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Isoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI.


ABSTRACT: 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. Methods: We prospectively recruited two 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 h 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. 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]: 7.00 [2.03-24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02-12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h 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]: 4.43 [1.30-15.1]). Conclusions: 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.

SUBMITTER: Lee MR 

PROVIDER: S-EPMC6616849 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Isoniazid Concentration and <i>NAT2</i> Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI.

Lee Meng-Rui MR   Huang Hung-Ling HL   Lin Shu-Wen SW   Cheng Meng-Hsuan MH   Lin Ya-Ting YT   Chang So-Yi SY   Yan Bo-Shiun BS   Kuo Ching-Hua CH   Lu Po-Liang PL   Wang Jann-Yuan JY   Chong Inn-Wen IW  

Journal of clinical medicine 20190606 6


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. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the <i>NAT2</i>, <i>CYP2E1</i>, and <i>AADAC</i> SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite lev  ...[more]

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