Dyslipidemia is a frequent side effect of combined antiretroviral therapy (cART), especially when boosted protease inhibitors are used. The lipid disorders usually consist of mixed hyperlipidemia, but isolated hypercholesterolemia and isolated hypertriglyceridemia can also occur. The management of protease inhibitor-associated dyslipidemia is controversial. A low-fat diet is recommended but is not always adequate. Three fibrates (gemfibrozil, bezafibrate, and fenofibrate) have been tested in this setting, reducing triglyceride levels by 41–58% on average [1,2]. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the most effective drugs for hypercholesterolemia and mixed dyslipidemia. Most statins are metabolized by CYP3A4 or are substrates of transporters (OATP-C) or both, whereas protease inhibitors potentially inhibit CYP3A4 or transporters or both [3,4]. Ritonavir is the most powerful CYP3A4 inhibitor. The use of statins in cART-treated patients is complicated by statin–protease inhibitor interactions, especially with ritonavir. Fluvastatin, pravastatin, and rosuvastatin are not metabolized by CYP3A4. Although pravastatin is the most widely prescribed statin in the context of HIV infection in France , rosuvastatin is the statin with the most potent effect on the LDL-cholesterol (LDL-c) level in the non HIV-1-infected population.
The primary objective of this randomized trial was to compare the efficacy of rosuvastatin and pravastatin, after 45 days treatment, on plasma lipid levels in HIV-1-infected patients taking a cART regimen containing at least one protease inhibitor boosted with ritonavir and whose LDL-c level exceeded 4.1 mmol/l.
This study (VIHstatine ANRS 126; ClinicalTrials.gov identifier NCT00117494) was a randomized, multicenter, open-label trial involving dyslipidemic HIV-1-infected patients and comparing rosuvastatin 10 mg per day and pravastatin 40 mg per day given for 45 days. This was the officially recommended rosuvastatin dose when the study was designed, while the pravastatin dose was the highest authorized dose that, in pilot studies, was well tolerated [6–8]. The primary endpoint was the change in the LDL-c level relative to baseline. The patients were centrally randomized, with blocks of size 6, using the SAS PLAN procedure. The Pitié-Salpêtrière Hospital institutional review board approved the protocol, and all the patients gave their written informed consent.
Patients were eligible for enrolment in this study if they had tested positive for anti-HIV-1 antibodies, had been receiving a stable cART regimen comprising a ritonavir-boosted protease inhibitor for at least 2 months (with no planned treatment modification for the following 2 months), and had a plasma HIV-1 RNA level of 10 000 copies/ml or less at randomization. Required fasting lipid status included LDL-c levels more than 4.1 mmol/l and triglyceridemia (triglyceride) less than 8.8 mmol/l. Transaminase levels had to be no more than three times the upper limit of normal [ULN ≤ 5 times in case of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, without cirrhosis], and the creatine phosphokinase level five times of ULN or less. Patients were not eligible if they had documented coronary heart disease, a muscle disorder, a previous muscular adverse reaction to a statin or fibrate, impaired hepatic function (prothrombin <70%) or renal function (creatinine clearance <30 ml/min), proteinuria exceeding ++, alcohol consumption over 40 g per day, an ongoing opportunistic infection, pregnancy or statin or fibrate exposure less than 2 months before the first dose of study treatment.
The patients had a physical examination and lipid assays at the screening visit (within 2 weeks before baseline), baseline (D0), D15, and D45. Adverse events were recorded at each visit during the study treatment. The CD4 cell count and plasma HIV-1 RNA level were determined at the screening visit, and HIV-1 RNA was also determined at D45. Lipid parameters [fasting serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), LDL-c and triglycerides] were determined locally at the screening visit and in a central laboratory on D0 and D45 (LDL-c was directly measured on D0 and D45).
Venous blood was collected in Vacutainer tubes with gel (Becton-Dickinson, Plymouth, UK) after a 12-h fast. Serum lipid levels were determined in a reference laboratory using standard enzymatic methods. Triglycerides were measured with the PAP 1000 enzymatic method (BioMérieux, Marcy-l'étoile, France) . Total cholesterol, direct LDL-c, and direct HDL-c were determined as recommended by ARCOL (Comité Français de coordination des recherches sur l'athérosclérose et le cholestérol) with automated enzymatic methods (Konelab Thermo Fisher Scientifics, Cergy-Pontoise, France) [10–12]. If the triglyceride level exceeded 2.28 mmol/l, free glycerol was measured independently by using the Randox colorimetric method (Randox Laboratories Ltd, Crumlin, United Kingdom). All lipid parameters were determined with a Konelab 30i analyzer (Thermo Electron Corporation, Waltham, Massachusetts, USA).
Protease inhibitor trough plasma concentrations were determined with a high-performance liquid chromatographic method (HPLC) as previously described  on D0 and D15 (at steady state), 12 ± 2 h after the last drug intake (except for atazanavir, which was determined 24 ± 4 h after the last drug intake). Pravastatin plasma concentrations were measured centrally in a unique laboratory by using an HPLC method . Rosuvastatin plasma concentrations were measured by Covance Laboratories, Inc. (Madison, Wisconsin, USA), as previously described .
We calculated that 39 patients per arm would be required to detect a between-group difference of 1 mmol/l in the change in LDL-c between baseline and D45, with a standard deviation of 1.25 mmol/l, a power of 90%, a type I error of 0.05, and a two-tailed nonparametric test. To account for the dilution effect associated with nonassessable patients, it was planned to enroll 43 patients per arm.
Variables were summarized by using proportions for categorical variables: the median and interquartile range (IQR) for age, time since HIV diagnosis, the CD4 cell count, and the time on cART; and the mean and standard deviation (SD) for continuous variables used as endpoints. The primary endpoint (LDL-c) and secondary lipid endpoints (total cholesterol, HDL-c, and triglycerides) were analyzed with an intent-to-treat approach (ITT), with the last observation carried forward, and also on available data. Changes from baseline were compared between the groups by using the nonparametric Mann–Whitney test. Two-way analysis of variance was used to test simultaneously for the randomized treatment effect and the protease inhibitor effect. Fisher's exact test was used to compare the proportions of patients with LDL-c levels less than 4.1 mmol/l in the two groups. All analyses were performed with the SPSS software package version 15.0 for Windows (SPSS, Inc., Illinois, Chicago, USA).
Between October 2005 and January 2007, 129 patients were screened and 88 patients were enrolled in 21 centers in France. As shown in Fig. 1, 83 patients initiated the study treatment and are included in the analyses. Lipid parameters could not be determined on D45 in three patients in the pravastatin arm, and the last-observation-carried-forward technique was used to include them in the ITT analysis, while they were excluded from the analysis on available data.
Characteristics of the patients
The baseline characteristics were well balanced between the two arms (Table 1). Three-quarters (77%) of the patients were men, and the median age was 47 years [(IQR 42–54]. The baseline median CD4 cell count was 482 × 106/l (IQR 314–678), and the plasma HIV-1 RNA level exceeded 400 copies/ml in seven patients (7%) (maximum 5238 copies/ml).
At the screening visit (day 15), the LDL-c level was above 4.1 mmol/l (1.6 g/l) in all the patients, in keeping with the inclusion criteria. At baseline (D0), the median LDL-c, HDL-c, triglyceride, and total cholesterolemia levels were 4.93 mmol/l [IQR 4.52–5.55], 1.27 mmol/l [IQR 1.05–1.50], 2.29 mmol/l [IQR 1.81–3.25], and 7.48 mmol/l [IQR 6.80–8.04], respectively, and were well balanced between the two arms. The LDL-c level was below 4.1 mmol/l in 22% of patients overall (26% in the pravastatin arm and 17% in the rosuvastatin arm).
Protease inhibitor therapy was well balanced between the two arms and mainly consisted of lopinavir (30%), atazanavir (28%), and fosamprenavir (23%), with slightly more patients receiving boosted atazanavir in the rosuvastatin arm as compared with the pravastatin arm (P = 0.09). The median time since cART initiation was 9 years [5,13]. A wide variety of nucleoside/nucleotide reverse transcriptase inhibitors or nonnucleoside reverse transcriptase inhibitors or both were being taken concomitantly (28 different regimens) with no difference between arms. Only six patients in the pravastatin arm and six patients in the rosuvastatin arm were receiving zidovudine, whereas only two patients in the rosuvastatin arm were receiving stavudine.
Changes in lipid parameters
After 45 days of statin therapy, the change in the LDL-c level was −0.92 ± 0.79 mmol/l with pravastatin and −1.69 ± 0.87 mmol/l with rosuvastatin (P < 0.001), corresponding to respective median reductions of 19% (30–6%) and 37% (42–23%) (P < 0.001) (Fig. 2). On D45, the LDL-c was below 4.1 mmol/l in 60 and 88% of patients (P = 0.006). The change in HDL-c levels between baseline and D45 did not differ between the arms (+0.05 ± 0.23 mmol/l with pravastatin and +0.01 ± 0.19 mmol/l with rosuvastatin; P = 0.750). The change in triglyceride levels was less marked with pravastatin than with rosuvastatin (−0.20 ± 0.95 mmol/l and–0.67 ± 1.02 mmol/l; P = 0.019), corresponding to respective median reductions of 7 and 19% (P = 0.035) (Fig. 2).
The differences in the treatment effects on LDL-c and triglycerides were not influenced by the protease inhibitors received (P values for the interactions, 0.990 and 0.799, respectively).
Protease inhibitor and statin concentrations
Statin therapy did not significantly modify trough plasma concentrations of atazanavir, amprenavir, or lopinavir. Changes in protease inhibitor trough plasma concentrations before and after initiation of the statin were not significantly different between the pravastatin arm and the rosuvastatin arm (P = 0.687 for atazanavir, P = 0.622 for amprenavir, and P = 0.364 for lopinavir).
The median plasma rosuvastatin concentration, determined in 30 of the 41 patients concerned, was 1.05 ng/ml [IQR 0.72–1.66] 24 h after the last drug intake and was not influenced by the nature of the protease inhibitor (P = 0.631). The median pravastatin trough concentration, determined in 29 of the 42 patients concerned, was 6 ng/ml [IQR 2–13] and was not influenced either by the nature of the protease inhibitor (P = 0.845).
Changes in creatininemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase, and proteinuria between D0 and D45 were not significantly different between the arms. Tenofovir, taken by 14 patients in the rosuvastatin arm and by 12 patients in the pravastatin arm, did not influence the frequency of proteinuria either at baseline or during statin therapy. Four adverse events were reported during the study, one in the pravastatin arm (tuberculosis) and three in the rosuvastatin arm (programmed colonoscopy, cataract surgery, and urinary tract infection). None was considered linked to the study drugs by the investigators. In particular, there were no renal, hepatic, or muscular events. Overall 92% had a plasma-HIV-1 RNA less than 400 copies/ml at day 45, as at baseline.
The present study shows that rosuvastatin is more effective than pravastatin on both LDL-c and triglyceride levels in HIV-1-infected patients with dyslipidemia receiving ritonavir-boosted protease inhibitor.
Although this was an open-label study, the statin treatments were randomized, there were few missing data, and the patients were receiving a wide range of boosted protease inhibitor-containing cART regimens (excepting the most recently marketed drug darunavir), and the efficacy of rosuvastatin compared with that of pravastatin was not different according to the boosted protease inhibitor received. In addition, the lipid parameters were determined in a central laboratory blinded to the treatment arm. Follow-up was short (45 days) but similar to that of the registration trials and sufficient to detect a difference in efficacy . The 10 mg/day rosuvastatin dose regimen was the only one authorized in Europe when the trial was designed in 2005. An initial dose of 5 mg/day has been recommended since 2006. However, no serious adverse effects occurred in our study.
Previously, the only available data in this setting came from small noncontrolled studies of rosuvastatin, in which the mean or median fall in LDL-c ranged from 22 to 33% [17,18]. In a more recent study, in which 10% of enrolled patients were excluded from the analysis, Calza  found a similar reduction in LDL-c but not in triglycerides, possibly owing to differences in the methods, the study design, the drug dosage, or the length of follow-up.
In the Mercury 1 study, involving HIV-seronegative patients, Stender et al. observed a mean percentage change in LDL-c of −29.9 ± 1.0% in the pravastastin arm (40 mg/day) and −46.7 ± 1.0% in the rosuvastatin arm (10 mg/day) after 8 weeks of therapy. The mean difference in efficacy between the statins (mean percentage change in LDL-c of 16.8%) was similar to that observed in our study (15.4%). However, the mean percentage changes were 13% lower in our study conducted in HIV-1-infected patients (mean percentage change: 17.4 ± 2.4% in the pravastatin arm versus 32.8 ± 2.4% in the rosuvastatin arm) for pravastatin and rosuvastatin (P < 0.01) as previously observed . In addition, we observed no significant impact of either drug on HDL-c, whereas Stender et al. observed a 9% increase in HIV-seronegative patients. This could suggest a difference in the mechanisms of hyperlipidemia in HIV-1-infected and uninfected patients. However, though smaller than for a non-HIV-1-infected patient, the clinical benefit of such LDL-c reduction is still important. As an example, let us consider a 45-year-old male smoker, without hypertension or diabetes, and a total cholesterolemia of 7 mmol/l with a normal HDL-c value. His 10-year risk of coronary artery disease would change from 26.6 to 19.7% using the Framingham equation when treated with rosuvastatin.
Trough plasma rosuvastatin concentrations were similar to those reported by van der Lee  and were not affected by the nature of the boosted protease inhibitor, including lopinavir. Likewise, the trough plasma pravastatin concentration did not depend on the protease inhibitor received. Trough plasma concentrations of pravastatin and rosuvastatin were both within the expected range with respect to the dose regimens, and no adverse effects were observed, including rhabdomyolysis and liver damage. This tends to rule out inhibitory/inducing effects on CYP450 enzymes, thus confirming results obtained in vitro.
Rosuvastatin is more effective than pravastatin on dyslipidemic HIV-1-infected patients treated with cART containing ritonavir-boosted protease inhibitors, in particular, with its effects on triglycerides. Long-term studies are now needed to evaluate the possible impact of rosuvastatin on cardiovascular events in this setting and also in normolipidemic HIV-1-infected patients.
The French National Agency for AIDS and Viral Hepatitis Research (ANRS) sponsored the trial and was involved in the study design. After approving the protocol, the sponsor had no involvement in the collection, analysis, or interpretation of the data, writing of the report, or the decision to submit the article for publication. This study was registered with clinicaltrials.gov, number NCT00117494. ANRS received a grant from Astra Zeneca for this study.
This work was presented at the 11th European AIDS Conference/EACS – 24–27 October 2007 – Madrid, Spain [Abstract LBPS7/2].
We are thankful to all the patients who participated in the study, to the nurses in the participating centers, and all the investigators and other contributors. Special thanks are due to Marie-Joseph Commoy.
Clinical centers are as follows: Hôpital Pitié-Salpétrière, Paris – N. Bentaleb, L. Schneider. and M.A. Valantin; Hôpital Avicenne, Bobigny – M. Bentata and F. Touam; Hôtel Dieu, Nantes – V. Reliquet; Hôpital Bichat, Paris –R. Landman; Hôpital de Bicêtre, Le Kremlin Bicêtre – M. De La Vaissiere and N. Medintzeff and C. Dumont; Hôpital Pitié-Salpétrière, Paris – A. Simon and M. Bonmarchand; Hôpital Les Oudiaries, La Roche sur Yon – P. Perré and S. Leautez-Mainville; Hôpital Tenon, Paris – G. Pialoux and L. Slama, E. Chakvetadze and C. Fontaine; Hôpital Lariboisière, Paris – V. Delcey and A. Rami and M. Parrinello; Hôpital Raymond Poincare, Garches – J.C. Melchior and P. Detruchis, T. Galperine; Hôpital Jean Verdier, Bondy – V. Jeantils and S. Tassi; Hôpital Foch, Suresnes – D. Zucman and C. Majerholc; Hôpital Louis Mourier, Colombes – E. Mortier and Z. Feng, C. Minozzi; Hôpital Saint Antoine, Paris – J.L. Meynard and B. Lefebvre, Z. Ouazene, and D. Bollens; Hôpital Saint André, Bordeaux – M. Bonarek and D. Lacoste, P. Morlat, and P. Mercie, D. Malvy, and I. Louis; Hôtel Dieu, Lyon – P. Miailhes; Hôpital Sainte Marguerite, Marseille – I. Poizot-Martin and E. Peyrouse, G. Fabre; Hôpital Guy De Chauliac, Montpellier – J. Reynes and C. Merle; Hôpital Gustave Dron, Tourcoing – Y. Yazdanpanah and S. Pavel, F. Ajana; Hôtel Dieu, Paris – E. Aslangul; Hôpital Saint Antoine, Paris – F. Boccara.
Biochemistry centers: Hôpital Pitié-Salpétrière, Paris – I. Beucler and D. Bonnefont-Rousselot, R. Bittar, and V. Ondet, C. Cherfils, and V. Fesel-Fouquier, M.C. Federspiel and S. Roux and L. Domingo; Hôpital Avicenne, Bobigny – M. Cadre; Nantes – J.L. Orsonneau and J.M. Barb; Hôpital Tenon, Paris – J. Capeau and J.P. Bastard; Hôpital Lariboisière, Paris – J.M. Launay; Hôpital de Bicêtre, Le Kremlin Bicêtre – C. Dumont; Hôpital Raymond Poincare, Garches – C. Boucly; Hôpital Jean Verdier, Bondy – J. Vaysse and M. Pintet; Hôpital Foch, Suresnes – L. Touboul; Hôpital Louis Mourier, Colombes – J.C. Deybach and J. Lamoril; Hôpital Saint Antoine, Paris – N. Masliah; Hôpital Saint André, Bordeaux – E. Peuchant; Hôtel Dieu-Hôpital Edouard Herriot, Lyon – M.C. Gagnieu; Hôpital Sainte Marguerite, Marseille – H. Portugal; Hôpital Bichat, Paris – F. Driss; Hôpital Guy De Chauliac, Montpellier – S. Badioux; Hôpital Les Oudiaries, La Roche sur Yon – A.S. Poirier; Hôtel Dieu, Paris – J. Cynober.
Dispensing pharmacist: Hôpital Pitié-Salpétrière, Paris – M.H. Fievet and M. Moad.
L.A., O.K., J.-C.M. and D.R. have no conflicts of interest to declare. E.A. has received travel grants from various pharmaceutical companies including Sanofi Aventis, Pfizer, and Bristol-Myers-Squibb. R.B. has received travelling grants and payment of registration fees from Gilead Sciences. F.B. received travel grants, honoraria, or study grants from Bristol-Myers-Squibb and AstraZeneca. D.C. has received travel grants, consultancy fees, honoraria, or study grants from various pharmaceutical companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, Glaxo-Smith-Kline, Janssen Merck, and Roche. M.-H.F. has received travel grants from various pharmaceutical companies including Bristol Myers-Squibb, Glaxo-Smith-Kline, Janssen Cilag. P.G. reports receiving lecture fees from Pfizer, AstraZenca, Solvay and travel grant from Merck. G.P. has received travel grants, consultancy fees, honoraria, or study grants from various pharmaceutical companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, Glaxo-Smith-Kline, Janssen Merck, and Roche. M.-A.V. has received lecture fees, travelling expenses, and payment of registration fees from Roche, Tibotec (Johnson & Johnson), Gilead, GlaxoSmithKline, Bristol-Myers Squibb, MSD, and Boehringer Ingelheim.
Contributors: Provision of study materials or patients were provided by E.A., M.-A.V., J.-C.M., F.B., P.G., G.P.
Statistical analysis was done by L.A., D.C.
Drafting of the article was done by L.A., E.A., D.C., G.P.
Study design, interpretation of the data, and critical revision of the article for important intellectual content and final approval of the article were done by all authors.
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