Evolving Recognition of Chronic Hepatitis C Infection as a Modifiable Risk Factor for CVD

Chronic hepatitis C (CHC) infection has a worldwide prevalence of 2.5% and is the leading cause of death from liver cirrhosis globally. Morbidity and mortality are not, however, restricted to the effects of chronic infection on the liver. Many studies have identified extrahepatic manifestation of chronic hepatitis C virus (HCV) infection, including associations with lymphoproliferative disorders, diabetes mellitus, and renal disease. 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.

Evidence for Subclinical Cardiovascular Diseases in Chronic Hepatitis C Infection

A recent review by Babiker et al¹ published in the Journal of Clinical and Translational Hepatology explores the evidence for an association between CHC infection and both subclinical and clinical cardiovascular diseases.

Twenty-one studies spanning 15 years identified subclinical cardiovascular disease (CVD), using various surrogate measures of vascular stiffness or atherosclerosis such as carotid intima media thickness or the presence of carotid plaques. Two meta-analyses^2,3 combining these data both found a positive correlation with subclinical CVD in CHC-infected patients. Aslam et al found significantly greater prevalence of carotid plaques (48.2% vs 20.7%; P =.05) in HCV-infected compared with uninfected individuals.³

Asked about whether this evidence should lead to a more vigorous approach to screening for CVD in HCV-infected patients, Dr Adeel Butt, professor of Medicine & Healthcare and Policy Research at Weill Cornell Medical College in New York City, told Infectious Disease Advisor: “I agree with more aggressive screening and more aggressive treatment of risk factors in HCV-infected [patients]. There are some data to suggest that treating HCV may reduce the risk of CVD events. However, both these findings need further study.” And should a cardiologist be involved? “A well-trained internist or family physician can manage most of these persons for CVD risk factors.”

Evidence for Clinical Cardiovascular Diseases in Chronic Hepatitis C Infection

Translation from these findings to various clinical cardiovascular disease outcomes has been extensively investigated. The review identified 8 studies with composite outcomes including 2 or more clinical events (coronary artery disease, myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, peripheral artery disease, and congestive heart failure) in the literature.

Across a variety of study designs (retrospective cohort, prospective cohort, cross-sectional), all but 2 demonstrated a positive association. A meta-analysis by Petta et al² aggregating data from 22 studies and a total of 468,000 patients found CHC infection associated with both cardiovascular (odds ratio [OR], 1.20; 95% CI, 1.03-1.40; P =.02) and cerebrovascular events (OR, 1.35; 95% CI, 1.00-1.82; P =.05).

“There is a growing body of literature that suggests that there may be an association between CHC and CVD. Interestingly, the association seems to be stronger between CHC and cerebrovascular disease than between CHC and acute myocardial infarction,”¹ Shashwatee Bagchi, MD, assistant professor at the Institute of Human Virology at the University of Maryland School of Medicine told Infectious Disease Advisor. Although not completely understood, the reason for the association with stroke may relate to the propensity of HCV to affect carotid vessels, leading to cerebrovascular disease. HCV RNA sequences have also been identified within the plaques of HCV-infected individuals, suggesting active local infection.⁴

All but 2 of the studies identified in the review assessing stroke in patients with CHC found a positive correlation. Younossi et al,⁵ using the National Health and Nutrition Examination Survey data set, did not find an association, but this may have been confounded by significant differences between the control group or HCV-uninfected group (n=19,568) and the CHC group (n=173) in terms of age, sex, smoking, insulin resistance, and hypertension.

In contrast, a large, population-based cohort study by Liao et al⁶ identified 4094 HCV-infected patients and compared them with 16,376 individuals in control group. After 97,752 person-years of follow-up, 1981 new strokes were found, giving an adjusted hazard ratio of 1.27 (95% CI, 1.14-1.41) for HCV infection.

“There are a fair amount of data now that indicate that HCV is an independent risk factor for CVD. Of course, the association is complex, since HCV-infected persons have a higher prevalence of some risk factors and lower prevalence of other CVD risk factors,” explained Dr Butt. “HCV-infected individuals have lower LDL lipid levels and a lower prevalence of hypertension than comparable HCV-uninfected persons. However, this does not protect them from CVD events.”⁷

“I do not believe current risk assessment tools recommended in the general population are adequate,” added Dr Bagchi.

Further evidence documents a greater incidence of cardiomyopathies^5,8 in CHC infection, and a single study has found higher frequency of peripheral arterial diseases.⁹ The review also discussed the mixed results for cardiovascular mortality. Although there are 2 large retrospective cohort studies that found no association, the preponderance of data demonstrate increased risk for CV death in CHC infection. A large retrospective cohort study based on the Taiwanese National Death Certification Registry by Lee et al¹⁰ with the longest follow-up time (16.2 years) identified an increase in both all-cause and circulatory disease mortality in those with HCV infection.

Effect of Treatment on Cardiovascular Outcomes

The significance of CHC as a putative CVD risk factor is magnified by the advent of direct-acting antivirals and the improved potential to achieve a sustained virologic response. “Limited data suggest that CVD risk may be lowered with HCV treatment, so this should be considered,” explains Dr Butt.

Several studies have demonstrated a protective effect of SVR, with cohorts of patients from France and Scotland showing reduction in composite CVD endpoints. Using data from the Taiwanese National Health Insurance Database, a prospective cohort study of 12,384 patients treatment with pegylated interferon and ribavirin significantly lowered the risk for both ischemic stroke (HR, 0.62; 95% CI, 0.46-0.83; P =.001) and acute coronary syndrome (HR, 0.77; 95% CI, 0.62-0.97; P =.026) compared with untreated matched controls.

Asked about whether consideration of CVD risk should affect timing of HCV treatment, Professor Patrice Cacoub, from Pierre and Marie Curie University and head of the Department of Internal Medicine and Clinical Immunology, La Pitié-Salpêtrière Hospital, Paris, said “To my view, yes, because CVD risk is 1 of the hidden faces of HCV chronic infection. Then my message is treat all HCV-infected patients early to control not only the liver consequences but also extrahepatic manifestations including CVD risk.”

According to Dr Bagchi, “First, we need to more firmly establish the apparent association between CHC and CVD. If this association was felt to be more conclusive, then there could be a powerful argument made to initiate HCV treatment based on considerations beyond staging of liver disease alone. I would go further and suggest that if CHC was conclusively shown to be an independent risk factor for the development of CVD, reducing the risk of developing cardiac events could be an indication for starting HCV therapy earlier especially in patients with other CVD risk factors. As such, HCV treatment could be used as one of the CVD prevention strategies among CHC-infected patients.”

References

1. Babiker A, Jeudy J, Kligerman S, Khambaty M, Shah A, Bagchi S. Risk of cardiovascular disease due to chronic hepatitis C infection: a review. J Clin Transl Hepatol. 2017;5:343-362.
2. Petta S, Maida M, Macaluso FS, Barbara M, Licata A, Craxì A. Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies. Gastroenterology. 2016;150:145-155.e4.
3. Aslam F, Alam M, Lakkis NM. Hepatitis C and carotid atherosclerosis: a retrospective analysis. Atherosclerosis. 2010;209:340-343.
4. Boddi M, Abbate R, Chellini B, et al. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol. 2010;47:72-75.
5. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37:647-652.
6. Liao CC, Su TC, Sung FC, Chou WH, Chen TL. Does hepatitis C virus infection increase risk for stroke? A population-based cohort study. PLoS One. 2012;7:e31527.
7. 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;49:225-232.
8. Tsui JI, Whooley MA, Monto A, Seal K, Tien PC, Shlipak M. Association of hepatitis C virus seropositivity with inflammatory markers and heart failure in persons with coronary heart disease: data from the Heart and Soul study. J Card Fail. 2009;15:451-456.
9. 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.
10. Lee MH, Yang HI, Lu SN, et al; R.E.V.E.A.L.-HCV Study Group. 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.