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1 November 2007

Volume 45, Number 9
Clinical Infectious Diseases 2007;45:1230–1237
© 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4509-0018$15.00
DOI: 10.1086/522175
HIV/AIDS MAJOR ARTICLE

Successful Efavirenz Dose Reduction in HIV Type 1–Infected Individuals with Cytochrome P450 2B6 *6 and *26

Hiroyuki Gatanaga,1

Tsunefusa Hayashida,1

Kiyoto Tsuchiya,1

Munehiro Yoshino,2

Takeshi Kuwahara,2

Hiroki Tsukada,4

Katsuya Fujimoto,5

Isao Sato,6

Mikio Ueda,7

Masahide Horiba,8

Motohiro Hamaguchi,9

Masahiro Yamamoto,10

Noboru Takata,11

Akiro Kimura,12

Takao Koike,5

Fumitake Gejyo,4

Shuzo Matsushita,13

Takuma Shirasaka,3

Satoshi Kimura,1 and

Shinichi Oka1

1AIDS Clinical Center, International Medical Center of Japan, Tokyo, 2Department of Pharmacy and 3AIDS Medical Center, Osaka National Hospital, Osaka, 4Division of Clinical Nephrology, Rheumatology, Respiratory Medicine and Infection Control and Prevention, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 5Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, 6Sendai Medical Center, Sendai, 7Department of Hematology and Immunology, Ishikawa Prefecture Central Hospital, Kanazawa, 8Department of Respiratory Medicine, Higashi Saitama Hospital, Hasuda, 9Nagoya Medical Center, Nagoya, 10Kyushu Medical Center, Fukuoka, 11Division of Blood Transfusion Services, 12Department of Hematology, Hiroshima University, Hiroshima, and 13Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Kumamoto University, Kumamoto, Japan

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.

Received 10 April 2007; accepted 6 July 2007; electronically published 24 September 2007.

Reprints or correspondence: Dr. Hiroyuki Gatanaga, AIDS Clinical Center, International Medical Center of Japan, 1‐21‐1 Toyama, Shinjuku‐ku, Tokyo 162‐8655, Japan ().

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