Antiviral Treatment for Hepatitis C Is Associated With a Reduced Risk of Atherosclerotic Cardiovascular Outcomes

A Systematic Review and Meta-analysis

Xin Su; Xin Zhao; Jia-Long Deng; Song-Nan Li; Xin Du; Jian-Zeng Dong; Chang-Sheng Ma

Disclosures

J Viral Hepat. 2021;28(4):664-671. 

In This Article

Discussion

To our knowledge, this is the first meta-analysis to explore the association between antiviral therapy and the risk of CVD events in patients with HCV infection. This meta-analysis demonstrated that antiviral therapy for HCV was associated with a reduced risk of CVD events. Besides, the risk of CVD events was lower in treated subjects with SVR compared with those without SVR.

As a systemic infection disease, chronic HCV infection can cause many extrahepatic organ manifestations, such as endocrine gland (diabetes mellitus), kidney (membranous glomerulonephritis), haematologic system (lymphoma) and skin (porphyria cutanea tarda).[3,33,34] Recently, emerging data show that HCV infection is associated with a greater risk of CAD, stroke and peripheral arterial disease.[4,6,7] It seems that chronic HCV infection may be a novel CVD risk factor. The pathogenesis of atherosclerosis caused by HCV infection may be multifactorial, and the pathogenesis may include endothelial dysfunction, lipid disturbances, metabolic disturbances, autoimmunity response, oxidative stress, cytokine activation and vascular injury.[35–37] HCV infection has been suggested to increase the risk of diabetes mellitus, which is a risk factor for CVD.[3] Besides, multiple studies have shown elevated levels of inflammatory biomarkers in patients with HCV infection.[38–40] In addition, it was found that HCV RNA was present within carotid plaques, and the existence of virus inside the plaque might promote the occurrence of atherosclerotic plaques.[41,42]

Recently, it has been found that antiviral treatment for HCV could reduce morbidity and overall mortality, which cannot be explained only by liver effects. Emerging data have suggested that there might be a relationship between antiviral therapy and long-term risk of CVD events.

A retrospective study showed that HCV infection could lead to endothelial dysfunction and changes in inflammatory markers, while antiviral therapy for HCV based on IFN treatment could reduce markers of endothelial dysfunction and inflammatory.[14] Schmidt et al[43] found that anti-HCV therapy based on DAA treatment could improve endothelial function and reduce soluble adhesion molecules. These studies indicated that antiviral therapy might reverse the progress of endothelial dysfunction in patients with HCV infection. Besides, a prospective cohort study involving 182 patients with HCV infection suggested that antiviral treatment by DAA could improve carotid atherosclerosis with reduced intima-media thickness and carotid thickening.[13] In addition, studies have demonstrated that anti-HCV therapy has a significant protective role in diabetes mellitus, which improves glycated haemoglobin and fasting glucose and decreases the demand for antidiabetic drugs.[44] DAA treatment was also beneficial to control blood sugar in liver transplant recipients with recurrent HCV.[45] Furthermore, Salomone et al[46] confirmed that HCV-infected patients were in oxidative stress, and antiviral therapy ameliorated the state of oxidative stress, which might be involved in the improvement of atherosclerosis. Therefore, it seems plausible that antiviral therapy for HCV may reduce the risk of CVD.

Although some studies have confirmed the association between antiviral therapy and the reduced risk of CVD events in patients with HCV infection, there is no consensus on this relationship. In a prospective cohort study of patients with HCV infection, antiviral therapy based on IFN was associated with a reduced risk of acute coronary syndrome, ischaemic stroke and end-stage renal disease, and this therapy was not related to the risk of autoimmune disease.[22] Hsu et al[19] also found that antiviral therapy for HCV was associated with improvement of cardiovascular and renal outcomes in diabetic patients, with reduced incidences of acute coronary syndrome, ischaemic stroke and end-stage renal disease. Meanwhile, a cohort study involving 1,395 HCV-infected patients with diabetes mellitus demonstrated that successful HCV treatment was related to a reduced risk of end-stage renal disease, acute coronary syndrome and ischaemic stroke.[31] Besides, Lin et al[28] showed that antiviral therapy for HCV might protect against vascular events (acute coronary syndrome, ischaemic stroke and peripheral arterial disease). Furthermore, in a prospective multicenter study involving 2,204 HCV-infected patients, HCV eradication was independently related to a reduced risk of CVD events (ischaemic heart disease and ischaemic stroke).[32]

On the contrary, several studies have not confirmed the relationship. Leone et al[24] reported that anti-HCV treatment in human immunodeficiency virus (HIV)/HCV-coinfected patients was associated with a lower incidence of diabetes but not related to CVD. Lin et al found that antiviral therapy in HCV-infected patients with chronic kidney disease had a significantly lower risk of haemorrhagic stroke but not of ischaemic stroke and acute myocardial infarction.[20] A retrospective cohort study showed that the risk of ischaemic stroke and acute myocardial infarction was comparable between the DAA-treated group and non-DAA group in patients with HCV infection.[29]

Besides, studies demonstrated that SVR in treated patients with HCV infection had a lower risk of CVD events. In a prospective study of HCV-infected patients with antiviral treatment, patients with SVR had a lower risk of overall mortality and CVD events than patients without SVR.[25] Cacoub et al[26] reported that SVR was associated with a reduced risk of cardiovascular events in HCV-infected patients receiving anti-HCV treatment. Moreover, Innes et al[23] also found that SVR was related to a decreased risk of a series of liver and non-liver (CVD and respiratory disorders) events.

In HCV-infected population, HCV eradication was related to a reduced risk of CVD events, but patients were not separated by treatment regimen in most studies. Recently, studies confirmed that DAAs were safer and more efficacious than IFN-based therapy.[47,48] In a large study of veterans infected with HCV, patients treated with DAA had a lower risk of CVD events than those treated with IFN (HR 0.80, 95% CI 0.67–0.96).[30] Therefore, it seems that DAA may bring greater cardiovascular benefits than IFN in patients with HCV infection. Of course, more data are needed to confirm this result.

However, moderate heterogeneity among studies was found in the analysis of CAD. The observed heterogeneity could be attributable to the different study designs, demographic characteristic inconsistency, countries, different antiviral regimens, statistical adjustments for potential confounders and how the studies were conducted. Although we were not always able to ascertain the source of heterogeneity, we have performed meta-regression analyses to explore the potential source of heterogeneity. As mentioned earlier, the presence of heterogeneity calls for caution in interpreting the current meta-analysis findings.

There are potential limitations in the present meta-analysis. Firstly, studies included in this meta-analysis were all observational studies, and the results could not determine the causal relationship. Secondly, confounding variables for the adjusted estimates in this meta-analysis were different, which might lead to bias in the analysis. Thirdly, only one study has reported the effect of different antiviral regimens on the risk of CVD events, and there were insufficient data to perform a meta-analysis to confirm whether DAA treatment had greater cardiovascular benefits than IFN treatment for HCV-infected patients.

In conclusion, this meta-analysis demonstrated that antiviral therapy for HCV was associated with a reduced risk of CVD events. In addition, the risk of CVD events was lower in subjects with SVR compared with those without SVR. With the development of antiviral therapy for HCV, we expect greater benefits of antiviral therapy, including reduced risk of CVD events.

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