Systematic Review and Meta-Analysis on Human African Trypanocide Resistance
Background Human African trypanocide resistance (HATr) is a challenge for the eradica- tion of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated wit...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI.
2023
|
| Subjects: | |
| Online Access: | http://hdl.handle.net/20.500.12493/926 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background Human African trypanocide resistance (HATr) is a challenge for the eradica-
tion of Human African Trypansomiaisis (HAT) following the widespread emergence of increased
monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that
are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases
and 3 Google search websites for human African trypanocide resistance were performed using a
keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications
were identified and included in this study using the PRISMA checklist. Data were analyzed using
RevMan and random effect sizes were computed for the statistics at the 95% confidence interval.
Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei
adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed
by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the
amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine
combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance
and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion
of total random effects was 68% (95% CI: 38.0–91.6); I2 = 96.99% (95% CI: 94.6–98.3). Treatment failure
rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94–59.09) and
6.56% (3.06–11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments
demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The
emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT
is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely
resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved
fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein
targets could help to reduce the emergence and spread of HATr. |
|---|