Accepted Manuscript. Hepatitis C virus infection, a new modifiable cardiovascular risk factor. Patrice Cacoub

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1 Accepted Manuscript Hepatitis C virus infection, a new modifiable cardiovascular risk factor Patrice Cacoub PII: S (19) DOI: Reference: YGAST To appear in: Gastroenterology Please cite this article as: Cacoub P, Hepatitis C virus infection, a new modifiable cardiovascular risk factor Gastroenterology (2019), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 1 Hepatitis C virus infection, a new modifiable cardiovascular risk factor Patrice Cacoub 1,2,3,4 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: 993 words, 20 references Correspondence should be addressed to: Pr Patrice Cacoub, MD, MSc, AP-HP, Hôpital Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, 83 boulevard de l hôpital. F-75013, Paris, France. Phone: + (33)(1) Fax: + (33)(1) 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, and Merck Sharp Dohme. Contributorship: drafting of the manuscript PC Sources of Funding: none Abbreviations used in this paper: HCV, hepatitis C virus; CV, cardiovascular; pegifn, pegylated interferon; RBV, ribavirin; DAA, direct acting antiviral; SVR, sustained virological response.

3 2 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 with many extrahepatic manifestations that can lead to poor quality of life and major economic burden [2,3]. Evidence of associations with stroke, coronary artery disease, peripheral arterial disease and heart failure suggested that HCV infection might be a new cardiovascular (CV) risk factor [4]. Patients with HCV infection frequently have CV-associated risk factors such as diabetes, chronic kidney disease or hypertension. However, it should be underlined that as for all diseases or events - risk factors are rigorously defined by four types of evidence: (1) observational studies showing the presence of the factor before the event appearance; (2) prospective translational or clinical studies demonstrating an increased prevalence rate of the factor in patients who will develop the event; (3) mechanism of action studies; and (4) most importantly, outcome studies showing risk reduction when the putative factor is corrected. The study by Butt et al [5] adds major information in this field. From a large cohort of HCV-infected Veterans, they found direct acting agent (DAA) treatment was associated with a 43% reduction and pegylated interfon plus ribavirin (pegifn/rbv) with a 22% reduction in risk of incident CV events compared with no treatment. Treatment with a DAAs was associated with lower event rates for all CV event compared with non-treated controls and those treated with a pegifn/rbv. This publication was the missing part of the puzzle which now sustains the following assertion, the factor (HCV infection) is a new reversible independent risk factor for CV disease ( the event ). Clinical studies demonstrated increased prevalence rate of HCV infection in patients who develop a major cardiovascular event

4 3 A meta-analysis (total N=68,365) showed an association between HCV infection and CV death (odds ratio 1.65; 95%CI )[6]. The risk of carotid plaques and carotid intima-media thickness was two-fold higher in HCV-infected individuals compared with uninfected controls [6]. Individuals with HCV infection compared with HCV-negative controls have increased incidence of stroke. Conversely, a higher prevalence of HCV infection have been found in patients with stroke than in age- and sex-matched controls [7]. In a cohort of 150,000 patients (82,082 of whom were HCV-positive), the prevalence of HCV infection was higher in patients with stable coronary artery disease (CAD) than in patients without CAD after adjusting for confounding factors [8]. In large prospective cohorts, HCV-infected patients had a higher incidence at a younger age of acute myocardial infarction than HCV-negative men [9]. HCV seropositivity was associated with cardiac dysfunction and increased risk of heart failure when compared with seronegative individuals [4]. Mechanism of action studies There are many potential direct and indirect mechanisms by which HCV could increase CV risk [4,10]. The insulin resistance associated with HCV leads to hyperglycemia, steatosis, endothelial dysfunction and low grade systemic inflammation all of which produce vessel damage and unstable plaques [7,11]. Non-obese, non-diabetic, treatment-naïve HCV infected patients have higher pro-inflammatory cytokine levels than blood donors [12]. The presence of HCV has been correlated with higher levels of inflammatory markers in patients with stroke [7]. 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 [13]. The incidence of CV events was higher in patients

5 4 with detectable HCV RNA levels and the risk of cerebrovascular death has been correlated with HCV RNA levels [9,14]. The virus has been shown to infect the brain endothelial cells [15]. Positive-strand HCV RNA was detected in carotid plaque tissues from HCV-positive patients and not in carotid plaque from HCV-negative patients [16]. HCV RNA has been found in myocardial tissue of patients with hypertrophic cardiomyopathy and those with dilated cardiomyopathy. Outcome studies showed CV risk reduction when the putative factor, that is HCV infection, 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 CV disease risk reduction. A decreased risk of acute CAD by 23% and ischaemic stroke by 38% have been found in a population of HCV-infected patients (n=293,480), 12,384 of whom had received pegifn/rbv [17]. The risk of lethal cerebrovascular events was lowest in HCV-positive patients with undetectable HCV RNA when compared with HCV-antibody negative patients [14]. A decrease of acute CAD and stroke rates was found in patients receiving pegifn compared with those not treated in a Taiwanese study [17]. Virological eradication was associated with an absolute risk reduction for CV disease in a Scottish cohort of HCV-infected patients who underwent pegifn/rbv therapy [18]. In a cohort of Japanese HCV-infected patients, sustained improvement in myocardial injury was observed only in patients who eradicate the virus after pegifn/rbv [19]. Up to a recent period, effect of DAAs on CV outcomes were limited. In a prospective cohort of patients with HCV-related compensated cirrhosis who received pegifn/rbv or IFN-free antivirals, the risk of major CV events was reduced in patients who achieved sustained virological response (SVR) compared with non-responders [20].

6 5 In a large cohort of HCV-infected patients, Butt et al [5] analysed treated patients (pegifn/rbv, or DAA) matched for age, race, sex, and baseline values with patients who had never received treatment. The rate of incident CV events was lower in the treated vs. the control group (7.2% vs. 13.8%). A SVR was associated with a 13% lower risk of incident CV events. To summarize, the availability of safe and effective antiviral regimens that eradicate HCV infection in most patients, together with evidence that HCV infection is a reversible CV risk factor, reinforce some practical messages: (1) 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 liver and cardiovascular outcomes.

7 References 6 1. WHO Guidelines on Hepatitis B and C Testing. Geneva: World Health Organization; 2017 Feb. 2. Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46 Suppl 5:S 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: Domont F, Cacoub P. Chronic hepatitis C virus infection, a new cardiovascular risk factor? Liver Int May;36(5): Butt et al (XX). Direct-acting Antiviral Therapy for HCV Infection is Associated with a Reduced Risk of Cardiovascular Disease Events. Gastroenterology 6. 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: e4; quiz e Adinolfi LE, Restivo L, Guerrera B, et al. Chronic HCV infection is a risk factor of ischemic stroke. Atherosclerosis Nov;231(1): Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49: 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: Negro F, Forton D, Craxì A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology Nov;149(6): Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol Jun;46(6): 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: Roed T, Kristoffersen US, Knudsen A, 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: Lee MH, Yang HI, Wang CH, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. Stroke. 2010;41: Fletcher NF, Wilson GK, Murray J, et al. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 2012;142: Boddi M, Abbate R, Chellini B, et al. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol Jan;47(1):72-5.

8 17. 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: Innes HA, McDonald SA, Dillon JF, et al. Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. Hepatology. 2015;62: Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol. 2013;58: 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. 7