The Journal of infectious diseases · 2026
NAT2 Polymorphisms and Antituberculosis-Induced Hepatotoxicity in Thai People Living With HIV: Insights From a Pharmacogenetic-Pharmacokinetic Cohort Study.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Hiranburana Napon, Sophonphan Jiratchaya, Kerr Stephen J, Ubolyam Sasiwimol, Usawakidwiree Warat, Torvorapanit Pattama, Suwanpimolkul Gompol, Phaisal Weeraya, Chariyavilaskul Pajaree, Cho Yong-Soon, Shin Jae-Gook, Mahasirimongkol Surakameth, Avihingsanon Anchalee
Аннотация
BACKGROUND: The N-Acetyltransferase (NAT2) slow acetylator phenotype has been associated with a higher risk of isoniazid (INH)-induced hepatotoxicity. We investigated the association between NAT2 genotypes with inferred acetylator status, hepatotoxicity, and INH pharmacokinetics in Thai people living with HIV (PLWH) receiving INH-based Tuberculosis (TB) preventive or treatment regimens.
METHODS: In this prospective cohort study of Thai PLWH initiating INH-based regimens; NAT2 genotyping classified participants as slow (SA), intermediate (IA), or rapid acetylators (RA). Hepatotoxicity was defined as transaminase elevations more than 2.5 times the upper limit of normal (ULN). Multivariable logistic regression identified genotypes and factors associated with hepatotoxicity. A pharmacokinetic (PK) substudy assessed INH exposure across phenotypes.
RESULTS: Of 894 participants, 32.4% were SA, 41.2% IA, and 26.4% RA. Hepatotoxicity occurred in 10.9% overall and was highest in SA (15.2%). SA had increased hepatotoxicity risk versus RA (adjusted odds ratio [aOR] 2.43; 95% CI: 1.32-4.48). Genotypes NAT2*6A/*6A (aOR 1.84) and NAT2*7B/*7B (aOR 4.46) were associated with increased risk; NAT2*4/*4 was protective (aOR 0.33). Other independent risk factors included high baseline alanine aminotransferase (ALT), HCV co-infection, 2HRZE/4HR regimen (vs 1HP), and efavirenz-based antiviral therapy (vs dolutegravir). In the PK substudy (n = 93), INH exposure assessed by the area under the concentration time curve from 0 to 24 h, was significantly increased by approximately 2-fold in SA, regardless of anti-TB regimen.
CONCLUSIONS: NAT2 SA phenotype, particularly *6A/*6A and *7B/*7B genotypes, is associated with an increased risk of anti-tuberculosis-induced hepatotoxicity and higher INH exposure in Thai PLWH. Incorporating NAT2-guided dosing may enhance safety of INH-containing regimens in PLWH.
METHODS: In this prospective cohort study of Thai PLWH initiating INH-based regimens; NAT2 genotyping classified participants as slow (SA), intermediate (IA), or rapid acetylators (RA). Hepatotoxicity was defined as transaminase elevations more than 2.5 times the upper limit of normal (ULN). Multivariable logistic regression identified genotypes and factors associated with hepatotoxicity. A pharmacokinetic (PK) substudy assessed INH exposure across phenotypes.
RESULTS: Of 894 participants, 32.4% were SA, 41.2% IA, and 26.4% RA. Hepatotoxicity occurred in 10.9% overall and was highest in SA (15.2%). SA had increased hepatotoxicity risk versus RA (adjusted odds ratio [aOR] 2.43; 95% CI: 1.32-4.48). Genotypes NAT2*6A/*6A (aOR 1.84) and NAT2*7B/*7B (aOR 4.46) were associated with increased risk; NAT2*4/*4 was protective (aOR 0.33). Other independent risk factors included high baseline alanine aminotransferase (ALT), HCV co-infection, 2HRZE/4HR regimen (vs 1HP), and efavirenz-based antiviral therapy (vs dolutegravir). In the PK substudy (n = 93), INH exposure assessed by the area under the concentration time curve from 0 to 24 h, was significantly increased by approximately 2-fold in SA, regardless of anti-TB regimen.
CONCLUSIONS: NAT2 SA phenotype, particularly *6A/*6A and *7B/*7B genotypes, is associated with an increased risk of anti-tuberculosis-induced hepatotoxicity and higher INH exposure in Thai PLWH. Incorporating NAT2-guided dosing may enhance safety of INH-containing regimens in PLWH.