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Background  The development of arsenical and diamidine resistance in  Trypanosoma brucei  is associated with loss of drug uptake by the P2 purine transporter as a result of alterations in the corresponding  T. brucei  adenosine transporter 1 gene ( TbAT1 ). Previously, specific  TbAT1  mutant type alleles linked to melarsoprol treatment failure were significantly more prevalent in  T. b. gambiense  from relapse patients at Omugo health centre in Arua district. Relapse rates of up to 30% prompted a shift from melarsoprol to eflornithine (α-difluoromethylornithine, DFMO) as first-line treatment at this centre. The aim of this study was to determine the status of  TbAT1  in recent isolates collected from  T. b. gambiense  sleeping sickness patients from Arua and Moyo districts in Northwestern Uganda after this shift in first-line drug choice.    Methodology and results  Blood and cerebrospinal fluids of consenting patients were collected for DNA preparation and subsequent amplification. All of the 105 isolates from Omugo that we successfully analysed by PCR-RFLP possessed the  TbAT1  wild type allele. In addition, PCR/RFLP analysis was performed for 74 samples from Moyo, where melarsoprol is still the first line drug; 61 samples displayed the wild genotype while six were mutant and seven had a mixed pattern of both mutant and wild-type  TbAT1 . The melarsoprol treatment failure rate at Moyo over the same period was nine out of 101 stage II cases that were followed up at least once. Five of the relapse cases harboured mutant  TbAT1 , one had the wild type, while no amplification was achieved from the remaining three samples.    Conclusions/significance  The apparent disappearance of mutant alleles at Omugo may correlate with melarsoprol withdrawal as first-line treatment. Our results suggest that melarsoprol could successfully be reintroduced following a time lag subsequent to its replacement. A field-applicable test to predict melarsoprol treatment outcome and identify patients for whom the drug can still be beneficial is clearly required. This will facilitate cost-effective management of HAT in rural resource-poor settings, given that eflornithine has a much higher logistical requirement for its application.

plos neglected tropical diseases

Genotypic Status of the TbAT1/P2 Adenosine Transporter of Trypanosoma brucei gambiense Isolates from Northwestern Uganda following Melarsoprol Withdrawal