title: Effect of CYP2B6 Gene Polymorphisms on Efavirenz Plasma Concentrations in Chinese Patients with HIV Infection.
abstract: OBJECTIVE
  The main aim of this study was to investigate the effect of CYP2B6 gene polymorphisms on efavirenz (EFV) plasma concentrations in Han Chinese patients with human immunodeficiency virus (HIV) infection.
  
  
  METHODS
  In total, 322 patients were recruited for study. EFV plasma concentrations at steady-state were determined using high-performance liquid chromatography. Genotyping for seven single nucleotide polymorphisms (SNPs), including 171+967C>A, 171+3212C>T, 171+4335T>C, 516G>T, 785A>G, 1295-913G>A, and *1355A>G of CYP2B6, was performed using ligase detection reaction (LDR). SPSS 18.0 and Haploview 4.2 were applied for statistical analyses.
  
  
  RESULTS
  The average EFV concentration of patients was 2.35±2.09 μg/mL. Overall, 22% patients displayed EFV concentrations out of the therapeutic range of 1-4 μg/mL (13.1% < 1 μg/mL, 9.3% > 4 μg/mL). We observed significant association of 171+967C>A, 171+4335T>C, 516G>T, 785A>G and *1355A>G with high plasma EFV levels (p<.01). The predictive accuracy values of 171+4335CC, 516TT and 785GG for EFV concentrations > 4 μg/mL were 56.7%, 56.7% and 60%, respectively. We observed strong linkage disequilibrium for 171+967C>A, 171+4335T>C, 516G>T and 785A>G, resulting in five haplotypes. The frequencies of the five haplotypes (high to low) were as follows: CCTG (0.328), ACTG (0.280), ACCT (0.189), ATTG (0.186) and ACCG (0.017). The frequency of CCTG (0.524) in patients with EFV plasma concentrations < 1 μg/mL was significantly higher than that in other patient groups, while that of ACCT (0.733) was significantly higher in patients with EFV concentrations > 4 μg/mL, relative to other patient groups. Average EFV concentrations of patients carrying ACTG (1.78 μg/mL), ACCT (7.50 μg/mL), and ATTG (1.92 μg/mL) haplotypes were markedly higher than those of patients carrying the CCTG haplotype. The predictive accuracy of ACCT for EFV > 4 μg/mL was 81%.
  
  
  CONCLUSIONS
  Chinese patients administered standard doses of EFV require therapeutic drug monitoring or personalized medication management. Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions.
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Administration, School of Pharmacy, Fudan University, Shanghai, China; Department of Pharmacy, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Yin
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Jiangrong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Yinzhong
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China; Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
authors.forename: Hongzhou
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Administration, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Cai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002681:China; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065695:Cytochrome P-450 CYP2B6 Inducers; D018894:Reverse Transcriptase Inhibitors; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz