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What is known about HCV comorbidities and viral clearance?
HCV infection has an estimated global prevalence of 1.0%, corresponding to roughly 71.1 million of infected individuals in 2015, with major geographical heterogeneity.1 Due to the large burden of infected individuals in the general population, the likelihood of co-occurrence of chronic HCV infection and common comorbidities is substantial regardless of causal linkages. Population-based studies show a higher overall mortality, both for liver-related and unrelated causes in HCV infected subjects compared with those uninfected, and cross-sectional and cohort studies identify HCV as an independent risk factor for extrahepatic manifestations.2 These issues are summarised in two meta-analyses reporting that HCV-infected patients are at higher risk of mixed cryoglobulinaemia, lymphoma, lichen planus, Sjögren’s syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, depression, chronic kidney or end-stage renal disease, type 2 diabetes and cardiovascular disorders/mortality.3 4 While the link between HCV and some of these comorbidities—mixed cryoglobulinaemia, lymphoma and glomerulonephritis—is well established and driven by recognised pathophysiological mechanisms, the nature of the association between the infection and other common extrahepatic comorbidities is less clear. Clinical and experimental evidences suggest an intrinsic link between HCV infection and insulin-resistance/diabetes driven by the ability of the virus to interfere with insulin signalling, even if the strength of this association is not always confirmed. Emerging data also support a link between HCV infection and cardiovascular alterations. However, relative to this topic, contrasting data exist and the basis of this association stems on associative data, theoretical speculations and inconclusive experimental evidence.5
This mass of data and the recent availability of highly effective antiviral regimens, able to clear HCV of all genotypes in most patients at any stage of infection and disease and safe to use in old patients with comorbidities and comedications, open a new major perspective: will HCV clearance improve extrahepatic conditions and their outcomes? Available evidences support a beneficial effect of HCV clearance on mixed cryoglobulinaemia and lymphoma, but only few data—mostly from Asian populations—exist about the impact of viral eradication on common comorbidities like chronic kidney disease, diabetes and cardiovascular alterations.
What is new?
In this issue of Gut, Mahale et al 6 report on the effect of HCV clearance on extrahepatic manifestations in a cohort of 160 875 HCV-infected veterans, 31 143 (19.4%) receiving interferon (IFN)-based antiviral therapy, of whom 10 575 (33.9%) obtained a sustained virological response (SVR). The authors confirmed the beneficial effect of the SVR on the risk of occurrence of mixed cryoglobulinaemia and lymphoma. Notably, when looking at more controversial topics, the authors observed that: (1) the risk for glomerulonephritis was reduced in patients with SVR compared with those without and in treated patients (with or without SVR) compared with those untreated; (2) the risk for diabetes was reduced in patients with SVR compared with those without or to those untreated, while increased in those without SVR compared with those untreated; (3) the risk for stroke was reduced in treated patients (with or without SVR) compared with those untreated, while was similar in patients with SVR compared with those without; (4) antiviral treatment did not affect the risk for coronary artery disease (CAD).
The study by Mahale et al qualifies as the largest western study ever reported on the relationship between IFN-based antiviral treatment and extrahepatic manifestations in HCV-infected individuals. In addition, the results were confirmed by sensitivity analyses after excluding patients with HBV and/or HIV coinfection(s) or after stratifying individuals according to the severity of hepatic fibrosis estimated by the AST to Platelet ratio index (APRI) score. These results however should be interpreted with caution because the study is retrospective and limited to a population of male veterans, one on four with advanced fibrosis and at high prevalence of obesity (27%), diabetes (21%), arterial hypertension (51%), smoking (51%) and alcohol intake (58%). Besides, the use of IFN-based treatments in a proportion of patients may have caused a selection bias.
Unsolved key questions about HCV infection, comorbidities and virological eradication
Current data and the study by Mahale et al raise at least two pressing questions:
Is the effect of SVR on cardiometabolic disorders driven by virological clearance? By IFN? By a population selection bias?
The greater proportion of studies assessing the impact of HCV eradication on cardiometabolic outcomes arises from cohorts of patients treated with IFN-based therapies. A Taiwanese cohort study observed a significant reduction for the risk of end-stage kidney disease, stroke and acute coronary syndrome in patients treated with IFN-based therapy compared with those untreated, the risk of cerebrocardiovascular events being similar in this last group compared with subjects without HCV infection.7 A Scottish study on more than 3000 patients with HCV found that SVR by IFN was associated with an absolute risk reduction for CVD.8 Arase et al, reported a protective effect of SVR on development of diabetes in an Asiatic cohort of HCV-infected patients.9 The present paper by Mahale et al on a US population, reported a beneficial effect of SVR by IFN on diabetes occurrence, a protective impact of antiviral treatment (with/without SVR) on stroke and kidney damage and no effect of therapy/treatment on CAD. All in all, these data raise the doubt whether SVR or IFN is the driver of improved extrahepatic outcomes, and whether, in some cases, the positive effect of SVR is only expression of a selection bias because patients eligible to interferon were healthier than HCV-untreated cohort and non-responder groups. Only one study assessed the impact of HCV clearance on cardiometabolic disorders in patients undergoing direct antiviral agent (DAA)-based therapies, showing a reduction for cardiovascular events.10 This study however included a mixed cohort of IFN and DAA-treated patients with cirrhosis and the number of patients underwent DAA therapy is too small to draw definitive conclusions.
Is the effect of HCV eradication the same in all HCV-infected individuals?
Available data, with all the above limitations, suggest overall a protective effect of HCV clearance on cardiometabolic disorders. A crucial point is to understand whether all patients will have the same gain, or—more probable—whether the impact of SVR is different in function of the length and the severity of the liver disease and of the associated comorbidities and according to the presence of other risk factors. Concerning the impact of the severity of liver damage on the effect of SVR on cardiometabolic outcomes, available results are very controversial, ranging from no impact of liver fibrosis to an improvement in cardiometabolic prognosis—as observed in the study by Mahale et al—to a more pronounced effect in patients with mild disease7 or in patients with advanced fibrosis/cirrhosis.8–10 Differences in baseline characteristics of patients, in cardiometabolic risk factors, in length of follow-up and in assessment of liver disease severity could explain the contrasting results. On the other hand, while our meta-analysis suggests that the impact of HCV on cardiovascular damage could be more pronounced in patients at higher cardiometabolic risk,4 no studies until now stratified the impact of HCV eradication on cardiometabolic outcomes according to cardiometabolic risk factors, age of the patients and previous history of cardiometabolic disorders.
All patients with HCV -infection should be treated with DAA-based regimens except than in case of limited life expectancy due to non-liver-related comorbidities. While the effect of SVR on liver-related outcomes in patients with both mild and severe liver disease is clear, available evidence suggests a beneficial effect of HCV clearance also on extrahepatic outcomes including cardiometabolic events. However, before turning these results into clinical recommendations, data on DAA-based therapies and identification of clinical settings at higher or lower extrahepatic benefit of SVR should be provided. Anyway, even if HCV eradication could be of help, it should not replace the control of traditional cardiometabolic risk factors that remain the main targets against cardiometabolic diseases.
Contributors SP and AC wrote the commentary.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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