title: High efficacy of artemether-lumefantrine and declining efficacy of artesunate + sulfadoxine-pyrimethamine against Plasmodium falciparum in Sudan (2010-2015): evidence from in vivo and molecular marker studies.
abstract: The present paper reports on studies that evaluated artesunate + sulfadoxine-pyrimethamine (AS + SP) which is the first-line drug and artemether-lumefantrine (AL) which is a second-line drug against uncomplicated falciparum malaria in Sudan. This evaluation was performed in twenty studies covering six sentinel sites during five successive annual malaria transmission seasons from 2010 to 2015.
  
  
  
  The standard World Health Organization protocol was used for a follow-up period of 28 days. The frequency distribution of molecular markers for antifolate resistance in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes was studied in pre-treatment samples in four sites in 2011.
  
  
  
  In the nine studies of AL conducted at five sites (n = 595), high PCR-corrected cure rates were found, ranging from 96.8 to 100 %. Among the eleven studies of AS + SP (n = 1013), a decline in the PCR-corrected cure rates was observed in Gedaref in Eastern Sudan: 91.0 % in the 2011-12 season and 86.5 % in the 2014-15 season. In the remaining sites, the AS + SP cure rates ranged between 95.6 and 100 %. The rate of clearance of microscopic gametocytaemia after treatment was not significantly different with AL or AS + SP on days 7, 14, 21 and 28 of follow-up. A total of 371 pre-treatment samples were analysed for molecular markers of SP resistance. The temporal changes and geographical differences in the frequency distribution of SP-resistance genotypes showed evidence of regional differentiation and selection of resistant strains.
  
  
  
  The findings of this study call for a need to review the Sudan malaria treatment policy. Epidemiological factors could play a major role in the emergence of drug-resistant malaria in eastern Sudan.
  
  
  
  Trial registration numbers 2011-2012: ACTRN12611001253998, 2013-2015: ACTRN12613000945729.
authors.affiliation: College of Medicine, King Saud University, Riyadh, Saudi Arabia. aaadeel@yahoo.com.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Adeel
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Fahad Awad Ali
authors.initials: FA
authors.lastname: Elnour
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Khalid Abdalmutalab
authors.initials: KA
authors.lastname: Elmardi
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Mona B
authors.initials: MB
authors.lastname: Abd-Elmajid
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Mai Mahmoud
authors.initials: MM
authors.lastname: Elhelo
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Mousab S
authors.initials: MS
authors.lastname: Ali
authors.affiliation: National Malaria Control Programme, Federal Ministry of Health, Khartoum, Sudan.
authors.forename: Mariam A
authors.initials: MA
authors.lastname: Adam
authors.affiliation: Malaria Control and Elimination, Division of Communicable Diseases Control, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt.
authors.forename: Hoda
authors.initials: H
authors.lastname: Atta
authors.affiliation: Malaria Control and Elimination, Division of Communicable Diseases Control, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt.
authors.forename: Ghasem
authors.initials: G
authors.lastname: Zamani
authors.affiliation: Global Malaria Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Marian
authors.initials: M
authors.lastname: Warsame
authors.affiliation: Global Malaria Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrette
authors.affiliation: Naval Medical Research Unit-3, Cairo, Egypt.
authors.forename: Hanan El
authors.initials: HE
authors.lastname: Mohammady
authors.affiliation: Naval Medical Research Unit-3, Cairo, Egypt.
authors.forename: Rania A
authors.initials: RA
authors.lastname: Nada
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000494:pharmacology / Q000627:therapeutic use*; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use*; D013397:Sudan; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D005819:Genetic Markers; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine
keywords: Artemether-lumefantrine antimalarial drugs; Artesunate; Drug resistance; Molecular markers; Sudan; Sulfadoxine-pyrimethamine; dhfr; dhps