Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo

• Published in: PLoS neglected tropical diseases 2014-10, Vol.8 (10), p.e3212-e3212
• Main Authors: Pyana Pati, Patient, Van Reet, Nick, Mumba Ngoyi, Dieudonné, Ngay Lukusa, Ipos, Karhemere Bin Shamamba, Stomy, Büscher, Philippe
• Format: Article
• Language: English
• Subjects: Adult; African trypanosomiasis; Animals; Antiparasitic agents; Aquaglyceroporins - genetics; Base Sequence; Biology and Life Sciences; Care and treatment; Democratic Republic of the Congo; Deoxyribonucleic acid; DNA; DNA, Protozoan - chemistry; DNA, Protozoan - isolation & purification; Dosage and administration; Drug resistance; Drug Resistance - genetics; Experiments; Female; Genotype; Humans; Medical treatment; Medicine and Health Sciences; Melarsoprol - pharmacology; Melarsoprol - therapeutic use; Mice; Molecular Sequence Data; Mutant Chimeric Proteins - genetics; Mutation; Parasites; Parasitic diseases; Patients; Pentamidine - pharmacology; Phenotype; Protozoa; Public health; Recurrence; Sequence Analysis, DNA; Studies; Trypanocidal Agents - pharmacology; Trypanocidal Agents - therapeutic use; Trypanosoma brucei gambiense; Trypanosoma brucei gambiense - drug effects; Trypanosoma brucei gambiense - genetics; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - parasitology
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0003212

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. 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. 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.