Abstract
We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long-term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.
Publication types
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Clinical Trial
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Multicenter Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Adult
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Alkynes
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Antiretroviral Therapy, Highly Active
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism
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Benzoxazines / administration & dosage
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Benzoxazines / blood
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Benzoxazines / pharmacokinetics*
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Biotransformation
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Cyclopropanes
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP3A / genetics
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Cytochrome P-450 CYP3A / metabolism
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Drug Administration Schedule
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Female
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Genotype
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HIV Infections / blood
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HIV Infections / drug therapy*
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Humans
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Hydroxylation
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Male
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Middle Aged
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism
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Phenotype
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Prospective Studies
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Reverse Transcriptase Inhibitors / administration & dosage
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Reverse Transcriptase Inhibitors / blood
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Reverse Transcriptase Inhibitors / pharmacokinetics*
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Sex Factors
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Tanzania
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Alkynes
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Benzoxazines
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Cyclopropanes
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Reverse Transcriptase Inhibitors
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Aryl Hydrocarbon Hydroxylases
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CYP2B6 protein, human
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CYP3A5 protein, human
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP3A
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Oxidoreductases, N-Demethylating
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efavirenz