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

BACKGROUND

slow metabolisers have higher efavirenz concentrations, which are further increased by isoniazid inhibiting efavirenz's accessory metabolic pathway.

OBJECTIVES

We investigated the association between 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 genotype. We explored associations between the 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 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. slow metabolisers had higher efavirenz concentrations on isoniazid than extensive metabolisers ( = 1.66 [95% CI 0.98-2.34]). slow metabolisers had greater increases in total ( = 0.44 mmol/L [95% CI 0.01-0.86]) and HDL-cholesterol ( = 0.39 mmol/L [95% CI 0.21-0.57]) than extensive metabolisers. There were no associations between efavirenz concentrations or genotype, and change in ALT, FPG, low-density lipoprotein (LDL)-cholesterol, triglycerides, sleep quality, or MMS scores.

CONCLUSION

slow metabolisers on isoniazid and efavirenz had greater efavirenz concentrations and increases in total and HDL-cholesterol. We found no association between genotype or efavirenz concentrations and sleep or psychiatric symptoms.