Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26.
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.
Gatanaga
Hiroyuki
H
AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan. higatana@imcj.acc.go.jp
Hayashida
Tsunefusa
T
Tsuchiya
Kiyoto
K
Yoshino
Munehiro
M
Kuwahara
Takeshi
T
Tsukada
Hiroki
H
Fujimoto
Katsuya
K
Sato
Isao
I
Ueda
Mikio
M
Horiba
Masahide
M
Hamaguchi
Motohiro
M
Yamamoto
Masahiro
M
Takata
Noboru
N
Kimura
Akiro
A
Koike
Takao
T
Gejyo
Fumitake
F
Matsushita
Shuzo
S
Shirasaka
Takuma
T
Kimura
Satoshi
S
Oka
Shinichi
S
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
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