Background:  Lopinavir/ritonavir (LPV/r) can cause hyperlipidemia in HIV-infected patients. Most statins are metabolized by cytochrome P450, while protease inhibitors (PI) are strong inhibitors of this enzyme. Rosuvastatin (ROS) is a new statin that is not metabolized by this enzyme and therefore no interaction with LPV/r is expected. This trial was performed to determine the effect of ROS on the pharmacokinetics of LPV/r and vice versa, and to determine the lipid lowering effect of ROS in HIV-infected patients.

Methods:  HIV-infected patients stable on LPV/r (viral load <400 copies/mL) with a total cholesterol >6.2 mmol/L (= 239 mg/dL) were treated with ROS for 12 weeks. Plasma trough levels (C_min) of LPV were drawn at baseline, week 4, 8, and 12, and ROS C_min was determined. If any of the predetermined fasting target values (TC <5.0 mmol/L [= 192 mg/dL]; high-density lipoproteins [HDL] >1.0 mmol/L [= 40 mg/dL]; low-density lipoproteins [LDL] <2.6 mmol/L [= 100 mg/dL]; triglycerides <2.0 mmol/L [= 175 mg/dL]) were not reached with the ROS dose of 10 mg once daily, the dose was escalated to 20 mg or 40 mg at week 4 and 8, respectively.

Results:  All 22 patients (median age 48 years [29 to 63]) completed the trial. At week 12, 1 patient used 10 mg, 7 patients 20 mg, and 14 patients 40 mg of ROS once daily. Median LPV C_min (9 to 15 hours after intake) (IQR) was 5.2 (3.7 to 6.5), 5.4 (4.1 to 7.6), 5.6 (4.2 to 7.8), and 5.2 (3.6 to 6.3) mg/L at week 0, 4, 8, and 12, respectively (p = 0.44, repeated-measures analysis). Median (IQR) ROS C_min for 10 mg, 20 mg, and 40 mg once daily was 0.97 (0.70 to 1.45), 2.52 (1.29 to 3.34), and 5.48 (3.30 to 8.83) ng/mL. This is 1.5- to 2-fold higher than in past HIV-negative controls for all ROS dosages. At week 0, median (IQR) fasting total cholestserol, LDL, HDL, and triglycerides were 7.1 (6.6 to 7.5), 4.3 (3.8 to 4.6), 1.2 (0.9 to 1.5), and 3.6 (2.1 to 4.9) mmol/L; at week 12, these levels were 4.7 (4.1 to 5.3), 2.4 (1.9 to 2.9), 1.2 (0.9 to 1.6), and 2.0 (1.3 to 2.8) mmol/L, respectively. Reduction (IQR) in total cholesterol and LDL comparing week 4 to 0 was 27% (22 to 30%) and 35% (21 to 46%), which is similar to the effect of 10 mg of ROS once daily in HIV-negative patients. Of the total, 3 patients experienced transient muscle pain.

Conclusions: ROS appears an effective statin in HIV-infected patients treated with LPV/r. This trial showed that LPV/r levels were not affected by ROS, whilst ROS levels unexpectedly appeared to be increased 1.5-2 fold over what would be expected from data of HIV-negative patients. These findings warrant further study to fully elucidate the pharmacokinetics and pharmacodynamics of the combined use of ROS and LPV/r.