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...
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| author | Keneth Iceland, Kasozi Ewan Thomas, MacLeod Susan Christina, Welburn |
| author_facet | Keneth Iceland, Kasozi Ewan Thomas, MacLeod Susan Christina, Welburn |
| author_sort | Keneth Iceland, Kasozi |
| collection | KAB-DR |
| description | 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. |
| format | Article |
| id | oai:idr.kab.ac.ug:20.500.12493-926 |
| institution | KAB-DR |
| language | English |
| publishDate | 2023 |
| publisher | MDPI. |
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| spelling | oai:idr.kab.ac.ug:20.500.12493-9262024-01-17T04:48:12Z Systematic Review and Meta-Analysis on Human African Trypanocide Resistance Keneth Iceland, Kasozi Ewan Thomas, MacLeod Susan Christina, Welburn Human African trypanosomiasis Trypanosomes Drug resistance Pentamidines Nifurtimox/eflornithine combination therapy; Exinidazole; NECT TbAT Amino-aquapurine trans- porters Amino acid transporters Trypanosoma brucei rhodesiense Trypanosoma brucei gambiense Neglected tropical diseases 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. Kabale University 2023-02-02T05:16:28Z 2023-02-02T05:16:28Z 2022-09-25 Article Kasozi, K.I.; MacLeod, E.T.; Welburn, S.C. Systematic Review and Meta-Analysis on Human African Trypanocide Resistance. Pathogens 2022, 11, 1100. https://doi.org/ 10.3390/pathogens11101100 http://hdl.handle.net/20.500.12493/926 en Attribution-NonCommercial-NoDerivs 3.0 United States http://creativecommons.org/licenses/by-nc-nd/3.0/us/ application/pdf MDPI. |
| spellingShingle | Human African trypanosomiasis Trypanosomes Drug resistance Pentamidines Nifurtimox/eflornithine combination therapy; Exinidazole; NECT TbAT Amino-aquapurine trans- porters Amino acid transporters Trypanosoma brucei rhodesiense Trypanosoma brucei gambiense Neglected tropical diseases Keneth Iceland, Kasozi Ewan Thomas, MacLeod Susan Christina, Welburn Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title | Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title_full | Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title_fullStr | Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title_full_unstemmed | Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title_short | Systematic Review and Meta-Analysis on Human African Trypanocide Resistance |
| title_sort | systematic review and meta analysis on human african trypanocide resistance |
| topic | Human African trypanosomiasis Trypanosomes Drug resistance Pentamidines Nifurtimox/eflornithine combination therapy; Exinidazole; NECT TbAT Amino-aquapurine trans- porters Amino acid transporters Trypanosoma brucei rhodesiense Trypanosoma brucei gambiense Neglected tropical diseases |
| url | http://hdl.handle.net/20.500.12493/926 |
| work_keys_str_mv | AT kenethicelandkasozi systematicreviewandmetaanalysisonhumanafricantrypanocideresistance AT ewanthomasmacleod systematicreviewandmetaanalysisonhumanafricantrypanocideresistance AT susanchristinawelburn systematicreviewandmetaanalysisonhumanafricantrypanocideresistance |