Objectives: We investigated the long-term effect of efavirenz autoinduction on its plasma/peripheral blood mononuclear cell (PBMC) exposure and the CD4 count, and the importance of sex and pharmacogenetic variations.
Methods: Treatment-naive HIV patients (n = 163) received efavirenz-based antiretroviral therapy. Plasma and intracellular (PBMC) concentrations of efavirenz and 8-hydroxyefavirenz were determined at weeks 4 and 16 of antiretroviral therapy. CD4 count was determined at baseline, and at weeks 12, 24 and 48. Genotyping for CYP2B6*6, CYP3A5*3, CYP3A5*6, CYP3A5*7, ABCB1 3435C/T and UGT2B7 (-327G→A, *2) was done.
Results: There was a significant increase in the median plasma (32%) and intracellular (53%) 8-hydroxyefavirenz concentrations with a decrease in the efavirenz metabolic ratio (MR) (calculated by dividing the concentration of efavirenz by that of 8-hydroxyefavirenz) (20% and 5%, respectively) by week 16 compared with at week 4. While the CYP2B6 genotype significantly influenced efavirenz pharmacokinetics at weeks 4 and 16, the effect of the UGT2B7 genotype and sex was significant only at week 16. The Wilcoxon matched pairs test indicated that the change in 8-hydroxyefavirenz concentration and efavirenz MR over time was significant in females and in CYP2B6*1 and UGT2B7*1 carriers. The intracellular 8-hydroxyefavirenz level at week 16 was a negative predictor of the CD4 count at week 24 (P = 0.03) and at week 48 (P = 0.007). CYP2B6 (P = 0.02) and UGT2B7 (P = 0.05) genotypes predicted the CD4 count at week 48. Among CYP2B6*1/*1 and UGT2B7*1/*1 carriers there was no significant change in the mean CD4 count after week 24, while it continuously increased until week 48 in CYP2B6*6 and UGT2B7*2 carriers.
Conclusions: The effects of long-term efavirenz autoinduction on its plasma/PBMC exposure and the CD4 count over time display wide interpatient variability, partly due to sex and CYP2B6 and UGT2B7 genetic variation. Patients with the CYP2B6*1/*1 and UGT2B7*1/*1 genotypes are at risk of suboptimal immune recovery due to pronounced long-term autoinduction.