Expert opinion on managing chronic HCV in patients with cardiovascular disease

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Sift through current research articles on the extrahepatic manifestations of hepatitis C, in particular an association between HCV and cardiovascular conditions.

Review

Expert opinion on managing chronic HCV in patients with cardiovascular disease

Cristina Vassalle1, Salvatore Petta2, Alessia Pepe3, Antonio Craxi2, Mark Bondin4, Patrice Cacoub

Abstract

Extrahepatic manifestations of chronic HCV infection include cardiovascular diseases and an increase in cardiovascular mortality. The pathogenic mechanisms by which HCV contributes to cardiovascular disease are not well defined, however, it is likely that systemic inflammation, and the promotion of other metabolic diseases are involved. In this Review, the evidence for HCV infection as a non-traditional risk factor for cardiovascular disease is evaluated. 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.

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Conclusions

HCV has a complex role in the atherosclerotic process, although the association between HCV and CVD has not been clearly defined. In particular, the biological significance of this association remains undefined. Thus, a pathogen resident in an atherosclerotic plaque may simply represent a ‘bystander’ rather than a ‘culprit’ or a diseased vessel may simply be more vulnerable to pathogens, including HCV. In any case, it would be superficial to consider as irrelevant a hypothesis that is reinforced by multiple lines of evidence, and by the involvement of systemic inflammation and the autoimmune response, which are both critical in HCV infection and atherosclerosis.

Currently, HCV-infected patients are not generally recognized as a high priority for cardiovascular assessment and/or treatment owing to the lack of definitive conclusions on the role of HCV in CVD. In view of present available evidence, it is important that clinicians begin to consider HCV as a non-traditional risk factor for CVD. Evidence of a beneficial effect of SVR after antiviral treatment on cardiovascular risk is encouraging, especially with the introduction of new IFN-free combinations that are more effective and better tolerated than IFN-based therapies. In this context, from a pathophysiological point of view, the observation that some patients with chronic HCV infection remained free of atherosclerosis, while others develop extensive disease, represents a challenging point that merits further investigation. Thus, it remains crucial for clinicians to consider their patients as a whole, and evaluate correlated factors and diseases that place the chronic HCV infection patient at risk for HCV-related extra-hepatic complications, including CVD. Specifically, it is critical for clinicians to recognize the multilevel dimensions of HCV disease and its natural history, in the attempt to optimize treatment, apply general guidelines, avoid adverse events and improve the quality of life for each patient. In this context, the assessment of additional factors and comorbidities (for example, steatosis, diabetes) or biomarkers (for example, inflammatory, lipids) might be helpful to eventually identify subgroups of patients at higher risk of developing atherosclerosis.

It is conceivable that all patients with chronic HCV infection would benefit from a detailed assessment of their cardiovascular status, whereas patients with CVD would benefit from the screening for HCV and other HCV-related parameters. In this scenario, a close collaboration between hepatologists and cardiologists is also desirable to correctly interpret patient-specific data and make the best recommendation for each patient.

Full-Text: https://www.intmedpress.com/journals/avt/article.cfm?id=3248&pid=88&sType=AVT

HCV in relation to cardiovascular conditions - Impact of direct-acting antiviral treatments?

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Sift through current research articles on the extrahepatic manifestations of hepatitis C, in particular HCV in relation to cardiovascular conditions.

World J Gastroenterol. Nov 7, 2018; 24(41): 4617-4621

Published online Nov 7, 2018. doi: 10.3748/wjg.v24.i41.4617

Editorial 
Chronic hepatitis C, atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments?

Luigi Elio Adinolfi, Luca Rinaldi, Riccardo Nevola

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Abstract

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.

Direct and indirect factors considered responsible for development of atherosclerosis and cardiovascular disease in chronic hepatitis C patients and the possible effect of hepatitis C virus clearance by direct-acting antiviral agents on cardiovascular outcomes. DAAs: Direct-acting antiviral agents; IR: Insulin resistance; OXS: Oxidative stress; LPS: Lipopolysaccharide (endotoxinemia). 

Read the editorial: https://www.wjgnet.com/1007-9327/full/v24/i41/4617.htm

Curing hepatitis C reduces the risk of cardiovascular events

Successful hepatitis C treatment lowers risk of cardiovascular events

Liz Highleyman
Published: 25 October 2018

Several studies have found that people with hepatitis C are more prone to developing cardiovascular conditions such as coronary artery disease, peripheral vascular disease, myocardial infarction and stroke; however, other studies have not seen this association.

A growing body of evidence shows that HCV treatment can help reverse this increased risk. A recent study from France, for example, found that curing hepatitis C reduces the risk of cardiovascular events in people with compensated cirrhosis. But again, some large studies from the interferon era did not see a similar benefit. 

Read the complete article: http://www.infohep.org/Successful-hepatitis-C-treatment-lowers-risk-of-cardiovascular-events/page/3357488/

On This Blog
A collection of current research articles on ailments related to HCV

Article directory on the extrahepatic manifestations of hepatitis C.

The following study investigated the prevalence of early signs of cardiovascular damage in patients with HCV cirrhosis. Is such damage reversible following treatment with DAAs? 

Full-text article available online @ Medscape, or purchase article, here. 

A Prospective Study

Aliment Pharmacol Ther. 2018 Oct;48(7):740-749. doi: 10.1111/apt.14934. Epub 2018 Aug 10.

Subclinical cardiovascular damage in patients with HCV cirrhosis before and after treatment with direct antiviral agents: a prospective study.

Novo G1, Macaione F1, Giannitrapani L2, Minissale MG2, Bonomo V1, Indovina F1, Petta S3, Soresi M2, Montalto G2, Novo S1, Craxi A3, Licata A2,3.

Abstract
BACKGROUND:
Cirrhosis is associated with morpho-functional cardiovascular alterations.

AIMS: 

To detect early features of cardiovascular damage in HCV-compensated cirrhotic patients using myocardial deformation indices and carotid arterial stiffness, and, further, to evaluate their short-term behaviour after HCV eradication with direct antiviral agents (DAAs).

METHODS: 

Thirty-nine consecutive patients with HCV cirrhosis, without previous cardiovascular events, were studied and matched for age, gender and cardiovascular risk factors to 39 controls without liver or cardiovascular disease. Patients and controls underwent a baseline echocardiographic evaluation including global longitudinal strain and ultrasound scan of carotid arteries. HCV-cirrhotics were reassessed by echocardiography and carotid ultrasound after obtaining sustained virological response (SVR) on DAAs.

RESULTS: 

HCV-cirrhotics showed at baseline a significantly reduced global longitudinal strain compared to controls -18.1 (16.3-20.5) vs -21.2 (20.4-22.3), P < 0.001. They also had a significantly higher pulse wave velocity 8.6 (7.7-9.1) m/s vs 6.6 (6.0-7.1) m/s, P = 0.0001, and β-stiffness index 12.4 (11.1-13.5) vs 8.6 (8.0-9.2) P = 0.0001. At multiple regression analysis, diabetes and HCV cirrhosis were independent predictors of global longitudinal strain. All HCV-cirrhotic patients had SVR on DAAs. Follow-up available in 32 of 39 (82%) at 9 (8-10) months showed a significant improvement of tricuspid annular plane systolic excursion (P = 0.01) and lateral E' velocity compared to baseline (P = 0.001).

CONCLUSIONS: 

HCV-cirrhotics show a significant rate of subclinical cardiac and vascular abnormalities. At a time when their survival is less linked to progression of liver disease, due to viral eradication on DAAs, cardiovascular morbidity and mortality may take a significant role.

Continue to full-text: https://www.medscape.com/viewarticle/902665
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Cardiovascular Risk Management and Hepatitis C: Combining Drugs

Cardiovascular Risk Management and Hepatitis C: Combining Drugs
Elise J. SmoldersPeter J. G. ter HorstSharon WoltersDavid M. Burger Elise J. Smolders

Article First Online: 27 September 2018

Abstract
Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug–drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.

Key Points

Drug-drug interactions (DDIs) can be of major concern in hepatitis C patients with cardiovascular issues as there are many potential DDIs.

Especially clopidogrel and ticagrelor are drugs of which the potential drug-interactions are complex and hard to manage.

With increasing number of new direct-acting antivirals (DAAs) available the number clinical relevant DDIs are decreasing.

Read full-text article online:

 https://link.springer.com/article/10.1007%2Fs40262-018-0710-1

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https://link.springer.com/content/pdf/10.1007%2Fs40262-018-0710-1.pdf

Hepatitis C Virus Eradication by Direct Antiviral Agents Improves Carotid Atherosclerosis in patients with Severe Liver Fibrosis

In case you missed it

J Hepatol. 2018 Mar 2. pii: S0168-8278(18)30132-6. doi: 10.1016/j.jhep.2018.02.015. [Epub ahead of print]

Article in Press

Hepatitis C Virus Eradication by Direct Antiviral Agents Improves Carotid Atherosclerosis in patients with Severe Liver Fibrosis
Salvatore Petta, Luigi Elio Adinolfi, Anna Ludovica Fracanzani, Francesca Rini, Rosalia Caldarella, Vincenza Calvaruso, Calogero Cammà, Marcello Ciaccio, Vito Di Marco, Stefania Grimaudo, Anna Licata, Aldo Marrone, Riccardo Nevola, Rosaria Maria Pipitone, Antonio Pinto, Luca Rinaldi, Daniele Torres, Antonino Tuttolomondo, Luca Valenti, Silvia Fargion, Antonio Craxì

DOI: https://doi.org/10.1016/j.jhep.2018.02.015

Atherosclerosis is a condition in which the arteries become narrow as a result of gradual plaque accumulation. Cholesterol plaque may slowly build up in the carotid artery wall, over decades. The growing plaque may eventually narrow the carotid artery, known as stenosis, and can lead to a stroke.

Highlights

•HCV eradication by direct antiviral agents improves carotid atherosclerosis.
•Atherosclerosis improvement is confirmed after stratification for cardiovascular risk factors.
•Atherosclerosis improvement is observed in patients with and without cirrhosis.

Abstract
Background and Aim
Recent studies suggest an association between HCV infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis.

Materials and Methods
One hundred eighty-two consecutive HCV patients with advanced fibrosis or compensated cirrhosis were evaluated by virological, anthropometric and metabolic measurements. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT≥1 mm) and carotid plaques, defined as focal thickening of ≥ 1.5 mm at the level of common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy.

Results
Fifty-six percent of patients were males, mean age was 63.1±10.4 years and 65.9% had compensated cirrhosis. One patient out of five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. Mean IMT was 0.94±0.29 mm, 42.9% had IMT≥1 mm, and 42.9% had carotid plaques. All patients achieved a 12-weeks sustained virological response. IMT significantly decreased from baseline to follow-up (0.94±0.29 mm vs. 0.81±0.27, p<0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p<0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p=0.34). These results were confirmed in sub-groups of patients stratified for cardiovascular risk factors and liver disease severity.

Conclusion
HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis without or with additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term.

Lay of Summary
Hepatitis C Virus (HCV) eradication by direct antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis

The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors

HCV eradication by DAA also lead to improvement in glucose homeostasis and increase in cholesterol levels

Of Interest:
HCV eradication with DAAs improves carotid thickening

March 6, 2018

Hepatitis C eradication by direct-acting antivirals improved carotid atherosclerosis in patients with severe fibrosis regardless of the presence of additional metabolic…

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Evolving Recognition of Chronic Hepatitis C Infection as a Modifiable Risk Factor for cardiovascular disease (CVD)

Increasingly, data have amassed exploring whether HCV infection acts as an independent risk factor for cardiovascular diseases. However, the results are conflicting and have led to some ambiguity.

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Risk of Cardiovascular Disease (CVD) Due to Chronic Hepatitis C Infection: A Review

The current data support the assertion that CHC infection increases the risk of subclinical and likely clinical CVD, through a multifactorial cascade which may include direct and indirect immune and inflammatory effects, metabolic derangements and possibly direct cardiotropism exhibited by the HCV virus. There is an urgent need for translational research to delineate these proposed mechanisms for the apparent association between HCV and CVD. Additionally, more prospective cohort studies conducted in different patient populations are needed to confirm the findings of HCV infection and increased subclinical and clinical CVD. Furthermore, larger, well-designed therapeutic studies are critical to establish whether CHC truly increases CVD risk and to evaluate if HCV treatment can attenuate or even eliminate that increased CVD risk. The promise of large-scale HCV therapy ushered in by the highly efficacious and well tolerated DAAs has arrived, and therefore understanding the relationship between HCV and CVD and how this relationship is affected by HCV eradication with treatment has substantial public health implications.

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Hepatitis C Virus Infection and Cardiovascular Disease Risk
A strong association between HCV infection and immune-related disorders, such as cryoglobulinemia, and metabolic alterations, such as insulin resistance, has been demonstrated. More recent evidence suggests HCV infection is linked to an increased risk for cardiovascular disorders. Whether a relationship between HCV infection and cardiovascular disease exists may have important implications for HCV treatment.

Infectious Disease Advisor spoke with David E. Bernstein, MD, from the Hofstra-Northwell School of Medicine, and Vincent Lo Re, MD, MSc, from the Perelman School of Medicine at the University of Pennsylvania, regarding the link between HCV infection and cardiovascular disease.

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Chronic Hepatitis C Virus Infection, a New Cardiovascular Risk Factor?

Chronic Hepatitis C Virus Infection, a New Cardiovascular Risk Factor?
Fanny Domont; Patrice Cacoub

Liver International. 2016;36(5):621-627.

Introduction
In addition to common cardiovascular risk factors (i.e. diabetes, hypertension, obesity, smoking, dyslipidemia, etc.), there appears to be new risk factors associated with certain infectious agents. Several infectious agents, notably Chlamydia pneumoniae, Cytomegalovirus and Human Immunodeficiency Virus (HIV), have been associated with the occurrence of cardiovascular manifestations. Hepatitis C virus (HCV) infection has been associated to a very large number of extrahepatic manifestations in various tissues and organs.^[1…6] Some authors have hypothesized that infections could contribute to the inflammatory cascade and result in atherosclerosis.^[7] Associations have been found between HCV infection and cardiomyopathies;^[8,9] coronary^[10,11] or carotid^[12,13] atherosclerosis; and hypertension.^[14] A recent epidemiological study showed that blood donors who were seropositive for HCV had higher mortality rates for cardiovascular diseases than non-HCV-infected blood donors without comorbidities.^[15] The pathogenic mechanisms connecting HCV infection, chronic liver disease and atherogenesis are not completely understood. It has been hypothesized that HCV may promote atherogenesis and its complications through several direct and indirect biological mechanisms involving HCV colonization and replication within arterial walls, liver steatosis and fibrosis, enhanced and imbalanced secretion of inflammatory cytokines, oxidative stress, endotoxemia, perturbed cellular and humoral immunity, hyperhomocysteinemia, insulin resistance, type 2 diabetes…

As cardiovascular risk factors rates increase with age and patients with HCV chronic infection ageing, it seems of major interest to assess the impact of HCV infection on the occurrence of cardiovascular events. This review assesses the current published data on HCV infection and cardiovascular diseases.

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Abstract and Introduction

HCV Infection and Carotid Atherosclerosis

HCV Infection and Cerebrovascular Involvement

HCV Infection and Ischaemic Heart Disease

Cardiovascular Disease-related Mortality in HCV-infected Patients

Impact of HCV Treatment on Cardiovascular Outcomes

Conclusion

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

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Gastroenterology & HepatologyVolume 12, Issue 5, May 2016

Robert J. Wong, MD, MS, and Robert G. Gish, MD

Dr Wong is an assistant clinical professor of medicine at the University of California, San Francisco in San Francisco, California, and the director of research and education in the Division of Gastroenterology and Hepatology at Highland Hospital in Oakland, California. Dr Gish is a professor consultant in the Department of Medicine in the Division of Gastroenterology and Hepatology at Stanford University in Stanford, California; principal of Robert G. Gish Consultants, LLC, in San Diego, California; and senior medical director at St Joseph’s Hospital and Medical Center in Phoenix, Arizona.

 

Address correspondence to:Dr Robert J. WongHighland HospitalHighland Care Pavilion, 5th FloorEndoscopy Unit1411 East 31st StreetOakland, CA 94602Tel: 510-437-6531E-mail: Rowong@alamedahealthsystem.org

 

Abstract:

Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality.

 

Chronic hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality, with studies estimating a prevalence of 3 to 7 million persons affected in the United States.^1-4 There have been major recent advances in antiviral therapy for the management of chronic HCV infection, with the majority of current therapies achieving sustained virologic response (SVR) in over 95% of chronic HCV-infected patients. Despite these improvements, the long-term impact of these therapies on viral clearance and prevention of disease progression to cirrhosis and cirrhosis-related complications (eg, hepatocellular carcinoma [HCC], liver failure) will take time to determine. Currently, chronic HCV infection remains the leading cause of HCC and decompensated cirrhosis requiring liver transplantation in the United States (Figure).^5-7 While the impact of chronic HCV infection on liver-related complications and outcomes has been well studied, extrahepatic sequelae and complications of chronic HCV infection that result from the systemic effects of persistent viral infection are less well emphasized.⁸ The early recognition of systemic effects of chronic HCV infection provides an opportunity to advocate for early initiation of antiviral therapy in which SVR may be achieved, as well as to treat all patients, thereby preventing further, and potentially permanent, hepatic and extrahepatic consequences of chronic HCV infection. This review highlights the metabolic manifestations and complications associated with chronic HCV infection.

 

Insulin Resistance

The association between chronic HCV infection and metabolic manifestations primarily involves the potential diabetogenic effect of persistent viral infection. Several studies have investigated and demonstrated the association between chronic HCV infection and insulin resistance.^9-14 Using data from the third National Health and Nutrition Examination Survey (1988-1994), Mehta and colleagues performed a cross-sectional study of adults in the United States.¹⁴ Among a study cohort of 9841 individuals, there was an 8.4% prevalence of diabetes mellitus and a 2.1% prevalence of individuals who were anti-HCV antibody–positive. After adjusting for multiple factors (including age, body mass index, and socioeconomic status), the authors demonstrated that adults age 40 years or older with HCV infection were nearly 4 times more likely to have concurrent diabetes than those without HCV infection.¹⁴ However, as the authors acknowledged, while this study and previous cross-sectional studies have demonstrated the association of chronic HCV infection with insulin resistance, it remains unclear whether chronic HCV infection preceded the development of diabetes or whether HCV infection itself contributed to incident diabetes.

 

To better address this question, Mehta and colleagues performed a follow-up study using data from the Atherosclerosis Risk in Communities Study.¹⁵ In this prospective case-control study of men and women between the ages of 44 and 65 years, 1084 adults without diabetes at baseline were evaluated to determine the association between antecedent chronic HCV infection and the development of diabetes. After risk stratification adjustments based on factors such as age and body mass index, the authors demonstrated that among individuals at high risk for developing diabetes, the presence of chronic HCV infection was associated with a greater than 11-fold higher risk of developing diabetes over 9 years of follow-up (hazard ratio [HR], 11.58; 95% CI, 1.39-96.6).¹⁵ Further supporting the increased risk of chronic HCV infection on insulin resistance, additional studies have demonstrated that successful clearance of HCV infection with antiviral therapy can lead to improved insulin resistance.^16-24 In a study by Romero-Gomez and colleagues, 1059 patients with chronic HCV infection were evaluated to determine the impact of achieving SVR on insulin resistance as measured by the homeostasis model assessment of insulin resistance.²⁴ The authors demonstrated that achieving SVR was an independent predictor of impaired fasting glucose or diabetes.²⁴

 

However, another study by Giordanino and colleagues evaluated 202 chronic HCV-infected patients without pretreatment glucose abnormalities to determine whether antiviral treatment response affected the incidence of developing glucose abnormalities.²⁵ After a median follow-up period of 8 years, the authors found no significant difference between patients who achieved long-term virologic response and those who were nonresponders with respect to their incidence of developing glucose abnormalities.²⁵ Another study of 2842 chronic HCV-infected patients treated with interferon monotherapy or in combination with ribavirin evaluated the impact of antiviral treatment on incident diabetes.²³ The investigators demonstrated a two-thirds reduction in the risk of developing incident diabetes associated with interferon treatment. Despite this seemingly conflicting study, the majority of studies continue to demonstrate the association of chronic HCV infection and insulin resistance, further emphasizing the potential metabolic benefit of achieving and maintaining viral clearance.

 

Cardiovascular Diseases

The association between chronic HCV infection and cardiovascular diseases has been well studied, and while potential mechanisms have been hypothesized, the current literature demonstrates variations in the degree of this association.^26-34 Mechanistically, the potential increased risk of cardiovascular diseases among patients with chronic HCV infection may stem from insulin resistance, hepatic steatosis contributing to increased systemic inflammatory markers, and/or endothelial dysfunction.^31,35-39 In addition, insulin resistance and hepatic steatosis are tightly linked and may further contribute to the development of other metabolic syndrome components such as hypertension and dyslipidemia.^39-41 However, a recent systematic review that evaluated published studies from 1995 to 2013 included a total of 5 studies that met inclusion and exclusion criteria.²⁶ The authors found 1 cohort study of US veterans that demonstrated a significantly increased risk of cardiovascular disease among patients with chronic HCV infection (HR, 1.27; 95% CI, 1.22-1.31); however, additional studies that also used US Veterans Affairs data, although from an earlier period, demonstrated a protective effect of chronic HCV infection on the development of cardiovascular disease.^30,32 The remaining studies included in this systematic review did not demonstrate a clear clinical association between chronic HCV infection and cardiovascular disease, leading the authors to conclude that more prospective studies are needed to better evaluate this association before more definitive statements regarding chronic HCV infection and its impact on cardiovascular disease can be made.²⁶

 

The difficulties in evaluating cardiovascular associations of chronic HCV infection are multifold. Different studies utilize varying definitions, categorizations, and surrogates of cardiovascular disease (eg, carotid artery intima-media thickness, subclinical atherosclerosis, congestive heart failure) and span large periods of time, during which antiviral treatment regimens have significantly improved with better efficacy and fewer side effects.²⁶ Furthermore, while several hypotheses have been discussed, it is likely that chronic HCV infection and clearance of HCV infection with treatment impart a multitude of systemic metabolic changes that may affect cardiovascular disease risk in multidirectional ways. For example, as previously discussed, clearance of HCV infection improves insulin resistance, which may contribute to reducing cardiovascular disease risk.^16-24 However, studies have also postulated that chronic HCV infection itself may be associated with lower serum lipid levels, and patients who achieve SVR may develop a significant rebound rise in lipid levels in the blood that may contribute to increased cardiovascular disease risks.^39-41 Thus, the cumulative impact of persistent viral infection and subsequent viral clearance with antiviral therapy is a complex interplay of different mechanistic pathways, and while not all studies demonstrate clear and convincing evidence supporting the association between chronic HCV infection and cardiovascular diseases, it cannot be argued that viral clearance has an overall beneficial effect. Large prospective studies that include -multivariate -analysis and sensitivity testing would permit a more refined understanding of this issue.

 

Nonalcoholic Fatty Liver Disease

The interplay between chronic HCV infection and nonalcoholic fatty liver disease (NAFLD) is complex. As discussed above, chronic HCV infection can contribute to metabolic derangements (including insulin resistance and dyslipidemia) that subsequently increase the risk of developing concurrent NAFLD. In addition, several studies have reported that chronic HCV infection itself may contribute to the development of hepatic steatosis, the presence of which feeds into the cycle of metabolic diseases contributing to disease progression and complications among patients with chronic HCV infection.^31,35,37,42 The strong association between chronic HCV infection and de novo hepatic steatosis is seen most prominently in patients with HCV genotype 3 infection.^35,42-45 In a large meta-analysis, Leandro and colleagues evaluated 3068 patients with histologically confirmed chronic HCV infection from 10 centers in Italy, Switzerland, France, Australia, and the United States, among whom 50.9% had histologic evidence of hepatic steatosis.⁴³ Hepatic steatosis was more commonly found, and was more severe, in patients with HCV genotype 3 infection. Interestingly, subsequent studies demonstrated that hepatic steatosis was significantly improved, and in some cases completely resolved, after antiviral therapy in patients with HCV genotype 3 infection.^42,45-47 However, patients with non–genotype 3 infection did not demonstrate the same improvement in hepatic steatosis, even among those who achieved SVR with antiviral therapy.^45-47 While the exact etiologies underlying these observations are not clear, several hypotheses have been raised. Studies have described the potential de novo lipogenic role of chronic HCV infection through activation of in vitro sterol regulatory element-binding proteins 1c and 2, both of which are transcription factors involved in lipogenesis.⁴⁸ Further studies observed an inhibition of fatty acid oxidation by HCV infection, contributing to triglyceride accumulation.^49-51 Other hypotheses have implicated impaired assembly and secretion of very low–density lipoprotein.^52,53 Although the exact mechanisms of HCV-induced fatty liver disease are likely multifactorial and involve multiple systemic pathways, the implications of HCV-induced fatty liver are paramount to fully appreciating the systemic metabolic effects of chronic HCV infection. While clearance of chronic HCV infection with antiviral treatment will be important not only to address the hepatic and extrahepatic manifestations associated with persistent viral replication, increased awareness of associated metabolic derangements is also critical to prevent complications such as diabetes and cardiovascular diseases.

 

Impact of Metabolic Diseases on the Natural History of Chronic Hepatitis C Virus Infection

Understanding whether chronic HCV infection increases the risk of developing metabolic complications deserves greater attention. However, it is also important to understand the impact of underlying metabolic diseases on the natural history of chronic HCV infection. Recognizing the impact of obesity and insulin resistance on disease progression among patients with chronic HCV infection is especially important given the rising prevalence of obesity and metabolic syndrome observed in the United States.^54,55

 

In a recent systematic review evaluating the impact of metabolic diseases on disease progression among patients with chronic HCV infection, Dyal and colleagues looked at literature from 2001 to 2014 and identified 20 cohort studies that met inclusion criteria.⁵⁶ Focusing primarily on obesity, diabetes mellitus, and hepatic steatosis, the authors evaluated the association of these concurrent risk factors with the development of advanced fibrosis in patients with chronic HCV infection.⁵⁶ The authors demonstrated that the presence of concurrent diabetes among patients with chronic HCV infection was associated with a significantly higher risk of developing advanced fibrosis, with effect measures ranging from odds ratios (ORs) of 2.25 to 9.24. The presence of hepatic steatosis was also significantly associated with an increased risk of developing advanced fibrosis, with effect measures ranging from ORs of 1.80 to 14.3.⁵⁶ While the authors found 7 studies showing an increased risk of advanced fibrosis associated with obesity, 4 additional studies in the systematic review failed to show a significant association between the 2 conditions.

 

Disease progression to advanced fibrosis and cirrhosis is an important outcome among chronic HCV-infected patients. The development of HCC is another feared complication of chronic HCV infection. In a follow-up study, Dyal and colleagues performed a systematic review to evaluate the impact of obesity, diabetes mellitus, and hepatic steatosis on the risk of HCC among patients with chronic HCV infection.⁵⁷ A total of 9 studies from 2001 to 2014 met inclusion criteria and were included in the analysis. The authors demonstrated that concurrent diabetes was significantly associated with higher risk of HCC among chronic HCV-infected patients, with effect measures ranging from a HR of 1.73 to a risk ratio of 3.52.⁵⁷ The study also demonstrated an increased risk of HCC associated with obesity and hepatic steatosis, although the evidence supporting these associations were less robust, and larger studies with longer-term follow-up are needed to further explore these associations.

Both of the aforementioned systematic reviews attempted to better clarify the impact of concurrent metabolic diseases on disease progression and the -natural history of chronic HCV infection; however, several limitations must be acknowledged when interpreting these results. The ideal method for exploring the impact of metabolic diseases on disease progression would be to identify patients with antecedent metabolic diseases who subsequently acquired HCV infection. However, many of these studies were observational in nature and either utilized a case-control or retrospective cohort study design, which inherently limit the true ability to understand causation.^56,57 Furthermore, the study period of the included studies spanned a period during which significant advancements in HCV therapies were introduced. Thus, improved therapies may have been a potential confounder or effect modifier that affected disease progression in chronic HCV-infected patients. Despite the general agreement that increasing rates of metabolic diseases undoubtedly contribute to worse outcomes such as cardiovascular diseases, the current studies suffer from heterogeneity in definitions of obesity and insulin resistance, and often do not take into account more accurate measures of metabolic risk such as waist circumference as a measure of visceral adiposity, which may be especially important when evaluating for metabolic diseases in ethnically diverse populations.^6,26,54,58 Nevertheless, greater awareness of underlying metabolic diseases among patients with chronic HCV infection is paramount in that targeted treatment of these diseases can translate not only into improved management of liver disease but into overall health, including cardiovascular diseases.

 

In the current era of highly effective direct-acting antiviral therapies for chronic HCV infection, the ability to eradicate HCV will not only improve HCV-related liver disease, but will likely impact the incidence and prevalence of HCV-related metabolic diseases, given the association between the 2 conditions. However, greater awareness is also needed for metabolic diseases unrelated to chronic HCV infection, including NAFLD and NAFLD-related complications.

 

Conclusion

Despite the improvements in diagnosis, linkage to care, treatment, and eradication of chronic HCV infection, this condition will continue to pose a major disease burden for the near future. Chronic HCV infection contributes to significant hepatic disease and complications; however, it is important to understand and appreciate the systemic effects of chronic HCV infection as it relates to metabolic manifestations and complications. The associations between chronic HCV infection and metabolic disease and between chronic HCV infection and cardiovascular diseases are especially important in light of the increasing prevalence of obesity and metabolic syndrome and their costs to patients, the health care system, and society.

 

Dr Wong has received research grants from and is on the advisory board for Gilead. Dr Gish has received grants/research support from AbbVie, Benitec Biopharma, Gilead, and Merck. He has served as a consultant and/or advisor to AbbVie, Akshaya Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Genentech, Gilead, F Hoffmann-La Roche, Ionis Pharmaceuticals, Janssen, Merck, Nanogen Biopharmaceutical, and Presidio Pharmaceuticals, and is currently on the scientific or clinical advisory board of AbbVie, AstraZeneca, Genentech, Gilead, Janssen, Merck, and Nanogen Biopharmaceutical. Additionally, he is a member of the speakers bureau for AbbVie, Bristol-Myers Squibb, Gilead, and Merck and is a minor stock shareholder of Cocrystal Pharma.

 

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Assessing cardiovascular risk in hepatitis C: An unmet need.

World J Hepatol 2015 September 8; 7(19): 2214-2219

Assessing cardiovascular risk in hepatitis C: An unmet need.
Javier Ampuero and Manuel Romero-Gómez.

Abstract

Chronic hepatitis C virus (HCV) is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Additionally, HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis. HCV infection represents an initial step in the chronic inflammatory cascade, showing a direct role in altering glucose metabolism. After achieving sustained virological response, the incidence of insulin resistance and diabetes dramatically decrease. HCV core protein plays an essential role in promoting insulin resistance and oxidative stress. On the other hand, atherosclerosis is a common disease in which the artery wall thickens due to accumulation of fatty deposits. The main step in the formation of atherosclerotic plaques is the oxidation of low density lipoprotein particles, together with the increased production of proinflammatory markers [tumor necrosis factor-α, interleukin (IL)-6, IL-18 or C-reactive protein]. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after the eradication of the virus. Consequently, the number of studies evaluating this association is growing. Data derived from these studies have demonstrated the strong link between HCV infection and the atherogenic process, showing a higher risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality.

Keywords: Hepatitis C, Atherosclerosis, Coronary artery disease, Cardiovascular risk, Oxidative stress, Inflammation

Core tip: Chronic hepatitis C is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Furthermore, hepatitis C virus seems to be an independent risk factor for cardiovascular diseases due to its association with insulin resistance, diabetes and steatosis. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after achieving the eradication of the virus.

INTRODUCTION

Hepatitis C virus (HCV) infection is a global health problem that affects 170 million people worldwide. Hepatitis C is responsible for about 100000 deaths annually[¹]. Chronic hepatitis C is associated with significant morbidity and mortality, which result mainly from the progression towards cirrhosis and hepatocellular carcinoma[²]. Extrahepatic manifestations are well-known complications of HCV infection. Similar to non-alcoholic fatty liver disease[^3,4], HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis[⁵]. However, our knowledge about this topic requires further studies. In fact, previous studies that assessed the association between HCV infection and CVD risk have been sometimes inconclusive[⁶]. In this review, our aim is to elucidate the role of HCV infection on the cardiovascular-related affectation.

HCV AND INFLAMMATION

HCV infection represents an initial step in the chronic proinflammatory cascade. It produces proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) alpha, leading to increased inflammation and liver fibrosis. In addition, HCV-related steatosis promotes increased expression of inflammatory markers. These molecules are able to inhibit the insulin signaling, causing insulin resistance and steatosis progression[⁷].

Insulin resistance

Several studies have established a direct role of HCV in altering the glucose metabolism, leading to insulin resistance and diabetes, especially in genotype 3[⁸]. This relationship could explain, at least in part, the impact of metabolic abnormalities on sustained virological response (SVR), regardless of other variables such as viral or IL28B genotypes. In fact, achieving SVR with antiviral therapy results in a dramatically decrease of the development of insulin resistance and the appearance of diabetes mellitus over time[⁹].

HCV core protein plays a fundamental role in the induction of insulin resistance. The PI3K/Akt pathway, whose phosphorylation is impaired upon insulin stimulation, is crucial for the inhibition of gluconeogenesis in the liver. HCV core protein is able to degrade the insulin receptor substrates (IRS) 1 and 2, by increasing the expression of TNFα and suppressing cytokine signalling-3, leading to defective downstream PI3K and Akt phosphorylation[¹⁰]. In fact, when viral clearance is obtained, the expression of IRS-1 and IRS-2 is restored and HOMA-IR index decreases, which indicates the independent role of HCV in insulin resistance[¹¹]. Furthermore, there are other non-structural proteins, like NS5A and NS5B, which also promote insulin resistance, enhancing TNFα and IL-6. The ability of these molecules to disturb insulin signaling is well recognized. IL-1β is other interesting molecule. It is produced by hepatic macrophages, and is related to liver inflammation and, ultimately, to disease progression[¹²]. Finally, the role of toll-like receptors is growing in importance. HCV infection activates these molecules, which are closely associated with proinflammatory cytokines, contributing to the vicious circle[¹³].

Oxidative stress

Oxidative stress is the other main pathway of HCV-mediated inflammation, as insulin resistance promotes fatty acid accumulation in the liver, resulting in increased β-oxidation and reactive oxygen species (ROS)[¹⁴]. On the one hand, mitochondrial fat oxidation upregulates nuclear factor κB (NF-κB). This latter activates the transcription of several proinflammatory genes and the production of proinflammatory cytokines[¹⁵]. On the other hand, ROS play an important role in fibrogenesis by proliferating hepatic stellate cells and collagen synthesis and by inducing tumor growth factor-β[¹⁶]. An imbalance between oxidant agents and antioxidant defenses is the final result of all these processes, causing oxidative damage to hepatocyte and altering the reparation of DNA.

ATHEROSCLEROSIS

Lipid oxidation

Atherosclerosis is a common disease in which the artery wall thickens due to the accumulation of fatty deposits, called atheromatous plaques. Cholesterol-rich low density lipoprotein (LDL) is the main atherogenic lipoprotein. LDL infiltrates into the endothelium and adheres to extracellular matrix components, resulting in accumulation in the vascular intima[¹⁷]. Interestingly, LDL particle size seems to facilitate the passing between the endothelial cells because small dense LDL represents a major component of an atherogenic lipoprotein phenotype[¹⁸].

The main step in the formation of atherosclerotic plaques is the oxidation of LDL particles, being the risk higher in the wall than in the bloodstream[¹⁹]. Monocytes penetrate into endothelium and are able to transform into macrophages. This latter kind of cells is able to phagocyte oxidized LDL (oxLDL) particles triggering a cascade of immune responses and producing an atherosclerotic plaque[²⁰]. During oxidation, LDL converts to oxLDL involving some enzymes (such as lipoprotein-associated phospholipase A2) with several consequences: (1) oxLDL activates T cells and macrophages, stimulating the production of foam cells; (2) oxLDL induces the expression of endothelial adhesion molecules and the stimulation of several growth factors; and (3) oxLDL affects nitric oxide releasing and vascular smooth muscles, contributing to impair the vascular contraction[²¹]. As a result, oxLDL is able to thicken the intima and enhance atherosclerosis.

Inflammation

Many markers, such as proinflammatory cytokines (TNFα, IL-6 and IL-18), C-reactive protein, and adhesion molecules, are increased in plasma in situation of chronic inflammation. C-reactive protein may promote inflammation and atherogenesis through effects on monocytes and endothelial cells[²²]. Regarding to proinflammatory cytokines, TNFα activates NF-κB after interacting with the vascular endothelium[²³]. On the other hand, there are other cells with the capacity of enhancing proinflammatory cytokines such as activated macrophages, Th1 lymphocytes, and foam cells. Furthermore, several receptors (i.e., CD-36 and toll-like receptors) located on the membrane of macrophages leads to uncontrolled phagocytosis of oxLDL[²⁴].

Diagnostic tests

Noninvasive and inexpensive tests to anticipate and facilitate the prediction of cardiovascular risk are growing in importance. Atherosclerosis can be detected by several methods, depending on the organ or tissue affected. Carotid intima-media thickness and the presence of carotid plaques serve as marker of subclinical atherosclerosis and can be measured by ultrasound. They are especially considered to be independent stroke predictors[²⁵] and related to cardiovascular events[²⁶]. Other tests have been developed with the same proposal. Coronary artery calcification, judged by computed tomography, is a good predictor of coronary heart disease[²⁷]. Brachial artery flow-mediated vasodilation is a test of endothelial dysfunction that is associated with early stages of atherosclerosis[²⁸]. Pulse-wave velocity seems to be the gold standard of arterial stiffness and an early indicator for atherosclerosis[²⁹]. Other methods, such as left ventricular hypertrophy (by electrocardiogram and echocardiogram)[³⁰] or peripheral arterial disease (PAD) (by ankle-brachial pressure index)[³¹], are not extended in clinical practice due to costs or specialized personal requirement.

BIOLOGICAL MECHANISMS LINKING HCV AND ATHEROSCLEROSIS

A large body of evidence shows that infective agents contribute to promote chronic inflammation which could be associated, ultimately, with atherosclerosis[³²]. Therefore, HCV infection has been widely assesed and biological mechanisms have been reported.

On the one hand, HCV infection seems to be associated with a higher risk of cardiovascular disease by indirect mechanisms. Firstly, HCV infection is strongly associated with metabolic abnormalities, including diabetes mellitus and liver steatosis, as well as metabolic syndrome. All of these risk factors are well-known predictors of cardiovascular disease[³³]. Secondly, HCV infection interrelates with the host immune response. As it is commented above, it is able to stimulate the production of proinflammatory cytokines[³⁴]. Thirdly, HCV infection comprises other extra-hepatic manifestations. In particular, cryoglobulinemia has been associated with higher prevalence of arterial hypertension and CVD compared to those patients without this entity[³⁵].

On the other hand, the HCV seems to be directly related to atherosclerosis. HCV RNA sequences have been investigated by highly sensitive reverse transcriptase-polymerase chain reaction in plaque tissues of patients who underwent to carotid revascularization, demonstrating the presence of genomic and antigenomic HCV RNA strands. Consequently, additionally to the role of HCV on the development of chronic inflammation due to insulin resistance and steatosis, HCV RNA sequences seems to play a local effect on the endothelium[³⁶].

IMPACT OF HCV-RELATED ATHEROSCLEROSIS

Coronary heart disease

Several studies have investigated the association between atherosclerosis and HCV infection, with conflicting results. In a systematic review, the majority of studies were of poor quality although revealed a tendency towards a higher risk of coronary heart disease (CHD) among patients with HCV infection. However, the studies showed heterogeneity in terms of methods and conclusions[³⁷]. Other studies have showed similar conclusions. Forde et al[³⁸] did not observe any difference in the incidence rates of CHD between HCV-infected and uninfected patients, as well as in terms of coronary revascularization procedures. Main limitation of studies showing no HCV-related effect on CHD is the inclusion of some patients who could have had spontaneously cleared HCV infection.

There are no many studies differentiating HCV antibody and RNA positivity, regarding to CHD events. In a very large study, authors found an increased risk of CHD in patients with HCV seropositivity, being an independent risk factor for CHD events. HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%). Additionally, patients with detectable HCV-RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive (5.9% vs 4.7%). Therefore, there was an increased incidence of CHD events in patients with HCV seropositivity and the incidence was much higher in patients with detectable HCV-RNA compared with patients with remote infection who were only antibody positive[³⁹]. 

Electrocardiogram abnormalities are strongly associated with cardiovascular disease. HCV infection has been associated with increased risk to ischemic electrocardiogram when compared with non-HCV subjects, revealing a possible relationship between HCV seropositivity and ischemic electrocardiogram[⁴⁰]. Other study, performed by Butt et al[⁴¹], demonstrated that HCV-infected subjects had lower lipid levels and a lower prevalence of hypertension than those non-infected. Despite a favorable risk profile, HCV infection was associated with a higher risk of CHD after adjustment for traditional risk factors. In diabetic population, similar results have been obtained. Authors included three cohorts: patients who received pegylated interferon plus ribavirin (treated cohort), HCV-matched patients (untreated cohort) and diabetic patients without HCV infection (uninfected cohort). Main conclusion was that the incidences of ischemic stroke and CHD were all lower in HCV-infected patients treated with peginterferon and ribavirin, compared with infected individuals without antiviral treatment and diabetic patients without HCV infection. It is interesting to note that the risk of ischemic stroke and CHD were not attenuated in treated patients with PAD. This finding suggests that the pathogenic role of HCV can be limited at the early phase of atherosclerosis and that antiviral treatment could not reduce cardiovascular morbidity at an advanced stage[⁴²].

Carotid atherosclerosis

A large body of evidence has assessed the association between HCV infection and carotid atherosclerosis. First study was carried out by Ishizaka et al[⁴³], in which they evaluated the relationship between positivity for HCV and carotid-artery plaque and carotid intima-media thickening. After adjustment for cofounding risk factors, HCV seropositivity was found to be associated with an increased risk of carotid-artery plaque (OR = 1.92) and carotid intima-media thickening (OR = 2.85). A definite study was performed by Petta et al[⁴⁴] One-hundred-and-seventy-four consecutive biopsy-proven HCV genotype 1 patients were evaluated by anthropometric and metabolic measurements and other 174 patients used as controls. Authors found that patients with HCV genotype 1 had a higher prevalence of carotid atherosclerosis compared with a control population (carotid plaques: 42% vs 23%; IMT: 1.04 ± 0.21 vs 0.90 ± 0.16). However, no direct association was found between viral load and atherosclerosis. The novel finding was the independent association of the presence of carotid plaques with severe hepatic fibrosis, after adjustment for age. Authors concluded that severe fibrosis and the associated cascade of proinflammatory and profibrogenic pathways generated in the liver might promote carotid atherosclerosis at a much younger age[⁴⁴].

Peripheral artery disease

PAD is an under-diagnosed and under-treated disease. Some data suggest that HCV influences on the presence of PAD. In a retrospective cohort study, 7641 HCV-infected patients and 30564 matched controls were included. An excess risk of PAD development in HCV-infected patients was observed compared with non-HCV patients. The increased incidence of PAD in HCV-infected patients appeared since within first year. This study showed that gender had no effect on the risk of PAD development, but did aging. However, this study showed lack of evaluation of smoking, obesity or exercise[⁴⁵].

Cardiovascular mortality

Given that the HCV infection seems to be related to several atherogenic processes, many authors have evaluated its role on CVD-associated mortality similar to other viral infections[⁴⁶]. Guiltinan et al[⁴⁷] performed a retrospective study including HCV antibody-positive and HCV antibody-negative patients matched for age and gender. HCV infection was associated with a significant increase in overall mortality including significantly increased mortality from liver and cardiovascular causes. In the REVEAL cohort, including 1095 anti-HCV-positive and 760 detectable HCV RNA, was observed that those anti-HCV-positive patients showed a higher risk of CVD-related mortality compared with seronegative subjects[⁴⁸].

CONCLUSION

New direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection[⁴⁹]. Infected patients are going to live longer due to the eradication of the virus, so other HCV-related comorbidities have emerged. Specifically, cardiovascular disease is a major concern in this scenario. All the data provided in this review suggest a strong relationship between HCV infection and the atherogenic process, showing a high risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality. However, little is known about the precise mechanisms by which HCV enhances atherogenic processes. Therefore, we should be cautious when patients achieve SVR because maybe the cardiovascular risk remains after the virus eradication.

Footnotes

P- Reviewer: Balaban YH, Chiang TA, Desai ND S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

Conflict-of-interest statement: None.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: January 30, 2015

First decision: March 20, 2015

Article in press: August 31, 2015

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