Stroke Risk Increased After Hepatitis C Infection

Hepatitis C virus (HCV) infection is a common cause of chronic liver disease worldwide and is associated with greater mortality compared with that in the general population or even mortality associated with HIV infection.^1,2 Although liver disease and liver cirrhosis account for the bulk of HCV-related disease burden and deaths, it is becoming increasingly evident that HCV infection is a systemic disease with extrahepatic manifestations.

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.¹

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.

HCV and Cardiovascular Risk: The Evidence

For evidence that supports the association between HCV and cardiovascular disorders, Dr Lo Re pointed to a meta-analysis of 22 studies that was published in Gastroenterology in 2016.² This meta-analysis found that compared with individuals without HCV, patients with HCV had a higher risk for carotid atherosclerosis (n=9083; odds ratio [OR], 2.27; P <.001), cerebrocardiovascular events such as ischemic stroke and myocardial infarction (n=390,602; OR, 1.30; P =.002), and death resulting from cardiovascular disease (n=68,365; OR, 1.65; P =.02).²

Although the pooled analyses suggested a link between HCV infection and cardiovascular disease, some of the individual studies included in the analyses did not demonstrate an association. Of 3 cohort studies evaluated for the effect of HCV infection on cardiovascular mortality, 1 study found a neutral effect. For HCV and carotid atherosclerosis, 8 of 9 studies showed that HCV infection increased the risk for carotid plaques, but this was a significant finding in only 5 studies. Finally, 3 of 8 studies actually reported lower rates of cerebrocardiovascular events among HCV-infected patients than among uninfected individuals.²

Dr Lo Re suggested that differences in study methodology may explain the contradictions in the data regarding HCV and cardiovascular risk. “Differences in the nature of the comparator groups among the different studies, particularly with regard to the stage of hepatic fibrosis…and presence of nonalcoholic fatty liver disease, as well as differences in potential confounding variables controlled for in the different analyses, could account for the conflicting results across the studies,” he said.

How exactly HCV might be related to increased cardiovascular risk is unclear, but several possible mechanisms have been proposed. According to Dr Lo Re, “Several studies have identified a higher prevalence of metabolic comorbidities related to HCV infection, particularly diabetes mellitus. Other studies have suggested that HCV-associated inflammation might promote atherosclerosis.”

“A direct viral activity has also been reported and could potentially explain these associations,” he added. Studies have reported a positive association between higher HCV-RNA viral loads and cardiovascular disorders such as carotid atherosclerosis and myocardial injury, and another study identified HCV-RNA in carotid plaques of individuals with positive serology for anti-HCV, but not in seronegative individuals.^3-5

HCV and Cardiovascular Risk: Treatment

Although prevalence studies overall demonstrate a link between HCV and cardiovascular disease, findings from long-term treatment studies also support this relationship, according to Dr Bernstein. “Treatment studies show that if we get rid of HCV, survival from cardiovascular conditions improves,” he said.

Several studies have shown that among patients with a history of HCV infection, those with undetectable HCV-RNA or sustained viral eradication have a lower risk for cardiovascular disease than those with detectable HCV-RNA. In a study of 200 HCV-infected patients treated with pegylated interferon, myocardial injury improved with viral eradication, worsened again with relapse, and remained unchanged with nonresponse to treatment.⁴

Another study in 19,636 patients found that patients with HCV with detectable HCV-RNA had higher cardiovascular mortality than uninfected individuals. This difference was not observed in patients with HCV without detectable HCV-RNA.⁶ Rates of fatal cerebrovascular events increased with viral load in a study of 23,665 patients with HCV, with patients with undetectable viral load at lowest risk.⁷

Cohort studies in patients with a history of HCV infection also showed that those treated with pegylated interferon had a significantly lower risk for stroke and acute coronary syndrome than those not treated with pegylated interferon.^8,9

According to Dr Bernstein, there is no evidence to support the use of 1 type of antiviral therapy over another for lowering cardiovascular risk related to HCV infection. “The studies showed improvement in all-cause mortality in patients who had HCV and were treated and cured, regardless of what the treatment was. You only see the improvement with cure, and we believe it doesn’t matter how you get to cure.”

“All of the studies that tell us that curing HCV leads to improved survival and decreased death from cardiovascular disease are from the interferon era,” he said. “We just don’t have the data yet for the new direct antiviral agents…because we’ve only been using those since 2014. We haven’t had enough time to follow those folks who are being treated with the new [agents].”

References

1. Petta S. Hepatitis C virus and cardiovascular: A review. J Adv Res. 2017;8(2):161-168.
2. 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.
3. Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221(2):496-502.
4. Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol. 2013;58(1):11-15.
5. Boddi M, Abbate R, Chellini B, et al. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol. 2010;47(1):72-75.
6. 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(4):469-477.
7. Lee MH, Yang HI, Wang CH, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. Stroke. 2010;41(12):2894-2900.
8. Hsu CS, Kao JH, Chao YC, et al. Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan. Aliment Pharmacol Ther. 2013;38(4):415-423.
9. Hsu YC, Lin JT, Ho HJ, et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology. 2014;59(4):1293-1302. 

This article originally appeared on Infectious Disease Advisor