10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

RITONAVIR 100 MG TWICE DAILY, BUT NOT 100 MG ONCE DAILY, INCREASES ADIPOPHILIN EXPRESSION: POTENTIAL EFFECT OF RITONAVIR ON CARDIOVASCULAR DISEASE (CVD)

Antiviral Therapy 2008; 13(Suppl. 4):A6 (abstract no. O-06)

M Boffito¹, S Collot-Teixeira², F De Lorenzo³, L Waters¹, C Fletcher¹, D Back⁴, S Mandalia¹, A Pozniak¹, J McGregor^2,5 and B Gazzard^1
1St. Stephen’s Centre, London, UK; ²King’s College London, UK; ³Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; ⁴University of Liverpool, UK; ⁵INSERM U689, Paris, France

BACKGROUND: We previously showed that, in healthy volunteers, ritonavir 100 mg twice daily, but not 100 mg once daily, increased triglyceride concentrations over 2 weeks; this increase was related to higher ritonavir exposure. Reduced HDL and CD36 expression were observed for both ritonavir doses. Several other markers are associated with atherogenesis and CVD. We aimed at investigating the role of ritonavir in altering proinflammatory marker concentrations (hs-CRP, sICAM-1 and CD40L) and adipophilin expression. Adipophilin is responsible for cellular lipid accumulation through the inhibition of cholesterol efflux.

METHODS: Non-smoking male and female healthy volunteers were randomized to arm 1 (ritonavir 100 mg once daily, washout and ritonavir 100 mg twice daily) or arm 2 (ritonavir 100 mg twice daily, washout and ritonavir 100 mg once daily); all study phases lasted 14 days. Proinflammatory markers and adipophilin expression were measured before and after ritonavir 14-day intake by standard validated methods. Full steady-state ritonavir pharmacokinetics was assessed on days 14 and 43 by high performance liquid chromatography mass spectrometry/mass spectrometry (HPLC-MS/MS). Paired t-test and Pearson’s correlation were used for statistical analysis.

RESULTS: The study was completed by 20 individuals (10 females). Median (range) age and body mass index were 28 (19–45) years and 22 (18–26) kg/m², respectively. Significant increases were observed for plasma sCD40L following ritonavir once daily (12%, P=0.008) and twice daily (19%, P=0.003) 14-day intake. No changes in hs-CRP and sICAM-1 were observed. Ritonavir induced an increase (30%, P=0.044) in adipophilin mRNA quantity in peripheral blood mononuclear cells in individuals treated twice daily, whereas no significant effect on adipophilin expression was seen when ritonavir was administered 100 mg once daily. No difference was observed in adipophilin gene expression between males and females. A significant correlation was observed between ritonavir plasma exposure and adipophilin gene expression (r=0.4, P=0.012).

CONCLUSIONS: In healthy volunteers, 100 mg twice daily ritonavir, but not 100 mg once daily ritonavir, led to an increase in adipophilin gene expression over 2 weeks; the increase was related to higher ritonavir exposure. Increased CD40L concentrations were measured for both ritonavir dosages.

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2008-11-06
O-06

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