Received 24 January 2011; returned 17 March 2011; revised 7 April 2011; accepted 25 April 2011

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1 J Antimicrob Chemother 2011; 66: doi: /jac/dkr202 Advance Access publication 28 May 2011 Treatment for hepatitis C virus with pegylated interferon-a plus ribavirin induces anti-atherogenic effects on cardiovascular risk biomarkers in HIV-infected and -uninfected patients Mar Masiá 1,2 *, Catalina Robledano 1, Natividad López 3, Clara Escolano 1 and Félix Gutiérrez 1,2 1 Infectious Diseases Unit, Hospital General Universitario de Elche, Elche, Alicante, Spain; 2 Department of Clinical Medicine, University Miguel Hernández, Elche, Alicante, Spain; 3 Biochemistry Section, Hospital General Universitario de Elche, Elche, Alicante, Spain *Corresponding author. Unidad de Enfermedades Infecciosas, Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Spain. Tel: ; Fax: ; marmasia@ya.com Received 24 January 2011; returned 17 March 2011; revised 7 April 2011; accepted 25 April 2011 Objectives: We investigated the influence of hepatitis C virus (HCV) therapy with pegylated interferon-a plus ribavirin on cardiovascular disease risk through the serial measurement of several laboratory markers in HCV-monoinfected and HCV/HIV-coinfected patients. Methods: In a longitudinal study, biomarkers of inflammation, coagulation and oxidative stress were measured during and after therapy. Results: A total of 56 patients were included; 32 (57.1%) were HCV/HIV coinfected and 24 (42.9%) were HCV monoinfected. Compared with baseline, during HCV therapy there was a significant decrease in the concentrations of matrix metalloproteinase-9 (P, 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (P 0.01) and oxidized low-density lipoproteins (P¼0.002). In contrast, levels of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 and fibrinogen increased during treatment. After treatment discontinuation, levels of ICAM-1, VCAM-1 and tumour necrosis factor-a were significantly lower compared with baseline, a change restricted to patients with sustained virological response. Decreases in transaminases and HCV- RNA from baseline correlated positively with the decrease in ICAM-1 concentration 6 months after treatment discontinuation. Changes in biomarkers were similar in HIV-infected and -uninfected patients. Conclusions: Treatment for HCV induces different changes in several cardiovascular risk biomarkers, most being anti-atherogenic effects, although only the anti-atherogenic effects remain after treatment discontinuation in patients with sustained virological response. Keywords: atherosclerosis, hepatitis C therapy, inflammation, VCAM, ICAM Introduction The relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) remains controversial. HCV has been linked with a higher risk of coronary artery disease and/or subclinical atherosclerosis in HIV-infected 1,2 and -uninfected patients, 3,4 although these findings have not been verified in all studies. 5,6 The combination of pegylated interferon-a and ribavirin (PEG-IFN-a/RBV) is currently the elective treatment for chronic HCV infection. 7 If HCV indeed increases CVD risk, viral clearance through HCV therapy might be accompanied by a reversal of the pro-atherogenic mechanisms associated with the virus. To investigate the effect of HCV treatment on CVD risk, we evaluated the profile of several cardiovascular-related biomarkers, including inflammation [matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), high-sensitivity C-reactive protein (hscrp), interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a)], oxidative stress [oxidized low-density lipoprotein (oxldl)] and coagulation [plasminogen activator inhibitor-1 (PAI-1) and fibrinogen] in HIV-seronegative and HIV-seropositive patients undergoing anti-hcv treatment with PEG-IFN-a/RBV. We also assessed the differential effects of the treatment in HIV-infected and HIV-uninfected patients. Methods A prospective longitudinal study including consecutive patients initiating HCV therapy under a clinical pathway between May 2006 and December Downloaded from at Pennsylvania State University on February 17, 2016 # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 1861

2 Masiá et al was conducted. Candidates for inclusion were HCV-infected subjects with age 18 and 70 years and detectable plasma HCV-RNA (.600 IU/mL). Patients with HIV infection were included if they had stable disease and a CD4 T cell count 250 cells/mm 3. Patients on antiretroviral therapy and/or cardiovascular risk factor therapy had to be on a stable treatment regimen for at least 6 months to be included. Exclusion criteria were decompensated cirrhosis and/or hepatocarcinoma, evidence of other malignancies, acute hepatitis B virus (HBV) or HCV infection, chronic HBV infection, hyper- or hypothyroidism, major depression, drug addiction, active alcoholism, pregnancy and thrombocytopenia ( platelets 10 9 /L). Patients lost to follow-up before the week 12 visit were also excluded. The study was approved by the local ethics committee, and all patients gave their informed consent. Baseline characteristics are listed in Table 1. There were no significant differences between HCV-monoinfected and HIV/ HCV-coinfected patients in demographic data or in the prevalence of cardiovascular risk factors. Only one patient, who was HIV coinfected, had a history of coronary disease. The majority (75%) of the HCV/HIV-coinfected patients were on antiretroviral therapy. Their median [interquartile range (IQR)] CD4 T cell count was 560 ( ) cells/mm 3, and most of them (75%) had an HIV-1-RNA,200 copies/ml. Of 8 HIV/HCV-coinfected patients who were not initially receiving antiretroviral therapy, 4 started therapy at weeks 8, 12 and 24. All patients on antiretroviral therapy remained virologically suppressed during the study. Treatment protocol All patients received a combination of subcutaneous pegylated interferon-a 2a weekly at a dose of 180 mg, plus daily oral ribavirin at a dose of 1000 mg/day in patients weighing,70 kg and 1200 mg/day in those with a weight 70 kg. Patients infected with HCV genotype 1 or 4 were treated for 48 weeks, and those infected with genotype 2 or 3 were treated for 24 weeks. All HIV-infected patients were treated for 48 weeks, independently of the viral genotype. Response to therapy was defined as an undetectable HCV-RNA or a decrease of 2 logarithms at week 12; in the last case, since the effect on the biomarkers of the suppression of viral replication was pursued in the study, patients had to have an undetectable HCV-RNA at week 16. Those who did not reach these criteria were considered non-responders. A follow-up visit was performed 6 months after treatment discontinuation in responders and non-responders. Sustained virological response was defined as an undetectable HCV-RNA at the follow-up visit. Clinical and laboratory measurements HCV infection was defined by a positive HCVantibody assay and a confirmatory positive HCV-RNA. Dyslipidaemia, diabetes and hypertension were defined by a previous diagnosis or by a current prescription of pharmacological therapy for any of such risk factors. At each visit, blood samples were collected after an 8 h overnight fast and plasma aliquots stored at 2808C. Frozen samples from baseline, weeks 12, 24 and 48 and post-treatment follow-up visits were simultaneously defrosted, and plasma levels of VCAM-1, ICAM-1, MCP-1, MMP-9, IL-6, TNF-a and PAI-1 were measured using commercially available ELISA kits (Quantikine, R&D Systems Europe Ltd, UK). oxldl was determined by ELISA (Biomedica Gruppe, Vienna, Austria). hscrp was measured using a chemiluminescent immunometric assay (Immulite 2000, Siemens) as previously described. 8 Fibrinogen was estimated with a coagulation analyser (Dade Behring BCS, GA, USA). All blood determinations were performed in a blinded fashion. Results Patients characteristics at baseline Sixty-one patients were initially included. Five of the 61 were excluded from the analysis because they were lost to follow-up before week 12, leaving 56 patients in the study. Thirty-two (57.1%) were HCV/HIV coinfected. Of the 56 patients, 49 (87.5%) met the criteria of response to therapy at week 12, 44 (78.6%) of them with undetectable HCV-RNA, and 7 (12.5%) were classified as non-responders. Forty-three (76.8%) completed anti-hcv therapy and 23 (53.5% of them) met the criteria of sustained virological response. Plasma biomarkers before and during HCV treatment Baseline concentrations of biomarkers are shown in Table 2. Levels of MMP-9 and oxldl were significantly higher in HCV-monoinfected than in HCV/HIV-coinfected patients (150.8 versus 50.0 ng/ml and versus mu/ml, respectively, P, in both cases). Conversely, there was a trend to higher VCAM-1 levels in HCV/HIV-coinfected patients (1326 versus 917 ng/ml, P¼0.07). Patients classified as nonresponders exhibited significantly higher baseline levels of VCAM-1 (1829 versus 1152 ng/ml, P¼0.02) and a trend to higher PAI-1 (4.69 versus 2.50 ng/ml, P¼0.05), MCP-1 (204.8 versus pg/ml, P¼0.08) and IL-6 (3.92 versus 1.05 pg/ml, P¼0.07) than those responding to antiviral therapy. Comparison of baseline biomarker concentrations by genotypes 1/4 versus genotypes 2/3 yielded no differences between the groups. Table 2 shows the changes in biomarkers during anti-hcv therapy. Compared with baseline, there was a significant decrease, lasting throughout the treatment period, in concentrations of MMP-9 and ICAM-1, while oxldl decreased significantly at week 12 and week 24. Contrarily, levels of VCAM-1, MCP-1 and fibrinogen increased in all on-treatment visits, and IL-6 rose at week 24 compared with baseline. No significant changes occurred during treatment in levels of hscrp, PAI-1 or the cytokine TNF-a. Changes in biomarkers did not differ between HCV-monoinfected and HCV/ HIV-coinfected patients, except for VCAM-1, which showed a higher increase at week 12 in HCV-monoinfected patients (+78.1%, P¼0.001). Likewise, analysis by genotypes 1/4 versus 2/3 did not show differences in the changes in the biomarkers; only VCAM-1 levels tended to increase more in patients with genotypes 2/3 (44.5% versus 19.9%, P¼0.09). Patients characteristics after HCV treatment discontinuation Thirty-two patients had completed the follow-up visit 6 months after treatment discontinuation (Table 1). Transaminases decreased significantly after treatment, with median values under normal limit values at the end of follow-up. Such decreases correlated positively with decreases in ICAM-1 [Spearman s r for alanine aminotransferase (ALT) ¼0.55, P¼0.003; and Spearman s r for aspartate aminotransferase (AST) ¼0.62, P, 0.001] and VCAM-1 (Spearman s r for ALT¼0.50, P¼0.01; and Spearman s r for AST¼0.57, P¼0.002), and ICAM-1 also correlated with decreases in HCV- RNA (Spearman s r¼0.51, P¼0.009) at the follow-up visit. HCV-RNA was undetectable in 23 (71.9%) of the 32 patients Downloaded from at Pennsylvania State University on February 17,

3 Table 1. Clinical characteristics of the patients at baseline and 6 months after hepatitis C treatment discontinuation Variable Baseline Follow-up all patients (N¼56) HIV+ (N¼32) HIV2 (N¼24) all patients (N¼32) HIV+ (N¼19) HIV2 (N¼13) Age, years 42.7 ( ) 42.5 ( ) 42.9 ( ) 43.4 ( ) 43.3 ( ) b 43.6 ( ) b,0.001 Sex, male 45 (80.4) 27 (84.4) 18 (75.0) 25 (78.1) 15 (78.9) 10 (76.9) 0.88 Smoking status 37 (66.1) 23 (71.9) 14 (58.3) 20 (62.5) 14 (73.7) 6 (46.2) 0.88 Hypertension 2 (3.6) 2 (6.3) Hyperlipidaemia 4 (7.1) 4 (12.5) 0 1 (3.1) 1 (5.3) Diabetes 1 (1.8) 1 (3.1) Weight, kg 70.7 ( ) 70.9 ( ) 67.6 ( ) 71.0 ( ) 70.7 ( ) 73.2 ( ) 0.37 Systolic blood pressure, mmhg ( ) 123 ( ) 125 ( ) 131 ( ) ( ) ( ) 0.02 Total cholesterol, mg/dl ( ) ( ) 162 ( ) ( ) ( ) b ( ) b HDL-cholesterol, mg/dl 43.0 ( ) 41.5 ( ) 42.6 ( ) 42.5 ( ) 40.2 ( ) 52.5 ( ) 0.58 LDL-cholesterol, mg/dl 91.0 ( ) 93.5 ( ) 91.0 ( ) ( ) ( ) b ( ),0.001 Triglycerides, mg/dl 98.0 ( ) ( ) 75 (49 123) c ( ) ( ) 80.5 ( ) 0.28 Framingham score, % 3.0 ( ) 3.5 ( ) 3.0 ( ) 4.5 ( ) 4.0 ( ) b 4.5 ( ) 0.01 AST, U/L 56 ( ) 55.5 ( ) 62.5 ( ) 24.5 ( ) 31.0 ( ) b 29.0 ( ) b,0.001 ALT, U/L 82.5 ( ) 90.5 ( ) 70.5 ( ) 29.5 ( ) 31.0 ( ) b 21.0 ( ) b,0.001 APTT, s 34.5 ( ) 34.5 ( ) 34.5 ( ) 33.2 ( ) 33.0 ( ) 33.6 ( ) 1 Genotype 1 or 4 28 (50) 16 (50) 12 (50) 16 (50) 9 (47.4) 7 (53.8) 1 Log 10 HCV-RNA, copies/ml 6.1 ( ) 6.3 ( ) 6.1 ( ) 0 (0 3.7) 0 (0 4.2) b 0 (0 4.3) P a Hepatitis C therapy and cardiovascular risk HDL, high-density lipoprotein; APTT, activated partial thromboplastin time. Data are no. (%) of patients for categorical variables and median (IQR) for continuous variables. a P for the comparison between baseline and follow-up values when all patients are included in the analysis (Wilcoxon test). b P,0.05 compared with baseline (Wilcoxon test). c P¼0.01 compared with HIV positive (Mann Whitney U-test). JAC 1863 Downloaded from at Pennsylvania State University on February 17, 2016

4 1864 Table 2. Changes in levels of biomarkers during and after treatment with PEG-IFN-a/RBV Biomarker Baseline (N¼56) Week 12 (N¼53) a P b Week 24 (N¼47) P b End of treatment (N¼43) P b Follow-up (N¼32) P b Masiá et al. MMP-9, ng/ml all patients 83.2 ( ) 29.2 ( ) [265.4%] responders 90.8 ( ) 30.0 ( ) [268.1%] non-responders 45.2 ( ) 28.4 ( ) [210.8%] HIV ( ) 18.0 ( ) [263.2%] HIV ( ) 46.8 ( ) [270.9%], ( ) [259.5%], ( ) [260.6%] ( ) [231.3%], ( ) [260.1%], ( ) [258.9%], ( ), ( ) [24.3%] 0.80, ( ), ( ) 0.78 [26.3%] ( ) ( ) [2.5%] 0.75, ( ), ( ) [8.0%] ( ) ( ) [212.8%] 0.21 MCP-1, pg/ml all patients ( ) responders ( ) non-responders ( ) HIV ( ) HIV ( ) ( ) [57.4%], ( ) [79.6%] ( ), ( ) [61.6%] [83.2%] ( ) [4.2%] ( ) [35.6%] ( ) [35%], ( ) [74.3%] ( ) ( ) [78.1%] [79.6%], ( ), ( ) [26.6%], ( ), ( ) [1.0%] ( ) ( ) [222.4%] ( ) ( ) [221.5%] ( ) ( ) [4.6%] ICAM-1, ng/ml all patients ( ) responders ( ) non-responders ( ) HIV ( ) HIV ( ) ( ) [214.8%], ( ) [218.8%] ( ), ( ) [214.4%] [218.5%] ( ) ( ) [24.9%] [216.4%] ( ) ( ) [219.1%] [220.6%] 308 (248 37) [211.9%], ( ) [217.2%] ( ) ( ) [218.6%] ( ) ( ) [227.1%] ( ) ( )[5.9%] ( ) ( ) [218.4%] ( ) ( ) [220.7%] 0.002, VCAM-1, ng/ml all patients 1197 ( ) 1716 ( ) [48.0%] responders 1152 ( ) 1702 ( ) [54.2%] non-responders 1829 ( ) 1898 ( ) [18.3%], ( ) [41.4%], ( ) [44.8%] ( ) [7.5%], ( ), ( ) [224.2%], ( ), ( ) [226.5%] ( ) ( ) [26.5%] Downloaded from at Pennsylvania State University on February 17, 2016

5 HIV ( ) 1687 ( ) [26.5%] HIV2 971 ( ) 1737 ( ) [78.1%] ( ) [33.7%], ( ) [51.6%] ( ) ( ) [226.5%], ( ), ( ) [216.7%] hscrp, mg/l all patients 0.51 ( ) 0.55 ( ) [0%] ( ) [0%] ( ) ( ) [7.7%] 0.20 responders 0.53 ( ) 0.56 ( ) [0%] ( ) [0%] ( ) ( ) [2.0%] 0.44 non-responders 0.36 ( ) 0.47 ( ) ( ) [31.8%] ( ) ( ) [9.1%] 0.25 [22.4%] HIV ( ) 0.56 ( ) [0%] ( ) [0%] ( ) ( ) [2.0%] 0.18 HIV ( ) 0.55 ( ) [216.7%] ( ) [0%] ( ) ( ) [28.4%] 0.89 IL-6, pg/ml all patients 1.16 ( ) 1.93 ( ) [24.4%] ( ) [44.8%] ( ) ( ) [26.4%] 0.81 responders 1.05 ( ) 1.87 ( ) [45.9%] ( ) [75.4%] ( ) ( ) [26.2%] 0.72 non-responders 3.92 ( ) 2.30 ( ) ( ) ( ) ( ) 0.28 [232.3%] [20.4%] [240.7%] HIV ( ) 1.91 ( ) [25.1%] ( ) [26.1%] ( ) ( ) [24.4%] 0.49 HIV ( ) 1.93 ( ) [63.6] ( ) [63.6%] ( ) ( ) [241.8%] Hepatitis C therapy and cardiovascular risk TNF-a, pg/ml all patients 1.95 ( ) 2.12 ( ) [221.2%] ( ) [213.0%] ( ) ( ) [252.0%] responders 1.92 ( ) 2.26 ( ) [0%] ( ) [5.3%] ( ) ( ) [252.0%] non-responders 2.33 ( ) 1.40 ( ) [242%] ( ) ( ) ( ) [239.1%] [260.9%] HIV ( ) 2.13 ( ) ( ) [24.3%] ( ) ( ) [221.8%] [234.9%] HIV ( ) 1.61 ( ) [0.5%] ( ) [217.7%] ( ) ( ) [279.3%] oxldl, mu/ml all patients ( ) responders ( ) non-responders ( ) HIV ( ) HIV ( ) ( ) [220.6%] ( ) [220.9%] ( ) [216.4%] ( ) [213.6%] ( ) [220.9%] ( ) [223.2%] ( ) [221%] ( ) [216%] ( ) [229%] ( ) [221%] ( ) ( ) [19.2%] ( ) ( ) [10.9%] ( ) ( ) [40.6%] ( ) ( ) [10.9%] ( ) ( ) [29.2%] Continued JAC Downloaded from at Pennsylvania State University on February 17, 2016

6 Masiá et al Table 2. Continued Biomarker Baseline (N¼56) Week 12 (N¼53) a P b Week 24 (N¼47) P b End of treatment (N¼43) P b Follow-up (N¼32) P b Fibrinogen, mg/dl all patients ( ) responders ( ) non-responders ( ) HIV ( ) HIV ( ) ( ) [25.0%] ( ) [20%] ( ) [26%] ( ) [33%] ( ) [15%], ( ) [29.8%], ( ) [30%] ( ) [37%] ( ) [30%] ( ) [29%], ( ), ( ) [12.3%], ( ), ( ) [10.9%] ( ) ( ) [10.5%] ( ) ( ) [9.9%] ( ) ( ) [13.6%] PAI-1, ng/ml all patients 2.73 ( ) 2.66 ( ) [219.7%] ( ) [211.4%] responders 2.50 ( ) 2.65 ( ) ( ) [221.4%] [28.4%] non-responders 4.69 ( ) 2.70 ( ) ( ) [217.7%] [249.6%] HIV ( ) 2.98 ( ) ( ) [220.3%] [28.4%] HIV ( ) 2.0 ( ) [219.7%] ( ) [235.4%] ( ) ( ) [27.8%] ( ) ( ) [20.7%] ( ) ( ) 0.46 [214.0%] ( ) ( ) [25.0%] ( ) ( ) [225.2%] 0.21 Data are median (IQR). Percentage change from baseline is presented in square brackets. Differences in biomarker levels before and after treatment were assessed using the non-parametric Wilcoxon test. a For comparisons between baseline and week 12, responders were considered to be patients with suppressed viral load at week 12. b Compared with baseline. Downloaded from at Pennsylvania State University on February 17, 2016

7 Hepatitis C therapy and cardiovascular risk JAC who completed the end-of-follow-up visit. Patients reaching the end of follow-up were 1 year older, and they also had a slightly higher systolic blood pressure and higher total cholesterol and LDL-cholesterol compared with baseline. Consequently, they had a slightly higher Framingham score (3% versus 4.5%). Plasma biomarkers after HCV treatment discontinuation Six months after treatment discontinuation, median ICAM-1 and VCAM-1 values were significantly lower compared with baseline, a change restricted to the subgroup of patients who maintained sustained virological response. Of note, in patients who did not achieve sustained virological response, the median change in ICAM-1 from baseline had a positive sign, in contrast to the negative change in the responders, and differed significantly between the groups (P,0.001). TNF-a was also significantly lower 6 months after treatment discontinuation (P¼0.03). Conversely, levels of hscrp, MMP-9, MCP-1, IL-6, oxldl and fibrinogen were not different from baseline (Table 2). No other differences were seen between treatment groups. The comparison of changes in the biomarkers between genotypes 1/4 versus 2/3 did not show significant differences. Discussion In this study, treatment for HCV infection with PEG-IFN-a/RBV induced different changes in a number of CVD-related biomarkers. During anti-hcv therapy, there was a decline in the inflammation and oxidative stress biomarkers MMP-9, ICAM-1 and oxldl, while no changes occurred in hscrp, IL-6, TNF-a and PAI-1, and an increase in levels of VCAM-1, MCP-1 and fibrinogen was observed. Some of them were non-lasting changes, since their concentrations returned to baseline values after treatment discontinuation. However, VCAM-1, ICAM-1 and TNF-a levels remained significantly lower after treatment conclusion in patients with sustained virological response. The effects were not different between HIV-infected and -uninfected patients. Of all biomarkers analysed, only three, namely VCAM-1, ICAM-1 and TNF-a, developed changes that persisted after PEG-IFN-a/RBV therapy, and all of them showed an anti-atherogenic trend as a result of the intervention. The surface glycoproteins VCAM-1 and ICAM-1 are mainly expressed on the vascular endothelium, and have been associated with endothelial dysfunction, an early event in the development of atherosclerosis. Additionally, they are also expressed in dendritic cells and hepatocytes, in which they have been demonstrated to correlate with the stage of liver histological activity. 9 Accordingly, we found a positive correlation between the decrease in transaminases and the decreases in both adhesion molecules at the follow-up visit, mainly with ICAM-1, which also correlated with the decrease in HCV-RNA. Levels of ICAM-1 decreased soon after the beginning of anti-hcv therapy, and remained significantly lower after treatment discontinuation. Notably, no changes in levels of ICAM-1 were detected in patients who did not achieve sustained virological response. Contrarily, treatment with PEG-IFN-a/RBV induced an increase in VCAM-1; however, following treatment discontinuation, VCAM-1 levels were significantly lower than at baseline, a finding not previously described. 9,10 The third inflammation biomarker undergoing lasting changes was the cytokine TNF-a. Although it did not change significantly during HCV therapy, a reduction in its level was observed after treatment discontinuation. Some of the other biomarkers, such as MCP-1 and fibrinogen or MMP-9 and oxldl, experienced pro- and anti-atherogenic changes, respectively, during PEG-IFN-a/RBV therapy, but all of them reverted after treatment discontinuation. Although we do not have a definite explanation for such findings, changes in these biomarkers might reflect the immunomodulatory trailing effect of interferon during treatment, rather than a sustained antiviral effect. Additionally, the real relevance of the mild increase in the Framingham score at the last follow-up visit as a result of the older age of the patients, and the slight elevation of total cholesterol and LDL-cholesterol and systolic blood pressure, is uncertain and cannot be determined from the present investigation. The concentrations of hscrp did not change during or after treatment with PEG-IFN-a/RBV, a finding described in HIV-monoinfected individuals, 11 but not yet explored in HCV/HIV-coinfected individuals. The main limitation of the study is the small number of patients reaching the last follow-up visit. This might have precluded finding differences between baseline and post-treatment values, although no trend to different levels was observed in most of the biomarkers measured. Another limitation is the short-term follow-up of the patients. Strengths are the high number of CVD-related biomarkers exploring different pathways of the atherogenic process, simultaneously analysed, the multiple measurements performed during the study and the consecutive sample of patients with precise inclusion/exclusion criteria in a clinical pathway, which led to the homogeneous characteristics of the population studied. Additionally, we had the opportunity to compare the changes of many previously unexplored biomarkers during HCV treatment in HCV/HIVcoinfected patients and their HCV-monoinfected counterparts. In summary, HCV therapy with PEG-IFN-a/RBV induces different changes in several cardiovascular risk biomarkers, most, but not all, being anti-atherogenic effects, although only the antiatherogenic effects remain after treatment discontinuation in patients with sustained virological response. These effects are similar in HIV-infected and -uninfected patients. Funding Supported in part by FIBELX (05/05, 07/20, 10/11, 10/12, 10/13), FIS (PI081893), Generalitat Valenciana (PI051338, 083/05, AP-091/07, AP-087/10), FIPSE (12655/07) and ISCIII-RETIC RD06/0027-Red Temática Cooperativa de Investigación en SIDA. Transparency declarations None to declare. References 1 Bedimo R, Westfall AO, Mugavero M et al. Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients. HIV Med 2010; 11: Freiberg MS, Cheng DM, Kraemer KL et al. The association between hepatitis C infection and prevalent cardiovascular disease among HIV-infected individuals. AIDS 2007; 21: Butt AA, Xiaoqiang W, Budoff M et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: Downloaded from at Pennsylvania State University on February 17,

8 Masiá et al. 4 Ishizaka N, Ishizaka Y, Takahashi E et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. Lancet 2002; 359: Arcari CM, Nelson KE, Netski DM et al. No association between hepatitis C virus seropositivity and acute myocardial infarction. Clin Infect Dis 2006; 43: e Tien PC, Schneider MF, Cole SR et al. Association of hepatitis C virus and HIV infection with subclinical atherosclerosis in the women s interagency HIV study. AIDS 2009; 23: Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: Masiá M, Bernal E, Padilla S 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: Lo Iacono O, García-Monzón C, Almasio Pet al. Soluble adhesion molecules correlate with liver inflammation and fibrosis in chronic hepatitis C treated with interferon-a. Aliment Pharmacol Ther 1998; 12: Itoh Y, Okanoue T, Ohnishi N et al. Serum levels of soluble tumor necrosis factor receptors and effects of interferon therapy in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1999; 94: Kalabay L, Nemesanszky E, Csepregi A et al. Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-a2b. Int Immunol 2004; 16: Downloaded from at Pennsylvania State University on February 17,