Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients.

Abstract

Comprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable. A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Plasma efavirenz concentrations were measured at 12 weeks. The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter. The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%). The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%). The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P < 0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P < 0.05). Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations. As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta = -1.084, P = 0.027) and high body weight (beta = -0.076, P = 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.

• Authors: Weerawat Manosuthi, Chonlaphat Sukasem, Aroon Lueangniyomkul, Wiroj Mankatitham, Supeda Thongyen, Samruay Nilkamhang, Sukanya Manosuthi, Somnuek Sungkanuparph
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 2 Pg. 1019-24 (Feb 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23254426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Anti-HIV Agents
• Antitubercular Agents
• Benzoxazines
• Cyclopropanes
• Organophosphonates
• Reverse Transcriptase Inhibitors
• Pyrazinamide
• Lamivudine
• Ethambutol
• Tenofovir
• Aryl Hydrocarbon Hydroxylases
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• Oxidoreductases, N-Demethylating
• Adenine
• efavirenz
• Isoniazid
• Rifampin

Topics

• Adenine (analogs & derivatives, therapeutic use)
• Adolescent
• Adult
• Alkynes
• Anti-HIV Agents (blood, therapeutic use)
• Antitubercular Agents (therapeutic use)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Benzoxazines (blood, therapeutic use)
• Cyclopropanes
• Cytochrome P-450 CYP2B6
• Drug Interactions
• Ethambutol (therapeutic use)
• Female
• Genotype
• HIV Infections (blood, complications, drug therapy)
• Humans
• Isoniazid (therapeutic use)
• Lamivudine (therapeutic use)
• Male
• Middle Aged
• Organophosphonates (therapeutic use)
• Oxidoreductases, N-Demethylating (genetics)
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Pyrazinamide (therapeutic use)
• Reverse Transcriptase Inhibitors (blood, therapeutic use)
• Rifampin (therapeutic use)
• Tenofovir
• Tuberculosis (complications, drug therapy)
• Young Adult