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.
Highlights
Tuberculosis (TB) remains one of the deadliest infectious diseases, with an estimated 10.0 million new cases and 1.6 million deaths in 2017 [1]
In the generalised estimating equation (GEE) model constructed for analysis of the C24 data, plasma INH level was associated with a higher risk of systemic drug reactions (SDR) development (OR [95% CI]: 1.61 [1.15–2.25], p = 0.006)
We discovered that N-acetyltransferase 2 (NAT2) and probably cytochrome P450 2E1 (CYP2E1), but not arylacetamide deacetylase (AADAC), gene single-nucleotide polymorphism (SNP) were associated with the development of SDRs among individuals receiving the 3HP regimen
Summary
Tuberculosis (TB) remains one of the deadliest infectious diseases, with an estimated 10.0 million new cases and 1.6 million deaths in 2017 [1]. Real-world data published in 1999 and obtained from an inner-city population in Atlanta, Georgia in the United States revealed that only 27% of subjects who received isoniazid (INH) preventive therapy completed their treatment [8]. A 2016 meta-analysis including 748,572 subjects in 58 studies found poor completion of LTBI programmes, with a 60% treatment completion rate [9]. In a pharmacokinetics study of RPT treatment in 35 TB patients during once-weekly continuation phase therapy, serious AEs were not linked with a higher area under the plasma concentration–time curve (AUC0~∞) of RPT [15]. We conducted this study to determine the predictors of SDRs during 3HP therapy by measuring the plasma levels of drugs and their major metabolites and by genotyping the three key drug-metabolising enzymes
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