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Residual risk of liver disease after hepatitis C virus eradication

  • Francesco Negro
    Correspondence
    Corresponding author. Address: Divisions of Gastroenterology and Hepatology and Clinical Pathology, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva 14, Switzerland. Tel.: +41 22 3729355, fax: +41 22 3729366.
    Affiliations
    Divisions of Gastroenterology and hepatology, Geneva University Hospitals, Geneva, Switzerland

    Divisions of Clinical pathology, Geneva University Hospitals, Geneva, Switzerland
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Published:December 01, 2020DOI:https://doi.org/10.1016/j.jhep.2020.11.040

      Summary

      Treatment of hepatitis C with direct-acting antivirals is safe and highly efficacious, resulting in viral clearance (sustained virological response [SVR]) in the vast majority of patients. Although SVR is mostly permanent and associated with a significant reduction of liver morbidity and mortality, some patients may still suffer from a major risk of progressive liver damage, potentially leading to severe complications – including liver decompensation, hepatocellular carcinoma and death. This concise review discusses some of the most important features of residual liver disease in patients with chronic hepatitis C who have achieved SVR after antiviral therapy.

      Keywords

      Introduction

      A sustained virological response (SVR), i.e. undetectable HCV RNA in the serum of patients with chronic hepatitis C 12 or 24 weeks after the end of antiviral treatment, defines treatment-induced viral clearance. Permanent in the vast majority of patients, SVR is also a surrogate marker of improved liver-related morbidity and mortality.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C: final update of the series.
      However, despite HCV clearance, some patients may still develop potentially fatal complications of liver disease. This concise review will discuss some of the most significant issues related to the persistence of liver damage in patients who have achieved an SVR.

      Quantifying liver-related morbidity and mortality after SVR

      Liver decompensation

      The large, real-world UK Expanded Access Program confirmed how the severity of liver disease at initiation of therapy was a strong predictor of persisting liver damage after SVR. Viral clearance was associated with a reduction in the incidence of decompensation events, from 18% in the first 6 months after the initiation of direct-acting antiviral (DAA) treatment to 7% during months 6 to 15.
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      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      Model for end-stage liver disease (MELD) scores improve in most patients with SVR, while remaining unchanged in 17%, and worsening in a quarter of patients. Patients with low MELD scores on a liver transplant list can even be delisted,
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      although the clinical improvement may not necessarily persist, and patients may still develop ascites or hepatocellular carcinoma (HCC), to the point of facing the risk of relisting or death.
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      A Scottish, real-world, hospital-based linkage study
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      Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis.
      reported an 86% reduction in the risk of decompensation in patients who achieved SVR compared to those who did not, while none of 457 patients cured of HCV developed decompensation 10 years after SVR in a study from Japan.
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      • Akuta N.
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      • Sezaki H.
      • et al.
      Long-term outcome of hepatocellular carcinoma occurrence, esophageal varices exacerbation, and mortality in hepatitis C virus-related liver cirrhosis after interferon-based therapy.

      Hepatocellular carcinoma

      Interferon (IFN)α-induced SVR has repeatedly been associated with a significantly reduced risk of developing HCC, including in patients who have received prior ablative treatment for HCC. In a large retrospective study, the yearly HCC incidence after SVR was 0.33%.
      • El-Serag H.B.
      • Kanwal F.
      • Richardson P.
      • Kramer J.
      Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection.
      In a similar study, the adjusted hazard ratio (HR) for HCC was 0.32 (95% CI 0.28–0.37) when comparing SVR to no SVR.
      • Ioannou G.N.
      • Green P.K.
      • Berry K.
      HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.
      The introduction of DAAs has allowed us to assess the benefit of viral clearance in patients with more advanced liver disease (hence at higher risk of HCC) in whom IFNα is contraindicated. There were 2 main questions, i.e. whether DAAs would reduce the incidence of de novo HCC, at least compared to the reduction reported upon successful therapy with IFNα-based regimens, and whether treatment with DAAs in patients who had received ablative therapy for HCC would effectively protect against HCC recurrence. Early reports suggested a paradoxical, pro-oncogenic effect of DAAs, with an increased risk of recurrent HCC compared to historical controls.
      • Reig M.
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      • Iñarrairaegui M.
      • Ribeiro A.
      • Lens S.
      • et al.
      Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy.
      The controversy that ensued was addressed by later meta-analyses,
      • Waziry R.
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      • Grebely J.
      • Amin J.
      • Law M.
      • Danta M.
      • et al.
      Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.
      ,
      • Saraiya N.
      • Yopp A.C.
      • Rich N.E.
      • Odewole M.
      • Parikh N.D.
      • Singal A.G.
      Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy.
      which showed that DAA therapy was not associated with higher HCC occurrence or recurrence with respect to IFNα-based therapy. Thus, if the reduction of de novo HCC incidence is comparable to that afforded by IFNα-based therapies, i.e. approaching 80%, as confirmed later,
      • Nahon P.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs.
      • Carrat F.
      • Fontaine H.
      • Dorival C.
      • Simony M.
      • Diallo A.
      • Hezode C.
      • et al.
      Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
      • Janjua N.Z.
      • Wong S.
      • Darvishian M.
      • Butt Z.A.
      • Yu A.
      • Binka M.
      • et al.
      The impact of SVR from direct-acting antiviral- and interferon-based treatments for HCV on hepatocellular carcinoma risk.
      • Lleo A.
      • Aglitti A.
      • Aghemo A.
      • Maisonneuve P.
      • Bruno S.
      • Persico M.
      • et al.
      Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.
      it is clear that the risk of HCC in SVR patients is not nil.

      Liver-related mortality

      Although significantly reduced, the risk of liver-related death may persist among patients who have cleared HCV.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • Bollani S.
      • Benvegnù L.
      • Mazzella G.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      • Lee M.H.
      • Yang H.I.
      • Lu S.N.
      • Jen C.L.
      • You S.L.
      • Wang L.Y.
      • et al.
      Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      According to a pooled analysis from several Western cohorts,
      • Van der Meer A.J.
      • Feld J.J.
      • Hofer H.
      • Almasio P.L.
      • Calvaruso V.
      • Fernández-Rodríguez C.M.
      • et al.
      Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
      death occurred in ∼6% of patients, equally contributed by liver- and non-liver-related causes. All liver failure cases occurred among patients with cirrhosis, with an 8-year cumulative incidence of liver failure of 4.1%. A concern with these studies was the fact that many prognostic factors for liver-related mortality were the same as those that predicted response to IFNα.
      • Masetti C.
      • Lleo A.
      • Colombo M.
      • Colombo M.
      • Aghemo A.
      Postsustained virological response management in hepatitis C patients.
      This debate became obsolete after the advent of DAAs, with SVR rates >95%. In the retrospective analysis of clinical trials of patients with HCV-associated decompensated cirrhosis treated with sofosbuvir-based regimens, SVR was associated with a significant reduction in the risk of transplantation or death (HR 0.12; 95% CI 0.04–0.38).
      • Simmons B.
      • Saleem J.
      • Heath K.
      • Cooke G.S.
      • Hill A.
      Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response.
      Real-world cohorts
      • McDonald S.A.
      • Pollock K.G.
      • Barclay S.T.
      • Goldberg D.J.
      • Bathgate A.
      • Bramley P.
      • et al.
      Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis.
      ,
      • Carrat F.
      • Fontaine H.
      • Dorival C.
      • Simony M.
      • Diallo A.
      • Hezode C.
      • et al.
      Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
      ,
      • Butt A.A.
      • Yan P.
      • Shaikh O.S.
      • Lo Re 3rd, V.
      • Abou-Samra A.B.
      • Sherman K.E.
      Treatment of HCV reduces viral hepatitis-associated liver-related mortality in patients: an ERCHIVES study [published online ahead of print, 2020 Mar 5].
      have confirmed this significant reduction in the risk of liver-related death: in the HEPATHER prospective cohort, patients with SVR showed a yearly incidence of liver-related mortality of 0.36% (vs. 0.96% in non-SVR). In patients with cirrhosis, the respective rates were 0.64% vs. 1.57%. Although in the Scottish
      • McDonald S.A.
      • Pollock K.G.
      • Barclay S.T.
      • Goldberg D.J.
      • Bathgate A.
      • Bramley P.
      • et al.
      Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis.
      and in the ERCHIVES studies
      • Butt A.A.
      • Yan P.
      • Shaikh O.S.
      • Lo Re 3rd, V.
      • Abou-Samra A.B.
      • Sherman K.E.
      Treatment of HCV reduces viral hepatitis-associated liver-related mortality in patients: an ERCHIVES study [published online ahead of print, 2020 Mar 5].
      the risk reduction was more pronounced (∼90%), the risk was never completely abolished. Thus, despite viral clearance, a small but worrying proportion of patients will still die from liver-related disease after SVR.
      Treatment of hepatitis C with direct-acting antivirals is safe and highly efficacious, leading to the permanent clearance of HCV in the vast majority of patients.

      Recognising the impact of comorbidities

      Overweight/obesity and the conundrum of increased body weight after SVR

      Liver enzymes may be persistently elevated after SVR in patients with chronic hepatitis C. Among 834 patients with SVR,
      • Welsch C.
      • Efinger M.
      • von Wagner M.
      • Herrmann E.
      • Zeuzem S.
      • Welzel T.M.
      • et al.
      Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response.
      about 10% had persistently elevated alanine aminotransferase (ALT), and another 25% had ALT levels considered above healthy levels according to more stringent criteria (i.e. <20 U/ml for women and <31 U/ml for men). Elevated BMI was strongly predictive of ALT elevations. These observations were later confirmed by a larger, multicentre German cohort of 1,477 patients,
      • Mauss S.
      • Buendgens L.
      • Christensen S.
      • Ingiliz P.
      • Berger F.
      • Hüppe D.
      • et al.
      Risk factors for remaining liver injury in patients with virological elimination of chronic hepatitis C.
      where ALT remained >35 U/L in 15% of patients with SVR. Higher BMI independently predicted elevated ALT. Among other comorbidities, like diabetes and excess alcohol consumption, elevated BMI was also one of the factors associated with persistently elevated ALT after SVR in 9.1% of 4,946 patients treated with DAAs in the German Hepatitis C-Registry.
      • Tacke F.
      • Boeker K.H.W.
      • Klinker H.
      • Heyne R.
      • Buggisch P.
      • Pathil A.
      • et al.
      Baseline risk factors determine lack of biochemical response after SVR in chronic hepatitis C patients treated with DAAs.
      Thus, increased BMI is an important predictor of persistent liver enzyme alterations after SVR, independently of other classical cofactors of liver disease. The clinical impact of increased BMI after viral clearance was suggested by the long-term evaluation of the German HCV-contaminated anti-D cohort,
      • Wiese M.
      • Fischer J.
      • Löbermann M.
      • Göbel U.
      • Grüngreiff K.
      • Güthoff W.
      • et al.
      Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection.
      where 6% of SVR patients developed advanced liver fibrosis after 35 years from infection, although none of them developed HCC or progressed to decompensated liver disease. In the multivariate analysis, BMI independently predicted cirrhosis, together with viral clearance. Similar data were reported in a large retrospective analysis of 33,003 US Veterans treated with DAAs, where obese participants were at higher risk of cirrhosis. However, this did not translate into higher risks of HCC and mortality, warranting further studies on this association (Table 1).
      • Benhammou J.N.
      • Moon A.M.
      • Pisegna J.R.
      • Su F.
      • Vutien P.
      • Moylan C.A.
      • et al.
      Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C.
      Table 1Impact of cofactors of liver disease progression on liver-related events after SVR from selected published series.
      CofactorAuthor (year)n with SVRFollow–upOutcome measure
      Overweight/obesityWiese et al. (2014)
      • Wiese M.
      • Fischer J.
      • Löbermann M.
      • Göbel U.
      • Grüngreiff K.
      • Güthoff W.
      • et al.
      Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection.
      14935 yearsCirrhosis: OR 1.125 (95% CI: 1.038-1.22)
      SteatosisPeleg et al. (2019)
      • Peleg N.
      • Issachar A.
      • Sneh Arbib O.
      • Cohen-Naftaly M.
      • Harif Y.
      • Oxtrud E.
      • et al.
      Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response.
      515Median 25 (range 4–39) yearsComposite endpoint (all–cause mortality and HCC):

      HR 7.51 (95% CI 3.61–13.36)
      Type 2 diabetesVan der Meer et al. (2017)
      • Van der Meer A.J.
      • Feld J.J.
      • Hofer H.
      • Almasio P.L.
      • Calvaruso V.
      • Fernández-Rodríguez C.M.
      • et al.
      Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
      630Median 5.7 (IQR 2.9–8.0) yearsHCC: HR 2.36 (95% CI 1.02–5.42)
      Degasperi et al. (2019)
      • Degasperi E.
      • D'Ambrosio R.
      • Iavarone M.
      • Sangiovanni A.
      • Aghemo A.
      • Soffredini R.
      • et al.
      Factors associated with increased risk of de novo or recurrent hepatocellular carcinoma in patients with cirrhosis treated with direct-acting antivirals for HCV infection.
      505 without HCC

      60 treated for HCC
      Median 25 (range 3–39) months

      Median 23 (range 7–37) months
      HCC: HR 2.52 (95% CI 1.08–5.87)

      HCC : HR 4.12 (95% CI 1.55–10.93)
      Benhammou et al. (2020)
      • Benhammou J.N.
      • Moon A.M.
      • Pisegna J.R.
      • Su F.
      • Vutien P.
      • Moylan C.A.
      • et al.
      Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C.
      29,887Mean 3.0 yearsDecompensated cirrhosis (aHR 1.21, 95% CI 1.05–1.38)
      Alcohol abuseNahon et al. (2018)
      • Nahon P.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs.
      336Median 21.2 (IQR 13.5–26.9) monthsHCC: 1.66 (95% CI (1.22–2.26)
      Ogasawara et al. (2019)
      • Ogasawara N.
      • Saitoh S.
      • Akuta N.
      • Fujiyama S.
      • Kawamura Y.
      • Sezaki H.
      • et al.
      Long-term outcome of hepatocellular carcinoma occurrence, esophageal varices exacerbation, and mortality in hepatitis C virus-related liver cirrhosis after interferon-based therapy.
      457Median 8.9 (range 1–26.7) yearsExacerbation of oesophageal varices: HR 8.09 (95% CI 1.04–62.9)
      Kanwal et al. (2020)
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      18,0762.93 years ± 0.56∗HCC: HR 1.24 (1.03-1.50)
      HCV genotype 3Kanwal et al. (2020)
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      18,0762.93 years ± 0.56∗HCC: HR 1.60 (1.08-2.38)
      aHR, adjusted HR; HCC, hepatocellular carcinoma; HR, hazard ratio; OR, odds ratio; SVR, sustained virological response. ∗Mean ± SD.
      These findings are even more relevant considering the intriguing, unexplained reports of body weight increases following SVR. In a single-centre, prospective study from Germany on 284 patients successfully treated with DAAs,
      • Schlevogt B.
      • Deterding K.
      • Port K.
      • Siederdissen C.H.Z.
      • Sollik L.
      • Kirschner J.
      • et al.
      Interferon-free cure of chronic Hepatitis C is associated with weight gain during long-term follow-up.
      a body weight gain (mean 1.45 kg) was observed in 44% of patients 48 weeks after therapy and predicted by age <60 years, but not by sex, diabetes, cirrhosis, or baseline BMI. A retrospective Egyptian study on 162 patients (29% with obesity at baseline) confirmed these results.
      • Kassas M.E.
      • Alboraie M.
      • Naguib M.
      • Omar H.
      • Tahan A.E.
      • Moaz I.
      • et al.
      A significant upsurge of body mass index in patients with chronic hepatitis C successfully treated with direct-acting antiviral regimens.
      In a more recent prospective study on 11,469 Veterans, 52.6% of patients gained weight and 19.8% even gained excess weight, defined as an increase ≥9 kg after 2 years of follow-up. This increase was deemed of interest considering an expected weight gain associated with aging (0.45 to 0.9 kg per year).
      • Do A.
      • Esserman D.A.
      • Krishnan S.
      • Lim J.K.
      • Taddei T.H.
      • Hauser 3rd, R.G.
      • et al.
      Excess weight gain after cure of hepatitis C infection with direct-acting antivirals.
      SVR was an independent predictor of weight gain together with younger age (<65 years), cirrhosis, fibrosis-4 (FIB-4) score >3.25, and being overweight at enrolment, while absence of alcohol drinking was protective.
      The mechanisms underlying body weight after SVR changes may involve neuropsychiatric changes or decreased circulating levels of proinflammatory cytokines. Chronic liver disorders are often characterised by lack of appetite and/or dysgeusia, and patients with hepatitis C have been reported to present with taste alterations.
      • Musialik J.
      • Suchecka W.
      • Klimacka-Nawrot E.
      • Petelenz M.
      • Hartman M.
      • Błońska-Fajfrowska B.
      Taste and appetite disorders of chronic hepatitis C patients.
      Curing HCV may reverse these symptoms, but whether this may be associated with increased food intake and consequently body weight changes remains to be proven. These results support the need for careful counselling before DAA therapy, especially in patients who are young and overweight or obese at presentation.

      Metabolic dysfunction-associated fatty liver disease

      Steatosis, or, more appropriately metabolic dysfunction-associated fatty liver disease (MAFLD), formerly referred to as non-alcoholic fatty liver disease (NAFLD),
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      is the most prevalent chronic liver disorder and a major cause of liver-related morbidity and mortality worldwide.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • Hardy T.
      • Henry L.
      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      Thus, it may frequently overlap with chronic hepatitis C, and contribute to its associated health burden. Patients with chronic hepatitis C and steatosis exhibit accelerated liver fibrosis progression, and an increased risk of developing HCC.
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.
      Although HCV clearance may result in partial to complete regression of liver steatosis, at least when directly caused by the virus (especially HCV genotype 3),
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.
      a significant proportion of patients with SVR may still have steatosis unrelated to HCV, depending on the local prevalence of overweight/obesity. A US study
      • Noureddin M.
      • Wong M.M.
      • Todo T.
      • Lu S.C.
      • Sanyal A.J.
      • Mena E.A.
      Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals.
      reported a staggering prevalence of steatosis of 47.5%, as determined by controlled attenuation parameter, after SVR.
      Thus, the coexistence of MAFLD in patients with chronic hepatitis C may be reflected by the discordance between biochemical and virological response after antiviral therapy. In 496 patients treated with IFNα-based regimens, the predictors of persistently elevated ALT, despite SVR, included obesity and steatosis at histology,
      • Chen C.H.
      • Huang J.F.
      • Huang C.F.
      • Yeh M.L.
      • Yang J.F.
      • Hsieh M.Y.
      • et al.
      Interferon-associated hepatic steatosis is related to discrepancies in biochemical and virological responses of chronic hepatitis C to IFN-based therapy.
      an observation confirmed by the German Hepatitis C-Registry.
      • Tacke F.
      • Boeker K.H.W.
      • Klinker H.
      • Heyne R.
      • Buggisch P.
      • Pathil A.
      • et al.
      Baseline risk factors determine lack of biochemical response after SVR in chronic hepatitis C patients treated with DAAs.
      Thus, the coexistence of MAFLD in patients with chronic hepatitis C may account for the progression of liver disease in patients with SVR and increased BMI. In a US study,
      • Noureddin M.
      • Wong M.M.
      • Todo T.
      • Lu S.C.
      • Sanyal A.J.
      • Mena E.A.
      Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals.
      liver stiffness decreased upon treatment with DAAs, but patients with post-SVR steatosis continued to have elevated mean stiffness values (≥7 kPa) compared to those without steatosis, and 6.25% had advanced fibrosis. In a retrospective study of 515 patients with advanced fibrosis who achieved SVR after DAA therapy, the multivariate analysis showed that pre-treatment steatosis was associated with a 7.5-fold increased risk of the composite endpoint of all-cause mortality and HCC, even after adjustment for components of the metabolic syndrome (Table 1).
      • Peleg N.
      • Issachar A.
      • Sneh Arbib O.
      • Cohen-Naftaly M.
      • Harif Y.
      • Oxtrud E.
      • et al.
      Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response.
      It is important to note that decompensation occurred in 24 patients during the 2-year follow-up, and that among the 27 deaths, liver failure was the most common cause of mortality (40.7%).

      Type 2 diabetes

      Type 2 diabetes is a major risk factor for clinical progression in chronic hepatitis C.
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.
      HCV perturbs glucose metabolism inducing insulin resistance, which may progress to type 2 diabetes.
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.
      Viral clearance reduces the risk of incident glucose metabolic alterations after therapy, but patients who already present with type 2 diabetes at the start of antiviral treatment remain diabetic irrespective of SVR, even though they may require lower doses of antidiabetic medicines.
      • Dawood A.A.
      • Nooh M.Z.
      • Elgamal A.A.
      Factors associated with improved glycemic control by direct-acting antiviral agent treatment in Egyptian type 2 diabetes mellitus patients with chronic hepatitis C genotype 4.
      HCV clearance induced by antivirals is associated with a significant decrease of liver morbidity and mortality.
      Thus, type 2 diabetes may continue affecting clinical progression of hepatitis C even after cure. In a large study pooling data on 1,000 patients with bridging fibrosis or cirrhosis who attained SVR, followed for a median of 5.7 years,22 51 patients developed HCC and 101 had clinical disease progression. A multivariate analysis identified older age, lower platelet count and diabetes as independently associated with the development of HCC. In another large, retrospective single-centre study,
      • Degasperi E.
      • D'Ambrosio R.
      • Iavarone M.
      • Sangiovanni A.
      • Aghemo A.
      • Soffredini R.
      • et al.
      Factors associated with increased risk of de novo or recurrent hepatocellular carcinoma in patients with cirrhosis treated with direct-acting antivirals for HCV infection.
      ex novo HCC occurred in 28/505 patients with cirrhosis treated with DAAs and followed-up for a median of 25 months. HCC was predicted largely by male sex (HR 6.17; 95% CI 1.44–26.47; p = 0.01), diabetes (HR 2.52; 95% CI 1.08–5.87; p = 0.03) and non-invasive markers of fibrosis. Diabetes was also the only independent predictor of HCC recurrence, in this case increasing the risk by about 4-fold. Finally, in the large retrospective study on 33,033 Veterans treated with DAAs and followed for an average of 3 years,
      • Benhammou J.N.
      • Moon A.M.
      • Pisegna J.R.
      • Su F.
      • Vutien P.
      • Moylan C.A.
      • et al.
      Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C.
      pre-treatment diabetes was associated with an increased risk of mortality (adjusted HR 1.25; 95% CI 1.10–1.42), cirrhosis (adjusted HR 1.31; 95% CI 1.16–1.48), liver decompensation (adjusted HR 1.74; 95% CI 1.31–2.31), and HCC (adjusted HR 1.32; 95% CI 1.01–1.72) among patients without baseline cirrhosis and irrespective of SVR (Table 1). Thus, despite viral clearance potentially ameliorating glucose metabolism disturbances, strict surveillance of diabetic patients after SVR is warranted.

      Alcohol abuse

      Alcohol abuse is, intuitively, a major cause of morbidity – not limited to the liver – after SVR. In a Scottish hospital-based linkage study on 1,215 patients with chronic hepatitis C and IFNα-induced SVR, there were significant rates of liver-related hospitalisations.
      • Innes H.A.
      • Hutchinson S.J.
      • Allen S.
      • Bhattacharyya D.
      • Bramley P.
      • Delahooke T.E.
      • et al.
      Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care.
      The adjusted standardized morbidity ratio was 10.5 (95% CI 8.7–12.9) in all SVR, and 5.9 (95% CI 4.5–8.0) among non-cirrhotic SVR cases compared to the general population. Alcohol abuse was suspected to be the cause of most of these hospitalisations. Alcohol intake was also independently associated with the exacerbation of portal hypertension, although not HCC development, in a Japanese cohort of 457 patients with compensated cirrhosis and IFNα-induced SVR.
      • Ogasawara N.
      • Saitoh S.
      • Akuta N.
      • Fujiyama S.
      • Kawamura Y.
      • Sezaki H.
      • et al.
      Long-term outcome of hepatocellular carcinoma occurrence, esophageal varices exacerbation, and mortality in hepatitis C virus-related liver cirrhosis after interferon-based therapy.
      The same Scottish group later reported the clinical outcomes of 1,073 patients with cirrhosis treated with DAAs.
      • McDonald S.A.
      • Pollock K.G.
      • Barclay S.T.
      • Goldberg D.J.
      • Bathgate A.
      • Bramley P.
      • et al.
      Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis.
      SVR reduced the risk of decompensated cirrhosis (HR 0.14; 95% CI 0.05–0.39), HCC (HR 0.17; 95% CI 0.04–0.79), and liver-related death (HR 0.13; 95% CI 0.05–0.34). However, liver-related mortality was also significantly increased by lack of compliance (HR 6.73; 95% CI 2.99–15.1), an issue notoriously associated with alcohol dependence.
      The large, carefully detailed, French prospective CirVir cohort enabled the incidence of HCC to be compared in patients with compensated cirrhosis treated with DAA therapy (n = 336) vs. those treated with IFNα-based regimens (n = 495).
      • Nahon P.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs.
      Independent predictors of HCC among DAA-induced SVR, apart from age >50, low platelet counts, elevated gamma glutamyltransferase (GGT) and HCV genotype 1, included excessive alcohol consumption (HR 1.66; 95% CI 1.22–2.26; p = 0.001). Finally, the clinical impact of alcohol consumption after SVR was reported in a recent retrospective analysis of 126 US Veterans who achieved SVR after DAAs.44 In this predominantly male series, excess alcohol consumption (but neither BMI nor diabetes, and marginally age) increased the risk of incident HCC, together with HCV genotype 3 (Table 1).

      Autoimmune liver disease

      In patients with hepatitis C and concomitant, bona fide autoimmune hepatitis, IFNα-based therapy exacerbated liver enzyme elevations;
      • Rigopoulou E.I.
      • Zachou K.
      • Gatselis N.
      • Koukoulis G.K.
      • Dalekos G.N.
      Autoimmune hepatitis in patients with chronic HBV and HCV infections: patterns of clinical characteristics, disease progression and outcome.
      therefore, ruling out autoimmune hepatitis before starting IFNα administration has been consistently mandated by international treatment recommendations. On the other hand, de novo autoimmune hepatitis requiring long-term immunosuppressive therapy in patients with hepatitis C treated with IFNα-based regimens has occasionally been reported both in the transplant
      • Kontorinis N.
      • Agarwal K.
      • Elhajj N.
      • Fiel M.I.
      • Schiano T.D.
      Pegylated interferon–induced immune-mediated hepatitis post–liver transplantation.
      ,
      • Casanovas T.
      • Argudo A.
      • Peña-Cala M.C.
      Effectiveness and safety of everolimus in the treatment of autoimmune hepatitis related to anti-hepatitis C virus therapy after liver transplant: three case reports.
      and non-transplant settings.
      • Shindo M.
      • Di Bisceglie A.M.
      • Hoofnagle J.H.
      Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C.
      ,
      • Garcia-Buey L.
      • Garcia-Monzon C.
      • Rodriguez S.
      • Borque M.J.
      • García-Sánchez A.
      • Iglesias R.
      • et al.
      Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C.
      These events are currently only of historical interest, due to the discontinuation of IFNα-based regimens in hepatitis C.

      How can we identify patients at risk of liver-related events after SVR?

      International guidelines recommend post-SVR surveillance by liver imaging and alpha-fetoprotein (AFP) testing every 6 months after SVR in patients with cirrhosis,
      • Ghany M.G.
      • Morgan T.R.
      AASLD-IDSA Hepatitis C Guidance Panel
      Hepatitis C guidance 2019 update: American association for the study of liver diseases-infectious diseases society of America recommendations for testing, managing, and treating hepatitis C virus infection.
      ,
      • Terrault N.A.
      • McCaughan G.W.
      • Curry M.P.
      • Gane E.
      • Fagiuoli S.
      • Fung J.Y.Y.
      • et al.
      International liver transplantation society consensus statement on hepatitis C management in liver transplant candidates.
      although EASL guidelines have also extended this recommendation to patients with advanced fibrosis (F3).
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C: final update of the series.
      Patients with lower stages of fibrosis may be discharged from specialised care, unless affected by liver comorbidities. Surveillance in patients without cirrhosis but with advanced fibrosis (F3) may be considered “based on individual risk assessment”, as per AASLD/IDSA guidelines.
      • Ghany M.G.
      • Morgan T.R.
      AASLD-IDSA Hepatitis C Guidance Panel
      Hepatitis C guidance 2019 update: American association for the study of liver diseases-infectious diseases society of America recommendations for testing, managing, and treating hepatitis C virus infection.
      However, at the time of writing, there is no consensus on how to assess this risk. Several algorithms – defining different levels of risk – have been proposed (see below), but they use different pre- and post-treatment parameters, with different thresholds, and they can hardly be summarised into a consensus recommendation.
      How long surveillance should last is currently undefined. In the recent retrospective study on 48,135 Veterans who achieved SVR after IFNα- or DAA-based regimens, the annual risk of HCC remained significant up to 10 years from SVR.
      • Pons M.
      • Rodríguez-Tajes S.
      • Esteban J.I.
      • Mariño Z.
      • Vargas V.
      • Lens S.
      • et al.
      Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals.
      However, the consensus is that prolonged surveillance programmes may suffer from poor effectiveness and unduly overcharge specialists, especially if unconditionally applied to all patients with advanced fibrosis and SVR.
      Despite the viral clearance, a minority of patients may still experience liver disease progression, leading to decompensation, hepatocellular carcinoma and death.
      Thus, scoring systems have been devised with the aim of tailoring post-SVR surveillance. These scoring systems include both clinical features, simple serum assays and non-invasive markers of fibrosis, which are inexpensive, easy to perform, and can be combined to increase their predictive accuracy. They can also be scaled up in extensive screening programmes. However, none of them have been integrated – at the time of writing – into official, international recommendations.

      Treating patients with decompensated liver disease

      Some patients with chronic hepatitis C may progress to liver decompensation despite SVR, e.g. in case of liver comorbidities. Alternatively, liver damage may have reached a “point-of-no-return”, irrespective of such comorbidities, and consequently worsen after therapy, with or without SVR. In such cases, antiviral treatment may even be futile. In the pooled analysis of 4 sofosbuvir-based trials of patients with HCV-associated decompensated cirrhosis, liver function improved in most patients, except for those with severely impaired liver function at the start of treatment.
      • El-Sherif O.
      • Jiang Z.G.
      • Tapper E.B.
      • Huang K.C.
      • Zhong A.
      • Osinusi A.
      • et al.
      Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection.
      Patients with Child-Pugh B (n = 502) or Child-Pugh C (n = 120) cirrhosis received antivirals and were then followed-up for a median of 255 days. The primary outcome was the reduction of Child-Pugh score to class A. Patients with ascites or encephalopathy, hypoalbuminemia (<3.5 g/dl), serum alanine aminotransferase <60 U/L, or BMI >25 were at increased risk of not achieving a reduction in Child-Pugh score to class A. In addition, those with profound hypoalbuminemia (<2.8 g/dl) or any hyperbilirubinemia were also at increased risk of liver transplantation or death. These authors developed a predictive scoring system exploiting 5 pre-treatment factors (1 point each for BMI <25, lack of encephalopathy, lack of ascites, alanine aminotransferase >60 IU/L and albuminemia >3.5 g/dl, hence dubbed the BE3A score, ranging from 0 to 5). A BE3A score of 4 or 5 was associated with a 75% chance of achieving Child-Pugh class A, while patients with a score of 0 or 1 had <5% and 25% chance of achieving Child-Pugh class A, respectively. Finally, those with a score of 0 had a 25% probability of death or a need for liver transplantation by week 36. Although this scoring system must be commended for its simplicity, it has to be noted that only a small proportion of patients (i.e. 22/622, or 3.5%) had scores predicting the highest chances of Child-Pugh class improvement. Patients with a baseline score of 0 (n = 106) or 1 (n = 219) would be the most likely to benefit from the implementation of the BE3A score, as their odds of achieving Child-Pugh A at 36 weeks would be a mere <5% and 25%, respectively, suggesting that they should probably be transplanted first, instead of undergoing antiviral therapy.
      A study by El-Sherif et al. raised an interesting question regarding the prognostic value of the MELD score in clinical decision-making.
      • El-Sherif O.
      • Jiang Z.G.
      • Tapper E.B.
      • Huang K.C.
      • Zhong A.
      • Osinusi A.
      • et al.
      Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection.
      Their multivariate analysis seems to suggest that the probabilities of clinical improvement already decreased at MELD scores of ≥12, questioning the predictive value of a score that fails to incorporate key features of decompensated cirrhosis, i.e. ascites and encephalopathy, which signal advanced portal hypertension and are instead part of the BE3A scoring algorithm. However, both the EASL guidelines1 and the ILTS consensus statement
      • Terrault N.A.
      • McCaughan G.W.
      • Curry M.P.
      • Gane E.
      • Fagiuoli S.
      • Fung J.Y.Y.
      • et al.
      International liver transplantation society consensus statement on hepatitis C management in liver transplant candidates.
      only recommend withholding antivirals in patients with an MELD score >20, based on the ELITA study.
      • Belli L.S.
      • Berenguer M.
      • Cortesi P.A.
      • Strazzabosco M.
      • Rockenschaub S.R.
      • Martini S.
      • et al.
      Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study.
      Treating patients with higher scores may lead to an improvement in MELD such that a patient no longer qualifies for liver transplantation while still being at risk of lethal complications and/or poor quality of life (a situation that has been dubbed “MELD purgatory”). Below that threshold, the recommendations suggest offering antiviral therapy with the hope of a stable improvement in liver function. However, recent data from the large real-world HCV-TARGET Cohort7 suggest that the decision to treat patients with MELD scores lower than 18 should still be taken on a case-by-case basis, considering the presence of other features of decompensated liver disease, especially portal hypertension. In this study, 642 patients with advanced/decompensated cirrhosis (MELD ≥10) were analysed. Out of 577 patients in the efficacy population, 302 reached SVR. Despite a clinically significant decrease in MELD score (i.e. ≥3 points) achieved by 80 patients across a short follow-up (9-26 weeks after the end of treatment), in the long-term (median follow-up of 4 years after DAA) the average MELD changes were marginal (-0.30 points). As many as 51 patients died and 22 had to be transplanted. A final MELD score decrease to <10 was achieved in 25%. Thus, even patients with low MELD scores may not fare well in the long term despite SVR. Further studies to validate the functional level that defines the point-of-no-return are urgently warranted.

      Scoring at-risk patients to determine post-SVR HCC risk

      It is of the utmost relevance to be able to use routinely obtained parameters to individualise HCC surveillance and detect HCC after SVR, especially because HCC is the most frequent liver-related event after SVR.
      • Ogasawara N.
      • Saitoh S.
      • Akuta N.
      • Fujiyama S.
      • Kawamura Y.
      • Sezaki H.
      • et al.
      Long-term outcome of hepatocellular carcinoma occurrence, esophageal varices exacerbation, and mortality in hepatitis C virus-related liver cirrhosis after interferon-based therapy.
      ,
      • Pons M.
      • Rodríguez-Tajes S.
      • Esteban J.I.
      • Mariño Z.
      • Vargas V.
      • Lens S.
      • et al.
      Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals.
      Several studies have evaluated the predictive value of individual factors, both before and after treatment.
      Before therapy, the presence of cirrhosis is the most important risk factor for the development of HCC after SVR.
      • Ioannou G.N.
      • Beste L.A.
      • Green P.K.
      • Singal A.G.
      • Tapper E.B.
      • Waljee A.K.
      • et al.
      Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores.
      • Ide T.
      • Koga H.
      • Nakano M.
      • Hashimoto S.
      • Yatsuhashi H.
      • Higuchi N.
      • et al.
      Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study.
      • Piñero F.
      • Mendizabal M.
      • Ridruejo E.
      • Herz Wolff F.
      • Ameigeiras B.
      • Anders M.
      • et al.
      Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma.
      This risk is accentuated in patients with decompensated liver disease
      • Shiha G.
      • Mousa N.
      • Soliman R.
      • Nnh Mikhail N.
      • Adel Elbasiony M.
      • Khattab M.
      Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: a prospective study.
      • Kozbial K.
      • Moser S.
      • Al-Zoairy R.
      • Schwarzer R.
      • Datz C.
      • Stauber R.
      • et al.
      Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment.
      • Calvaruso V.
      • Cabibbo G.
      • Cacciola I.
      • Petta S.
      • Madonia S.
      • Bellia A.
      • et al.
      Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents.
      • Ogata F.
      • Kobayashi M.
      • Akuta N.
      • Osawa M.
      • Fujiyama S.
      • Kawamura Y.
      • et al.
      Outcome of all-oral direct-acting antiviral regimens on the rate of development of hepatocellular carcinoma in patients with hepatitis C virus genotype 1-related chronic liver disease.
      • Na S.K.
      • Lee S.J.
      • Cho Y.K.
      • Kim Y.N.
      • Choi E.K.
      • Song B.C.
      • et al.
      Aspartate aminotransferase-to-platelet ratio or FIB-4 index predicts the development of hepatocellular carcinoma in chronic hepatitis C patients with sustained virologic response to interferon therapy.
      or in the presence of severe portal hypertension, defined by a low platelet count,
      • Nahon P.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs.
      ,
      • Lleo A.
      • Aglitti A.
      • Aghemo A.
      • Maisonneuve P.
      • Bruno S.
      • Persico M.
      • et al.
      Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ,
      • Calvaruso V.
      • Cabibbo G.
      • Cacciola I.
      • Petta S.
      • Madonia S.
      • Bellia A.
      • et al.
      Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents.
      oesophageal varices
      • Lleo A.
      • Aglitti A.
      • Aghemo A.
      • Maisonneuve P.
      • Bruno S.
      • Persico M.
      • et al.
      Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.
      or increased VITRO (von Willebrand factor (in %) to platelets (in G/L) ratio).
      • Semmler G.
      • Binter T.
      • Kozbial K.
      • Schwabl P.
      • Hametner-Schreil S.
      • Zanetto A.
      • et al.
      Non-invasive risk stratification after HCV-eradication in patients with advanced chronic liver disease.
      At the other end of the spectrum, patients with cirrhosis but low FIB-4 scores (i.e. <3.25) have extremely low risk of developing HCC after SVR.
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      ,
      • Ioannou G.N.
      • Beste L.A.
      • Green P.K.
      • Singal A.G.
      • Tapper E.B.
      • Waljee A.K.
      • et al.
      Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores.
      This is very important because it led the AASLD/IDSA guidelines to change from recommending surveillance in all those with advanced fibrosis (F3 or F4) to only those with cirrhosis.
      • Ghany M.G.
      • Morgan T.R.
      AASLD-IDSA Hepatitis C Guidance Panel
      Hepatitis C guidance 2019 update: American association for the study of liver diseases-infectious diseases society of America recommendations for testing, managing, and treating hepatitis C virus infection.
      Factors associated with the progression of liver disease in patients with treatment-induced viral clearance are partially known and include advanced liver fibrosis, age, male sex, comorbidities (diabetes, steatosis, excess alcohol consumption), and both genetic and epigenetic factors.
      After therapy, HCC risk has been associated with persistently increased GGT15,
      • Huang C.F.
      • Yeh M.L.
      • Tsai P.C.
      • Hsieh M.H.
      • Yang H.L.
      • Hsieh M.Y.
      • et al.
      Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication.
      or AFP levels. These are frequently lowered during therapy with DAAs, possibly due to reduced necroinflammation, but they may remain high in some patients despite viral clearance and normalisation of liver enzymes, preceding the development of either de novo
      • Ogata F.
      • Kobayashi M.
      • Akuta N.
      • Osawa M.
      • Fujiyama S.
      • Kawamura Y.
      • et al.
      Outcome of all-oral direct-acting antiviral regimens on the rate of development of hepatocellular carcinoma in patients with hepatitis C virus genotype 1-related chronic liver disease.
      ,
      • Nakano M.
      • Koga H.
      • Ide T.
      • Kuromatsu R.
      • Hashimoto S.
      • Yatsuhashi H.
      • et al.
      Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: a prospective multicenter cohort study.
      or recurrent
      • Na S.K.
      • Lee S.J.
      • Cho Y.K.
      • Kim Y.N.
      • Choi E.K.
      • Song B.C.
      • et al.
      Aspartate aminotransferase-to-platelet ratio or FIB-4 index predicts the development of hepatocellular carcinoma in chronic hepatitis C patients with sustained virologic response to interferon therapy.
      HCC. Non-invasive markers of liver fibrosis are also very promising, because pre- and/or post-treatment, elevated values of Fibroscan®,
      • Janjua N.Z.
      • Wong S.
      • Darvishian M.
      • Butt Z.A.
      • Yu A.
      • Binka M.
      • et al.
      The impact of SVR from direct-acting antiviral- and interferon-based treatments for HCV on hepatocellular carcinoma risk.
      ,
      • Calleja J.L.
      • Crespo J.
      • Rincón D.
      • Ruiz-Antorán B.
      • Fernandez I.
      • Perelló C.
      • et al.
      Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort.
      FIB-4
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      ,
      • Ide T.
      • Koga H.
      • Nakano M.
      • Hashimoto S.
      • Yatsuhashi H.
      • Higuchi N.
      • et al.
      Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study.
      ,
      • Na S.K.
      • Lee S.J.
      • Cho Y.K.
      • Kim Y.N.
      • Choi E.K.
      • Song B.C.
      • et al.
      Aspartate aminotransferase-to-platelet ratio or FIB-4 index predicts the development of hepatocellular carcinoma in chronic hepatitis C patients with sustained virologic response to interferon therapy.
      and aspartate aminotransferase-to-platelet ratio index (APRI)
      • Na S.K.
      • Lee S.J.
      • Cho Y.K.
      • Kim Y.N.
      • Choi E.K.
      • Song B.C.
      • et al.
      Aspartate aminotransferase-to-platelet ratio or FIB-4 index predicts the development of hepatocellular carcinoma in chronic hepatitis C patients with sustained virologic response to interferon therapy.
      ,
      • Romano A.
      • Angeli P.
      • Piovesan S.
      • Noventa F.
      • Anastassopoulos G.
      • Chemello L.
      • et al.
      Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study.
      also seem to predict HCC after SVR in patients with lower degrees of liver fibrosis. The role of FIB-4 and APRI in predicting HCC was analysed in 295 patients with SVR after IFNα-based therapy.
      • Na S.K.
      • Lee S.J.
      • Cho Y.K.
      • Kim Y.N.
      • Choi E.K.
      • Song B.C.
      • et al.
      Aspartate aminotransferase-to-platelet ratio or FIB-4 index predicts the development of hepatocellular carcinoma in chronic hepatitis C patients with sustained virologic response to interferon therapy.
      Patients with higher scores at the end of treatment were at higher risk of HCC (1.67% incidence for those with APRI >0.5 vs. 0.07% among those with APRI <0.5, p <0.0001; 1.49% incidence for those with a post-treatment FIB-4 ≥2.5 vs. 0.01% among those with FIB-4 <2.5, p = 0.0003). In a very large study on 18,076 Veterans with SVR,
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      544 HCC cases occurred after an average follow-up of 2.9 years. FIB-4 and APRI were measured sequentially before and after therapy in a large subgroup of patients. HCC incidence rates were 3.3–6.5 per 100 person-years (py) in patients with cirrhosis and persistently high FIB-4/APRI. Although lower (0.6–2.8 per 100 py), HCC incidence remained above 1.9 per 100 py for most quarters in patients with cirrhosis and declining FIB-4/APRI, while HCC incidence was constantly low (0.2–1) in those with cirrhosis and low scores. HCC incidence rates remained very low (0.1–0.4) in most patients without cirrhosis, except in those with a high baseline FIB-4/APRI, where the rate varied between 0.4 and 1.6 per 100 py. Thus, a persistent elevation of FIB-4 (>3.25) and/or APRI (>1.5) after viral clearance predicted HCC, even among those without a definite diagnosis of cirrhosis. These simple observations may have important practical implications in terms of risk stratification: while patients with a definite diagnosis of cirrhosis may require long-term surveillance, unless proven otherwise (see below), those without histological or clinical evidence of cirrhosis but with high FIB-4 scores – which can be easily calculated even in non-specialist settings – may still have cirrhosis and a high risk of post-SVR HCC.
      The best risk stratification is, however, achieved by combining risk factors into algorithms. Features under consideration include routine clinical and laboratory parameters collected before therapy (gender, age, presence of diabetes, fibrosis stage at histology or estimated by Fibroscan®, FIB-4 or APRI, presence of oesophageal varices, platelet count, AFP, HCV genotype, history of IFNα-based therapy) and at follow-up (Fibroscan®, FIB-4, APRI, ALT, AFP, albuminemia, and VITRO score)
      • Lleo A.
      • Aglitti A.
      • Aghemo A.
      • Maisonneuve P.
      • Bruno S.
      • Persico M.
      • et al.
      Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.
      ,
      • Pons M.
      • Rodríguez-Tajes S.
      • Esteban J.I.
      • Mariño Z.
      • Vargas V.
      • Lens S.
      • et al.
      Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals.
      ,
      • Semmler G.
      • Binter T.
      • Kozbial K.
      • Schwabl P.
      • Hametner-Schreil S.
      • Zanetto A.
      • et al.
      Non-invasive risk stratification after HCV-eradication in patients with advanced chronic liver disease.
      ,
      • Watanabe T.
      • Tokumoto Y.
      • Joko K.
      • Michitaka K.
      • Horiike N.
      • Tanaka Y.
      • et al.
      Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection.
      • Chun H.S.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • Ahn S.H.
      • Han K.H.
      • et al.
      Design and validation of risk prediction model for hepatocellular carcinoma development after sustained virological response in patients with chronic hepatitis C.
      • Ganne-Carrié N.
      • Azzi J.
      • Dorival C.
      • Cagnot C.
      • Fontaine H.
      • Iusivka-Nzinga C.
      • et al.
      Predictive models for hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C and sustained virological response (SVR) achieved with direct-acting antiviral (DAA) included in the ANRS CO22 hepather cohort.
      • Ogawa E.
      • Takayama K.
      • Hiramine S.
      • Hayashi T.
      • Toyoda K.
      Association between steatohepatitis biomarkers and hepatocellular carcinoma after hepatitis C elimination.
      • Boursier J.
      • Nahon P.
      • Guettier M.
      • Moreau C.
      • Riou J.
      • Audureau E.
      • et al.
      The dynamics of FIB4 after sustained viral response predicts the risk of liver-related complication in HCV cirrhosis (ANRS CO12 CirVir).
      (Table 2). Some of these algorithms allow a reasonable risk stratification (low, intermediate and high HCC risk) but, at the time of writing, none of them has met with international consensus or been incorporated into official recommendations.
      Table 2Selected scoring systems to assess the risk of liver-related events in chronic hepatitis C patients who have achieved SVR.
      Author (year)Components of the scoreOutcomeRisk categoriesRisk of event per groupComments
      Lleo et al., (2019)18Oesophageal varices, platelet count >110 G/L, LS <25 at SVRHCCNo oesophageal varices, platelets >110, LS <25

      No oesophageal varices, platelets ≤110 or LS ≥25

      Any oesophageal varices
      0.4 per 100 py

      1.6 per 100 py

      4.0 per 100 py
      Large (n = 1,927) prospective multicentre
      Watanabe et al. (2019)68Pre-treatment FIB-4 ≥4, end-of-treatment AFP ≥6 ng/mlHCC at 2 yearsLow (score 0)

      Intermediate (1)

      High (2)
      0.4%

      3.2%

      14.4%
      Large (n = 1,212) prospective multicentre
      Chun HS et al. (2020)69HCC-SVR score (male gender, AFP >6 ng/ml, FIB-4 (<1.45, 1.45-3.25, >3.25) at SVRHCC at 6 yearsLow (score 0-2)

      Intermediate (3-7)

      High (8-9)
      0.01%

      0.04%

      0.28%
      Validated

      Low number of events
      Pons et al. (2020)52LS (Fibroscan®) and albuminemia at follow-upHCCLS <10 or LS 10-20 and albuminemia >4.4 g/dl

      LS 10-20 and albuminemia <4.4 g/dl or LS >20
      0.4–0.9 per 100 py

      1.9–3.7 per 100 py
      Two-centre prospective study

      Low number of events
      Ganne-Carrié et al. (2020)70Male gender, age >64 (at SVR), F3 or F4, HCV genotype 3, oesophageal varices, pre-treatment AFP >5.5 ng/ml, APRI >2 at end of therapy, past IFNα-based therapyHCC at 3 yearsLow (<11)

      Intermediate (11-18)

      High (>19-28)
      1.13%

      8.34%

      18%
      Largest prospective study (HEPATHER Cohort, n = 7,752)
      Shiha et al. (2020)56GES Score (male sex, age >54 years, AFP >20 ng/ml, cirrhosis, albuminemia <3.8 g/dl)HCC at 3 yearsLow (≤6)

      Intermediate (6-7.5)

      High (>7.5)
      1.9%

      5.8%

      9.5%
      Two validation cohorts

      Only genotype 4
      Semmler et al., (2020)61LS (Fibroscan®) and von Willebrand factor (in %) to platelets (in G/L) ratio (VITRO) after the end of treatmentCirrhosis decompensation at 3 yearsLS <12.4 kPa and/or VITRO <0.95

      LS 12.4-25.3 and/or VITRO 0.95-3.3

      LS >25.3 and/or VITRO >3.3
      2.7%

      5.6%

      25.6%
      Two validation cohorts

      The score may be used to rule-in or rule-out clinically significant portal hypertension, associated with high or low risk of decompensation, respectively
      Ogawa et al., (2020)71FAST score (Fibroscan® and AST 12 weeks after the end of therapy)HCC (median

      FU 4.2 years)
      FAST score ≥0.35HR 4.42 (95% CI 1.02–19.9, p = 0.043)Risk was adjusted to age, albumin, AFP, PNPLA3 rs738409 genotype, liver stiffness by Fibroscan® and FIB-4 markers at 12 weeks after therapy, NAFLD score
      Alonso-López et al. (2020)74Pre-treatment albuminemia (<4.2 g/dl) and LS (Fibroscan®) (>17.3 kPa), and 1-year decrease in LS (<25.5%)HCC at 3 yearsScore 0

      Score 1

      Score 2

      Score 3
      0%

      2.1%

      5.8%

      16.3%
      Large (n = 993) multicentre cohort with detailed follow-up. Retrospective, incomplete collection of pre-treatment data on comorbidities
      Alonso-López et al. (2020)74Pre-treatment albuminemia (<4.2 g/dl) and FIB-4 (>3.7), and 1-year FIB-4 (>3.3) and GGT (>42 IU/L)HCC at 3 yearsScore 0

      Score 1-2

      Score 3-4

      Score 5-6
      0.4%

      1.7%

      6.5%

      19%
      The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤17.3 kPa, albumin >4.2 g/dl, and 1-year DeltaLSM >25.5%) vs. 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. AFP, alpha-fetoprotein; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; HR, hazard ratio; IFN, interferon; LS(M), liver stiffness (measurement); NAFLD, non-alcoholic fatty liver disease; SVR, sustained virological response; TE, transient elastography.
      An interesting study from Austria
      • Semmler G.
      • Binter T.
      • Kozbial K.
      • Schwabl P.
      • Hametner-Schreil S.
      • Zanetto A.
      • et al.
      Non-invasive risk stratification after HCV-eradication in patients with advanced chronic liver disease.
      deserves a comment as it suggests the use of non-invasive, surrogate markers of portal hypertension (liver stiffness measurement by transient elastography and von Willebrand Factor (in %) / platelet count (in G/L) ratio, or VITRO) to identify patients with SVR who remain at risk of liver decompensation after IFNα-free therapy. In 284 patients, both markers independently predicted hepatic decompensation after SVR. The combined approach (liver stiffness <12.4 kPa and/or VITRO <0.95 at follow-up, corresponding to a lack of clinically significant portal hypertension) enabled the identification of patients at very low risk of decompensation (2.7% at 3 years). Patients with liver stiffness >25.3 kPa and/or VITRO >3.3 at follow-up presented a very high risk (25.6%) of decompensation within 3 years from treatment. Those with intermediate scores had an intermediate risk, but still relatively low (5.6%). This algorithm may be useful to rule-in or rule-out clinically significant portal hypertension, associated with high or low risk of decompensation, respectively.
      Two additional, preliminary studies exploited the detailed database of the French prospective CirVir cohort.
      • Boursier J.
      • Nahon P.
      • Guettier M.
      • Moreau C.
      • Riou J.
      • Audureau E.
      • et al.
      The dynamics of FIB4 after sustained viral response predicts the risk of liver-related complication in HCV cirrhosis (ANRS CO12 CirVir).
      ,
      • Audureau E.
      • Carrat F.
      • Layese R.
      • Cagnot C.
      • Asselah T.
      • Guyader D.
      • et al.
      Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.
      In the first study, a predictive model including FIB-4 at baseline and across follow-up, along with the occurrence of diabetes, enabled stratification of patients into 4 levels of risk (not only of HCC but also of cirrhosis complications). The second study relied on a machine learning approach
      • Audureau E.
      • Carrat F.
      • Layese R.
      • Cagnot C.
      • Asselah T.
      • Guyader D.
      • et al.
      Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.
      to identify different predictors of HCC depending on SVR status. The hope is that these algorithms based on routinely collected variables may facilitate stratification of patients at risk of HCC after SVR in a cost-effective way.
      Finally, a recent multicentre cohort study from Spain underlined the predictive value of dynamic changes in non-invasive fibrosis scores after the end of DAA therapy.
      • Alonso López S.
      • Manzano M.L.
      • Gea F.
      • Gutiérrez M.L.
      • Ahumada A.M.
      • Devesa M.J.
      • et al.
      A model based on noninvasive markers predicts very low hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis.
      The algorithm proposed by these authors could identify a subgroup of patients at very low risk of HCC development across the first 3 years of follow-up. As in other studies,
      • Shiha G.
      • Mousa N.
      • Soliman R.
      • Nnh Mikhail N.
      • Adel Elbasiony M.
      • Khattab M.
      Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: a prospective study.
      ,
      • Watanabe T.
      • Tokumoto Y.
      • Joko K.
      • Michitaka K.
      • Horiike N.
      • Tanaka Y.
      • et al.
      Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection.
      ,
      • Ganne-Carrié N.
      • Azzi J.
      • Dorival C.
      • Cagnot C.
      • Fontaine H.
      • Iusivka-Nzinga C.
      • et al.
      Predictive models for hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C and sustained virological response (SVR) achieved with direct-acting antiviral (DAA) included in the ANRS CO22 hepather cohort.
      longer follow-up data is still required.

      Can we measure factors involved in immune surveillance to predict HCC risk?

      The early claim that DAA therapy may favour oncogenesis
      • Reig M.
      • Mariño Z.
      • Perelló C.
      • Iñarrairaegui M.
      • Ribeiro A.
      • Lens S.
      • et al.
      Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy.
      raised a question regarding the hypothetical interference of antivirals on intrahepatic immune surveillance. However, the available data are contradictory and there is no evidence that any specific factor involved in immune surveillance may predict HCC risk after SVR. A study analysed total RNA extracted from tumour and non-tumour tissues of 20 patients (10 with DAA-induced SVR and 10 controls) using a Nanostring technology targeting immuno-oncology markers.
      • Amaddeo G.
      • Nguyen C.T.
      • Maillé P.
      • Mulé S.
      • Luciani A.
      • Machou C.
      • et al.
      Intrahepatic immune changes after hepatitis C virus eradication by direct-acting antiviral therapy.
      HCV clearance was associated with minor downregulation of interferon-stimulated genes, judged insufficient to promote oncogenesis. Another interesting study analysed the T cell responses to HCC-associated epitopes and plasma cytokine profiles before and during treatment, and after DAA-induced viral clearance.
      • Owusu Sekyere S.
      • Schlevogt B.
      • Mettke F.
      • Kabbani M.
      • Deterding K.
      • Wirth T.C.
      • et al.
      HCC immune surveillance and antiviral therapy of hepatitis C virus infection.
      Importantly, SVR was associated with a reduced T cell reactivity to several immunodominant HCC-associated HLA-A2-restricted epitopes. This was apparently due to altered expression of inflammatory cytokines, especially IL-12. Whether these interesting data can be used to tailor surveillance after SVR remains to be independently validated.

      Genetic and epigenetic factors in oncogenesis

      Recent observations have pinpointed the potential involvement of genetic and epigenetic factors in the development of HCC after SVR.
      Among candidate gene studies, Simili et al.
      • Simili A.
      • Mazzella G.
      • Ravaioli F.
      • Festi D.
      • Bacchi-Reggiani M.L.
      • Porro A.
      • et al.
      Interleukin 28 polymorphisms and hepatocellular carcinoma development after direct acting antiviral therapy for chronic hepatitis C.
      analysed 197 patients with DAA-associated SVR, and found a significant association between the IFNL3 (also known as IL28B) rs12979860 TT genotype and HCC development (odds ratio 4.728; CI 95% 1.222–18.297; p = 0.024), while other markers, including RBP4, TM6SF2, MBOAT7, TIMP1, TIMP2, the NF-kB promoter and, surprisingly, PNPLA3, failed to show any association. Interestingly, a Japanese study on 195 patients with chronic hepatitis C treated with DAAs reported that serum IFN-λ3 levels were significantly higher after SVR in patients who developed HCC, although they bore no correlation with IFNL3 genotypes, in part probably due to the rarity of the rs8099917 genotype GG among Japanese patients.
      • Inoue-Shinomiya E.
      • Murakawa M.
      • Asahina Y.
      • Nakagawa M.
      • Tsuchiya J.
      • Sato A.
      • et al.
      Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.
      Finally, Huang et al.
      • Huang C.F.
      • Wang S.C.
      • Yeh M.L.
      • Huang C.I.
      • Tsai P.C.
      • Lin Z.Y.
      • et al.
      Association of serial serum major histocompatibility complex class I chain-related A measurements with hepatocellular carcinoma in chronic hepatitis C patients after viral eradication.
      analysed variants of the major histocompatibility complex class I chain-related A (MICA) marker rs2596542 in 42 patients who developed HCC and 84 age-, sex- and cirrhosis propensity score-matched controls who did not develop HCC, all after SVR. Although serum MICA levels predicted HCC, the correlation between increased MICA levels and HCC risk was only present in patients with the GG genotype.
      Patients who have cleared HCV after antiviral therapy should undergo prolonged surveillance in case of advanced fibrosis at baseline, or persistence of abnormal liver parameters (e.g. liver enzymes, alfa-fetoprotein, non-invasive markers of liver fibrosis) despite viral eradication.
      Candidate gene-based analyses are subjected to limitations, as they may frequently lead to false positive associations. A genome-wide association (GWA) study carried out on 456 Japanese patients with SVR to IFNα-based therapy, who either developed HCC (n = 123) or did not (n = 333), identified a strong association between the variants rs17047200 AT/TT, situated within the intron of the tolloid like 1 (TLL1) gene, and development of HCC.
      • Matsuura K.
      • Sawai H.
      • Ikeo K.
      • Ogawa S.
      • Iio E.
      • Isogawa M.
      • et al.
      Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection.
      The association was independent of sex, age, hypoalbuminemia, advanced fibrosis, diabetes, and higher post-treatment level of AFP. The finding was confirmed by a validation cohort of 486 patients and reached a GWA level of significance when combining the 2 cohorts. TLL1 is a metalloprotease with activity on procollagen C-propeptides. The authors also showed that TLL1 mRNA expression was increased in 2 different rodent models of liver fibrogenesis, and in liver tissues of patients with fibrosis. The authors suggested that TLL1 may promote carcinogenesis via accelerated fibrogenesis, and later published additional data on a larger cohort, wherein the development of HCC after SVR was independently associated with higher levels of AFP, FIB-4 and the same TLL1 variant.
      • Iio E.
      • Matsuura K.
      • Shimada N.
      • Atsukawa M.
      • Itokawa N.
      • Abe H.
      • et al.
      TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy.
      The association between TLL1 variants and HCC has however been questioned by subsequent, independent studies conducted in different ethnic settings.
      • John M.
      • Metwally M.
      • Mangia A.
      • Romero-Gomez M.
      • Berg T.
      • Sheridan D.
      • et al.
      TLL1 rs17047200 increases the risk of fibrosis progression in Caucasian patients with chronic hepatitis C.
      A study
      • Degasperi E.
      • Galmozzi E.
      • Facchetti F.
      • Farina E.
      • D'Ambrosio R.
      • Soffredini R.
      • et al.
      TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct-acting antivirals.
      analysed the same rs17047200 variant in 452 Caucasian patients with cirrhosis treated with DAAs (96% SVR). The incidence of HCC was the same in those with TLL1 AA (9%) vs. those with the AT/TT variants (7%) (p = 0.55). The TLL1 genotypes were not associated with HCC even after considering another 348 patients without cirrhosis. Therefore, whether the association between the TLL1 marker rs17047200 and HCC may hold true irrespective of ethnicity requires further study.
      Genetic polymorphisms of 4 major genes, i.e. PNPLA3, MBOAT7, TM6SF2 and GCKR, all involved in liver fat accumulation, have recently been incorporated into a genetic risk score together with some clinical predictors (male gender, diabetes and albuminemia).
      • Degasperi E.
      • Galmozzi E.
      • Pelusi S.
      • D'Ambrosio R.
      • Soffredini R.
      • Borghi M.
      • et al.
      Hepatic fat - genetic risk score predicts hepatocellular carcinoma in HCV cirrhotic patients treated with DAAs.
      Although patients with ≥3 risk factors had a significantly higher risk of de novo HCC development during a 4-year follow-up, this study requires independent validation before this risk score can be introduced into clinical practice.
      Liver biopsy cannot be proposed for all patients who have achieved SVR. Nonetheless, the availability of liver tissue after cure may provide invaluable material for interesting molecular analyses of potential prognostic value, such as epigenetic changes. Possibly, fine-needle aspiration biopsy may be proposed as a more acceptable alternative for patients, while being able to provide suitable material for such studies. HCV increases the acetylation of histone H3K27, compared to uninfected controls, leading to mRNA and protein expression changes that persist after viral clearance.
      • Hamdane N.
      • Jühling F.
      • Crouchet E.
      • El Saghire H.
      • Thumann C.
      • Oudot M.A.
      • et al.
      HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response.
      In a humanised mouse model, these changes were associated with liver cancer. Through extensive analysis, these authors correlated H3K27 acetylation with deregulation of certain oncogenic genes in a large cohort of patients with HCV, both before and after cure. HCC risk was associated with increased expression of SPHK1, a lipid kinase that phosphorylates sphingosine leading to the formation of sphingosine-1-phosphate, an important regulator of cell proliferation and apoptosis which is increased in patients with HCC.
      • Cai H.
      • Xie X.
      • Ji L.
      • Ruan X.
      • Zheng Z.
      Sphingosine kinase 1: a novel independent prognosis biomarker in hepatocellular carcinoma.
      The latter finding remains to be confirmed, because in an extensive analysis of sphingolipid changes before and after successful DAA-based therapy in 166 patients with HCV-related cirrhosis,
      • Mücke V.T.
      • Thomas D.
      • Mücke M.M.
      • Waidmann O.
      • Zeuzem S.
      • Sarrazin C.
      • et al.
      Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response.
      de novo HCC development was only associated with increases in serum C24 dihydroceramide, C24:1 dihydroceramide and C16 ceramide levels, while sphingosine-1-phosphate levels were significantly reduced following viral clearance.
      Another important study
      • Perez S.
      • Kaspi A.
      • Domovitz T.
      • Davidovich A.
      • Lavi-Itzkovitz A.
      • Meirson T.
      • et al.
      Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals.
      reported an epigenetic signature associated with HCC persisting after viral clearance. Changes were confirmed in HCV in vitro infection models and reversed by drugs known to inhibit epigenetic modifying enzymes and by the epidermal growth factor receptor inhibitor, erlotinib. The genes identified included WNT10A, JUNB, FOSL2, TNFAIP3, KLF4 and EDN1 (all increased) plus MYCN and PCSK9 (decreased), which are implicated in, among other biological processes, cell differentiation, growth and proliferation, cell death, cell transformation and immune responses.

      Concluding remarks

      This review aimed to address some of the most important features of residual liver disease in patients with chronic hepatitis C who have achieved SVR after antiviral therapy. Currently available evidence supports some simple recommendations for these patients (Fig. 1). Although viral clearance leads to significantly reduced liver-related mortality, subsequent to reduced odds of developing decompensated liver disease or HCC, progressive liver damage may persist in some cases, leading to liver-related morbidity and mortality. Recognising patients who may still require specialised care after SVR is mandatory. While some of these cases are related to liver comorbidities, such as metabolic steatosis, alcohol consumption and diabetes, in other cases the underlying mechanisms are unclear and may involve persisting epigenetic alterations. At the time of writing, EASL recommendations advise surveillance of all patients with advanced liver fibrosis or cirrhosis after SVR, with particular focus on the risk of HCC. It remains to be seen whether this attitude will be maintained in the future, and whether international guidelines will incorporate risk scores to tailor preventive measures and increase their effectiveness. To this aim, scoring systems using readily available variables (e.g. the FIB-4) may prove very useful for risk stratification, especially in non-specialist settings, if their predictive value is confirmed, especially their negative predictive value, i.e. enabling patients at low risk of post-SVR HCC to be excluded from surveillance programmes. Thus, future recommendations will have to consider at what level of risk it is acceptable to forgo surveillance. Although cost-effectiveness analyses have already suggested that a ∼1% yearly incidence of HCC is an appropriate threshold,
      • Farhang Zangneh H.
      • Wong W.W.L.
      • Sander B.
      • Bell C.M.
      • Mumtaz K.
      • Kowgier M.
      • et al.
      Cost effectiveness of hepatocellular carcinoma surveillance after a sustained virologic response to therapy in patients with hepatitis C virus infection and advanced fibrosis.
      any decision on such a sensitive issue will have to reach a wide consensus among all stakeholders.
      Figure thumbnail gr1
      Fig. 1Factors that could be used to devise an algorithm to identify the risk of post-SVR liver-related events. AFP, alpha-fetoprotein; ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4; GGT, gamma-glutamyltransferase; SVR, sustained virological response; VITRO, von Willebrand factor (in %) to platelets (in G/L) ratio.

      Abbreviations

      AFP, alpha-fetoprotein; ALT, alanine aminotransferase; APRI, aminotransferase-to-platelet ratio index; DAA, direct-acting antiviral; FIB-4, fibrosis-4; GGT, gamma-glutamyltransferase; GWA, genome-wide association; HCC, hepatocellular carcinoma; HR, hazard ratio; IFN, interferon; MAFLD, metabolic dysfunction-associated fatty liver disease; MELD, model for end-stage liver disease; MICA, major histocompatibility complex class I chain-related A; py, person-years; TLL1, tolloid like 1; SVR, sustained virological response; VITRO, von Willebrand factor (in %) to platelets (in G/L) ratio.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      Research grant from Gilead Sciences, and Advisory/Speaker fees from Gilead Sciences, Merck, and AbbVie.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The author wishes to thank Sophie Clément, Nicolas Goossens, Eirini Tseligka and Alessio Aghemo for critically revising the manuscript.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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