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Toussaint Rouamba,1,2 Paul Sondo,1 Karim Derra,1 Seydou Nakanabo-Diallo,1,3 Biebo Bihoun,1 Eli Rouamba,1 Zekiba Tarnagda,1 Adama Kazienga,1 Innocent Valea,1 Hermann Sorgho,1 Franco Pagnoni,4 Fati Samadoulougou-Kirakoya,2 Halidou Tinto1 1Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Centre National de la Recherche Scientifique et Technologique, Ouagadougou, Burkina Faso; 2Center for Research in Epidemiology, Biostatistics and Clinical Research, School of Public Health, Université Libre de Bruxelles (ULB), Bruxelles, Belgium; 3Department of Clinical Research, Centre Muraz, Bobo-Dioulasso, Burkina Faso; 4World Health Organization, Geneva, SwitzerlandCorrespondence: Toussaint RouambaClinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Centre National de la Recherche Scientifique et Technologique, 42, Avenue Kumda-Yonre, 11 BP 218 Ouaga CMS 11, Ouagadougou, Burkina FasoTel +226 6665 3204Email rouambatoussaint@gmail.comBackground and purpose: Resource-limited countries face challenges in settingup effective pharmacovigilance systems. This study aimed to monitor the occurrence ofadverseevents (AEs) after theuse of artemisinin-based combination therapies (ACTs), identify potential drivers of reporting suspected adversedrugreactions (ADRs) and monitor AEs among women who were inadvertently exposed to ACTs in the firsttrimester of pregnancy.Patients and methods: We conducted a prospective observational study from May 2010 to July 2012 in Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso. The HDSS area was divided into active and passivesurveillance areas to monitor AEs among patients (regardless of age or sex) who received a first-line ACT (artemether–lumefantrine or artesunate–amodiaquine). In the activesurveillance area, patients were followedup for 28 days, while in the passivesurveillance area, patients were encouraged to return voluntarily to the health facility to report any occurrence of AEs until day 28 after drug intake. We assessed the crude incidence rates of AEsin both cohorts and performed Cox regression with mixed random effects to identify potential drivers of ADR occurrence.Results: In total, 3170 participants were included in the study. Of these, 40.3% had reported at least one AE, with 39.6% and 44.4% from active and passivesurveillance groups, respectively. The types of ADRs were similar in both groups. The most frequent reported ADRs were anorexia, weakness, cough, dizziness and pruritus. One case of abortion and eight cases of death were reported, but none of them was related to the ACT. The variance in random factors showed a high variability of ADR occurrence between patients in both groups, whereas variability between health facilities was low in theactivesurveillance group and high in passivesurveillance group. Taking more than two concomitantmedications was associated with high hazard in ADR occurrence, whereas therainyseason was associated with low hazard.Conclusion: This study showed that both passive and activesurveillance approaches were useful tools. The HDSS allowed usto capture a few cases of exposure during thefirsttrimester of pregnancy. The passivesurveillance approach, which is more likely to be implemented by malaria control programs, seems to be more relevant in the Sub-Saharan African context.Keywords: HDSS, artemisinin-based combination therapies, safety, pregnancy, malaria, rural, Burkina Faso

Toussaint Rouamba,1,2 Paul Sondo,2 Isidore W Yerbanga,2 Adelaide Compaore,2 Maminata Traore-Coulibaly,2 Franck S Hien,2 Nassirou A Diande,2 Daniel Valia,2 Innocent Valea,2 Patricia Akweongo,3 Rita Baiden,4 Fred Binka,4 Fati Kirakoya-Samadoulougou,1 Halidou Tinto2 1Center for Research in Epidemiology, Biostatistics and Clinical Research, School of Public Health, Université libre de Bruxelles (ULB), Brussels, Belgium; 2Clinical Research Unit of Nanoro, Institute for Research in Health Sciences, National Center for Scientific and Technological Research, Ouagadougou, Burkina Faso; 3Epidemiology and Disease Control Department, University of Ghana, Accra, Ghana; 4INDEPTH-Network, Accra, Ghana Purpose: In 2005, Burkina Faso changed its first-line treatment for uncomplicated malaria from chloroquine to artemisinin-based combination therapies (ACTs). Patient adherence to ACTs regimen is a keystone to achieve the expected therapeutic outcome and prevent the emergence and spread of parasite resistance. Eleven years after the introduction of ACTs in the health system, this study aimed to measure adherence level of patients in rural settlement and investigate the determinants of nonadherence.Patients and methods: The study was carried out at public peripheral health facilities from May 2017 to August 2017 in Nanoro health district, Burkina Faso. An electronic semi-structured questionnaire was used for data collection from patients with an ACT prescription at their medical consultation exit visit and during home visit at day 5±2. Adherence level was measured through self-report and pill counts. Logistic regression was performed to identify factors for nonadherence.Results: The analysis was conducted on 199 outpatients who received ACT as prescription. About 92.5% of ACT prescriptions included artemether-lumefantrine tablets. Adherence level was measured in 97.0% of included patients at day 5±2. Of these, 86.0% were classified as “complete adherent” and 14.0% as “nonadherent”. In univariate analysis, patients/caregivers who considered that affordability of ACTs was easy seemed to be less adherent to the treatment regimen (OR: 0.26; 95% CI: 0.07–0.70). In univariate and multivariable analyses, patients/caregivers who did not receive advices from health care workers (HCWs) were more likely to be nonadherent to the prescribed ACTs (adjusted OR: 3.21; 95% CI: 1.13–9.12).Conclusion: This study demonstrates that majority of those who get an ACT prescription comply with the recommended regimen. This emphasizes that in rural settings where ACTs are provided free of charge or at a subsidized price, patient adherence to ACTs is high, thus minimizing the risk of subtherapeutic concentrations of the drug in blood which is known to increase resistance and susceptibility to new infections. Therefore, to address the problem of patient nonadherence, strategy to strengthen communication between HCWs and patients should be given greater consideration. Keywords: malaria, hyperendemic area, drug prescription, artemether-lumefantrine, amodiaquine-artesunate &nbsp

Background Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. Methods A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. Results Both the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4–1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. Conclusion Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

Declining malaria transmission and known difficulties with current diagnostic tools for malaria, such as microscopy and rapid diagnostic tests (RDTs) in particular at low parasite densities, still warrant the search for sensitive diagnostic tests. Molecular tests need substantial simplification before implementation in clinical settings in countries where malaria is endemic. Direct blood PCR (db-PCR), circumventing DNA extraction, to detect Plasmodium was developed and adapted to be visualized by nucleic acid lateral flow immunoassay (NALFIA). The assay was evaluated in the laboratory against samples from confirmed Sudanese patients (n = 51), returning travelers (n = 214), samples from the Dutch Blood Bank (n = 100), and in the field in Burkina Faso (n = 283) and Thailand (n = 381) on suspected malaria cases and compared to RDT and microscopy. The sensitivity and specificity of db-PCR-NALFIA compared to the initial diagnosis in the laboratory were 94.4% (95% confidence interval [CI] = 0.909 to 0.969) and 97.4% (95% CI = 0.909 to 0.969), respectively. In Burkina Faso, the sensitivity was 94.8% (95% CI = 0.88.7 to 97.9%), and the specificity was 82.4% (95% CI = 75.4 to 87.7%) compared to microscopy and 93.3% (95% CI = 87.4 to 96.7%) and 91.4% (95% CI = 85.2 to 95.3%) compared to RDT. In Thailand, the sensitivity and specificity were 93.4% (CI = 86.4 to 97.1%) and 90.9 (95% CI = 86.7 to 93.9%), respectively, compared to microscopy and 95.6% (95% CI = 88.5 to 98.6%) and 87.1% (95% CI = 82.5 to 90.6) compared to RDT. db-PCR-NALFIA is highly sensitive and specific for easy and rapid detection of Plasmodium parasites and can be easily used in countries where malaria is endemic. The inability of the device to discriminate Plasmodium species requires further investigation.