HCV Infection May Be a Modifiable Cardiovascular Risk Factor

For the estimated 71 million people worldwide who live with chronic hepatitis C virus (HCV) infection, the risk for cirrhosis and liver cancer is well established. These individuals often experience extrahepatic complications, such as endocrine, hematologic, renal, and neurologic impairments.^1,2 In addition, a growing body of research points to HCV infection as a risk factor for cardiovascular events, such as coronary artery disease (CAD) and heart failure.³

Most recently, a study published in March 2019 in Gastroenterology found that HCV treatment was associated with a significant reduction in the risk for cardiovascular events among 242,680 veterans with chronic HCV infection who were treated with direct-acting antiviral (DAA) therapy (n=12,667) or a pegylated interferon and ribavirin regimen (n=4436) compared with a no-treatment control group.⁴ Participants were without a history of cardiovascular events at baseline.

The results were as follows:

• Rates of incident cardiovascular disease events were 7.2% and 13.8% in the treatment and control groups, respectively.

• Compared with controls, there was a significantly lower risk for cardiovascular disease events among patients treated with a DAA regimen (hazard ratio [HR], 0.57; 95% CI, 0.51-0.65) or pegylated interferon and ribavirin (HR, 0.78; 95% CI, 0.71-0.85).

• Incidence rates for cardiovascular disease events were 30.4 per 1000 patient-years (95% CI, 29.2-31.7) in the control group; 23.5 per 1000 patient-years (95% CI, 21.8-25.3) in the pegylated interferon/ribavirin group; and 16.3 per 1000 patient-years (95% CI, 14.7–18.0) in the DAA group.

• A sustained virologic response was linked with a lower risk for incident cardiovascular disease events (HR, 0.87; 95% CI, 0.77-0.98).

In a related editorial published in the same issue of Gastroenterology, Patrice Cacoub, MD, professor of internal medicine at the Pierre and Marie Curie University and head of the department of internal medicine at La Pitié-Salpêtrière Hospital in Paris, states that these latest results round out the evidence implicating HCV as a risk factor for cardiovascular events.³

He notes that risk factors are generally “defined by 4 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 important, outcome studies showing risk reduction when the putative factor is corrected.”

The March 2019 study fulfills the fourth type of evidence needed to establish HCV as a cardiovascular risk factor. A range of research findings, including those summarized below, provide support for the other categories of evidence.

Clinical studies show increased HCV prevalence in patients in whom a major cardiovascular event occurs:

• In a meta-analysis with a combined sample of 68,365 patients, an association was found between HCV infection and cardiovascular-related death (odds ratio, 1.65; 95% CI, 1.07-2.56).⁵
• Individuals with HCV infection demonstrated a 2-fold higher risk for carotid plaques and carotid intima-media thickness vs those without HCV infection.³
• A higher incidence of stroke has been noted in HCV-infected vs HCV-uninfected individuals, and a higher HCV prevalence has been observed in patients with stroke compared with matched controls.³
• A higher prevalence of HCV infection was found in patients with vs without CAD in a cohort of 150,000 patients (82,082 were HCV positive).⁶
• Prospective cohort studies have identified an increased risk for cardiac dysfunction and heart failure in patients with vs without HCV seropositivity.³

Studies show potential mechanisms of action in HCV-cardiovascular risk link:

• HCV-related insulin resistance can lead to vessel damage and unstable plaques through processes including hyperglycemia, endothelial dysfunction, and systemic inflammation.³
• Higher levels of inflammatory markers have been observed in nonobese, nondiabetic, treatment-naive people infected with HCV compared with controls, and in those who have had a stroke with vs without HCV infection.³
• Compared with controls, people infected with HCV have demonstrated elevated biomarkers predictive of CAD, including “high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin.”³
• Elevated serum levels of HCV RNA have been linked with a greater incidence of cardiovascular events and higher risk for cerebrovascular death.³
• Other results reveal that “positive-strand HCV RNA was detected in carotid plaque tissues from HCV-positive patients and not in carotid plaque from HCV-negative patients … [and] HCV RNA has been found in the myocardial tissue of patients with hypertrophic cardiomyopathy and those with dilated cardiomyopathy,” Dr Cacoub wrote.³

Outcome studies show reduced cardiovascular risk with eradication of HCV:

• A cohort study of patients treated with pegylated interferon/ribavirin (n=12,384) showed reductions in the risk for CAD (HR, 0.77; 95% CI, 0.62-0.97; P =.026) and ischemic stroke (HR, 0.62; 95% CI, 0.46-0.83; P =.001) compared with 24,768 untreated controls. “These favourable associations were invalid in incompletely treated patients with duration <16 weeks,” wrote the researchers.⁷
• Lower rates of CAD and stroke have been noted in patients treated with pegylated interferon vs untreated patients, and successful treatment with pegylated interferon/ribavirin was associated with an absolute risk reduction for cardiovascular disease in another cohort.³
• In patients with HCV-related compensated cirrhosis, those who achieved sustained virologic response to pegylated interferon/ribavirin or interferon-free antivirals showed a lower risk for major cardiovascular events compared with those who did not respond to treatment.³

“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 cardiovascular risk factor, reinforce some practical messages,” Dr Cacoub concluded.³ All HCV-infected patients should have access to DAAs and should undergo a complete cardiovascular check-up, and liver specialists and other physicians should be aware the potential for DAAs to improve cardiovascular outcomes in addition to liver outcomes.

References

1. World Health Organization. Hepatitis C. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c. July 18, 2018. Accessed May 22, 2019.

2. Badawi A, Di Giuseppe G, Arora P. Cardiovascular disease risk in patients with hepatitis C infection: results from two general population health surveys in Canada and the United States (2007-2017). PLoS One. 2018;13(12):e0208839.

3. Cacoub P. Hepatitis C virus infection, a new modifiable cardiovascular risk factor. Gastroenterology. 2019;156(4):862-864.

4. Butt AA, Yan P, Shuaib A, Abou-Samra AB, Shaikh OS, Freiberg MS. Direct-acting antiviral therapy for HCV infection is associated with a reduced risk of cardiovascular disease events.Gastroenterology. 2019;156(4):987-996.

5. 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(1):145-155.e4.

6. 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(2):225-232.

7. Hsu YC, Ho HJ, Huang YT, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut. 2015;64:495–503.