title: Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26.
abstract: BACKGROUND
  Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a G-->T polymorphism at position 516 (516G-->T) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV.
  
  
  METHODS
  CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516G-->T carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516G-->T carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high.
  
  
  RESULTS
  CYP2B6 516G-->T was identified in the *6 allele (found in 17.9% of our subjects) and a novel allele, *26 (found in 1.3% of our patients). All EFV-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma EFV concentrations (>6000 ng/mL) while receiving the standard dosage. EFV dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV-1 loads. EFV-containing treatment was initiated at 400 mg in 4 CYP2B6 *6/*6 carriers and one *6/*26 carrier. Two of them still had a high plasma EFV concentration while receiving that dose, and the dose was further reduced to 200 mg, with successful HIV-1 suppression. CNS-related symptoms improved with dose reduction in 10 of the 14 patients, although some had not been aware of the symptoms at initial dosage.
  
  
  CONCLUSIONS
  Genotype-based EFV dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce EFV-associated CNS symptoms.
authors.affiliation: AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan. higatana@imcj.acc.go.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Tsunefusa
authors.initials: T
authors.lastname: Hayashida
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Munehiro
authors.initials: M
authors.lastname: Yoshino
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwahara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsukada
authors.forename: Katsuya
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Isao
authors.initials: I
authors.lastname: Sato
authors.forename: Mikio
authors.initials: M
authors.lastname: Ueda
authors.forename: Masahide
authors.initials: M
authors.lastname: Horiba
authors.forename: Motohiro
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Takata
authors.forename: Akiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.forename: Takuma
authors.initials: T
authors.lastname: Shirasaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
mesh_terms: D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005787:Gene Frequency; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic
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; C098320:efavirenz