CYP2B6 18492T->C polymorphism compromises efavirenz concentration in coinfected HIV and tuberculosis patients carrying CYP2B6 haplotype *1/*1.

Abstract

Data regarding the effect of the CYP2B6 18492T→C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C→T, 499C→G, 516G→T, 785A→G, 1375A→G, 1459C→T, and 21563C→T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T→C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean±standard deviation (SD)], 56±10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T→C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (±SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8±1.6, 1.7±0.9, and 1.4±0.5 mg/liter, respectively (P=0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4±0.8, 1.7±0.8, and 1.2±0.4 mg/liter, respectively (P=0.003). A low efavirenz concentration was independently associated with 18492T→C (β=-0.937, P=0.004) and high body weight (β=-0.032, P=0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P=0.254). In summary, the CYP2B6 18492T→C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis.

• Authors: Weerawat Manosuthi, Chonlaphat Sukasem, Supeda Thongyen, Samruay Nilkamhang, Sukanya Manosuthi, Somnuek Sungkanuparph
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 4 Pg. 2268-73 ( 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24492364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• Reverse Transcriptase Inhibitors
• Aryl Hydrocarbon Hydroxylases
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• efavirenz

Topics

• Adult
• Alkynes
• Anti-HIV Agents (pharmacokinetics, therapeutic use)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Benzoxazines (pharmacokinetics, therapeutic use)
• Coinfection
• Cyclopropanes
• Cytochrome P-450 CYP2B6
• Female
• HIV Infections (blood, drug therapy)
• Haplotypes (genetics)
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Reverse Transcriptase Inhibitors (pharmacokinetics, therapeutic use)
• Tuberculosis (blood, drug therapy)