Background:
Genetic polymorphisms are known contributors to the risk of toxicity and the overall effectiveness of antitubercular therapy. Understanding these associations is crucial for optimizing treatment regimens and improving patient safety, particularly in diverse populations where drug metabolism and pharmacokinetics can vary significantly. This study aims to characterize how specific genetic variants influence adverse events and treatment outcomes among adults treated for tuberculosis (TB) in Brazil.
Abstract:
Methods: This prospective observational study followed adults with culture-confirmed, drug-sensitive pulmonary TB within the RePORT-Brazil network between 2015 and 2019. Participants received a standard 6-month treatment regimen and were followed for 24 months. The analysis examined 43 polymorphisms across 20 genes related to drug pharmacokinetics or hepatotoxicity, and whole-exome sequencing was performed in a nested case-control subgroup.
Results: Among 903 participants, the NAT2 slow acetylator status was significantly associated with an increased risk of treatment-related adverse events of grade 2 or higher, including hepatotoxicity. A polymorphism in GSTM1 (rs412543) also correlated with increased adverse events, while SLCO1B1 variants were linked to both hepatotoxicity and treatment failure/recurrence. Conversely, NR1I2 polymorphisms were associated with a reduced risk of adverse events but an increased risk of treatment failure. While NAT2 rapid acetylators were more likely to experience treatment failure or recurrence, this result did not reach statistical significance.
Conclusion: In a clinical cohort representative of three Brazilian regions, NAT2 acetylator status is a key predictor of treatment-related toxicity. These findings underscore the potential for pharmacogenetic screening to improve TB care, though further investigation in larger populations is warranted for other identified polymorphisms.
Keywords: Tuberculosis, Pharmacogenetics, NAT2, Hepatotoxicity, Treatment Outcome, Adverse Events.
Clique aqui
- Data de Publicação: 01/02/2025
- Autores: Gustavo Amorim 1, James Jaworski 2, Jing Yang 13, Marcelo Cordeiro-Santos 45 Afrânio L Kritski, Marina C Figueiredo 7, Megan Turner 7, Bruno B Andrade 89 10 11 12 13 Digna R Velez Edwards 14,,Adalberto R Santos 15 Valeria C Rolla 16, Timothy R Sterling 7, David W Haas 7 17.
