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The Genetic Determinants of High-density Lipoprotein Cholesterol Changes in HIV-1-infected Adults on Efavirenz-based Regimens
Tabitha Mahungu*1,2, D Nair1, C Smith1, F Turner1, M Youle1, M Johnson1, D Egan2, S Khoo2, D Back2, and A Owen2
1Royal Free NHS Trust, London, UK and 2Univ of Liverpool, UK
Background: NNRTI are associated with a well-described
favorable increase in high-density lipoprotein cholesterol (HDL-c). Isolated
studies have found a direct correlation between HDL-c and efavirenz (EFV) exposure.
Here we explore the effect of single nucleotide polymorphisms (SNP) associated
with EFV exposure on HDL-c. We also explore the effect of SNP in apolipoprotein
A5 (APOA5) and ABCB1.
Methods: We assessed retrospectively 76 patients (22
black African, 13 female) on first-line, EFV-based regimens. Using real-time polymerase
chain reaction (RT-PCR), 4 SNP at 3 different loci (CYP2B6 [516G>T],
ABCB1 [3435C>T], APOA5 [–1131T>C, 64C>G]) were identified. The
mean change in HDL-c over 48 weeks was compared between different genotypes. The
cumulative effect of genotypes associated with mean HDL-c change (p <0.10)
was also assessed.
Results: At baseline age, weight, gender, ethnicity,
CD4 count, and the individual genotypes did not have a significant impact on mean
HDL-c (1.1 mmol/L). There was a significant 0.32 mmol/L (p <0.001)
increase in mean HDL-c over 48 weeks that was not associated with the
nucleoside backbone. At 48 weeks, there was a significant association between ABCB1
C3435T and mean HDL-c change: (CC 0.26 mmol/L [n = 20]; CT 0.17 mmol/L [n = 31];
TT 0.54 mmol/L [n = 25] pANOVA = 0.003). A trend was observed
between CYP2B6 G516T and mean HDL-c change: (GG 0.28 mmol/L [n=34]; GT
0.29 mmol/L [n = 37]; TT 0.72 mmol/L [n = 5] pANOVA = 0.08). No
association was found between APOA5 polymorphisms and mean HDL-c change: T-1131C
(TT 0.29 mmol/l [n = 66]; TC 0.50 mmol/L [n = 10], p = 0.15) and C64G (GG
0.32 mmol/L [n = 70]; GC 0.27 mmol/L [n = 5]; CC 0.20 mmol/L [n = 1] pANOVA
= 0.96). The association between the cumulative number of predictive
genotypes and mean HDL-c change was significant when analysed using a composite
of CYP2B6 516TT and ABCB1 3435TT genotypes: Zero 0.20
mmol/L (n = 49); One 0.47 mmol/L (n = 24); Two 1.00 mmol/L (n = 3);
p <0.0001 (figure).
Conclusions: In this analysis we have demonstrated the
cumulative effect of drug metabolizing and drug transport variants on mean
HDL-c changes in ethnically diverse patients on EFV. These findings need to be
validated in independent, ethnically diverse cohorts. The mechanisms underlying
EFV-induced HDL-c increases are yet to be elucidated.
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