title: High Rate of Treatment Failures in Nonimmune Travelers Treated With Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Sweden: Retrospective Comparative Analysis of Effectiveness and Case Series.
abstract: BACKGROUND
  Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether-lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults.
  
  
  METHODS
  A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures.
  
  
  RESULTS
  Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases.
  
  
  CONCLUSIONS
  Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment.
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet; klara.sonden@ki.se.
authors.forename: Klara
authors.initials: K
authors.lastname: Sondén
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet.|Department of Emergency Medicine, Karolinska University Hospital Solna.
authors.forename: Katja
authors.initials: K
authors.lastname: Wyss
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.
authors.forename: Irina
authors.initials: I
authors.lastname: Jovel
authors.affiliation: Department of Clinical Pharmacology, Karolinska University Hospital Huddinge.
authors.forename: Antero
authors.initials: A
authors.lastname: Vieira da Silva
authors.affiliation: Department of Clinical Pharmacology, Karolinska University Hospital Huddinge.|Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet.
authors.forename: Anton
authors.initials: A
authors.lastname: Pohanka
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Asghar
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet.
authors.forename: Manijeh Vafa
authors.initials: MV
authors.lastname: Homann
authors.affiliation: Department of Clinical Pharmacology, Karolinska University Hospital Huddinge.|Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet.
authors.forename: Lars L
authors.initials: LL
authors.lastname: Gustafsson
authors.affiliation: Department of Infectious Diseases, Karolinska University Hospital; and.|Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Hellgren
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet.|Department of Infectious Diseases, Karolinska University Hospital; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Färnert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D013548:Sweden / Q000453:epidemiology; D014195:Travel; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes
keywords: artemisinin-based combination therapy; effectiveness; malaria; mefloquine; travelers.