CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusions: Although clinically indistinguishable, myco-IRIS and KAD demonstrate unique immune profiles with differential activation of signaling pathways within T-cell and monocyte subsets. These different pathways may represent novel treatment targets for future interventional clinical trials.

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Isoniazid Exposure Among Patients With Tuberculosis and Diabetes in Brazil Felipe Ridolfi 1 , Gustavo Amorim 1 , Cody Staats 1 , Marcelo Cordeiro-Santos 2 , Afrânio L. Kritski 3 , Marina C. Figueiredo 1 , Bruno B. Andrade 4 , Timothy Sterling 1 , Valeria C. Rolla 5 , for the Regional Prospective Observational Research in Tuberculosis (RePORT) - Brazil Consortium 1 Vanderbilt University Medical Center, Nashville, TN, USA, 2 Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil, 3 Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 4 Instituto Gonçalo Moniz, Salvador, Brazil, 5 Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, Brazil Background: We previously demonstrated that individuals with tuberculosis (TB) and uncontrolled diabetes mellitus (DM) had a lower risk of TB-treatment related adverse drug reactions. Hypothesizing that this could be related to low TB drug levels, we correlated isoniazid (INH) plasma concentrations with glycated hemoglobin (HbA1c) levels. Methods: We included culture-confirmed, drug-susceptible, pulmonary TB participants from the RePORT-Brazil cohort, who received standard TB treatment between 2015-2019. We considered baseline HbA1c as both a continuous and categorical variable (HbA1c<5.7% was considered normal, HbA1c ≥5.7%-<6.5% was pre-DM, and HbA1c ≥6.5% was DM). Plasma samples were collected within 8 hours of the previous TB drug dose at two time points (months 1, 2) and drug concentrations for INH were quantified by liquid chromatography-mass spectrometry (SCIEX6500 Qtrap, Redwood City, CA). We log-transformed the INH concentration (log-INH) and we considered the time since last dose in hours. We built time-to-concentration curves, and we used Spearman correlation to compare the INH according to HbA1c levels and categories. Results: There were 657 samples available from 379 participants who met the inclusion criteria. The median baseline HbA1c was 5.9 (Interquartile Range [IQR] 5.5-6.4); and the median time since last dose was 3 hours (IQR 2.1-3.9). There were 131 (34%) participants with normal HbA1c, 154 (41%) had pre-DM, and 94 (25%) had DM. The correlation between HbA1c level and log-INH revealed a coefficient of -0.099 (p=0.01); whereas for the HbA1c categories, the coefficient was -0.117 (p=0.003), indicating lower INH concentration among participants with pre-DM and DM ( Figure 1 ). Conclusions: Our study identified an inverse relationship between HbA1c and INH plasma concentration in individuals with TB and DM. Despite the weak explanatory power of the model, the significant negative association suggests that individuals with pre-DM and DM may have reduced INH exposure, which potentially contributes to the lower risk of adverse drug reactions observed in this population.

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NAT-2 Polymorphism and Risk of Antituberculosis-Induced Hepatotoxicity in Thai People With HIV

Napon Hiranburana 1 , Warat Usawakidwiree 2 , Sasiwimol Ubolyam 3 , Jiratchaya Sophonphan 1 , Stephen Kerr 4 , Gompol Suwanpimolkul 2 , Pattama Torvorapanit 2 , Pajaree Chariyavilaskul 4 , Weeraya Phaisal 2 , Anchalee Avihingsanon 5 1 HIV Netherlands Australia Thailand Research Collaboration, Bangkok, Thailand, 2 King Chulalongkorn Memorial Hospital, Bangkok, Thailand, 3 Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 4 Chulalongkorn University, Bangkok, Thailand, 5 HIV-NAT, Thai Red Cross AIDS and Infectious Disease Research Centre, Bangkok, Thailand Background: The NAT2 slow acetylator phenotype is associated with a higher risk of isoniazid-induced hepatitis. There is a high prevalence of slow acetylators in the Thai population. This study aimed to explore the link between NAT2 genotypes and hepatitis risk in Thai people living with HIV (PLWH) after initiating isoniazid containing regimens for TB preventive therapy (TPT) or TB treatment. Methods: A prospective cohort of 500 Thai PLWH receiving isoniazid with rifapentine (1HP/3HP) for TPT or HRZE for active TB were genotyped for six NAT2 single nucleotide polymorphisms (SNPs). Hepatotoxicity (Grade 2 or higher) was assessed across NAT2 phenotypes (rapid, intermediate, slow acetylator). Multiple logistic regression adjusting for HIV-related factors, viral hepatitis co-infection and antituberculosis regimen were used to assess associations between NAT2 genotypes/phenotypes and hepatotoxicity. Results: Among the 500 participants, 440 (88%) received TPT, while 60 (12%) underwent treatment for active TB. Classified by phenotypes, 209 (41.8%) were slow, 154 (30.8%) intermediate, and 137 (27.4%) rapid acetylators. Age, BMI, HBV or HCV co-infection, liver enzyme levels were comparable between the acetylator phenotypes. However, the slow acetylator group had the shortest ART duration before anti-TB drug initiation (30 vs. 58 vs. 60 days; p < 0.001). Hepatotoxicity (grade 2-4) occurred in 53 participants (10.6%) overall: 29 (54.7)% slow, 19 (35.8%) intermediate, and 5 (9.4%) rapid acetylators (p < 0.001). As a percentage of each acetylator group, hepatotoxicity was observed in 13.9% of slow, 12.3% of intermediate, and 3.6% of rapid acetylators (p < 0.001). The NAT2 *6A/*6A genotype was associated with a significantly increased risk of hepatotoxicity (adjusted OR 2.6 (95%CI 1.3-5.5), p = 0.01), whereas NAT2 *4/*4, the wild-type fast acetylator genotype and the most common (24.0%), provided a protective effect (adjusted OR 0.14 (95%CI 0.03-0.6), p = 0.01). Slow acetylators had a markedly higher risk of hepatotoxicity compared to rapid acetylators, with an adjusted OR of 8.7 (95%CI1.9-38.1, p = 0.004). ( Table ) Conclusions: This cohort of Thai PLWH demonstrates that the NAT2 *6A/*6A genotype and slow acetylator phenotype significantly increase the risk of isoniazid-induced hepatitis. Incorporating NAT2 genotyping an theraputic drug monitoring into clinical practice could help optimize isoniazid dosing and reduce the risk of hepatotoxicity, especially in populations with a high susceptible to hepatotoxicity.

Poster Abstracts

CROI 2025 301