Efavirenz Plasma Concentrations and Cytochrome 2B6 Polymorphisms

Lindfelt, Tristan A.; O'Brien, J.R.; Song, Jessica; Patel, Rajul A.; Winslow, Dean L.

doi:10.1345/aph.1p141

Cited by 16 publications

(14 citation statements)

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“…Studies have reported an association between CYP2B6 genotypes and the pharmacokinetics of EFV and NVP in HIV‐infected patients of European and African ethnicities (Cabrera et al, ; Haas et al, ; Mahungu et al, ; Motsinger et al, ; Ribaudo et al, ; Rotger et al, ; Schipani et al, ; Wyen et al, ). Also, similar studies have been published in other ethnically diverse patients (Carr, Porte, Pirmohamed, Owen, & Cortes, ; Chen et al, ; Lindfelt, O'Brien, Song, Patel, & Winslow, ; Puthanakit, Tanpaiboon, Aurpibul, Cressey, & Sirisanthana, ; Ramachandran et al., ; To et al, ). In India, it is believed that we have different gene pools in south, north, east, and west regions.…”

Section: Introductionsupporting

confidence: 66%

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV‐associated hepatotoxicity

Singh

Lata

Dhole

et al. 2019

Molec Gen & Gen Med

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Background Hepatic enzyme cytochrome P450 2B6 (CYP2B6) plays a role in the metabolism of efavirenz drugs. CYP2B6 516G>T variation showed an implication for HIV treatment. Methods CYP2B6 516G>T polymorphism was genotyped in a total 165 HIV patients that include 34 with and 131 without hepatotoxicity and 155 healthy individuals by the PCR‐RFLP. Results In patients with hepatotoxicity, the prevalence of CYP2B6 516TT genotype was higher as compared to healthy individuals (35.3% vs. 30.5%, OR = 1.74). Patients with hepatotoxicity using tobacco had a higher prevalence of genotypes CYP2B6 516GT, 516TT, 516GT+TT as compared to healthy individuals (28.57% vs. 25.93%; 57.14% vs. 29.63%; 85.71% vs. 55.56%). Likewise, hepatotoxicity in patients consuming alcohol showed higher distributions of CYP2B6 516GT, 516TT, 516GT+TT genotypes (57% vs. 25.93%; 42.86% vs. 33.33%; 71.43% vs. 59.26%). Nevirapine users with hepatotoxicity overrepresented genotypes CYP2B6 TT and 516GT+TT as compared to efavirenz users (47.83% vs. 45.45%, OR = 6.88, 65.22% vs. 54.55%, OR = 1.56). Similarly, in nevirapine +alcohol users with hepatotoxicity, the frequency of CYP2B6 516GT, 516GT+TT genotypes was higher than with nevirapine +alcohol nonusers (40.0% vs. 11.11%, OR = 8.00, 80.0% vs. 27.78%, OR = 4.00). In HIV patients, nevirapine users had higher frequency of CYP2B6 516GT, 516GT+TT genotypes as compared to efavirenz users (42.02% vs. 25.00%, OR = 2.53; 72.27% vs. 58.33%, OR = 1.86). Likewise, in HIV patients, genotypes CYP2B6 516GT, 516GT+TT were predominant with nevirapine +alcohol users as compared to nevirapine +alcohol nonusers (57.89% vs. 34.57%, OR = 2.46; 78.95% vs. 69.14%, OR = 1.67). In multivariate logistic regression, taking nevirapine had a protection for severity of ARV‐associated hepatotoxicity (OR = 0.23, p = 0.005). Conclusions No significant association was detected between CYP2B6 516G>T polymorphism and susceptibility to ARV‐associated hepatotoxicity.

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Section: Introductionsupporting

confidence: 66%

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV‐associated hepatotoxicity

Singh

Lata

Dhole

et al. 2019

Molec Gen & Gen Med

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“…To our knowledge, the association of c.516G Ն T with efavirenz pharmacokinetics is well established [26][27][28] but the impact of CYP2B6 haplotype, GAC (516G, 785A and g.21563C) on steady-state efavirenz plasma concentrations is not well-defined. It is unclear why the g.21563C>T polymorphisms, which are unlikely to impact on the functional effect of CYP2B6, were associated.…”

Section: Discussionmentioning

confidence: 97%

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

Sukasem

Cressey

Prapaithong

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interindividual variability in efavirenz plasma concentrations is associated with CYP2B6 genetic polymorphisms.• Twenty‐nine different alleles of the CYP2B6 gene are listed. CYP2B6*6, *9, *16, *26, *27 and *28 carriers are reported to be associated with slower efavirenz oral clearance.• The allelic variant 516G>T is associated with diminished activity of CYP2B6 and high efavirenz plasma concentrations are associated with an increase risk of neuropsychological toxicity.WHAT THIS STUDY ADDS• This study identified three SNPs in the CYP2B6 gene which could potentially act as additional independent predictors of efavirenz plasma concentrations beyond that provided by the CYP2B6 c.516G>T polymorphism.• The GAC‐CYP2B6 haplotype (G516T/A785G/C21563T) is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.• The CYP2B6 g.18492 T>C polymorphism was significantly associated with lower efavirenz concentrations than those with the homozygous wild‐type.AimsTo investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV‐1 infection.MethodsGenotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real‐time PCR‐based allelic discrimination on blood samples from 52 HIV‐infected adults who had received an efavirenz‐based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography.ResultsThe minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations.ConclusionsOur data indicate that the GAC‐CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.

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“…15 Plasma efavirenz concentrations may vary among patients based on a number of personal characteristics, such as genetics and weight. 15 Lindfelt et al 16 observed that Hispanics and Asians had increased concentrations of efavirenz and a higher rate of adverse drug reactions due to a possible polymorphism of CYP2B6.The investigators reported that the mean plasma efavirenz concentration at midpoint after a dose was 1.59 mg/ mL in Caucasians and 3.15 mg/mL in Hispanics.…”

Section: Discussionmentioning

confidence: 99%

Decreased plasma efavirenz concentrations in a patient receiving rifabutin

Hsu

Hill

Kim

et al. 2010

American Journal of Health-System Pharmacy

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Efavirenz Plasma Concentrations and Cytochrome 2B6 Polymorphisms

Abstract: Trough efavirenz concentrations were significantly higher in patients with the 785 (A to G) and 516 (G to T) variants. Midpoint efavirenz concentrations in Latinos were significantly higher than those of whites.

Cited by 16 publications

References 15 publications

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV‐associated hepatotoxicity

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV‐associated hepatotoxicity

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

Decreased plasma efavirenz concentrations in a patient receiving rifabutin

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