title: Long-term effect of efavirenz autoinduction on plasma/peripheral blood mononuclear cell drug exposure and CD4 count is influenced by UGT2B7 and CYP2B6 genotypes among HIV patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.forename: Wondwossen
authors.initials: W
authors.lastname: Amogne
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ueda
authors.forename: Alemayehu
authors.initials: A
authors.lastname: Worku
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Lars
authors.initials: L
authors.lastname: Lindquist
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D048588:Benzoxazines / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004790:Enzyme Induction; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C098320:efavirenz; C570209:8-hydroxyefavirenz