Dataset Information

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

ABSTRACT: Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p?=?0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

SUBMITTER: Vujkovic M

PROVIDER: S-EPMC6151142 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Vujkovic Marijana M Bellamy Scarlett L SL Zuppa Athena F AF Gastonguay Marc R MR Moorthy Ganesh S GS Ratshaa Bakgaki B Han Xiaoyan X Steenhoff Andrew P AP Mosepele Mosepele M Strom Brian L BL Bisson Gregory P GP Aplenc Richard R Gross Robert R

The pharmacogenomics journal 20180601 5

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs2839943 ...[more]

PMID: 29855606

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Project description:BACKGROUND:There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. OBJECTIVES:We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. METHODS:We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. RESULTS:We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (??=?0.38, P?=?2.7?×?10-03), plasma 7-hydroxy-efavirenz (??=?0.59, P?=?3.7?×?10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (??=?-0.31, P?=?1.8?×?10-04) and CSF efavirenz (??=?0.36, P?=?0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (??=?-0.55, P?=?3.5?×?10-05), ABCB1 rs115780656 (??=?-0.65, P?=?4.1?×?10-05) and CYP2A6?-48A?C (??=?-0.59, P?=?0.01). CYP2A6?-48A?C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (??=?0.54, P?=?0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P?<?0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. CONCLUSIONS:We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.

Project description:The effects of genetic variation of cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) on efavirenz (EFV) plasma concentration was evaluated among 312 HIV patients in Nairobi Kenya. The EFV plasma concentration at steady-state were determined using ultra-high-performance liquid chromatography with a tandem quadruple mass spectrometer (LC-MS/MS). Thirteen CYP2B6 (329G>T, 341T>C, 444 G>T/C, 15582C>T, 516G>T, 548T>G, 637T>C, 785A>G, 18492C>T, 835G>C, 1459C>T and 21563C>T) and one CAR (540C>T) single nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction. HIV drug resistance mutations were detected using an in-house genotypic assay. The EFV concentration of patients ranged from 4 ng/mL to 332697 ng/mL (median 2739.5 ng/mL, IQR 1878-4891.5 ng/mL). Overall, 22% patients had EFV concentrations beyond therapeutic range of 1000-4000 ng/mL (4.5%% < 1000 ng/mL and 31.7% > 4000 ng/mL). Five SNPs (15582C>T, 516G>T, 785A>G, 983T>C and 21563C>T) were associated with higher EFV plasma concentration while 18492C>T with lower EFV plasma concentration (p<0.05). Strong linkage disequilibrium (LD) was observed for 15582C>T, 516G>T, 785A>G, 18492C>T, 983T>C, 21563C>T, 1459C>T and CAR 540C>T. Sixteen haplotypes were observed and CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT were associated with high EFV plasma concentration. In multivariate analysis, factors significantly associated with EFV plasma concentration included; the presence of skin rash (β = 1379, 95% confidence interval (CI) = 3216.9-3416.3; p < 0.039), T allele of CYP2B6 516G>T (β = 1868.9, 95% CI 3216.9-3416.3; p < 0.018), the C allele of CYP2B6 983T>C (β = 2638.3, 95% CI = 1348-3929; p < 0.0001), T allele of CYP2B6 21563C>T (β = 1737, 95% CI = 972.2-2681.9; p < 0.0001) and the presence of 5 to 7 numbers of SNPs per patient (β = 570, 95% CI = 362-778; p < 0.0001) and HIV viral load ≤1000 cells/mL (β = -4199.3, 95% CI = -7914.9 --483.6; p = 0.027). About 36.2% of the patients had EFV plasma concentrations beyond therapeutic window, posing high risk of treatment failure or toxicity. The SNPs of CYP2B6 516G>T, CYP2B6 983T>C, 21563C>T, presence of higher numbers of SNPs per patient and haplotypes CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT could efficiently serves as genetic markers for EFV plasma concentration and could guide personalization of EFV based ART treatment in Kenya.

Dataset Information

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Publications

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

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