Background:  The role of ritonavir (RTV) in inducing cardiovascular disease (CVD) is unclear. This study investigated the relationship between low-dose RTV plasma exposure and short-term changes in lipids (total cholesterol [TC], HDL, LDL, and triglycerides [TG]), monocyte scavenger receptor (CD36), vascular inflammation markers (VIM = hsCRP, sICAM-1, sCD40L).

Methods:  Non-smoking male and female healthy volunteers were randomized to:  arm 1 (RTV 100 mg once daily-washout-RTV 100 mg twice daily) or arm 2 (RTV 100 mg twice daily-washout-RTV 100 mg once daily), all study phases lasted 14 days. Lipids, CD36 expression and VIM were measured before and after RTV 14-day intake by standard validated methods. Full steady-state RTV 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 subjects (10 females). Median (range) age and body mass index were 28 (19 to 45) and 22 (18 to 26). Median (range) RTV AUC0-24 (ng·h/mL) and C_max (ng/mL) for once and twice daily were 5773 (2466 to 18848) and 751 (298 to 1896), and 14,525 (6862 to 46370) and 1431 (597 to 3874). Significant decreases in HDL (6%, p = 0.010 and 10%, p <0.001) and CD36 (14%, p = 0.012 and 16%, p = 0.006) were seen following RTV once- and twice-daily intake. However, a significant increase in TG was seen only when RTV was given twice daily (32%, p = 0.044). No changes in VIM were observed. There was a significant correlation between RTV plasma exposure and the change in TG and HDL (r = 0.34, p = 0.030 and r = 0.33, p = 0.040, all subjects).

Conclusions:  In healthy volunteers, 100 mg twice daily of RTV, but not 100 mg once-daily RTV gave rise to an increase in TG over 2 weeks; the increase was related to higher RTV exposure. Reduced HDL and CD36 expression were observed for both RTV dosages.