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

Meng-Rui Lee1, Hung-Ling Huang2,3,4, Shu-Wen Lin5

  • 1Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu 30059, Taiwan. sheepman1024@gmail.com.

Journal of Clinical Medicine
|June 9, 2019
PubMed

Insights

Weekly rifapentine and isoniazid therapy (3HP) for latent tuberculosis infection (LTBI) can cause drug reactions. The NAT2 gene variant and higher isoniazid levels are linked to these systemic drug reactions (SDRs).

Area of Science:

  • Pharmacogenomics
  • Infectious Diseases
  • Clinical Pharmacology

Background:

  • Weekly rifapentine and isoniazid (3HP) is a common treatment for latent tuberculosis infection (LTBI).
  • Systemic drug reactions (SDRs) are a significant concern with 3HP therapy.
  • Identifying factors contributing to SDRs is crucial for optimizing LTBI treatment.

Purpose of the Study:

  • To investigate genetic (SNP) and pharmacokinetic (PK) factors associated with SDRs in patients receiving 3HP therapy.
  • To validate candidate genetic markers in a separate cohort.

Main Methods:

  • Prospective recruitment of two LTBI cohorts for 3HP therapy.
  • SNP analysis of NAT2, CYP2E1, and AADAC genes in one cohort.
  • Plasma drug and metabolite level measurements in a PK cohort.
  • Statistical modeling (generalized estimating equation) to identify SDR predictors.
  • Validation of candidate SNPs in the PK cohort.

Main Results:

  • 14% (SNP cohort) and 10% (PK cohort) of participants developed SDRs.
  • NAT2 rs1041983 and CYP2E1 rs2070673 SNPs were associated with SDRs in the SNP cohort.
  • Higher isoniazid levels at 24 hours post-3HP administration were linked to SDRs in the PK cohort.
  • The association between NAT2 rs1041983 and SDRs was confirmed in the PK cohort.

Conclusions:

  • Isoniazid levels and specific NAT2 genetic variations play a role in 3HP-related SDRs.
  • These findings may inform the development of safer and more effective LTBI treatment regimens.
  • Personalized approaches considering genetic and PK profiles could mitigate SDRs.
Keywords:
N-acetyltransferase 2isoniazidlatent tuberculosis infectionrifapentinesystemic drug reaction

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