AVALIAÇÃO DOS EFEITOS ADVERSOS EM PACIENTES EM TRATAMENTO DE ILTB FRENTE A ADMINISTRAÇÃO DE DOSE MODIFICADA DE ISONIAZIDA

Abstract

Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis, can manifest as a either latent or active disease. The treatment of latent TB infection (LTBI) typically involves drugs such as isoniazid, the metabolism of which depends on the NAT2 enzyme responsible for drug acetylation. NAT2 activity is genetically determined by classifying individuals as slow, intermediate, or fast acetylators, which can influence pharmacokinetics, therapeutic efficacy, and susceptibility to adverse events. Slow acetylators are at higher risk of drug toxicity, whereas fast acetylators metabolize the drug more rapidly, potentially affecting plasma concentrations and treatment response.Methods: This study was a Phase 1 clinical trial integrating point-of-care pharmacogenomic testing to optimize isoniazid dosing for LTBI treatment. The participants included people living with HIV, healthcare professionals, household contacts of confirmed pulmonary TB cases, prison system workers, and incarcerated individuals. Acetylation profiles were determined based on NAT2 enzyme activity and were classified as slow, intermediate, or fast. The participants received 12 weekly doses of treatment, with experimental dose adjustments of isoniazid in the second week according to the acetylation profile. The standard adult dose (>40 kg) consisted of 900 mg rifapentine and 900 mg isoniazid orally, combined with 50 mg vitamin B6 to prevent peripheral neuropathy.Results and Discussion: In total, 172 participants were included in the study, with acetylation phenotypes identified in 163: 85 intermediate, 63 slow, and 15 rapid. Of these, 78 initiated the treatment. Analyses showed that age, sex, and race/color had no statistically significant association with adverse events (AEs), although higher frequencies were observed in individuals over 50 years of age and in females. Stratification by acetylation profile revealed a higher concentration of AEs in intermediates, persistent recurrence in slow acetylators, and a lower frequency in rapid acetylators. Temporal analysis indicated that most events occurred in the first week, predominantly in the gastrointestinal tract. In addition, a high proportion of multiple events per participant was identified. Keywords: N-acetyltransferase 2 (NAT2). Adverse reactions. Tuberculosis