Exploring strategies to address trypanocide resistance: lessons from Uganda

Abstract

BACKGROUND: Trypanosomiasis is a zoonotic disease with a divergent evolutionary history, and gene speciation which has influenced gene flow. Aim: The objective of the study was to generate evidence on the development of African trypanocide resistance, explore current trypanocide usage practices in Uganda and justify the importance of multidisciplinary collaborations to address local epidemics such as trypanosomiasis in Uganda during the COVID-19 pandemic.

METHODS: We conducted systematic reviews, cross-sectional studies, drug quality analytics, and key informant interviews for 30 months involving farmers, drug handlers and policymakers in Uganda.

RESULTS: Major species in human African trypanosomiasis (HAT) are T. brucei gambiense and T. b. rhodesiense while in African trypanosomiasis (AAT) are T. evansi, T. vivax, T. congolense, T. simiae, and T. brucei species. Trypanocides developed in the 20th century have developed resistance and the 21st century as seen new therapies developed for human consumption, however little progress has been taken against AAT. Resistance against African trypanocides has been associated with T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP 2 and 3) among diamidines (includes both Pentamidines in HAT while Diminazene aceturate in AAT). This has led to the development of novel and combination therapies to address resistant genotypes. Nifurtimox/eflornithine combination therapy (NECT) was discovered in the 21st century, however the development of NECT resistance associated with AAT6 and nitroreductase loss complicates Melarsoprol treatment. In livestock populations, resistance against all the available trypanocides i.e., DA, Isometamidium chloride (ISM) and Homidium bromide (HB) justifies the need to develop novel therapies and policies to control antimicrobial resistance (AMR) in rural communities. This study provides evidence on drivers of AATr in Uganda where we identify farmers who continue to administer trypanocides with little regard to proper pharmaceutical principles on dosing, and withdrawal periods regardless of breed. In southwestern Uganda, we report farmers abusing DA highest while withdrawal periods are not observed. We also identified the presence of unregistered veterinary drugshops in all districts visited, and identified new brands of trypanocides mainly from China and South Korea which were cheaper than most European brands. This demonstrates critical economic drivers in the dairy sector within the study area i.e., farmers prefer cheaper trypanocides regardless of drug quality. On further analysis, a majority of the trypanocide brands were substandard and a very low compliance rate was established against DA, ISM and HB within the study area. For the management of trypanosomiasis and AMR, strong policy decisions under a One Health framework could help galvanize support both locally and internationally. Major challenges for the operationalization of One Health in Uganda were associated with individuals working in silos, conflicts of interest, corruption and poor education systems which are responsible for the poor One Health perceptions in rural communities in the pandemic age.

CONCLUSION: African trypanocide resistance in developing countries is propagated by poor regulatory policies which continue to weaken One Health control strategies against AMR.