Objectives:To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda.Design:Randomized single-blinded clinical trial.Setting:Apac, Uganda, an area of very high malaria transmission intensity.Participants:Children aged 6 mo to 10 y with uncomplicated falciparum malaria.Intervention:Treatment of malaria with AL or DP, each following standard 3-d dosing regimens.Outcome measures:Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.Results:Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%–26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%–19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%–12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%–16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.Conclusion:DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.

BackgroundUganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission.Methodology/Principal FindingsPatients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0–28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI −0.2–7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated.Conclusions/SignificanceDP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda.Trial RegistrationControlled-Trials.com ISRCTN75606663

BackgroundMalaria is a leading cause of disease burden in Uganda, although surprisingly few contemporary, age-stratified data exist on malaria epidemiology in the country. This report presents results from a total population survey of malaria infection and intervention coverage in a rural area of eastern Uganda, with a specific focus on how risk factors differ between demographic groups in this population.MethodsIn 2008, a cross-sectional survey was conducted in four contiguous villages in Mulanda, sub-county in Tororo district, eastern Uganda, to investigate the epidemiology and risk factors of Plasmodium species infection. All permanent residents were invited to participate, with blood smears collected from 1,844 individuals aged between six months and 88 years (representing 78% of the population). Demographic, household and socio-economic characteristics were combined with environmental data using a Geographical Information System. Hierarchical models were used to explore patterns of malaria infection and identify individual, household and environmental risk factors.ResultsOverall, 709 individuals were infected with Plasmodium, with prevalence highest among 5-9 year olds (63.5%). Thin films from a random sample of 20% of parasite positive participants showed that 94.0% of infections were Plasmodium falciparum and 6.0% were P. malariae; no other species or mixed infections were seen. In total, 68% of households owned at least one mosquito although only 27% of school-aged children reported sleeping under a net the previous night. In multivariate analysis, infection risk was highest amongst children aged 5-9 years and remained high in older children. Risk of infection was lower for those that reported sleeping under a bed net the previous night and living more than 750 m from a rice-growing area. After accounting for clustering within compounds, there was no evidence for an association between infection prevalence and socio-economic status, and no evidence for spatial clustering.ConclusionThese findings demonstrate that mosquito net usage remains inadequate and is strongly associated with risk of malaria among school-aged children. Infection risk amongst adults is influenced by proximity to potential mosquito breeding grounds. Taken together, these findings emphasize the importance of increasing net coverage, especially among school-aged children.

Objectives:To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.Design:Randomized single-blind controlled trial.Setting:Tororo, Uganda, an area of high-level malaria transmission.Participants:Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.Interventions:Amodiaquine + artesunate or artemether–lumefantrine.Outcome Measures:Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.Results:Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether–lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether–lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%–24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether–lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%–25.2%). Amodiaquine + artesunate and artemether–lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.Conclusions:Amodiaquine + artesunate and artemether–lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether–lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.

BackgroundHeath facility-based sentinel site surveillance has been proposed as a means of monitoring trends in malaria morbidity but may also provide an opportunity to improve malaria case management. Here we described the impact of a sentinel site malaria surveillance system on promoting laboratory testing and rational antimalarial drug use.Methodology/Principal FindingsSentinel site malaria surveillance was established at six health facilities in Uganda between September 2006 and January 2007. Data were collected from all patients presenting to the outpatient departments including demographics, laboratory results, diagnoses, and treatments prescribed. Between the start of surveillance and March 2010, a total 424,701 patients were seen of which 229,375 (54%) were suspected of having malaria. Comparing the first three months with the last three months of surveillance, the proportion of patients with suspected malaria who underwent diagnostic testing increased from 39% to 97% (p<0.001). The proportion of patients with an appropriate decision to prescribe antimalarial therapy (positive test result prescribed, negative test result not prescribed) increased from 64% to 95% (p<0.001). The proportion of patients appropriately prescribed antimalarial therapy who were prescribed the recommended first-line regimen artemether-lumefantrine increased from 48% to 69% (p<0.001).Conclusions/SignificanceThe establishment of a sentinel site malaria surveillance system in Uganda achieved almost universal utilization of diagnostic testing in patients with suspected malaria and appropriate decisions to prescribed antimalarial based on test results. Less success was achieved in promoting prescribing practice for the recommended first-line therapy. This system could provide a model for improving malaria case management in other health facilities in Africa.