Plasma Concentration of Isoniazid and Single-Nucleotide Polymorphisms of N-Acetyltransferase 2 Predict Risk of Systemic Drug Reactions During Weekly Rifapentine and Isoniazid Therapy for Latent Tuberculosis Infection: A Prospective Observational Cohort Study

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Background: Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Little, however, is known regarding the predictors of 3HP-related SDRs. Methods: We prospectively recruited 2 LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 hours after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. Findings: A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs CC CT, odds ratio [OR] [95% CI]: 7.38 [2.17-25.1]) and CYP2E1 rs2070673 (AA vs TT TA, OR [95% CI]: 3.49 [1.02-12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 hours after 3HP administration (OR [95% CI]: 1.61 [1.15-2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs CC CT, OR [95% CI]: 4.14 [1.24-13.8]). Interpretations: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. Funding: The study was supported by grants from the Ministry of Health and Welfare (MOHW106-CDC-C-11400104 and MOHW107-CDC-C-114-000105) and the Ministry of Science and Technology (MOST106-2314-B-002-055, MOST107-2314-B-002-191 and MOST107-2314-B-037-106-MY3). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: The study was approved by the institutional ethics committees of both medical centres (NTUH REC 201609044RINB and KMUHIRB-G[II]-20170033).