{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:53:08Z","timestamp":1778133188338,"version":"3.51.4"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD)\u00a0primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk\u2013benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether\u2013lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether\u2013lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization\u00a0on day 3, precluding assessment of primaquine efficacy. Prevalence of the <jats:italic>CYP2D6<\/jats:italic>*4, <jats:italic>CYP2D6<\/jats:italic>*10 and <jats:italic>CYP2D6<\/jats:italic>*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the <jats:italic>CYP2D6<\/jats:italic>*4\/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the <jats:italic>G6PD<\/jats:italic> deficient (A\u2212) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop &gt;\u20092\u00a0g\/dL; this was not associated with primaquine treatment but may be associated with <jats:italic>G6PD<\/jats:italic> genotype [52.9% (9\/17) with A\u2212 genotype vs. 31% (36\/116) with other genotypes (p\u2009=\u20090.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether\u2013lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients\u00a0who completed 42-day follow-up.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Safety, tolerability, <jats:italic>CYP2D6<\/jats:italic> and <jats:italic>G6PD<\/jats:italic> variant data from this study support the deployment of the WHO-recommended SLD primaquine without <jats:italic>G6PD<\/jats:italic> testing to advance malaria elimination in South African districts with low-intensity residual transmission.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/pactr.samrc.ac.za\/TrialDisplay.aspx?TrialID=1859\">https:\/\/pactr.samrc.ac.za\/TrialDisplay.aspx?TrialID=1859<\/jats:ext-link><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-019-2841-8","type":"journal-article","created":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T14:39:40Z","timestamp":1561387180000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial"],"prefix":"10.1186","volume":"18","clinical-trial-number":[{"clinical-trial-number":"pactr201611001859416","registry":"10.18810\/pactr"}],"author":[{"given":"Jaishree","family":"Raman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Allen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Workman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Mabuza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendrik","family":"Swanepoel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian","family":"Malatje","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Frean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0107-3063","authenticated-orcid":false,"given":"Karen I.","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"2841_CR1","doi-asserted-by":"crossref","unstructured":"The malERA Refresh consultative panel on characterising the reservoir and measuring transmission. An updated research agenda for characterising the reservoir and measuring transmission in malaria elimination and eradication. PLoS Med. 2017;14:e1002452.","DOI":"10.1371\/journal.pmed.1002452"},{"key":"2841_CR2","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1093\/infdis\/jiy014","volume":"217","author":"I Chen","year":"2018","unstructured":"Chen I, Diawara H, Mahamar A, Sanogo K, Keita S, Kone D, et al. Safety of single-dose primaquine in G6PD-deficient and G6PD-normal males in Mali without malaria: an open-label, phase 1, dose adjustment trial. J Infect Dis. 2018;217:1298\u2013308.","journal-title":"J Infect Dis"},{"key":"2841_CR3","unstructured":"WHO. Updated WHO Policy Recommendation: Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva: World Health Organization; 2012. http:\/\/www.who.int\/malaria\/pq_updated_policy_recommendation_en_102012.pdf Accessed 09 Dec 2018."},{"key":"2841_CR4","unstructured":"WHO. Policy brief on single-dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva: World Health Organization; 20122015. http:\/\/www.who.int\/malaria\/publications\/atoz\/who_htm_gmp_2015.1.pdf. Accessed 09 Dec 2018."},{"key":"2841_CR5","unstructured":"WHO. Guidelines for the treatment of malaria. Third edition. Geneva: World Health Organization; 20122015. http:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/162441\/9789241549127_eng.pdf;jsessionid=6A8BD95D41D35B441DB453E032AE1905?sequence=1. Accessed 09 Dec 2018."},{"key":"2841_CR6","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1128\/AAC.48.4.1329-1334.2004","volume":"48","author":"S Pukrittayakamee","year":"2004","unstructured":"Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicro Agents Chemother. 2004;48:1329\u201335.","journal-title":"Antimicro Agents Chemother."},{"key":"2841_CR7","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/S1473-3099(13)70268-8","volume":"14","author":"AC Eziefula","year":"2014","unstructured":"Eziefula AC, Bousema T, Yeuny S, Kamya M, Owaraganise A, Gabagaya G, et al. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomized, controlled, double-blind, dose-ranging trial. Lancet Infect Dis. 2014;14:130\u20139.","journal-title":"Lancet Infect Dis."},{"key":"2841_CR8","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/S1473-3099(12)70198-6","volume":"13","author":"NJ White","year":"2013","unstructured":"White NJ. Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis. 2013;13:175\u201381.","journal-title":"Lancet Infect Dis."},{"key":"2841_CR9","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1186\/1475-2875-11-418","volume":"11","author":"NJ White","year":"2012","unstructured":"White NJ, Qiao IG, Qi G, Luzzatto L. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in a population where G6PD deficiency is common. Malar J. 2012;11:418.","journal-title":"Malar J."},{"key":"2841_CR10","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s12879-015-0887-y","volume":"15","author":"J Gerardin","year":"2015","unstructured":"Gerardin J, Eckhoff P, Wenger EA. Mass campaigns with antimalarial drugs: a modelling comparison of artemether\u2013lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination. BMC Infect Dis. 2015;15:144.","journal-title":"BMC Infect Dis"},{"key":"2841_CR11","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1093\/infdis\/jit077","volume":"207","author":"P Sawa","year":"2013","unstructured":"Sawa P, Shekalaghe SA, Drakeley CJ, Sutherland CJ, Mweresa CK, Baidjoe AY, et al. Malaria transmission after artemther-lumefantrine and dihydroartemisinin\u2013piperaquine: a randomized trial. J Infect Dis. 2013;207:1637\u201345.","journal-title":"J Infect Dis"},{"key":"2841_CR12","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1086\/503051","volume":"193","author":"JT Bousema","year":"2006","unstructured":"Bousema JT, Schneider P, Gauagna LC, Drakeley CJ, Tostmann A, Houben R, et al. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis. 2006;193:1151\u20139.","journal-title":"J Infect Dis"},{"key":"2841_CR13","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s12936-015-0714-3","volume":"14","author":"I Chen","year":"2015","unstructured":"Chen I, Piorot E, Newman M, Kandula D, Shah R, Hwang J, et al. An assessment of the supply, programmatic use, and regulatory issues of the single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa. Malar J. 2015;14:204.","journal-title":"Malar J."},{"key":"2841_CR14","doi-asserted-by":"publisher","first-page":"4971","DOI":"10.1128\/AAC.02889-14","volume":"58","author":"AC Eziefula","year":"2014","unstructured":"Eziefula AC, Pett H, Grignard L, Opus S, Kiggundu M, Kamya MR, et al. Glucose-6-phosphate dehydrogenase status and risk of hemolysis in Plasmodium falciparum-infected African children receiving a single-dose primaquine. Antimicrob Agents Chemother. 2014;58:4971\u20133.","journal-title":"Antimicrob Agents Chemother"},{"key":"2841_CR15","doi-asserted-by":"publisher","first-page":"e1001339","DOI":"10.1371\/journal.pmed.1001339","volume":"9","author":"RE Howes","year":"2012","unstructured":"Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, et al. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med. 2012;9:e1001339.","journal-title":"PLoS Med."},{"key":"2841_CR16","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1182\/blood.V54.5.961.961","volume":"54","author":"L Luzzatto","year":"1979","unstructured":"Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood. 1979;54:961\u201376.","journal-title":"Blood"},{"key":"2841_CR17","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1186\/1475-2875-13-483","volume":"13","author":"NJ White","year":"2014","unstructured":"White NJ, Ashley EA, Recht J, Delves MJ, Ruecker A, Smithuis FM, et al. Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria. Malar J. 2014;13:483.","journal-title":"Malar J."},{"key":"2841_CR18","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.hoc.2015.11.006","volume":"30","author":"L Luzzatto","year":"2016","unstructured":"Luzzatto L, Nannelli C, Notaro R. Glucose-6-phophate dehydrogenase deficiency. Hematol Oncol Clin North Am. 2016;30:373\u201393.","journal-title":"Hematol Oncol Clin North Am"},{"key":"2841_CR19","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/1475-2875-10-241","volume":"10","author":"N Carter","year":"2011","unstructured":"Carter N, Pamba A, Duparc S, Waitumbo JN. Frequency of glucose-6-phosphate dehydrogenase deficiency in malaria patients from six African countries enrolled in two randomized anti-malarial clinical trials. Malar J. 2011;10:241.","journal-title":"Malar J."},{"key":"2841_CR20","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/1475-2875-12-112","volume":"12","author":"L von Seidlein","year":"2013","unstructured":"von Seidlein L, Auburn S, Espino F, Shanks D, Cheng Q, McCarthy J, et al. Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report. Malar J. 2013;12:112.","journal-title":"Malar J."},{"key":"2841_CR21","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1186\/1475-2875-13-418","volume":"13","author":"EA Ashley","year":"2014","unstructured":"Ashley EA, Recht J, White NJ. Primaquine: the risks and the benefits. Malar J. 2014;13:418.","journal-title":"Malar J."},{"key":"2841_CR22","doi-asserted-by":"publisher","first-page":"e0006230","DOI":"10.1371\/journal.pntd.0006230","volume":"12","author":"J Recht","year":"2018","unstructured":"Recht J, Ashley EA, White NJ. Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: divergent policies and practices in malaria endemic countries. PLoS Negl Trop Dis. 2018;12:e0006230.","journal-title":"PLoS Negl Trop Dis."},{"key":"2841_CR23","first-page":"247","volume":"69","author":"P Beighton","year":"1986","unstructured":"Beighton P, Botha MC. Inherited disorders in the black population of southern Africa. Part 1. Genetic haematological conditions. SAMJ. 1986;69:247\u20139.","journal-title":"SAMJ."},{"key":"2841_CR24","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/BF00207056","volume":"89","author":"MJ Coetzee","year":"1992","unstructured":"Coetzee MJ, Bartleet SC, Ramsay M, Jenkins T. Glucose-6-phosphate dehydrogenase (G6PD) electrophoretic variants and the PvuII polymorphism in southern African populations. Hum Genet. 1992;89:111\u20133.","journal-title":"Hum Genet"},{"key":"2841_CR25","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/1475-2875-12-212","volume":"12","author":"BS Pybus","year":"2013","unstructured":"Pybus BS, Marcsisin SR, Jin X, Deye G, Sousa JC, Li Q, et al. The metabolism of primaquine to its active metabolite is dependent on CYP2D6. Malar J. 2013;12:121.","journal-title":"Malar J."},{"key":"2841_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pharmthera.2016.03.011","volume":"161","author":"SR Marcsisin","year":"2016","unstructured":"Marcsisin SR, Reichard G, Pybus BS. Primaquine pharmacology in the context of CYP2D6 pharmacogenomics: current state of the art. Pharmacol Ther. 2016;161:1\u201310.","journal-title":"Pharmacol Ther."},{"key":"2841_CR27","first-page":"30073","volume":"18","author":"T Saito","year":"2018","unstructured":"Saito T, Gutierrez-Rico EM, Kikuchi A, Kaneko A, Kumondai A, Akai F, et al. Functional characterization of 50 CYP2D6 allelic variants by assessing primaquine 5-hydroxylation. Drug Metab Pharmacokinet. 2018;18:30073\u20139.","journal-title":"Drug Metab Pharmacokinet"},{"key":"2841_CR28","doi-asserted-by":"publisher","first-page":"55","DOI":"10.2133\/dmpk.DMPK-11-RV-121","volume":"27","author":"LK Teh","year":"2012","unstructured":"Teh LK, Bertilsson L. Pharmcogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27:55\u201367.","journal-title":"Drug Metab Pharmacokinet"},{"key":"2841_CR29","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1248\/bpb.29.1655","volume":"29","author":"AT Naveen","year":"2006","unstructured":"Naveen AT, Adithan C, Soya S, Gerard N, Krishnamoorthy R. CYP2D6 genetic polymorphism in South Indian Populations. Biol Pharm Bull. 2006;29:1658\u201365.","journal-title":"Biol Pharm Bull"},{"key":"2841_CR30","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s12936-016-1145-5","volume":"15","author":"PL St Jean","year":"2016","unstructured":"St Jean PL, Xue Z, Carter N, Koh GC, Duparc S, Taylor M, et al. Tafenoquine\u00a0treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial. Malar J. 2016;15:97.","journal-title":"Malar J."},{"key":"2841_CR31","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/gim.2016.80","volume":"19","author":"A Gaedigk","year":"2016","unstructured":"Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2016;19:69\u201376.","journal-title":"Genet Med."},{"key":"2841_CR32","first-page":"77","volume":"71","author":"A Wennerholm","year":"2002","unstructured":"Wennerholm A, Dandara C, Sayi J, Svensson J-O, Abdi AA, Ingelman-Sundberg M, et al. The Africa-speciic CYP2D6*17 allele encodes an enzyme with changed substrate specificity. Pharmocogenet Genomics. 2002;71:77\u201387.","journal-title":"Pharmocogenet Genomics."},{"key":"2841_CR33","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1517\/17425255.2014.894020","volume":"10","author":"S Dandara","year":"2014","unstructured":"Dandara S, Swart M, Mpeta B, Wonkam A, Masimirembwa C. Cytochrome P450 pharmacogenetics in African populations: implications for public health. Expert Opin Drug Metab Toxicol. 2014;10:769\u201385.","journal-title":"Expert Opin Drug Metab Toxicol."},{"key":"2841_CR34","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1186\/s12936-016-1497-x","volume":"15","author":"J Raman","year":"2016","unstructured":"Raman J, Morris N, Frean J, Brooke B, Blumberg L, Kruger P, et al. Reviewing South Africa\u2019s malaria elimination strategy (2012\u20132018): progress, challenges and priorities. Malar J. 2016;15:438.","journal-title":"Malar J."},{"key":"2841_CR35","volume-title":"Malaria elimination strategy for South Africa 2012\u20132018","author":"South African National Department of Health","year":"2012","unstructured":"South African National Department of Health. Malaria elimination strategy for South Africa 2012\u20132018. Pretoria: South African National Department of Health; 2012."},{"key":"2841_CR36","unstructured":"Southern African Development Community (SADC). SADC Malaria Report; 2017."},{"key":"2841_CR37","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1093\/infdis\/jix237","volume":"216","author":"W Stone","year":"2017","unstructured":"Stone W, Sawa P, Lanke K, Rijpma S, Oriango R, Nyaurah M, et al. A molecular assay to quantify male and female Plasmodium falciparum gametocytes: results from 2 randomized controlled trials using primaquine for gametocyte clearance. J Infect Dis. 2017;216:457\u201367.","journal-title":"J Infect Dis"},{"key":"2841_CR38","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/S1473-3099(15)00479-X","volume":"16","author":"A Dicko","year":"2016","unstructured":"Dicko A, Brown JM, Diawara H, Baber I, Mahamar A, Soumare HM, et al. Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomized phase 2 trial. Lancet Infect Dis. 2016;16:674\u201384.","journal-title":"Lancet Infect Dis."},{"key":"2841_CR39","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1186\/s12936-016-1430-3","volume":"15","author":"R Mwaiswelo","year":"2016","unstructured":"Mwaiswelo R, Ngasala BE, Jovel I, Aydin-Schmidt B, Gosling R, Premji Z, et al. Adding a single low-dose of primaquine (0.25\u00a0mg\/kg) to artemether\u2013lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial. Malar J. 2016;15:435.","journal-title":"Malar J."},{"key":"2841_CR40","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1186\/1475-2875-13-297","volume":"13","author":"SP Silal","year":"2014","unstructured":"Silal SP, Little F, Barnes KI, White LJ. Towards malaria elimination in Mpumalanga, South Africa: a population-level mathematical modelling approach. Malar J. 2014;13:297.","journal-title":"Malar J."},{"key":"2841_CR41","unstructured":"South Africa National Department of Health. National malaria diagnosis quality assurance guidelines: 2011. Technical report, South African Department of Health, Pretoria, South Africa; 2011."},{"key":"2841_CR42","unstructured":"South African National Department of Health. National guidelines for the treatment of malaria, South Africa, 2018. Technical report, South African Department of Health, Pretoria, South Africa; 2018."},{"key":"2841_CR43","first-page":"91","volume":"8","author":"J Govere","year":"2000","unstructured":"Govere J, Durrheim DN, Coetzee M, Hunt RH, la Grange JJ. Captures of mosquitoes of the Anopheles gambiae complex (Diptera: Culicidae) in the Lowveld Region of Mpumalanga Province. South Africa. Afr Entomol. 2000;8:91\u20139.","journal-title":"South Africa. Afr Entomol."},{"key":"2841_CR44","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1111\/j.1365-3156.2006.01785.x","volume":"12","author":"EA Ashley","year":"2007","unstructured":"Ashley EA, Stepniewska K, Lindegardh N, McGready R, Annerberg A, Hutagalung R, et al. Pharmacokinetic study of artmether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Trop Med Int Health. 2007;12:201\u20138.","journal-title":"Trop Med Int Health."},{"key":"2841_CR45","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/1471-2288-13-140","volume":"13","author":"EN Allen","year":"2013","unstructured":"Allen EN, Mushi AK, Massawe IS, Vestergaard LS, Lemnge M, Staedke SG, et al. How experiences become data: the process of eliciting adverse event, medical history and concomitant medication reports in antimalarial and antiretroviral interaction trials. BMC Med Res Methodol. 2013;13:140.","journal-title":"BMC Med Res Methodol"},{"key":"2841_CR46","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1186\/1475-2875-12-325","volume":"12","author":"EN Allen","year":"2013","unstructured":"Allen EN, Chandler CIR, Mandimika N, Pace C, Mehta U, Barnes KI. Evaluating harm associated with anti-malarial drugs: a survey of methods used by clinical researchers to elicit, assess and record participant-reported adverse events and related data. Malar J. 2013;12:325.","journal-title":"Malar J."},{"key":"2841_CR47","unstructured":"ICH E2A Clinical safety data management: definitions and standards for expedited reporting; 1994. https:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E2A\/Step4\/E2A_Guideline.pdf. Accessed 09 Dec 2018."},{"key":"2841_CR48","unstructured":"Medical Dictionary for Regulatory Activities. https:\/\/www.meddra\/org. Accessed 09 Dec 2018."},{"key":"2841_CR49","doi-asserted-by":"publisher","first-page":"114","DOI":"10.4269\/ajtmh.2008.78.114","volume":"78","author":"G Mlambo","year":"2008","unstructured":"Mlambo G, Vasquez Y, LeBlanc R, Sullivan D, Kumar N. A filter paper method for the detection of Plasmodium falciparum gametocytes by reverse transcription polymerase chain reaction. Am J Trop Med Hyg. 2008;78:114\u20136.","journal-title":"Am J Trop Med Hyg"},{"key":"2841_CR50","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1179\/000349803125002977","volume":"97","author":"D Padley","year":"2003","unstructured":"Padley D, Moody AH, Chiodini PL, Saldanha J. Use of a rapid, single-round multiplex PCR to detect malarial parasites and identify the species present. Ann Trop Med Parasitol. 2003;97:131\u20137.","journal-title":"Ann Trop Med Parasitol"},{"key":"2841_CR51","doi-asserted-by":"publisher","first-page":"e0136099","DOI":"10.1371\/journal.pone.0136099","volume":"10","author":"E Talundzic","year":"2015","unstructured":"Talundzic E, Chenet SM, Goldman IF, Patel DS, Nelson JA, Plucinski MM, et al. Genetic analysis and species specific amplification of the artemisinin resistance-associated kelch propeller domain in P. falciparum and P. vivax. PLoS ONE. 2015;10:e0136099.","journal-title":"PLoS ONE."},{"key":"2841_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12916-018-1207-3","volume":"17","author":"WWARN k13 genotype-phenotype study group","year":"2019","unstructured":"WWARN k13 genotype-phenotype study group. Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments\u2014a WWARN individual patient data meta-analysis. BMC Med. 2019;17:1.","journal-title":"BMC Med."},{"key":"2841_CR53","doi-asserted-by":"publisher","first-page":"455","DOI":"10.4269\/ajtmh.2008.78.455","volume":"78","author":"AA Djimde","year":"2008","unstructured":"Djimde AA, Fofana B, Sagara I, Sidibe B, Toure S, Dembele D, et al. Efficacy, safety and selection of molecular markers of drug resistance by two ACTs in Mali. Am J Trop Med Hyg. 2008;78:455\u201361.","journal-title":"Am J Trop Med Hyg"},{"key":"2841_CR54","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1093\/jac\/dkm104","volume":"59","author":"CJ Sutherland","year":"2007","unstructured":"Sutherland CJ, Haustein T, Gadalla N, Amstrong M, Doherty JF, Choidini PL. Chloroquine-resistant Plasmodium falciparum infections among UK travellers returning with malaria after chloroquine prophylaxis. Antimicrob Agents Chemother. 2007;59:1197\u20139.","journal-title":"Antimicrob Agents Chemother"},{"key":"2841_CR55","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/S0140-6736(04)16767-6","volume":"364","author":"RN Price","year":"2004","unstructured":"Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:438\u201347.","journal-title":"Lancet"},{"key":"2841_CR56","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/S0035-9203(97)90539-3","volume":"91","author":"LC Ranford-Cartwright","year":"1997","unstructured":"Ranford-Cartwright LC, Taylor J, Umasunthar T, Taylor LH, Babiker HA, Lell B, Schmidt-Ott JR, et al. Molecular analysis of recrudescent parasites in a Plasmodium falciparum drug efficacy trial in Gabon. Trans R Soc Trop Med Hyg. 1997;91:719\u201324.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2841_CR57","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.jpba.2007.07.015","volume":"45","author":"D Blessborn","year":"2007","unstructured":"Blessborn D, Romsing S, Annerberg A, Sundquist D, Bjorkman A, Lindeg\u00e5rdh N, et al. Development and validation of an automated solid-phase extraction and liquid chromatographic method for the determination of lumefantrine in capillary blood on sampling paper. J Pharmaceut Biomed Anal. 2007;45:282\u20137.","journal-title":"J Pharmaceut Biomed Anal."},{"key":"2841_CR58","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","volume":"42","author":"PA Harris","year":"2009","unstructured":"Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)\u2014a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377\u201381.","journal-title":"J Biomed Inform"},{"key":"2841_CR59","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/sj.clpt.6100406","volume":"83","author":"A Gaedigk","year":"2008","unstructured":"Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a quantitative measure of phenotype. Clin Pharmacol Ther. 2008;83:234\u201342.","journal-title":"Clin Pharmacol Ther"},{"key":"2841_CR60","doi-asserted-by":"publisher","first-page":"261","DOI":"10.2217\/pgs.12.207","volume":"14","author":"LK Montan\u00e9 Jaime","year":"2013","unstructured":"Montan\u00e9 Jaime LK, Lalla A, Steimer W, Gaedigk A. Characterization of the CYP2D6 gene locus and metabolic activity in Indo- and Afro-Trinidadians: discovery of novel allelic variants. Pharmacogenomics. 2013;14:261\u201376.","journal-title":"Pharmacogenomics."},{"key":"2841_CR61","unstructured":"WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization; 2011 (WHO\/NMH\/NHD\/MNM\/11.1). http:\/\/www.who.int\/vmnis\/indicators\/haemoglobin.pdf. Accessed 20 May 2019."},{"key":"2841_CR62","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1186\/s12916-015-0515-0","volume":"13","author":"WWARN Lumefantrine PK\/PD Study Group","year":"2015","unstructured":"WWARN Lumefantrine PK\/PD Study Group. artemether\u2013lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data. BMC Med. 2015;13:277.","journal-title":"BMC Med."},{"key":"2841_CR63","first-page":"CD008152","volume":"2","author":"PM Graves","year":"2018","unstructured":"Graves PM, Choi L, Gelband H, Garner P. Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission. Cochrane Database Syst Rev. 2018;2:CD008152.","journal-title":"Cochrane Database Syst Rev."},{"key":"2841_CR64","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1186\/s12936-016-1341-3","volume":"15","author":"R Mwaiswelo","year":"2016","unstructured":"Mwaiswelo R, Ngasala BE, Jovel I, Gosling R, Premji Z, Poirot E, et al. Safety of a single low-dose of primaquine in addition to standard artemether\u2013lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Malar J. 2016;15:316.","journal-title":"Malar J."},{"key":"2841_CR65","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s12916-016-0581-y","volume":"14","author":"BP Gon\u00e7alves","year":"2016","unstructured":"Gon\u00e7alves BP, Tiono AB, Ou\u00e9draogo A, Guelb\u00e9ogo WM, Bradley J, Nebie I, et al. Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether\u2013lumefantrine in children with asymptomatic infection: a randomized, double-blind, placebo-controlled trial. BMC Med. 2016;14:40.","journal-title":"BMC Med."},{"key":"2841_CR66","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1093\/cid\/cix355","volume":"65","author":"RC Tine","year":"2017","unstructured":"Tine RC, Sylla K, Faye BT, Poirot E, Fall FB, Sow D, et al. Safety and efficacy of adding a single low dose of primaquine to the treatment of adult patients with Plasmodium falciparum malaria in Senegal, to reduce gametocyte carriage: a randomized controlled trial. Clin Infect Dis. 2017;65:535\u201343.","journal-title":"Clin Infect Dis"},{"key":"2841_CR67","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1186\/s12936-018-2271-z","volume":"17","author":"SS Awandu","year":"2018","unstructured":"Awandu SS, Raman J, Makhanthisa TI, Kruger P, Frean J, Bousema T, et al. Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa. Malar J. 2018;17:120.","journal-title":"Malar J."},{"key":"2841_CR68","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1186\/s12936-016-1410-7","volume":"15","author":"E Poirot","year":"2016","unstructured":"Poirot E, Soble A, Ntshalintshali N, Mwandemele A, Mkhonta N, Malame C, et al. Development of a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine and artemether\u2013lumefantrine to treat Plasmodium falciparum infections in Swaziland: a pilot study. Malar J. 2016;15:384.","journal-title":"Malar J."},{"key":"2841_CR69","first-page":"538","volume":"34","author":"YS Wang","year":"2006","unstructured":"Wang YS, Brown PP. Clinical study on artemether combined with primaquine for Pf cases treatment. Tianjin Med J. 2006;34:538 (in Chinese).","journal-title":"Tianjin Med J."},{"key":"2841_CR70","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S1473-3099(10)70187-0","volume":"10","author":"F Smithuis","year":"2010","unstructured":"Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomized trial. Lancet Infect Dis. 2010;10:673\u201381.","journal-title":"Lancet Infect Dis."},{"key":"2841_CR71","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.ebiom.2016.10.032","volume":"13","author":"J Okebe","year":"2016","unstructured":"Okebe J, Bousema T, Affara M, DiTanna GL, Dabira E, Gaye A, et al. The gametocytocidal efficacy of different single doses of primaquine with dihydroartemisinin-piperaquine in asymptomatic parasite carriers in The Gambia: a randomized controlled trial. EBioMed. 2016;13:348\u201355.","journal-title":"EBioMed"},{"issue":"12","key":"2841_CR72","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/nrmicro3364","volume":"12","author":"T Bousema","year":"2014","unstructured":"Bousema T, Okell L, Felger I, Drakeley C. Asymptomatic malaria infections: detectability, transmissibility and public health relevance. Nat Rev Microbiol. 2014;12(12):833\u201340.","journal-title":"Nat Rev Microbiol"},{"key":"2841_CR73","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s12936-018-2290-9","volume":"17","author":"E Davlantes","year":"2018","unstructured":"Davlantes E, Dimbu PR, Ferreira CM, Joao MF, Pode D, Felix J, et al. Efficacy and safety of artemether\u2013lumefantrine, artesunate-amodiaquinne, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola, 2017. Malar J. 2018;17:144.","journal-title":"Malar J."},{"key":"2841_CR74","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s12936-017-1712-4","volume":"16","author":"MM Plucinski","year":"2017","unstructured":"Plucinski MM, Dimbu PR, Macaia AP, Ferreira CM, Samutondo C, Quivinja J, et al. Efficacy of arthmether-lumefantrine, artesunate-amodiaquinne, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Angola, 2015. Malar J. 2017;16:62.","journal-title":"Malar J."},{"key":"2841_CR75","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3201\/eid2401.170864","volume":"24","author":"H Gupta","year":"2018","unstructured":"Gupta H, Macete E, Bulo H, Salvador C, Warsame M, Carvalho E, et al. Drug-resistant polymorphisms and copy numbers in Plasmodium falciparum, Mozambique, 2015. Emerg Infect Dis. 2018;24:40\u20138.","journal-title":"Emerg Infect Dis"},{"key":"2841_CR76","doi-asserted-by":"publisher","first-page":"833","DOI":"10.4269\/ajtmh.14-0031","volume":"91","author":"M Venkatesan","year":"2014","unstructured":"Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C, Moriera C, et al. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether\u2013lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg. 2014;91:833\u201343.","journal-title":"Am J Trop Med Hyg."},{"key":"2841_CR77","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1186\/1475-2875-11-434","volume":"11","author":"CH Vaughan-Williams","year":"2012","unstructured":"Vaughan-Williams CH, Raman J, Raswiswi E, Immelman E, Reichel H, Gate K, et al. Assessment of the therapeutic efficacy of artemether\u2013lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in northern KwaZulu-Natal: an observational cohort study. Malar J. 2012;11:434.","journal-title":"Malar J."},{"key":"2841_CR78","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","volume":"371","author":"E Ashley","year":"2014","unstructured":"Ashley E, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411\u201323.","journal-title":"N Engl J Med"},{"key":"2841_CR79","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1056\/NEJMoa1513137","volume":"374","author":"D Menard","year":"2016","unstructured":"Menard D, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, Rahim-Awab G, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med. 2016;374:2453\u201364.","journal-title":"N Engl J Med"},{"key":"2841_CR80","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.1056\/NEJMc1713777","volume":"379","author":"S Das","year":"2018","unstructured":"Das S, Saha B, Hati AK, Roy S. Evidence of artemisinin-resistance Plasmodium falciparum malaria in Eastern India. N Engl J Med. 2018;379:1962\u20134.","journal-title":"N Engl J Med."}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-019-2841-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12936-019-2841-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-019-2841-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T16:20:24Z","timestamp":1628612424000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-019-2841-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,24]]},"references-count":80,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["2841"],"URL":"https:\/\/doi.org\/10.1186\/s12936-019-2841-8","relation":{},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,24]]},"assertion":[{"value":"31 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Approval for this study was obtained from the South African Health Products Regulatory Authority (20151033) and the ethics committees of Mpumalanga Provincial Department of Health (MP_2016RP52_878) and the Universities of Cape Town (737\/2015), Pretoria (85\/2018) and Witwatersrand (M151129).This trial was registered as PACTR201611001859416\u00a0with the Pan African Clinical Trial Registry on 11 November 2016 ().All participants and parents\/guardians\/caregivers of participants <\u200918\u00a0years of age provided written informed consent, prior to enrolment. Assent was obtained from participant aged between 7 and 18\u00a0years.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"209"}}