hepatitis and the cvd

1. HEPATITIS C VIRUS INFECTION, A
NEW MODIFIABLE
CARDIOVASCULAR RISK FACTOR
IHAB MAHMOUD MD CARDIOLOGY
CONSULTANT CARDIOLODIST ACDS

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

3. • Evidence of associations with stroke, coronary artery disease (CAD), 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 4 types of evidence

4. • (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.
• (4) most important, outcome studies showing risk reduction when the putative
factor is corrected.

5. • From a large cohort of HCV-infected veterans, the investigators found direct-
acting agent (DAA) treatment was associated with a 43% reduction and pegylated
interferon plus ribavirin (pegIFN/RBV) with a 22% reduction in risk of incident CV
events compared with no treatment. Treatment with a DAA was associated with
lower event rates for all CV event compared with nontreated 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 [Butt et al5 ].

6. CLINICAL STUDIES DEMONSTRATED INCREASED
PREVALENCE RATE OF HCV INFECTION IN PATIENTS WHO
DEVELOP A MAJOR CV EVENT
• A meta-analysis (total N = 68,365) showed an association between HCV infection and CV death
(odds ratio, 1.65; 95% confidence interval, 1.07–2.56).6
• The risk of carotid plaques and carotid intima-media thickness was 2-fold higher in HCV-
infected individuals compared with uninfected controls.6
• Individuals with HCV infection compared with HCV-negative controls have an increased
incidence of stroke.
• Conversely, a higher prevalence of HCV infection has been found in patients with stroke than in
age- and sex-matched controls.7

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 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

8. 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
• Nonobese, nondiabetic, treatment-naïve HCV-infected patients have higher
proinflammatory cytokine levels .12
• The presence of HCV has been correlated with higher levels of inflammatory
markers in patients with stroke.7

9. • Biomarkers predictive of CAD were more elevated in HCV-infected patients than
among controls, that is, 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 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

10. • 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 the myocardial tissue of patients with hypertrophic
cardiomyopathy and those with dilated cardiomyopathy.

11. OUTCOME STUDIES SHOWED CV RISK REDUCTION
WHEN THE PUTATIVE FACTOR (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 ischemic 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 were found in patients receiving pegIFN
compared with those not treated in a Taiwanese study.17

12. • Virologic 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

13. • Up to a recent period, the 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 virologic response compared with nonresponders.20
• In a large cohort of HCV-infected patients, analyzed 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 versus
the control group (7.2% vs 13.8%). A sustained virologic response was associated
with a 13% lower risk of incident CV events. 5

14. 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 important non liver physician should be aware of the benefit of
DAA to improve liver and CV outcomes.

15. •THANK YOU

16. REFERENCES
1 -WHO guidelines on hepatitis B and C testing. World Health Organization, Geneva2017
2-Cacoub P.Gragnani L.Comarmond C.et al.Extrahepatic manifestations of chronic hepatitis C virus infection.Dig Liver Dis. 2014; 46: S165-S173
3-Lee M.H.Yang H.I.Lu S.N.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
4-Domont F.Cacoub P.Chronic hepatitis C virus infection, a new cardiovascular risk factor?.Liver Int. 2016; 36: 621-627
5-Butt A.A.Yan P.Shuaib A.et al.Direct-acting antiviral therapy for HCV infection is associated with a reduced risk of cardiovascular disease
events.Gastroenterology. 2019; 156: 987-996
6-Petta S.Maida M.Macaluso F.S.et al.Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational
studies.Gastroenterology. 2016; 150 (quiz e15-16): 145-155.e4
7-Adinolfi L.E.Restivo L.Guerrera B.et al.Chronic HCV infection is a risk factor of ischemic stroke.Atherosclerosis. 2013; 231: 22-26
8-Butt A.A.Xiaoqiang W.Budoff M.et al.Hepatitis C virus infection and the risk of coronary disease.Clin Infect Dis. 2009; 49: 225-232
9-Pothineni N.V.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
10-Negro F.Forton D.Craxì A.et al.Extrahepatic morbidity and mortality of chronic hepatitis C.Gastroenterology. 2015; 149: 1345-1360

17. 11-Targher G.Bertolini L.Padovani R.et al.Differences and similarities in earlyatherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C.J Hepatol. 2007; 46: 1126-1132
12-Oliveira C.P.Kappel C.R.Siqueira E.R.et al.Effects of hepatitis C virus on cardiovascular risk in infected patients: a comparative study.Int J Cardiol. 2013; 164: 221-226
13-Roed T.
Kristoffersen U.S.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: 55-62
14-Lee M.H.Yang H.I.Wang C.H.et al.Hepatitis C virus infection and increased risk of cerebrovascular disease.Stroke. 2010; 41: 2894-2900
15-Fletcher N.F.Wilson G.K.Murray J.et al.Hepatitis C virus infects the endothelial cells of the blood-brain barrier.Gastroenterology. 2012; 142: 634-643
16-Boddi M.Abbate R.Chellini B.et al.Hepatitis C virus RNA localization in human carotid plaques.J Clin Virol. 2010; 47: 72-75
17-Hsu Y.C.Ho H.J.Huang Y.T.et al.Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.Gut. 2015; 64: 495-503
18-Innes H.A.McDonald S.A.Dillon J.F.et al.Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes.
Hepatology. 2015; 62: 355-364
19-Maruyama S.Koda M.Oyake N.et al.Myocardial injury in patients with chronic hepatitis C infection.J Hepatol. 2013; 58: 11-15
20-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