EU Seventh Framework Programme.

Background For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. Methods The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure–response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. Results A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. Conclusion The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1

Background: Distance sampling methods are widely used in ecology to estimate and map the abundance of animal and plant populations from spatial survey data. The key underlying concept in distance sampling is the detection function, the probability of detecting the occurrence of an event as a function of its distance from the observer, as well as other covariates that may influence detection. In epidemiology, the burden and distribution of infectious disease is often inferred from cases that are reported at clinics and hospitals. In areas with few public health facilities and low accessibility, the probability of detecting a case is also a function of the distance between an infected person and the "observer" (e.g. a health centre). While the problem of distance-related under-reporting is acknowledged in public health; there are few quantitative methods for assessing and correcting for this bias when mapping disease incidence. Here, we develop a modified version of distance sampling for prediction of infectious disease incidence by relaxing some of the framework's fundamental assumptions. We illustrate the utility of this approach using as our example malaria distribution in rural Burkina Faso, where there is a large population at risk but relatively low accessibility of health facilities. Results: The modified distance-sampling framework was used to predict the probability of reporting malaria infection at 8 rural clinics, based on road-travel distances from villages. The rate at which reporting probability dropped with distance varied between clinics, depending on road and clinic positions. The probability of case detection was estimated as 0.3-1 in the immediate vicinity of the clinic, dropping to 0.1-0.6 at a travel distance of 10 km, and effectively zero at distances > 30-40 km. Conclusions: To enhance the method's strategic impact, we provide an interactive mapping tool (as a self-contained R Shiny app) that can be used by non-specialists to interrogate model outputs and visualize how the overall probability of under-reporting and the catchment area of each clinic is influenced by changing the number and spatial allocation of health centres.

BackgroundAccording to the guidelines of the Burkina Faso National Malaria Control Programme, artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first-line drugs for uncomplicated malaria treatments. However, in some contexts where individuals will experience more than 1 episode of clinical malaria per year, it is unknown to what extent giving any of these ACTs repeatedly is safe. In the framework of the activities of the West African Network for Antimalarial Drugs (WANECAM) network, we have compared the efficacy and tolerability of repeated use of dihydroartemisinin-piperaquine (DHA-PQ) or artesunate-pyronaridine (PYR) with artesunate-amodiaquine (ASAQ).MethodsA randomised open-label parallel 3 arms trial was conducted to compare the efficacy of a three-day regimen of DHA-PQ and PYR with ASAQ. The trial involved children and adults with uncomplicated falciparum malaria. Participants were randomly assigned to one of the three treatment arms at the first clinical episode. During the subsequent clinical episodes, the same drug was administered. Follow-up duration was 42 days for each episode. Study duration was two years for each participant. Primary endpoints were the incidence rate of uncomplicated malaria over a period of 2 years and PCR corrected/uncorrected ACPR at day 28 and day 42. Safety parameters were also assessed.ResultsOf the 763 patients enrolled, the incidence rate of clinical malaria was 1.4, 1.2, and 1.5 episodes / person-year at risk in the ASAQ, DHA-PQ and PYRAMAX arms, respectively. The PCR-uncorrected efficacy at day 28 versus day 42 was: ASAQ 93.4%vs79.5%; PYR 98.1%vs74.8%; and DHA-PQ 99.5%vs95.2%. Bronchitis, rhinitis, abdominal pain, cough, QTc prolongation, headache, and vomiting were registered as the main adverse events in each of the three groups.ConclusionsThe findings from our study support the current recommendations for using artemisinin-based combinations in the treatment of uncomplicated malaria in areas of high malaria transmission such as Burkina Faso.

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BackgroundArtemisinin-based combination therapies (ACTs) constitute the worldwide recommended antimalarial drug as first-line treatment of uncomplicated malaria. However, the safety of repeated administration of a given ACT is poorly documented. The aim of this study was to evaluate the safety of repeated administration of ACTs in malaria patients over a period of 2 years.MethodsA randomised, open-label phase IIIb/IV comparative three arms trial comparing pyronaridine tetraphosphate/artesunate (PA), dihydroartemisinine-pipéraquine (DHA-PQP) and artesunate-amodiaquine (ASAQ) was carried out in Burkina Faso site as part of the WANECAM (West African Network for Clinical Trials of Antimalarial Drugs) global study. The study involved patients from 6 months of age presenting with uncomplicated malaria (fever/history of fever andPlasmodiumspp. density <200,000). The patients were treated repeatedly with the same ACT they were assigned to at enrolment. Safety assessments consisted with electrocardiographic and laboratory evaluations.ResultsA total of 763 participants with uncomplicated microscopically confirmedPlasmodiumspp. malaria were included. The proportion in ASAQ treated patients with creatinin abnormal value did not differ significantly between episode 1 and repeated malaria episodes (16.14% versus 13.98%, p=0.31). The proportion of patients with abnormal value of ALAT decreased significantly from baseline (25/234 versus 16/787, p< 0.01), but there is no difference in haemoglobin mean between the different episode (p>0.05) within each treatment arms. No evidence was found in the risk of QTc interval prolongation during repeated treatment in any arm.ConclusionsThe findings showed that safety was similar on first malaria treatment versus retreatment of subsequent episodes. The safety parameters were also comparable between the 3 treatment arms. These results support the repeated use of the three ACTs in uncomplicated malaria patients in Burkina Faso.

BackgroundHyperparasitaemia in malaria infection represents a worsening circumstance of the patient's condition; however, it still remains a concept with a controversial definition and seems likely to be understudied. The present study in the framework of the WANECAM activities aimed to assess the protective effect of 3ACTs on the emergence of the hyper-parasitaemia when repeatedly administrated over a period of two years to patients with uncomplicated malaria.MethodsA two-year prospective longitudinal study (763 adults and children) was conducted in a malaria endemic area of Burkina Faso. Passive detection of malaria cases with parasitaemia ≥200000 trophozoites/µl was done. Malaria smear was performed for hyperparasitaemia confirmation; a clinical examination and demographic data were recorded. Each patient was repeatedly treated with one of the three anti-malarials, pyronaridine-artesunate, dihydroartemisinin-piperaquine or artesunate-amodiaquine, at any uncomplicated malaria episode.ResultsA total of 107 cases of malaria with hyperparasitaemia were diagnosed; 63.55% occurred in under-five years children. The geometric mean of parasite density was 283366 trophozoites/µl (CI 95%: 264644–302087). The 46 cases recorded in the pyronaridine-artesunate treatment arm (224 patients) was higher compared to the 39 cases in the artesunate-amodiaquine arm (315 patients), (p=0.0024) and to the 22 cases in the dihydroartemisinin-piperaquine arm (224 patients), (p=0.0022). The difference between dihydroartemisinin-piperaquine and artesunate-amodiaquine treatment arms was not statistically significant (p=0.40).ConclusionsFrom this study, children under five year of age were mostly at risk of hyperparasitaemia. Dihydroartemisinin-piperaquine and artesunate-amodiaquine seem the most protective antimalarial against the occurrence of hyperparasitaemia.