Southern African Journal of HIV Medicine (Mar 2025)

Pharmacokinetics, pharmacogenetics, and toxicity of co-administered efavirenz and isoniazid

  • Jessica Taylor,
  • Gary Maartens,
  • Simiso Sokhela,
  • Nomathemba Chandiwana,
  • Godspower Akpomiemie,
  • Francois Venter,
  • Phumla Sinxadi

DOI
https://doi.org/10.4102/sajhivmed.v26i1.1661
Journal volume & issue
Vol. 26, no. 1
pp. e1 – e11

Abstract

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Background: CYP2B6 slow metabolisers have higher efavirenz concentrations, which are further increased by isoniazid inhibiting efavirenz’s accessory metabolic pathway. Objectives: We investigated the association between CYP2B6 genotype and toxicity in people living with HIV (PLWH) on isoniazid and efavirenz. Method: We enrolled participants from the efavirenz arm of the ADVANCE trial (reference no.: NCT03122262), who received isoniazid and consented to genotyping. We compared efavirenz concentrations on and off isoniazid, stratified by CYP2B6 genotype. We explored associations between the CYP2B6 genotype and efavirenz concentrations on isoniazid; and changes over 24 weeks in lipids, alanine aminotransferase (ALT), fasting plasma glucose (FPG), sleep quality, and Modified Mini Screen (MMS) scores. Results: A total of 168 participants, median age 31 years, 57% female, had classifiable CYP2B6 genotypes. Efavirenz concentrations on isoniazid were higher (pseudo-median difference 0.49 µg/mL (95% confidence interval [CI] [0.19–0.91]) and associated with increases in total and high-density lipoprotein (HDL)-cholesterol. CYP2B6 slow metabolisers had higher efavirenz concentrations on isoniazid than extensive metabolisers (β = 1.66 [95% CI 0.98–2.34]). CYP2B6 slow metabolisers had greater increases in total (β = 0.44 mmol/L [95% CI 0.01–0.86]) and HDL-cholesterol (β = 0.39 mmol/L [95% CI 0.21–0.57]) than extensive metabolisers. There were no associations between efavirenz concentrations or CYP2B6 genotype, and change in ALT, FPG, low-density lipoprotein (LDL)-cholesterol, triglycerides, sleep quality, or MMS scores. Conclusion: CYP2B6 slow metabolisers on isoniazid and efavirenz had greater efavirenz concentrations and increases in total and HDL-cholesterol. We found no association between CYP2B6 genotype or efavirenz concentrations and sleep or psychiatric symptoms.

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