100 mg Once- and Twice-daily Ritonavir (Norvir) Decreases HDL and CD36 Expression, but Only Twice-daily Dosing Increases Triglycerides

Most current HIV protease inhibitors (PIs) are used in combination with a low dose of ritonavir (Norvir) to raise their levels in the blood. This has led to interest in determining the impact of low-dose ritonavir on changes in blood lipids among patients using boosted PIsIn the current study, presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) last month in Boston, researchers investigated the possible role of ritonavir in contributing to cardiovascular disease.

Specifically, the study explored the relationship between low-dose ritonavir plasma exposure and short-term changes in lipids and vascular inflammatory markers in healthy, HIV negative volunteers. Lipids measured were total cholesterol (TC), high-density lipoprotein (HDL or "good") cholesterol, low-density lipoprotein (LDL or "bad") cholesterol, and triglycerides (TG).

The study included 20 non-smoking healthy volunteers (10 men, 10 women). The median age was 28 years and the median body mass index was 22. Participants were randomized to 1 of 2 study arms:

Arm 1: 100 mg once-daily ritonavir, followed by a washout period, then 100 twice-daily ritonavir;

Arm 2: 100 mg twice-daily ritonavir, followed by a washout period, then 100 once-daily ritonavir

All study phases lasted 14 days. Lipid levels, CD36 expression and vascular inflammatory markers were measured before and after 14 day of ritonavir intake by standard validated methods. Full steady-state ritonavir pharmacokinetics was assessed on days 14 and 43 by high performance liquid chromatography and mass spectrometry.

Results

Significant decreases in HDL were seen following once- and twice-daily administration of ritonavir (6% [P = 0.010] and 10% [P < 0.001], respectively).

CD36 also decreased following once- and twice-daily intake (14% [P = 0.012] and 16% [P = 0.006], respectively).

However, a significant increase in TG was seen only when ritonavir was given twice daily (32%; P = 0.044).

No changes in vascular inflammatory markers were observed.

There was a significant correlation between ritonavir plasma exposure and changes in TG and HDL (R = 0.34 [P = 0.030] and R = 0.33 [P = 0.040], respectively, all subjects).

Conclusion

Based on these findings, the investigators concluded that in healthy volunteers, "100 mg twice-daily ritonavir, but not 100 mg once-daily ritonavir, gave rise to an increase in TG over 2 weeks."

In addition, they noted that the increase was related to higher ritonavir exposure. Finally, they wrote, "Reduced HDL and CD36 expression were observed for both ritonavir dosages."

St Stephen's Ctr, London, UK; King's College London, UK; Chelsea and Westminster Hosp NHS Fndn Trust, London, UK; Univ of Liverpool, UK.

3/11/08

Reference


M Boffito, S Collot-Teixeira, F De Lorenzo, and others. Plasma exposure of 100 mg once (OD) and twice daily (BID) decreases HDL and CD36 expression but only BID dosing increases triglycerides: potential effect of ritonavir on cardiovascular disease. 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008). Boston, MA. February 3-6, 2008. Abstract 930.