CYP2B6 (c.516G-->T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients

Abstract

Aims: Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G-->T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients.

Methods: Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5'-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions.

Results: CYP2B6 c.516G-->T, CYP2B6 c.983T-->C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P= 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G-->T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively.

Conclusions: Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.

Figure 1

Correlation of mid-dose efavirenz concentrations in plasma from 65 human immunodeficiency virus-infected Ghanaian patients measured 4 weeks (abscissa) and 8 weeks (ordinate) after commencing treatment. Shown are the Spearman correlation coefficient (Rs) and associated P-value for the correlation analysis, and the line of identity representing perfect correlation

Figure 2

Influence of CYP2B6 c.516G→T and CYP2B6 c.983T→C polymorphisms (A) and of CYP2A6*9 and CYP2A6*17 polymorphisms (B) on efavirenz mid-dose concentrations (average of 4-week and 8-week samples) in human immunodeficiency virus (HIV) and HIV/tuberculosis co-infected patients in Ghana. Differences between groups were examined by Mann–Whitney rank sum test (two genotype groups) or by anova (three genotype groups) with post hoc Student–Newman–Keuls pair-wise multiple comparisons testing

Figure 3

Influence of CYP2A6 slow metabolizer genotypes (*9B and/or *17) and CYP2B6 c.516G→T genotypes on efavirenz mid-dose concentrations (average of 4-week and 8-week samples). Shown are the P-values from the two-way anova (including analysis of gene–gene interactions) and post hoc multiple pair-wise comparisons (Student–Newman–Keuls test) within genotype groups