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Patrice Cacoub
To cite this version:
Patrice Cacoub. Hepatitis C Virus Infection, a New Modifiable Cardiovascular Risk Factor. Gastroen-terology, WB Saunders, 2019, 156 (4), pp.862-864. �10.1053/j.gastro.2019.02.009�. �hal-02272021�
Hepatitis C virus infection should be added to the list of modifiable cardiovascular risk factors
Patrice Cacoub1,2,3,4
1
Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and
Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; 2 INSERM, UMR_S 959, F-75013, Paris, France; 3 CNRS, FRE3632, F-75005, Paris, France; 4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France;
This paper includes:
Correspondence should be addressed to: Patrice Cacoub, AP-HP, Hôpital
Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, 83 boulevard de l’hôpital. F-75013, Paris, France
Phone: + (33)(1) 42 17 80 09. Fax: + (33)(1) 42 17 80 33. E Mail: patrice.cacoub@aphp.fr.
Disclosures
Patrice Cacoub has received consulting and lecturing fees from Abbvie, Astra Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, Merck Sharp Dohme, Roche, Servier and Vifor.
Contributorship
Drafting of the manuscript: PC
Sources of Funding
Abbreviations used in this paper: DAA, direct acting antiviral; HCV, hepatitis C virus; IFN, interferon; SVR, sustained virological response;
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Chronic hepatitis C virus (HCV) infection is a leading cause of liver-related morbidity and mortality worldwide [1]. In addition, chronic HCV infection is considered a systemic infection that can lead to extrahepatic manifestations [2,3]. Among the latter, it has been suggested that HCV infection might be a new cardiovascular (CV) risk factor (Domont). The potential burden of CV disease (CVD) in patients with HCV infection is relevant owing to the high proportion of HCV-infected patients with CVD-associated risk factors such as diabetes, chronic kidney disease or hypertension. Evidence of
associations with stroke, coronary artery disease, peripheral arterial disease, and heart failure suggest a link between HCV infection and CVD [12,13]. Despite the association of HCV with insulin resistance, type 2 diabetes mellitus, and hepatic steatosis, until recently it was unclear whether HCV is an independent risk factor for cardiovascular disease. We have to keep in mind that risk factors are rigorously defined by four types of evidence: (1) observational studies showing the presence of the factor before event appearance; (2) prospective translational or clinical studies demonstrating an increased prevalence rate of the factor in patients who develop the event; (3) mechanism of action studies based on experimental models; and (4) outcome studies showing risk reduction when the putative factor is corrected. Recent data from Butt et al…. XXX. Lets’ summarize what are the published evidence available today of the following assertion i.e. the “factor” (HCV infection) is a new reversible risk factor for CVD (“the event”).
Observational studies: HCV as a non-traditional risk factor for cardiovascular disease HCV infection has been associated with increased cardiovascular death. A meta-analysis (total N=68,365) revealed an association between HCV infection and cardiovascular death (OR 1.65; 95% CI 1.07–2.56)[24]. The results have been confirmed in a prospective 5-year study in patients receiving hemodialysis (N=1,077), in which chronic HCV infection,
but not cured HCV infection, was an independent risk factor for CVD mortality [61]. HCV infection has been associated with increased rates of symptomatic atherothrombosis whatever the territory involved, i.e. cerebrovascular, coronary or peripheral artery. Many studies have found an increased risk of cerebrovascular atherosclerosis disease (carotid plaques, stroke) in HCV infected individuals. A meta-analysis from nine case-control studies showed a two-fold higher risk of carotid plaques in HCV-infected
individuals compared with uninfected controls [24]. Similar results were obtained when carotid intima media thickness was considered as the outcome, instead of carotid plaques. Epidemiological studies have reported an increased incidence of stroke in people with HCV infection compared with HCV-negative controls [25,26] or a higher prevalence of HCV infection in patients with stroke than in age- and sex-matched controls [27].
In a cohort of 150,000 patients (82,082 of whom were HCV-positive), the prevalence of HCV infection was higher in patients with angiographic evidence of chronic coronary artery disease (CAD) compared with patients without CAD (6.3% vs. 2.0%; P<0.05)[31]. HCV infection was associated with a higher risk of CAD after adjusting for confounding factors, in a comparison of cohorts of HCV-infected and HCV-negative patients [30, 31]. HCV-infected men had a higher risk of acute MI than HCV-negative men with higher total cholesterol/low-density lipoprotein levels; the risk of acute MI in HCV-infected men was more pronounced at a younger age [32]. In a prospective cohort study, HCV-infected patients had a higher incidence of CAD events than HCV-negative patients (4.9% vs 3.2%; P<0.001) [35]. The incidence of acute coronary syndromes was higher in 13,983
treatment-naïve HCV-infected patients than in 55,932 HCV-negative individuals in a large cohort study [36]. Some studies have also shown a lack of association between HCV
infection and acute myocardial infarction [38,39]. However, these studies have flaws such as retrospective design, short follow-up period, and a broad definition of chronic HCV infection including spontaneous clearance. HCV infection has also been shown to be an independent risk factor for peripheral arterial disease [40] and peripheral arterial stiffness [41].
Clinical studies have shown a link between HCV infection and cardiac dysfunction [4,12,13]. HCV seropositivity was associated with an increased risk of heart failure (HR 2.13; 95% CI 1.19–3.80) when compared with seronegative individuals in a cohort of patients with stable CAD [47]. An association between HCV infection and the risk of congestive heart failure (OR 2.49; 95% CI 1.04–5.96) was observed in the US National Health and Nutrition Examination Survey (NHANES) [48].
The contradictory findings regarding HCV infection and cardiovascular disease may be due to differences in the characteristics of populations studied or in the assessment of end points or adjustments for confounding factors.
(3) Mechanism of action studies
There are many potential direct and indirect mechanisms by which HCV could increase CV risk [14,15, Negro]. Metabolic factors may play a role; the insulin resistance
associated with HCV leads to hyperglycemia, endothelial dysfunction, and inflammation, all of which produce vessel damage and unstable plaques. Although metabolic factors, such as steatosis [Adinolfi], may play a role, systemic chronic inflammation seems more likely to be a central factor, together with endothelial dysfunction [Targher],
HCV replication in extrahepatic cells, genetic and environmental factors. The presence of HCV infection is associated with low grade chronic systemic inflammation, which may induce chronic endothelial lesions and accelerate
atherosclerosis. Non-obese, non-diabetic, treatment-naïve patients with HCV infection have an intermediate Framingham risk score and significantly higher pro-inflammatory cytokine levels than blood donors [34]. The presence of HCV has been correlated with higher levels of inflammatory markers in patients with stroke [27]. The risk of
cerebrovascular death has been correlated with HCV RNA levels [28]. HCV has been shown to infect the brain endothelial cells (Fletcher). Positive-strand HCV RNA was detected in carotid plaque tissues from anti-HCV-positive patients whereas it was not detected in carotid plaque tissues obtained from anti-HCV-negative patients (Boddi). The incidence of CV events was higher in patients with detectable HCV RNA levels than in HCV antibody-positive patients with undetectable HCV RNA levels [35]. Biomarkers predictive of CAD were more elevated in HCV-infected patients than among controls, i.e. high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1 and soluble E-selectin (Roed). HCV RNA has been found in myocardial tissue of patients with dilated cardiomyopathy from 26.0% of
patients with hypertrophic cardiomyopathy and 11.5% of those with dilated cardiomyopathy [49,52]. Genes of the major histocompatibility complex II,
HLADQB1*0303 and HLA-DRB1*0901 were more prevalent in HCV-infected patients with hypertrophic cardiomyopathy, and DRB1*1201 was more prevalent in HCV-infected patients with dilated cardiomyopathy [57].
(4) Outcome studies showing risk reduction when the putative factor is corrected.
If active HCV infection is associated with CV risk, then eradication of HCV might reduce that risk and reduce the incidence of CV events. Antiviral treatment have shown positive impact on CVD risk reduction. However, the majority of the conclusions were drawn from indirect evidence and from studies on patients healthy enough to be eligible for IFN-based therapies. Treatment with pegylated interferon (pegIFN) plus ribavirin (RBV) decreased the risk of ACS (HR 0.77; 95% CI 0.62–0.97; P=0.026), and ischaemic stroke (HR 0.62; 95% CI 0.46–0.83; P=0.001) in a large population of HCV-infected patients (n=293,480), 12,384 of whom had received pegIFN/RBV [37]. The risk of lethal
cerebrovascular events was lowest in HCV-positive patients with undetectable HCV RNA and it increased with viral load when compared with anti-HCV-antibody negative
patients [28]. A decrease of rates of ACS and stroke was observed in patients receiving pegIFN-based antiviral therapy compared with those not treated in a large Taiwanese cohort study [37]. Virological eradication was associated with a significant absolute risk reduction for CVD in a large Scottish cohort of HCV-infected patients who underwent pegIFN/RBV therapy [62]. In a cohort of 200 Japanese individuals with chronic HCV infection and without overt heart disease, improvement in myocardial injury was observed in patients who achieved a SVR, transient improvement in patients who
relapsed, and no improvement in non-responders after treatment with pegIFN/RBV [44]. Up to a recent period, data on the effect of direct-acting antivirals (DAAs) treatment on CV outcomes were limited. Regimen with DAAs were available in a small number of patients, and long follow-up data were missing. In a large prospective cohort of French 1323 patients with biopsy-proven HCV-related compensated cirrhosis who received
pegIFN/RBV or IFN-free antiviral therapy, the risk of all or major adverse CV events was reduced in patients who achieved SVR compared with non-responders [17,18]. The protective effect of virological eradication was observed for both IFN-based and IFN-free therapies. The severity of liver disease, together with classical cardiovascular risk factors, was an independent predictor of cardiovascular events [17].The paper by Butt et al (XX) brings major information in this field. From a large cohort of 242,680 HCV-infected male Veterans, authors were able to analyze incident CVD events in patients who had been treated with a pegIFN/RBV regimen (n=4436) or a DAA-containing regimen (12,667), and among patients with vs without SVR to therapy. Of note, treated patients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection (n=17,103 controls). There were a total of 1239 (7.2%) incident CVD events in the treated group and 2361 (13.8%) events in the control group. DAA treatment was associated with a 43% reduction and pegIFN/RBV with a 22% reduction in risk of incident CVD events compared with no treatment (controls). An SVR was associated with a lower risk of incident CVD events (hazard ratio, 0.87; 95% CI, 0.77–0.98). Treatment with a DAA regimen was associated with lower event rates for all event types (cardiac, cerebrovascular and peripheral) compared with controls and those treated with a pegIFN/RBV regimen.
To summarize, the availability of safe and effective antiviral regimens (DAA) that
eradicate HCV infection in most patients (independently of the severity of the underlying liver disease and of the number and severity of comorbidities), together with evidence that HCV infection is a reversible CV risk factor, reinforces some practical messages: (1) as defined by the WHO, all HCV infected patients should have access to DAAs; (2) all HCV infected patients should benefit of a complete CV check-up; (3) liver and more
importantly non-liver physician should be aware of the benefit of DAA to improve cardiovascular outcomes.
Finally, a key clinical issue, is to identify groups of patients in which virologic eradication could have a minor or major impact on cardiovascular prognosis. It is in fact possible to expect the length and the severity of both liver disease and cardiovascular alterations, as well as the age and the comorbidity of patients could strongly affect the impact of SVR on cardiovascular outcomes.
In particular, HCV could be added to the list of infectious agents that play a clinically relevant role in the aetiology of cardiovascular disease (CVD). Furthermore, practical advice to evaluate cardiovascular disease risk and disease in chronic hepatitis C patients are included for help in daily clinical practice. Despite the advances in therapies for the treatment of HCV, there remains a need for increased awareness among specialists so that patients are more likely to obtain the treatment required to mitigate disease progression.
Competing interests None
Acknowledgments
References
(59) Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis.
2012;206:469-477.
Domont F, Cacoub P. Chronic hepatitis C virus infection, a new cardiovascular risk factor ? Liver Int. 2016 May;36(5):621-7.(44) Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol. 2013;58:11-15.
Petta S, Macaluso FS, Craxì A. Cardiovascular diseases and HCV infection: a simple association or more? Gut. 2014 Mar;63(3):369-75.
(2) Younossi Z, Park H, Henry L, Adeyemi A, Stepanova M. Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden. Gastroenterology.
2016;150:1599-1608.
(3) Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46 Suppl 5:S165-73.
(5) AASLD and IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. 2017; Available at: http://www.hcvguidelines.org/.(17) Nahon P, Bourcier V, Layese R, et al. Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications. Gastroenterology. 2017;152:142-156.e2.
(18) Cacoub P, Nahon P, Layese R, et al. HCV eradication reduces the occurrence of major adverse cardiovascular events in hepatitis C cirrhotic patients: data from the prospective ANRS CO12 CirVir cohort. J Hepatol. 2017;66:S20-S21.
(24) Petta S, Maida M, Macaluso FS, et al. Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. Gastroenterology. 2016;150:145-155.e4; quiz e15-6.
(40) Hsu YH, Muo CH, Liu CY, et al. Hepatitis C virus infection increases the risk of developing peripheral arterial disease: a 9-year population-based cohort study. J Hepatol. 2015;62:519-525. (37) Hsu YC, Ho HJ, Huang YT, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut. 2015;64:495-503.
(33) Hsu YC, Lin JT, Ho HJ, et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology. 2014;59:1293-1302. (27) Adinolfi LE, Restivo L, Guerrera B, Lonardo A, Ruggiero L, et al. Chronic HCV infection is a risk factor of ischemic stroke. Atherosclerosis. 2013;231:22-26.
(28) Lee MH, Yang HI, Wang CH, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. Stroke. 2010;41:2894-2900.
Boddi M, Abbate R, Chellini B, Giusti B, Giannini C, Pratesi G, Rossi L, Pratesi C, Gensini GF, Paperetti L, Zignego AL. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol. 2010
Jan;47(1):72-5.
Younossi Z, Papatheodoridis G, Cacoub P, Negro F, Wedemeyer H, Henry L, Hatzakis A.The
comprehensive outcomes of hepatitis C virus infection: A multi-faceted chronic disease. J Viral Hepat. 2018 Nov;25 Suppl 3:6-14.
Negro F, Forton D, Craxì A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology. 2015 Nov;149(6):1345-60.
Perticone M, Miceli S, Maio R, et al. Chronic HCV infection increases cardiac left ventricular mass index in normotensive patients. J Hepatol 2014;61:755–760
Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol. 2014 Nov;61(1 Suppl):S69-78.
[126] Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, et al. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 2012;142:634–643.
[127] Roed T, Kristoffersen US, Knudsen A, Wiinberg N, Lebech AM, Almdal T, et al. Increased prevalence of coronary artery disease risk markers in patients with chronic hepatitis C – A cross-sectional study. Vasc Health Risk Manag 2014;10:55–62.
Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with nonalcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007;46:1126–1132
(49) Matsumori A, Matoba Y, Sasayama S. Dilated cardiomyopathy associated with hepatitis C virus infection. Circulation. 1995;92:2519-2525.
(52) Matsumori A, Yutani C, Ikeda Y, Kawai S, Sasayama S. Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy. Lab Invest. 2000;80:1137-1142.
(57) Matsumori A, Ohashi O, Ito H, Furukawa Y, Hasegawa K, Sasayama S, et al. Genes of the major histocompatibility complex class II influence the phenotype of cardiomyopathies associated with hepatitis C virus infection. In: Matsumori A, editor. Cardiomyopathies and Heart Failure Boston: Kluwer Academic; 2003. p. 515-521.
(34) Oliveira CP, Kappel CR, Siqueira ER, et al. Effects of hepatitis C virus on cardiovascular risk in infected patients: a comparative study. Int J Cardiol. 2013;164:221-226.
(35) Pothineni NV, Delongchamp R, Vallurupalli S, et al. Impact of hepatitis C seropositivity on the risk of coronary heart disease events. Am J Cardiol. 2014;114:1841-1845.
Butt et al (XX). Direct-acting Antiviral Therapy for HCV Infection is Associated with a Reduced Risk of Cardiovascular Disease Events. Gastroenterology ……
