles. Drug stock-outs were still prominent in several countries, and iCCM indicators were sometimes not integrated into the national health management information system. There were no clearly defined motivation packages for both salaried and unsalaried workers, and there were several supervision challenges. Community-based performance-financing, use of technology with mobile devices (mHealth), small procedural improvements, and provision of targeted rather than universal services, were some of the promising interventions for improved iCCM institutionalization. Conclusion: Sustainable iCCM will require improved ownership by the benefiting communities and the local and central governments. Government commitment should be evident in budgeting processes and implementation strategies.

BACKGROUND In treating malaria in Uganda, artemether-lumefantrine (AL) has been associated with a lower risk of recurrent parasitemia, compared with artesunate-amodiaquine (AS/AQ), but changing treatment practices may have altered parasite susceptibility. METHODS We enrolled 602 children aged 6-59 months with uncomplicated falciparum malaria from 3 health centers in 2013-2014 and randomly assigned them to receive treatment with AS/AQ or AL. Primary outcomes were risks of recurrent parasitemia within 28 days, with or without adjustment to distinguish recrudescence from new infection. Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed. RESULTS Of enrolled patients, 594 (98.7%) completed the 28-day study. Risks of recurrent parasitemia were lower with AS/AQ at all 3 sites (overall, 28.6% vs 44.6%; P < .001). Recrudescences were uncommon, and all occurred after AL treatment (0% vs 2.5%; P = .006). Recovery of the hemoglobin level was greater with AS/AQ (1.73 vs 1.39 g/dL; P = .04). Both regimens were well tolerated; serious adverse events were uncommon (1.7% in the AS/AQ group and 1.0% in the AL group). AS/AQ selected for mutant pfcrt/pfmdr1 polymorphisms and AL for wild-type pfcrt/pfmdr1 polymorphisms associated with altered drug susceptibility. CONCLUSIONS AS/AQ treatment was followed by fewer recurrences than AL treatment, contrasting with older data. Each regimen selected for polymorphisms associated with decreased treatment response. Research should consider multiple or rotating regimens to maintain treatment efficacies.

Three years following a mass bed net distribution campaign, the addition of school-based distribution to antenatal care (ANC) distribution in Cross River State, Nigeria, increased household ownership of any net to nearly 80%, whereas ownership in the comparison area was below 50%. School distribution was nearly equitable among rich and poor, and very few households obtained nets from both ANC and schools, suggesting complementary reach., Background: In 2013, the World Health Organization recommended distribution through schools, health facilities, community health workers, and mass campaigns to maintain coverage with insecticide-treated nets (ITNs). We piloted school distribution in 3 local government areas (LGAs) of Cross River State, Nigeria. Methods: From January to March 2011, all 3 study sites participated in a mass ITN campaign. Baseline data were collected in June 2012 (N=753 households) and school distribution began afterward. One ITN per student was distributed to 4 grades once a year in public schools. Obubra LGA distributed ITNs in 2012, 2013, and 2014 and Ogoja LGA in 2013 and 2014 while Ikom LGA served as a comparison site. Pregnant women in all sites were eligible to receive ITNs through standard antenatal care (ANC). Endline survey data (N=1,450 households) were collected in March 2014. Data on ITN ownership, population access to an ITN, and ITN use were gathered and analyzed. Statistical analysis used contingency tables and chi-squared tests for univariate analysis, and a concentration index was calculated to assess equity in ITN ownership. Results: Between baseline and endline, household ownership of at least 1 ITN increased in the intervention sites, from 50% (95% confidence interval [CI]: 44.7, 54.3) to 76% (95% CI: 71.2, 81.0) in Ogoja and from 51% (95% CI: 35.3, 66.7) to 78% (95% CI: 71.5, 83.1) in Obubra, as did population access to ITN, from 36% (95% CI: 32.0, 39.5) to 53% (95% CI: 48.0, 58.0) in Ogoja and from 34% (95% CI: 23.2, 45.6) to 55% in Obubra (95% CI: 48.4, 60.9). In contrast, ITN ownership declined in the comparison site, from 64% (95% CI: 56.4, 70.8) to 43% (95% CI: 37.4, 49.4), as did population ITN access, from 47% (95% CI: 40.0, 53.7) to 26% (95% CI: 21.9, 29.9). Ownership of school ITNs was nearly as equitable (concentration index 0.06 [95% CI: 0.02, 0.11]) as for campaign ITNs (−0.03 [95% CI: −0.08, 0.02]), and there was no significant oversupply or undersupply among households with ITNs. Schools were the most common source of ITNs at endline and very few households (

Background Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are the primary tools for malaria prevention in Africa. It is not known whether reductions in malaria can be sustained after IRS is discontinued. The aim of this study was to assess changes in malaria morbidity in a historically high transmission area of Uganda where IRS was discontinued after a four-year period of effective control followed by a universal LLIN distribution campaign. Methods Individual-level malaria surveillance data were collected from one outpatient department and one inpatient setting in Apac District, Uganda from July 2009 through November 2015. Rounds of IRS were delivered approximately every six months from February 2010 through May 2014 followed by universal LLIN distribution in June 2014. Temporal changes in the malaria test positivity rate (TPR) were estimated during and after IRS using interrupted time series analyses, controlling for age, rainfall, and autocorrelation. Results Data include 65,421 outpatient visits and 13,955 pediatric inpatient admissions for which a diagnostic test for malaria was performed. In outpatients under five years, baseline TPR was 60-80% followed by a rapid and then sustained decrease to 15-30%. Over 4-18 months following discontinuation of IRS, absolute TPR values increased by an average of 3.29% per month (95% CI 2.01-4.57%), returning to baseline levels. Similar trends were seen in outpatients over five years of age and pediatric admissions. Conclusions Discontinuation of IRS in a historically high transmission intensity area was associated with a rapid increase in malaria morbidity to pre-IRS levels.