Cardiovascular disease is more frequent in HIV-infected patients than in the general population, possibly owing to lipid disorders, viral infection, inflammation and antiretroviral therapy (ART), especially ritonavir (RTV)-boosted protease inhibitors [1–3]. Elevated levels of high-sensitivity C-reactive protein (hsCRP), a marker of persistent inflammation, are linked to an increased risk of cardiovascular events in the general population , whereas elevated hsCRP levels in HIV-infected patients are associated with a higher incidence of myocardial infarction  and death [6,7]. In the general population, rosuvastatin has been shown to reduce hsCRP levels by about one third and also to lower the risk of death and cardiovascular events . Several studies have reported that hsCRP levels are higher in HIV-infected patients than those in the general population [9,10]. The role of combination ART (cART) is discussed [11–13]. Elevated CRP levels have also been linked to other cardiovascular risk factors, such as high low-density lipoprotein (LDL) levels, low high-density lipoprotein levels and smoking, in addition to ART . The aim of this study was to examine changes in levels of hsCRP, soluble tumor necrosis factor-α receptors (TNFRs) and the endothelial markers intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) after a 45-day course of rosuvastatin or pravastatin in dyslipidemic HIV-infected patients participating in the Agence Nationale de Recherche sur le SIDA (ANRS126) VIHstatine trial; all the patients had good viral control on a RTV-boosted protease inhibitor regimen .
The VIHstatine randomized, double-blind, multicenter trial (NCT00117494) was designed to assess the impact of a 45-day course of rosuvastatin 10 mg per day or pravastatin 40 mg per day on lipid values in dyslipidemic (LDL > 4.1 mmol/l) HIV-infected patients receiving RTV-boosted protease inhibitors . The present substudy focused on patients for whom frozen samples were available both at baseline and after the 45-day course of statin therapy, and who had a baseline CRP value below 10 mg/l, as values above 10 mg/l are suggestive of other inflammatory processes, as indicated by the American Heart Association . Fifty-eight of the 83 patients enrolled in the VIHstatine trial were eligible for this substudy and were equally distributed between the two statin arms.
HsCRP was measured by immunonephelometry on an IMMAGE analyzer (Beckman-Coulter, Villepinte, France). sTNFR1, sTNFR2, ICAM-1 and VCAM-1 levels were measured with commercial ELISA kits from R&D Systems (Oxford, UK), using the manufacturer's protocols.
Results are reported as median [interquartile range (IQR)]. Baseline hsCRP, sTNFR1, sTNFR2, ICAM-1 and VCAM-1 levels, and changes between baseline and day 45, were compared between the two statin arms by using the Mann–Whitney nonparametric test, whereas changes between baseline and day 45 were compared with the nonparametric paired Wilcoxon test. Correlations between changes in parameters were tested with Spearman's nonparametric test. All reported P-values are two tailed. The Bonferroni rule was used to take multiplicity issues into account: we used nine Mann–Whitney tests and nine Wilcoxon tests, yielding the significance threshold at P-value less than 0.0055, and 30 Spearman correlation tests, yielding the significance threshold at P-value less than 0.0017. The SPSS software package version 13.0 for Windows (SPSS Inc., Chicago, Illinois, USA) and SAS statistical software version 9.1 (SAS Institute Inc., Cary, North Carolina, USA) were used for all analyses.
The patients were mainly men (74%) and white (91%) and had a median age of 49 years (IQR 42–56). Plasma HIV-1-RNA levels were below 400 copies/ml in 90% of patients and the median CD4 cell count was 490 cells/μl (IQR 314–704). The median duration of cART was 9 years (IQR 5–13). Baseline values of lipid, inflammation and endothelial parameters are reported in Table 1. After 45 days of statin therapy, the median change in the hsCRP concentration was −20% overall (−0.6 mg/l, P < 0.001), and, respectively, −22 and −16% in the pravastatin and rosuvastatin groups (P = 0.932). There was no significant change in sTNFR1 and sTNFR2 levels or in ICAM-1 and VCAM-1 levels (Table 1).
The LDL-cholesterol level fell by a median of 19% in the pravastatin group and 37% in the rosuvastatin group (P < 0.001 for difference between groups), whereas triglyceride levels fell by, respectively, 3% and 26% (P = 0.008 for difference between groups), values similar to those obtained in the original VIHstatine trial . As shown in Table 1, LDL-cholesterol, total cholesterol and triglyceride levels also fell significantly in the entire substudy. There was no correlation between the change in the hsCRP level and changes in the markers of lipid, endothelial and inflammatory status [LDL-cholesterol (r = −0.071, P = 0.598); total cholesterol (r = −0.176, P = 0.188); and triglycerides (r = −0.273, P = 0.038)].
This is the first study of the effect of statins on inflammatory status in HIV-infected patients on effective ART. We observed a reduction in the CRP level, but not in the levels of sTNFR1 and sTNFR2, two other inflammatory markers. It is interesting to note that sTNFR1 and sTNFR2 levels were reported to fall in HIV-infected patients starting first-line ART, whereas CRP levels were unaffected . Together, these data suggest that these markers reflect different phenomena: sTNFRs may reflect control of HIV infection, whereas CRP elevation could result from other proinflammatory mechanisms not resolved by the control of viral load.
We show here that pravastatin 40 mg per day and rosuvastatin 10 mg per day induce similar significant falls in hsCRP, even during brief administration. In addition, the fall in hsCRP did not correlate with the improvement in lipid parameters or with modifications in endothelial status, as reflected by ICAM-1 and VCAM-1 serum concentrations. The fact that the effect of a statin on the level of hsCRP do not correlate with its effect on LDL-cholesterol is already known ; this may explain why, although rosuvastatin and pravastatin did not have the same effect on lipid parameters in this trial, their effect was similar on the hsCRP level. The impact of statin on immune activation, which has been recently shown in HIV-naive patients, might be the mechanism by which the hsCRP level was influenced .
In the general population, statins induce a dose-dependent fall in hsCRP levels . HsCRP continues to fall during the course of statin treatment, especially at higher doses . In the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, 20 mg per day rosuvastatin reduced hsCRP levels by 37% after 1.9 years of treatment . Thus, the fall in CRP observed here in HIV-infected patients during short-term statin therapy could be accentuated during long-term treatment.
In conclusion, a 45-day course of rosuvastatin or pravastatin reduced not only lipid levels but also hsCRP levels in HIV-infected patients treated with RTV-boosted protease inhibitors. Clinical trials are warranted to determine the potential benefit of long-term statin treatment on the risk of cardiovascular events and death in at-risk HIV-infected patients.
The authors thank Agence Nationale de Recherche sur le SIDA for funding, and Lydie Hossou and Sandra Raabon for their excellent technical support.
Conception and design of the substudy was performed by E.A., J.-P.B., J.C. and D.C.
Provision of study materials or patients was conducted by E.A., S.F., J.-P.B. and J.C.
Statistical analysis was performed by L.K.A. and D.C.
Interpretation of the data was performed E.A., S.F., L.K.A., J.-P.B., J.C. and D.C.
Drafting of the article was done by E.A., L.K.A., J.-P.B., J.C. and D.C.
Critical revision of the article for important intellectual content and final approval of the article were performed E.A., S.F., L.K.A., J.-P.B., J.C. and D.C.
1. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al
. Increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population. AIDS 2010; 24:1228–1230.
2. Martinez E, Larrousse M, Gatell JM. Cardiovascular disease and HIV infection: host, virus, or drugs? Curr Opin Infect Dis 2009; 22:28–34.
3. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007; 92:2506–2512.
4. Ridker P. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev 2007; 65(12 Pt 2):S253–S259.
5. Triant VA, Regan S, Lee H, Sax PE, Meigs JB, Grinspoon SK. Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. J Acquir Immune Defic Syndr 2010; 55:615–619.
6. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al
. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
7. Tien PC, Choi AI, Zolopa AR, Benson C, Tracy R, Scherzer R, et al
. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 2010; 55:316–322.
8. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al
. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207.
9. Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, Ganz P, et al
. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 2009; 23:1059–1067.
10. Neuhaus J, Jacobs DR Jr, Baker JV, Calmy A, Duprez D, La Rosa A, et al
. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–1795.
11. Baker JV, Neuhaus J, Duprez D, Kuller LH, Tracy R, Belloso WH, et al
. Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. J Acquir Immune Defic Syndr 2011; 56:36–43.
12. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care 2010; 33:2244–2249.
13. Smith KY, Patel P, Fine D, Bellos N, Sloan L, Lackey P, et al
. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009; 23:1547–1556.
14. Masia M, Bernal E, Padilla S, Graells ML, Jarrin I, Almenar MV, et al
. The role of C-reactive protein as a marker for cardiovascular risk associated with antiretroviral therapy in HIV-infected patients. Atherosclerosis 2007; 195:167–171.
15. Aslangul E, Assoumou L, Bittar R, Valantin MA, Kalmykova O, Peytavin G, et al
. Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial. AIDS 2010; 24:77–83.
16. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al
. Markers of inflammation and cardiovascular disease: application to clinical and public health practice – a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511.
17. Carr A. Statins as anti-inflammatory therapy in HIV disease? J Infect Dis 2011; 203:751–752.
18. Ganesan A, Crum-Cianflone N, Higgins J, Qin J, Rehm J, Metcalf J, et al
. High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. J Infect Dis 2011; 203:756–764.
19. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al
. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175–1182.
20. Bonnet J, McPherson R, Tedgui A, Simoneau D, Nozza A, Martineau P, Davignon J. Comparative effects of 10-mg versus 80-mg atorvastatin on high-sensitivity C-reactive protein in patients with stable coronary artery disease: results of the CAP (Comparative Atorvastatin Pleiotropic effects) study. Clin Ther 2008; 30:2298–2313.