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15th Annual Conference of the British HIV Association1-3 April 2009, Liverpool, UK |
NUCLEAR RECEPTOR POLYMORPHISMS AND BOOSTED SAQUINAVIR PLASMA CONCENTRATIONS IN HIV-INFECTED SUBJECTS
HIV Med 2009 Apr 1-3 (Suppl 1);15:11 (abstract no. O23)
A Chaikan, D Egan, S Gibbons, SH Khoo, A Owen and D Back
University of Liverpool, Liverpool, UK
BACKGROUND: The expression of many CYP enzymes and transporter genes are regulated by nuclear hormone receptors such as PXR, CAR and HNF4alpha. The aim of this study was to investigate whether nuclear receptor polymorphisms influence saquinavir (SQV) plasma concentrations, since like most protease inhibitors SQV is a substrate for CYP3A and transporter proteins.
METHODS: Seventy-nine patients from the Liverpool TDM registry were included. All patients received SQV/RTV 1000/100 mg twice daily. SQV plasma concentrations (4–14 hr) were measured. Genomic DNA from plasma was genotyped for CAR (rs2307424C>T), PXR (rs1523130T>C, rs2472677C>T and rs6785049A>G), and HNF4alpha (rs1800961C>T, rs1884613C>G, rs2144908A>G, rs2425640A>G and rs35078168C>T) using real-time PCR based allelic discrimination. A Mann–Whitney U-test and Spearman’s rank correlation were used for analysis of categorical and continuous data, respectively. Finally, multiple linear regression was used for multivariate analysis.
RESULTS: The allele frequencies of CAR (rs2307424T), PXR (rs1523130C, rs2472677T and rs6785049G), and HNF4alpha (rs1800961T, rs1884613G, rs2144908G, rs2425640G and rs35078168T) were 0.26, 0.49, 0.53, 0.54, 0.03, 0.18, 0.86, 0.65 and 1 respectively. Following multivariate analysis, SQV plasma concentrations were significantly associated with HNF4alpha (rs1884613C>G) (P=0.03). The median (range) SQV plasma concentrations for CC, CG and GG were 585 (38–3703; n=56), 896 (70–4504; n=18) and 2196 (503–3033; n=5) ng/mL, respectively. The other SNPs, age, gender and tenofovir administration did not correlate with SQV concentrations (P> 0.05).
CONCLUSIONS: HNF4alpha (rs1884613G) SNPs may, in part, explain inter-individual variability in SQV concentrations. Further studies are required to confirm the influence of nuclear receptor polymorphisms on other boosted protease inhibitor pharmacokinetics.
2009-04-01
O23
Copyright © 2009 - British HIV Association (BHIVA) Reproduction of this abstract (other than one copy for personal reference) must be cleared through the BHIVA Organising Secretariat 1 Mountview Court, 310 Friern Barnet Lane, London N20 0LD