Editorial perspective:
HCV cure is associated with a global hepatic and extra-hepatic- benefit, still questions on hematological malignancies long-term risk !
Pr Stanislas Pol
Necker Hospital - Paris

The clinical hepatic and extra-hepatic benefits associated with sustained virologic response (SVR) in HCV-infected treated patients have been previously reported in large series, and they were mainly reported in patients with significant fibrosis ^(1-3). Most of these studies were retrospective and included patients with different procedure of fibrosis evaluation (liver biopsy, liver stiffness or biochemical noninvasive test). The large French ANRS CO12 CirVir prospective cohort (1323 patients), based on a rigorous approach (biopsy-proven non decompensated cirrhosis, propensity score, long-term follow-up) adds further evidence of the positive impact of SVR viral in reducing the entire spectrum of liver-related complications (cirrhosis decompensation, bacterial infection, hepatocellular carcinoma) as well as of extra-hepatic mortality, leading to a significant improvement of 5-year survival and reduction of liver-related mortality ^(4-5). Comorbidities, such as the metabolic syndrome and chronic alcohol consumption influence long-term complications and should be taken into account ⁽⁵⁾. Preliminary results of NASH and anti-fibrotic treatments presented at the last AASLD (Nov 2016) are encouraging but suggest that combination therapies including statins, metformin, alpha-tocopherol and other new therapies will be likely necessary to obtain a clear benefit ^(6-9).

A major information is also the prospective confirmation of the significant reduction in extrahepatic mortality (5-year specific survival, 97.6% vs 93.4%; HR, 0.44; IQR, 0.24–0.82; P 1/4 .010) in these cirrhotic patients achieving SVR ⁽⁵⁾, which had already been suggested in the Taiwan cohort (about a 2-fold increased risk of extra-hepatic mortality in HCV RNA-positive as compared to HCV RNA-negative or anti-HCV-negative subjects) ^(10-11). The reduction of the vascular events associated with SVR argues for a systematic treatment of HCV-infected patients whatever the fibrosis stage which are in line with the latest EASL guidelines in 2016. The positive impact of SVR on cardiovascular events is underlined further by the lower incidence of MACE observed in these patients. The link between HCV chronic infection and vascular disease remains unclear despite convincing ⁽¹¹⁾. A higher incidence of vascular events has been reported in HCV-infected compared with uninfected patients, but question remains whether it is related to HCV infection per se and/or its interference with metabolic/inflammatory dysfunctions triggering vascular injury and what is the impact of fibrosis (extensive fibrosis or cirrhosis is more frequently associated with carotid atherosclerosis) ⁽¹²⁾. A convincing correlation between the severity of liver necroinflammation caused by HCV infection and cardiovascular morbidity has been shown, possibly modulated by viral clearance. Direct viral mechanisms appear to promote atherosclerosis, as suggested by higher serum HCV-RNA levels in patients with vascular conditions ⁽¹³⁾ or even by the presence of a positive HCV-RNA strand in carotid plaques of HCV-infected patients ⁽¹⁴⁾.

While the hepatic and extra-hepatic overall benefits od SVR is now fully demonstrated, there is no evidence that SVR is associated with a reduction of extra-hepatic cancers. The development of B-cell non-Hodgkin lymphomas, preferentially of marginal zone lymphomas and diffuse large B-cell lymphomas has been associated with HCV infection with a relative risk of around 1.5. Direct transformation related to the presence of the virus and/or chronic antigenic stimulation are the two non-exclusive mechanisms generating HCV-related lymphoma. HCV does infect not only hepatocytes but other cells and does also induces chronic inflammation with qualitative and quantitative alterations of the immune repertoire that could favour the occurrence of cancers. Studies suggest a standardized rate of almost 49 times higher for liver cancer and between1.5 and 2.5 times for the pancreas, rectum, kidney, non-Hodgkin lymphoma and lung tumors. Cancers in subjects with HCV infection seem to occur not only more frequently but also at a younger age and with a poorer prognosis, even in patients not consuming alcohol or without diabetes among non-smokers and in patients without overweight. A systematic review and critical meta-analysis retains mainly a significant risk of lymphoma, intrahepatic cholangiocarcinoma and cancer pancreas in hepatitis C infection which is linked to inflammation and thus is an indirect risk.

In the ANRS CO12 CirVir study (5), risk of occurrence of lymphomas and hemopathies was similar for SVR and non-SVR patients. Whether this observation is related to the increased survival of this population or to other HCV-related factors requires further analyses with longer follow-up.

References:

1. van der Meer AJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308: 2584–2593.
2. Morgan RL, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329–337.
3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: mangement of chronic hepatitis C virus infection. J Hepatol 2011; 55(2):245-64.
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6. Sato K, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015 Jul-Aug;31(7-8):923-30.
7. Oscarsson J, et al. NASH/antifibrotic AASLD. Effects of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, and free omega-3 carboxylic acids on liver steatosis and hepatocyte damage biomarkers in Type 2 diabetes patients with non-alcoholic fatty liver disease, AASLD 2016, Abs. 1098
8. Loomba R, et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. AASLD 2016, Abs. LB-3
9. Sanyal AJ, et al.. Cenicriviroc placebo for the treatment of non-alcoholic steatohepatitis with liver fibrosis: Results from the Year 1 primary analysis of the Phase 2b CENTAUR study. AASLD 2016, Abs. LB-1
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