Article
Association of a constitutive androstane receptor polymorphism (rs2307424) with treatment discontinuation in HIV+ patients receiving efavirenz
Zusammenhang vom konstitutiven Androstane Rezeptor Polymorphismus (rs2307424) mit dem Therapieabbruch bei HIV+ Patienten, die mit Efavirenz therapiert wurden
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Published: | June 2, 2010 |
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Objectives: The constitutive androstane receptor (CAR) and the pregnane-X-receptor (PXR) both regulate CYP2B6 expression. CYP2B6 is primarily responsible for metabolic clearance of efavirenz (EFV) and SNPs in the CYP2B6 gene are associated with EFV pharmacokinetics. A correlation between both these nuclear receptors and CYP2B6 expression was reported in liver, in the absence of xenobiotics. Since CAR and PXR are correlated with CYP2B6 and EFV is a potent substrate for this enzyme, SNPs in CYP2B6, CAR and PXR were investigated for their association with early (<3 months) discontinuation of EFV therapy.
Methods: Patients initiating therapy with an EFV based regimen were included (80 female; 95 black). The median (range) age was 46 (26–82), viral load was <50 (<50–1x106) and CD4 count was 406.5 (0–3233). Following informed consent, DNA was extracted from whole blood and genotyping for CYP2B6 (516G>T, rs3745274), CAR (rs2307424) and PXR (44477T>C, rs1523130; 63396C>T, rs2472677; 69789A>G, rs763645) were conducted using standard methodology. Multivariate regression by backwards method was used to assess the influence of SNPs and demographics on whether patients discontinued therapy within the first 3 months.
Results: Of the 373 patients, 131 withdrew from therapy within the first 3 months. The multivariate model had an adjusted R2=0.042; F=5, p<0.001. Ethnicity (β=–0.17; P=0.002, CAR (β=–0.12; P=0.02), and possibly CYP2B6 516G>T (β=0.09; P=0.07) and PXR 63396C>T (β=0.10; P=0.07) were associated with discontinuation within three months.
Conclusion: These data indicate that genetic variability in CYP2B6, CAR and PXR contribute to early treatment discontinuation in response to EFV-based antiretroviral regimens. Furthermore, as yet uncharacterised ethnic differences are also likely to contribute.