title: Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo.
abstract: BACKGROUND
  Sleeping sickness caused by Trypanosoma brucei (T.b.) gambiense constitutes a serious health problem in sub-Sahara Africa. In some foci, alarmingly high relapse rates were observed in patients treated with melarsoprol, which used to be the first line treatment for patients in the neurological disease stage. Particularly problematic was the situation in Mbuji-Mayi, East Kasai Province in the Democratic Republic of the Congo with a 57% relapse rate compared to a 5% relapse rate in Masi-Manimba, Bandundu Province. The present study aimed at investigating the mechanisms underlying the high relapse rate in Mbuji-Mayi using an extended collection of recently isolated T.b. gambiense strains from Mbuji-Mayi and from Masi-Manimba.
  
  
  RESULTS
  Forty five T.b. gambiense strains were used. Forty one were isolated from patients that were cured or relapsed after melarsoprol treatment in Mbuji-Mayi. In vivo drug sensitivity tests provide evidence of reduced melarsoprol sensitivity in these strains. This reduced melarsoprol sensitivity was not attributable to mutations in TbAT1. However, in all these strains, irrespective of the patient treatment outcome, the two aquaglyceroporin (AQP) 2 and 3 genes are replaced by chimeric AQP2/3 genes that may be associated with resistance to pentamidine and melarsoprol. The 4 T.b. gambiense strains isolated in Masi-Manimba contain both wild-type AQP2 and a different chimeric AQP2/3. These findings suggest that the reduced in vivo melarsoprol sensitivity of the Mbuji-Mayi strains and the high relapse rates in that sleeping sickness focus are caused by mutations in the AQP2/AQP3 locus and not by mutations in TbAT1.
  
  
  CONCLUSIONS
  We conclude that mutations in the TbAQP2/3 locus of the local T.b. gambiense strains may explain the high melarsoprol relapse rates in the Mbuji-Mayi focus but other factors must also be involved in the treatment outcome of individual patients.
authors.affiliation: Département de Parasitologie, Institut National de Recherche Biomédicale, Kinshasa Gombe, Democratic Republic of the Congo.
authors.forename: Patient
authors.initials: P
authors.lastname: Pyana Pati
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: Van Reet
authors.affiliation: Département de Parasitologie, Institut National de Recherche Biomédicale, Kinshasa Gombe, Democratic Republic of the Congo.
authors.forename: Dieudonné
authors.initials: D
authors.lastname: Mumba Ngoyi
authors.affiliation: Département de Parasitologie, Institut National de Recherche Biomédicale, Kinshasa Gombe, Democratic Republic of the Congo.
authors.forename: Ipos
authors.initials: I
authors.lastname: Ngay Lukusa
authors.affiliation: Département de Parasitologie, Institut National de Recherche Biomédicale, Kinshasa Gombe, Democratic Republic of the Congo.
authors.forename: Stomy
authors.initials: S
authors.lastname: Karhemere Bin Shamamba
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Büscher
mesh_terms: D000328:Adult; D000818:Animals; D051397:Aquaglyceroporins / Q000235:genetics*; D001483:Base Sequence; D016054:DNA, Protozoan / Q000737:chemistry / Q000302:isolation & purification; D015023:Democratic Republic of the Congo; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008549:Melarsoprol / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics; D009154:Mutation; D010419:Pentamidine / Q000494:pharmacology; D010641:Phenotype; D012008:Recurrence; D017422:Sequence Analysis, DNA; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014347:Trypanosoma brucei gambiense / Q000187:drug effects* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology*
chemical_list: D051397:Aquaglyceroporins; D016054:DNA, Protozoan; D050506:Mutant Chimeric Proteins; D014344:Trypanocidal Agents; D010419:Pentamidine; D008549:Melarsoprol