[O-02] Nevirapine increases high density lipoprotein- cholesterol by stimulation of apolipoprotein AI synthesis

9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

19-21 July 2007, Sydney, Australia

NEVIRAPINE INCREASES HIGH DENSITY LIPOPROTEIN-CHOLESTEROL BY STIMULATION OF APOLIPOPROTEIN AI SYNTHESIS

Antiviral Therapy 2007; 12(Suppl. 2):L5 (abstract no. O-02)

RR Sankatsing¹, R Franssen¹, E Hassink², HP Sauerwein¹, K Brinkman³, R Oesterholt¹, A Arenas-Pinto⁴, I Williams⁴, S Storfer⁵, JJ Kastelein¹, P Reiss¹ and ES Stroes¹
¹Academic Medical Center, Amsterdam, the Netherlands; ²IATEC bv, Amsterdam, the Netherlands; ³Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; ⁴Royal Free & University College Medical School, London, UK; ⁵Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, USA

OBJECTIVES: Combination therapy for HIV-1 infection including protease inhibitors (PI), but not non-nucleoside reverse transcriptase inhibitors (NNRTI) is associated with increased cardiovascular (CVD) risk. Whereas many PI are associated with atherogenic lipid changes, NNRTI exert more favourable changes, notably increases in HDLc. We therefore investigated the mechanism by which the NNRTI nevirapine (NVP) increases HDLc.

METHODS: Thirteen HIV-1-infected patients with plasma HIV-1 RNA <50 copies/ml on AZT/3TC/abacavir for ≥6 months added NVP at usual dose for 24 weeks. Before (week 0), and 6 and 24 weeks later patients received a primed bolus infusion of stable isotope L-[1-13C]-valine for 12 h to study apolipoprotein A-I (apoAI) kinetics. Using SAAM-II modelling, absolute production rates (APR) and fractional catabolic rates (FCR) of apoAI were calculated. All HDLc-modulating enzymes were assessed. Analyses by ITT. Wilcoxon signed rank test for % change in large HDL particles and % change from week 6 to week 24; mixed model repeated measures for other analyses.

RESULTS: See Table 1. Other HDL-modulating enzymes, including hepatic lipase, lecithin:cholesterol acyl transferase and phospholipid transfer protein remained unchanged.

Table 1. (Abstract 0-02)
		% change week 0 to:
	Week 0*	Week 6†	Week 24†
HDLc, mmol/l	1.1 (1.0–1.4)	4 (-5–12)	19 (8–31)‡,¶
ApoA1, g/l	1.2 (1.1–1.4)	-4 (-19–11)	14 (5–23)‡,¶
Large HDL particles, µmol/l	4.6 (2.2–5.0)	17 (-6–40)*	42 (28–110)*,¶
CETP activity, %	84% (81–91)	10 (2–18)§	14 (6–23)‡
APR, mg/kg/day	721.6 (646.8–817.5)	-7 (-31–16)	17 (2–31)§,¶
FCR, pools/day	0.18 (0.15–0.20)	-6 (-19–8)	2 (-9–13)

*Median (IQR); †Estimated mean (95%CI); ‡P<0.01; §0.01=P<0.05; ¶change from wk6 to wk24 0.01=P<0.05

CONCLUSIONS: NVP increased apoAI and HDLc by selectively promoting apoAI production without affecting HDL catabolism. This may contribute to why the increased CVD risk with PI-based therapy has not been found with treatment including NNRTI. Moreover, in view of the recent disappointing results of HDL increasing strategies with the CETP inhibitor torcetrapib targeting HDL degradation, our findings may lead to the identification of more promising novel targets for increasing HDLc.

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2007-07-24
O-02

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