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Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection?

Open AccessPublished:September 23, 2021DOI:https://doi.org/10.1016/j.ejim.2021.08.023

      Highlights

      • Hepatocellular carcinoma (HCC) and variceal bleeding are common complications of cirrhosis.
      • Direct-acting antivirals (DAA) achieve high sustained virological response (SVR) rates in patients with HCV-related cirrhosis.
      • DAA-induced SVR reduces but not eradicates the risk of cirrhosis-related complications.
      • In absence of validated risk tools, HCC surveillance should continue after SVR for patients with cirrhosis.
      • With favorable Baveno criteria, it appears safe to omit varices surveillance after SVR.

      Abstract

      Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.

      Keywords

      Abbreviations

      AFP
      alpha-fetoprotein
      CSPH
      clinically significant portal hypertension
      CT
      computed tomography
      DAAs
      direct-acting antivirals
      EBL
      endoscopic band ligation
      FIB-4
      Fibrosis-4
      GEV
      gastroesophageal varices
      HCC
      hepatocellular carcinoma
      HBV
      hepatitis B virus
      HCV
      hepatitis C virus
      HVPG
      hepatic venous pressure gradient
      ICER
      incremental cost-effectiveness ratio
      LSM
      liver stiffness measurement
      MRI
      magnetic resonance imaging
      NPV
      negative predictive value
      NSBB
      non-selective beta-blocker
      SVR
      sustained virological response
      US
      ultrasound

      1. General introduction

      Hepatitis C virus (HCV) infection is a major global health problem. In 2019, approximately 58 million people were chronically infected worldwide, and their overall survival is substantially impaired [

      World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Available at: https://www.who.int/publications/i/item/9789240027077externalicon.

      ,
      • Lee MH
      • Yang HI
      • Lu SN
      • Jen CL
      • You SL
      • Wang LY
      • et al.
      Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
      ]. This mainly results from the progressive development of hepatic fibrosis, due to the presence of chronic hepatitis, which may result in cirrhosis. At this universal end-stage of chronic liver disease, patients are at risk of clinical complications such as hepatocellular carcinoma (HCC) and variceal bleeding [
      European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Heimbach JK
      • Kulik LM
      • Finn RS
      • Sirlin CB
      • Abecassis MM
      • Roberts LR
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ,
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. Therefore, surveillance and primary prophylaxis strategies have been developed to optimize patient outcomes. In case of HCV eradication, patients have shown an improved clinical course [
      • van der Meer AJ
      • Feld JJ
      • Hofer H
      • Almasio PL
      • Calvaruso V
      • Fernández-Rodríguez CM
      • et al.
      Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
      ]. In the past, PEG-interferon and ribavirin combination therapy was used. For patients with cirrhosis, this resulted in sustained virological response (SVR) rates of, on average, 30% for genotype 1/4 and 50% for genotype 2/3 [
      • Vezali E
      • Aghemo A
      • Colombo M.
      A review of the treatment of chronic hepatitis C virus infection in cirrhosis.
      ]. Nowadays, two to three months of therapy with direct-acting antivirals (DAAs) results in SVR in >95% of patients with compensated liver disease and ∼80% of those with decompensated cirrhosis, with minimal side effects [
      • Krassenburg LAP
      • Maan R
      • Ramji A
      • Manns MP
      • Cornberg M
      • Wedemeyer H
      • et al.
      Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.
      ]. The general risk of post-SVR liver-related complications increases now that DAAs are more often used in patients with more advanced liver disease. Therefore, the optimal management of patients with cirrhosis and cured HCV infection should be evaluated as studies with prolonged follow-up after DAA-induced SVR are surfacing.

      2. Hepatocellular carcinoma

      Based on older natural history studies, the annual risk of HCC among patients with cirrhosis and ongoing HCV infection ranges from 3% to 7% [
      • Lok AS
      • Seeff LB
      • Morgan TR
      • di Bisceglie AM
      • Sterling RK
      • Curto TM
      • et al.
      Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.
      ,
      • Singal AG
      • Volk ML
      • Jensen D
      • Di Bisceglie AM
      • Schoenfeld PS.
      A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus.
      ]. The incidence of HCV-related HCC has increased over the recent decades, and the peak of HCV-related cirrhosis still lies ahead of us [
      • Beste LA
      • Leipertz SL
      • Green PK
      • Dominitz JA
      • Ross D
      • Ioannou GN
      Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US Veterans, 2001-2013.
      ,
      • Davis GL
      • Alter MJ
      • El–Serag H
      • Poynard T
      • Jennings LW
      Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of hcv prevalence and disease progression.
      ]. If not diagnosed at an early stage, HCC has an extremely poor 5-year survival [
      • Llovet JM
      • Burroughs A
      • Bruix J.
      Hepatocellular carcinoma.
      ]. A recent Swedish national cohort including over 3000 patients with HCC demonstrated median survival rates of 4.6 years following resection, 3.1 years after ablation, 1.4 years after trans-arterial chemoembolization, 0.5 years with sorafenib and 0.3 years with best supportive care [
      • Henriksson M
      • Björnsson B
      • Sternby Eilard M
      • Lindell G
      • Strömberg C
      • Hemmingsson O
      • et al.
      Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv.
      ]. Those who qualified for liver transplantation had the best outcome with 75% survival at 5 years. Although high-level evidence is absent, HCC surveillance in patients with HCV-related cirrhosis is therefore currently advised to detect HCC early, when curative therapy (i.e. resection, ablation or liver transplantation) is still possible [
      European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Heimbach JK
      • Kulik LM
      • Finn RS
      • Sirlin CB
      • Abecassis MM
      • Roberts LR
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ].

      2.1 Detection of HCC

      Current guidelines recommend HCC surveillance using abdominal ultrasound (US) as imaging modality [
      European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Heimbach JK
      • Kulik LM
      • Finn RS
      • Sirlin CB
      • Abecassis MM
      • Roberts LR
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ]. Although safe and inexpensive, the operator-dependent accuracy of US is a disadvantage. Furthermore, especially in patients with a nodular transformed cirrhotic liver it can be difficult to distinguish small malignant lesions from benign histological changes (e.g. regenerative nodules). A recent meta-analysis including 13,367 patients with cirrhosis indicated that the sensitivity of US for HCC of any stage was 84%. However, US was found to be less accurate for the detection of early HCC, with a sensitivity of only 47% [
      • Tzartzeva K
      • Obi J
      • Rich NE
      • Parikh ND
      • Marrero JA
      • Yopp A
      • et al.
      Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
      ]. The addition of alpha-fetoprotein (AFP) (at a frequently used cut-off of 20 ng/mL) to US improves the sensitivity to detect HCC in a curative stage compared with US alone (63% vs. 45%, respectively) [
      • Tzartzeva K
      • Obi J
      • Rich NE
      • Parikh ND
      • Marrero JA
      • Yopp A
      • et al.
      Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
      ]. However, false-positively elevated AFP levels due to HCV-induced inflammation reduce surveillance specificity [
      • Tzartzeva K
      • Obi J
      • Rich NE
      • Parikh ND
      • Marrero JA
      • Yopp A
      • et al.
      Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
      ,
      • Di Bisceglie AM
      • Sterling RK
      • Chung RT
      • Everhart JE
      • Dienstag JL
      • Bonkovsky HL
      • et al.
      Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial.
      ]. Therefore, current guidelines are not conclusive about the value of adding AFP in HCC surveillance [
      European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Heimbach JK
      • Kulik LM
      • Finn RS
      • Sirlin CB
      • Abecassis MM
      • Roberts LR
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ].
      Computed tomography (CT) is not advised as general HCC surveillance strategy. While an improved sensitivity of CT over US for HCC detection is debated, additional downsides include potential contrast-induced nephrotoxicity and repetitive radiation exposure [
      • Pocha C
      • Dieperink E
      • McMaken KA
      • Knott A
      • Thuras P
      • Ho SB.
      Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography - a randomised study.
      ]. Magnetic resonance imaging (MRI) is time-consuming and associated with higher costs. Nevertheless, in a prospective study among 407 patients with a high annual risk of HCC (>5%), MRI did show a significantly higher HCC detection rate (86% vs. 28%) with fewer false-positives than US [
      • Kim SY
      • An J
      • Lim YS
      • Han S
      • Lee JY
      • Byun JH
      • et al.
      MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma.
      ]. Especially in case of severe steatosis, which substantially reduces the reliability of US for the detection of HCC, MRI can be considered. Prospects include shortened MRI scanning protocols, which might overcome the limited availability while preserving a high sensitivity [
      • Singal AG
      • Pillai A
      • Tiro J.
      Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
      ].

      2.2 Efficacy of HCC surveillance in cirrhosis

      A large controlled trial with cluster-randomisation showed that HCCs detected through surveillance were more frequently treated with surgical resection and these patients had a substantially better outcome than those diagnosed with HCC outside of a surveillance program [
      • Zhang BH
      • Yang BH
      • Tang ZY.
      Randomized controlled trial of screening for hepatocellular carcinoma.
      ]. However, the trial was performed over 20 years ago among Chinese patients with predominantly hepatitis B virus (HBV) infection and a median age of ∼40 years. Current practices in patients with HCV-related cirrhosis in Western countries are therefore mainly based on the results of cohort studies. A pivotal meta-analysis included 15,158 patients with cirrhosis (of any aetiology) and HCC from 47 studies [
      • Singal AG
      • Pillai A
      • Tiro J.
      Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
      ]. The 3-year survival rate of 51% following surveillance-detected HCC was significantly higher than the 3-year survival of 28% following HCC detected outside of surveillance (pooled OR 1.9, 95%CI 1.7–2.2), which remained in studies that adjusted for lead-time bias. Increasing the uptake of curative therapy for early HCC may represent a route through which the benefit of surveillance can be maximized. Whereas in a meta-analysis and a more recent cohort study 63–71% of HCC detected through surveillance was early stage HCC, uptake of curative therapy was only 35–52% [
      • Singal AG
      • Pillai A
      • Tiro J.
      Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
      ,
      • Singal AG
      • Mittal S
      • Yerokun OA
      • Ahn C
      • Marrero JA
      • Yopp AC
      • et al.
      Hepatocellular carcinoma screening associated with early tumor detection and improved survival among patients with cirrhosis in the US.
      ]. In multiple European cohorts the median survival after HCC diagnosis was indeed higher among those compliant with the biannual surveillance recommendation, while reducing the imaging interval to three months was not found to be beneficial [
      • Costentin CE
      • Layese R
      • Bourcier V
      • Cagnot C
      • Marcellin P
      • Guyader D
      • et al.
      Compliance with hepatocellular carcinoma surveillance guidelines associated with increased lead-time adjusted survival of patients with compensated viral cirrhosis: a multi-center cohort study.
      ,
      • Santi V
      • Trevisani F
      • Gramenzi A
      • Grignaschi A
      • Mirici-Cappa F
      • Del Poggio P
      • et al.
      Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival.
      ,
      • Trinchet JC
      • Chaffaut C
      • Bourcier V
      • Degos F
      • Henrion J
      • Fontaine H
      • et al.
      Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.
      ,
      • Van Meer S
      • De Man RA
      • Coenraad MJ
      • Sprengers D
      • Van Nieuwkerk KMJ
      • Klümpen HJ
      • et al.
      Surveillance for hepatocellular carcinoma is associated with increased survival: results from a large cohort in the Netherlands.
      ]. Still, there remains controversy regarding the clinical benefit of HCC surveillance in patients with cirrhosis, as not all cohort studies reported positive outcomes [
      • Moon AM
      • Weiss NS
      • Beste LA
      • Su F
      • Ho SB
      • Jin GY
      • et al.
      No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis.
      ]. This might partly explain the low uptake of the clear surveillance recommendations in society guidelines [
      • Singal AG
      • Tiro JA
      • Murphy CC
      • Marrero JA
      • McCallister K
      • Fullington H
      • et al.
      Mailed outreach invitations significantly improve HCC surveillance rates in patients with cirrhosis: a randomized clinical trial.
      ].
      At present, HCC surveillance with biannual abdominal US with or without AFP is considered to be cost-effective in patients with an average annual HCC risk of 1.5% [
      • Heimbach JK
      • Kulik LM
      • Finn RS
      • Sirlin CB
      • Abecassis MM
      • Roberts LR
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ]. While a recent study suggested that MRI-based surveillance might be even more cost-effective among patients with a sufficiently high risk of HCC [
      • Kim HL
      • An J
      • Park JA
      • Park SH
      • Lim YS
      • Lee EK
      Magnetic resonance imaging is cost-effective for hepatocellular carcinoma surveillance in high-risk patients with cirrhosis.
      ], those with cirrhosis and ongoing HCV infection are already well above this threshold. However, among patients with HCV-related cirrhosis and successfully treated HCV infection this should be re-assessed as both the average HCC rate and the risk of other cirrhosis-related complications are substantially reduced by curative treatment.

      2.2.1 Should SVR influence the surveillance strategy?

      While viral eradication might not influence the performance of abdominal US for the detection of HCC in patients with HCV-related cirrhosis in the short term, this may be different for AFP due to decreased hepatic inflammation. Successful antiviral therapy was shown to reduce AFP with hardly any patients remaining above 10 ng/mL in absence of HCC [
      • Oze T
      • Hiramatsu N
      • Yakushijin T
      • Miyazaki M
      • Yamada A
      • Oshita M
      • et al.
      Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.
      ]. Repeating prior studies on the performance of US and AFP for HCC detection following successful DAA therapy is thus relevant. Considering the impact of SVR on liver-related clinical endpoints, cost-efficacy of HCC surveillance for patients with cirrhosis after HCV eradication should be assessed separately as well. This was recently done in a Canadian modelling study, which described a strong and exponential relation between the annual HCC risk and the incremental cost-effectiveness ratios (ICER) of biannual US [
      • Farhang Zangneh H
      • Wong WWL
      • Sander B
      • Bell CM
      • 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.
      ]. The ICER was estimated to be below the commonly suggested willingness to pay threshold of 50,000 Canadian dollars from an annual HCC risk of 1.3% onwards. The assumptions driving these analyses should, however, be reviewed when interpreting its results in light of other health care systems. Furthermore, several developments could have lowered the risk cut-off for cost-effective HCC surveillance post-SVR. First, the clinical efficacy of surveillance might have increased over time as improved US quality could have eased the detection of HCC, although this can be challenged by an increase in fatty liver disease [
      • Di Bisceglie AM
      • Sterling RK
      • Chung RT
      • Everhart JE
      • Dienstag JL
      • Bonkovsky HL
      • et al.
      Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial.
      ]. Second, there are potentially more life-years to be gained following an early diagnosis due to better HCC management options today [
      • Noone A
      • Howlader N
      • Krapcho M
      • et al.
      SEER cancer statistics review, 1975-2015.
      ]. Third, two multicenter studies indicated that DAA therapy among patients with successfully treated early HCC was independently associated with a lower risk of death (adjusted HR 0.4-0.5) [
      • Singal AG
      • Rich NE
      • Mehta N
      • Branch AD
      • Pillai A
      • Hoteit M
      • et al.
      Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma.
      ,
      • Cabibbo G
      • Celsa C
      • Calvaruso V
      • Petta S
      • Cacciola I
      • Cannavò MR
      • et al.
      Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients.
      ]. Finally, future risk stratification tools could further improve the cost-efficacy of HCC surveillance.

      2.2.2 What is the risk of HCC after SVR?

      Long-term follow-up studies including patients with advanced hepatic fibrosis who were treated with interferon-based therapy indicated that the risk of HCC was reduced approximately 4-fold following SVR [
      • Morgan RL
      • Baack B
      • Smith BD
      • Yartel A
      • Pitasi M
      • Falck-Ytter Y.
      Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
      ,
      • van der Meer AJ
      • Veldt BJ
      • Feld JJ
      • 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.
      ]. Still, successful treatment did not eliminate the HCC risk, as the annual incidence of HCC was still 1.1–1.4% depending on the background population studied [
      • van der Meer AJ
      • Feld JJ
      • Hofer H
      • Almasio PL
      • Calvaruso V
      • Fernández-Rodríguez CM
      • et al.
      Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
      ,
      • El-Serag HB
      • Kanwal F
      • Richardson P
      • Kramer J.
      Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection.
      ]. Regarding DAAs, the first small and uncontrolled studies alarmed the field because of a high rate of HCC occurrence and recurrence after successful DAA therapy. Larger and better-designed cohort studies hereafter soon indicated that the higher HCC rate following DAAs was predominantly observed because DAAs cure patients with more advanced liver disease and inherently higher HCC risk [
      • Innes H
      • Barclay ST
      • Hayes PC
      • Fraser A
      • Dillon JF
      • Stanley A
      • et al.
      The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen.
      ,
      • Ioannou GN
      • Green PK
      • Berry K.
      HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.
      ,
      • Kanwal F
      • Kramer J
      • Asch SM
      • Chayanupatkul M
      • Cao Y
      • El-Serag HB.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
      ]. Importantly, in the largest cohort study including 62,354 chronic HCV-infected patients, the HCC risk reduction with SVR was similar in those cured with DAAs (adjusted HR 0.3, 95%CI 0.2–0.4) and those cured with interferon-based therapy (adjusted HR 0.3, 95%CI 0.3–0.4) [
      • Ioannou GN
      • Green PK
      • Berry K.
      HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.
      ]. Nevertheless, we should expect to encounter HCC after SVR more frequently in the upcoming years since patients with more advanced cirrhosis and higher HCC risk are now treated and cured. Based on current short-term follow-up studies, the annual HCC risk after DAA-induced SVR ranges between 1.0% and 4.3% (Table 1) [
      • van der Meer AJ
      • Veldt BJ
      • Feld JJ
      • 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.
      ,
      • Innes H
      • Barclay ST
      • Hayes PC
      • Fraser A
      • Dillon JF
      • Stanley A
      • et al.
      The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen.
      ,
      • Ioannou GN
      • Green PK
      • Berry K.
      HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.
      ,
      • Kanwal F
      • Kramer J
      • Asch SM
      • Chayanupatkul M
      • Cao Y
      • El-Serag HB.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
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      • Mariño Z
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      Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: relevance of non-characterized nodules.
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      • Park H
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      • Stauber R
      • et al.
      Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment.
      ]. While the annual HCC risk did not decline sufficiently during the first 4 years after DAA-induced SVR, the long-term experience following interferon-induced SVR learned us that there was no further reduction of the annual HCC risk over 10 years of follow-up [
      • van der Meer AJ
      • Feld JJ
      • Hofer H
      • Almasio PL
      • Calvaruso V
      • Fernández-Rodríguez CM
      • et al.
      Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
      ,
      • Kanwal F
      • Kramer JR
      • Asch SM
      • Cao Y
      • Li L
      • El-Serag HB.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      ,
      • Ioannou GN
      • Beste LA
      • Green PK
      • Singal AG
      • Tapper EB
      • Waljee AK
      • 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.
      ].
      Table 1Studies reporting incidence of hepatocellular carcinoma after DAA-induced SVR in patients with HCV-related advanced liver disease.
      Author, yearStudy DesignPatients with SVR and cirrhosis (n)Mean/median Follow-up (years)HCC cases (n)(Calculated) Annual HCC Incidence Rate#
      Cheung 2016*
      • Cheung MCM
      • Walker AJ
      • Hudson BE
      • Verma S
      • McLauchlan J
      • Mutimer DJ
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      Prospective3171.3174.3%
      Kanwal 2017
      • Kanwal F
      • Kramer J
      • Asch SM
      • Chayanupatkul M
      • Cao Y
      • El-Serag HB.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
      Retrospective74951.01391.8%
      Mettke 2018
      • Mettke F
      • Schlevogt B
      • Deterding K
      • Wranke A
      • Smith A
      • Port K
      • et al.
      Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis.
      Prospective1581.362.9%
      Innes 2018
      • Innes H
      • Barclay ST
      • Hayes PC
      • Fraser A
      • Dillon JF
      • Stanley A
      • et al.
      The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen.
      Retrospective2721.7122.5%
      Romano 2018
      • 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.
      Prospective24971.4 (IQR 1.0-1.9)311.0%
      Ioannou 2018
      • Ioannou GN
      • Green PK
      • Beste LA
      • Mun EJ
      • Kerr KF
      • Berry K.
      Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C.
      Retrospective76892.03442.2%
      Calvaruso 2018
      • 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.
      Prospective21401.2 (Range 6-24)642.6%
      Kozbial 2018
      • 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.
      Retrospective3931.3 (IQR 0.3-3.0)163.3%
      Nahon 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.
      Retrospective2741.8 (IQR 1.1-2.2)71.4%
      Ioannou 2019
      • Ioannou GN
      • Beste LA
      • Green PK
      • Singal AG
      • Tapper EB
      • Waljee AK
      • 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.
      Retrospective75333.0619FIB-4 <3.25: 0.5-1.4% FIB-4 ≥3.25: 2.4-3.8%
      Mariño 2019
      • Mariño Z
      • Darnell A
      • Lens S
      • Sapena V
      • Díaz A
      • Belmonte E
      • et al.
      Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: relevance of non-characterized nodules.
      Retrospective10701.6 (IQR 1.4–1.9)563.1%
      Park 2019
      • Park H
      • Wang W
      • Henry L
      • Nelson DR.
      Impact of all-oral direct-acting antivirals on clinical and economic outcomes in patients with chronic hepatitis C in the United States.
      Retrospective1218**1.2 (SD 0.7)17**1.2%
      Degasperi 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.
      Retrospective5462.1 (range 0.3–3.3)28**3.4% (first year)
      Carrat 2019
      • 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.
      Prospective23292.8 (IQR 1.8-3.4)166**2.2%
      Piñero 2019
      • 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.
      Prospective6531.3 (IQR 0.8-1.9)282.8%
      Shiha 2020
      • 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.
      Prospective17342.0 (SD 0.7)1012.9%
      Tani 2020
      • Tani J
      • Morishita A
      • Sakamoto T
      • Takuma K
      • Nakahara M
      • Fujita K
      • et al.
      Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct–acting antiviral treatment: all Kagawa liver disease group study.
      Retrospective1911.2101.9% (first year)
      Kanwal 2020
      • Kanwal F
      • Kramer JR
      • Asch SM
      • Cao Y
      • Li L
      • El-Serag HB.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      Retrospective69382.9 (SD 0.6)NA+1.3-2.3%
      Pons 2020
      • Pons M
      • Rodríguez-Tajes S
      • Esteban JI
      • 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.
      Prospective5722.9 (range 0.3–3.8)251.5%
      Degasperi 2020
      • Degasperi E
      • Galmozzi E
      • Pelusi S
      • D'Ambrosio R
      • Soffredini R
      • Borghi M
      • et al.
      Hepatic fat—genetic risk score predicts hepatocellular carcinoma in patients with cirrhotic HCV treated with DAAs.
      Retrospective – prospective4523.6 (IQR 0.3-4.8)362.3%
      Tanaka 2020
      • Tanaka Y
      • Ogawa E
      • Huang CF
      • Toyoda H
      • Jun DW
      • Tseng CH
      • et al.
      HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort.
      Retrospective3902.5293%
      Alonso Lopez 2020
      • Alonso López S
      • Manzano ML
      • Gea F
      • Gutiérrez ML
      • Ahumada AM
      • Devesa MJ
      • et al.
      A model based on noninvasive markers predicts very low hepatocellular carcinoma risk after viral response in hepatitis C virus–advanced fibrosis.
      Observational9933.8 (IQR 1.1-4.4)351.5%
      Ogawa 2020
      • Ogawa E
      • Nomura H
      • Nakamuta M
      • Furusyo N
      • Kajiwara E
      • Dohmen K
      • et al.
      Incidence of hepatocellular carcinoma after treatment with sofosbuvir-based or sofosbuvir-free regimens in patients with chronic hepatitis C.
      Observational4433.569$2.9%
      Abe 2020
      • Abe K
      • Wakabayashi H
      • Nakayama H
      • Suzuki T
      • Kuroda M
      • Yoshida N
      • et al.
      Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis.
      Retrospective1883.6192.9%
      Tamaki 2021
      • Tamaki N
      • Kurosaki M
      • Yasui Y
      • Mori N
      • Tsuji K
      • Hasebe C
      • et al.
      Change in fibrosis 4 index as predictor of high risk of incident hepatocellular carcinoma after eradication of hepatitis C virus.
      Retrospective10003.0148$3.4%
      *Only patients with decompensated cirrhosis were included. **Reported number in all DAA-treated patients (not specifically those with SVR). #When the annual HCC rate was not reported, this was calculated based on the presented data. ¥Analyses performed in all DAA-treated patients (not specifically those SVR). +In the entire cohort of 18,076 patients with DAA-induced SVR there were 544 patients who were diagnosed with HCC. The adjusted hazard ratio of cirrhosis with respect to HCC was 4.2 (95%CI 3.3-5.1). $Number of HCC cases not specified for patients with cirrhosis.
      Abbreviations: DAA: direct-acting antivirals. SVR: Sustained Virological Response. HCV: Hepatitis C Virus. HCC: hepatocellular carcinoma. NA: not available. IQR: interquartile range.

      2.2.3 Can non-invasive tools be used to select patients for post-SVR HCC surveillance?

      While the optimal surveillance protocol might vary depending on the HCC rate, the most prudent question is whether risk stratification can reliably identify SVR patients with a negligible risk of HCC. Apart from lacking cost-efficacy, HCC surveillance might be more likely to harm such patients [
      • Rich NE
      • Parikh ND
      • Singal AG.
      Overdiagnosis: an understudied issue in hepatocellular carcinoma surveillance.
      ]. The harms of surveillance require more attention but include emotional distress, financial costs, and physical injuries as a result of invasive diagnostics or even treatment of false-positive nodules. Parameters most frequently associated with HCC risk after interferon-induced SVR included age, ethnicity, features of the metabolic syndrome and non-invasive markers of liver disease severity. In line, a recently developed risk model among American Veterans with HCV-related cirrhosis and SVR showed that such readily available and objective clinical parameters prior to antiviral therapy could accurately assess the risk of HCC after SVR [
      • Ioannou GN
      • Green PK
      • Beste LA
      • Mun EJ
      • Kerr KF
      • Berry K.
      Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C.
      ]. Although the mean follow-up of two years was limited, this cohort registered 344 HCC cases among 7,689 patients with cirrhosis.
      While external validation needs to be awaited before implementation in daily practice, further attention goes towards the predictive relevance of the evolution of non-invasive markers of liver disease severity following DAA-induced SVR [
      • Kanwal F
      • Kramer JR
      • Asch SM
      • Cao Y
      • Li L
      • El-Serag HB.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      ,
      • Pons M
      • Rodríguez-Tajes S
      • Esteban JI
      • 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.
      ,
      • Ioannou GN
      • Beste LA
      • Green PK
      • Singal AG
      • Tapper EB
      • Waljee AK
      • 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.
      ]. The largest study included 7,553 patients with cirrhosis and SVR, of whom 619 were diagnosed with HCC during a mean follow-up of 3.0 years [
      • Ioannou GN
      • Beste LA
      • Green PK
      • Singal AG
      • Tapper EB
      • Waljee AK
      • 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.
      ]. Those with a decline in their Fibrosis-4 Index (FIB-4; score to assess hepatic fibrosis based on age, platelet count, AST and ALT) from ≥3.25 prior to treatment, which indicates a high likelihood of cirrhosis, to <3.25 at SVR showed an HCC incidence of 2.5% per year. This was far above the threshold for cost-effective surveillance. Nevertheless, it was approximately half the incidence of patients with a FIB-4 that persisted ≥3.25 (5.1%/year) [
      • Ioannou GN
      • Beste LA
      • Green PK
      • Singal AG
      • Tapper EB
      • Waljee AK
      • 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.
      ]. The annual HCC risk in patients with cirrhosis and a FIB-4 <3.25 before and after successful DAA therapy was 1.2%, which is still around the cut-off for cost-effective surveillance. While efforts continue, there is currently no validated method to identify patients with HCV-related cirrhosis and SVR who have a low enough HCC risk to omit surveillance [
      • Alonso López S
      • Manzano ML
      • Gea F
      • Gutiérrez ML
      • Ahumada AM
      • Devesa MJ
      • et al.
      A model based on noninvasive markers predicts very low hepatocellular carcinoma risk after viral response in hepatitis C virus–advanced fibrosis.
      ]. Important to consider is that non-invasive liver disease parameters have yet to be validated following HCV eradication, so that the stage of liver disease should be assessed based on pre-treatment values. So far, the diagnostic accuracy of non-invasive tests for assessment of liver fibrosis in patients with SVR has been shown to be suboptimal [
      • Berzigotti A
      • Tsochatzis E
      • Boursier J
      • Castera L
      • Cazzagon N
      • Friedrich-Rust M
      • et al.
      EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis –2021 update.
      ]. To illustrate, liver stiffness measurement (LSM) with Fibroscan®, a non-invasive tool with an accurate diagnostic value for advanced fibrosis or cirrhosis in patients with ongoing HCV infection, may lower or even normalize post-SVR while additional liver biopsy frequently reveals persistent cirrhosis [
      • D'Ambrosio R
      • Aghemo A
      • Fraquelli M
      • Rumi MG
      • Donato MF
      • Paradis V
      • et al.
      The diagnostic accuracy of Fibroscan® for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response.
      ,
      • Sultanik P
      • Kramer L
      • Soudan D
      • Bouam S
      • Meritet J-F
      • Vallet-Pichard A
      • et al.
      The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.
      ]. As the readily available clinical parameters may have insufficient discriminative ability to exclude patients from surveillance, it is important that novel molecular biomarkers and genetic factors are actively explored through innovative translational research [
      • Calvaruso V
      • Bruix J.
      Towards personalized screening for hepatocellular carcinoma: still not there.
      ,
      • Fujiwara N
      • Friedman SL
      • Goossens N
      • Hoshida Y.
      Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.
      ].

      3. Portal hypertension and gastroesophageal varices

      Elevation of the pressure within the mesenteric circulation (i.e. portal hypertension) as a result of cirrhosis is a multifactorial syndrome. Driving factors are increased intrahepatic vascular resistance and increased portal venous blood inflow due to splanchnic vasodilatation. Portal pressure can be estimated by measuring the hepatic venous pressure gradient (HVPG) through catheterisation of the hepatic veins. An HVPG ≥10 mmHg indicates clinically significant portal hypertension (CSPH) [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. Many of the clinical complications of cirrhosis can be attributed to portal hypertension, including the development of gastroesophageal varices (GEV). GEV are shunts between the portal and caval venous systems through which portal blood can bypass the cirrhotic liver. While ectopic varices also exist, variceal bleeding is mostly encountered in case of GEV.
      In general, patients without CSPH do not have GEV [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. However, patients with compensated cirrhosis develop de novo GEV at a rate of approximately 7% per year [
      • D'Amico G
      • Garcia-Tsao G
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      ,
      • Groszmann RJ
      • Garcia-Tsao G
      • Bosch J
      • Grace ND
      • Burroughs AK
      • Planas R
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ,
      • Merli M
      • Nicolini G
      • Angeloni S
      • Rinaldi V
      • De Santis A
      • Merkel C
      • et al.
      Incidence and natural history of small esophageal varices in cirrhotic patients.
      ]. Progression from small to large GEV (cut-off 5 mm) is seen in about 10% each year [
      • Merli M
      • Nicolini G
      • Angeloni S
      • Rinaldi V
      • De Santis A
      • Merkel C
      • et al.
      Incidence and natural history of small esophageal varices in cirrhotic patients.
      ]. When GEV are present, the annual variceal bleeding rate ranges between 5% and 15%, and mainly depends on variceal size, presence of red wale sign (indicating thinning of the variceal wall) and Child-Pugh class as a measure of liver disease severity [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • D'Amico G
      • Garcia-Tsao G
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      ,
      • Merli M
      • Nicolini G
      • Angeloni S
      • Rinaldi V
      • De Santis A
      • Merkel C
      • et al.
      Incidence and natural history of small esophageal varices in cirrhotic patients.
      ,
      • Angeli P
      • Bernardi M
      • Villanueva C
      • Francoz C
      • Mookerjee RP
      • Trebicka J
      • et al.
      EASL clinical practice guidelines for the management of patients with decompensated cirrhosis.
      ]. In contrast, variceal bleeding is seldom seen in patients with an HVPG <12 mmHg [
      • Garcia-Tsao G
      • Groszmann RJ
      • Fisher RL
      • Conn HO
      • Atterbury CE
      • Glickman M.
      Portal pressure, presence of gastroesophageal varices and variceal bleeding.
      ].

      3.1 Primary prophylaxis of variceal bleeding

      Variceal bleeding is a severe cirrhosis-related complication. The 6-week mortality in patients with decompensated cirrhosis is in the range of 10–25%, while mortality in patients with compensated cirrhosis is low [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ,
      • Angeli P
      • Bernardi M
      • Villanueva C
      • Francoz C
      • Mookerjee RP
      • Trebicka J
      • et al.
      EASL clinical practice guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Augustin S
      • Muntaner L
      • Altamirano JT
      • González A
      • Saperas E
      • Dot J
      • et al.
      Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis.
      ,
      • Abraldes JG
      • Villanueva C
      • Bañares R
      • Aracil C
      • Catalina MV
      • García-Pagán JC
      • et al.
      Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy.
      ]. Multiple randomized clinical trials have assessed the clinical efficacy of primary bleeding prophylaxis in patients with high-risk GEV. Both non-selective beta-blockers (NSBB) and endoscopic band ligation (EBL) are effective methods to reduce bleeding incidence (RR 0.6 and 0.4, respectively, when compared with no prophylaxis) [
      • D'Amico G
      • Pagliaro L
      • Bosch J
      • Patch D.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      ,
      • Vadera S
      • Yong CWK
      • Gluud LL
      • Morgan MY.
      Band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices.
      ]. Both primary prophylaxis strategies also improved all-cause mortality (RR 0.55-0.85 [
      • D'Amico G
      • Pagliaro L
      • Bosch J
      • Patch D.
      Pharmacological treatment of portal hypertension: an evidence-based approach.
      ,
      • Vadera S
      • Yong CWK
      • Gluud LL
      • Morgan MY.
      Band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices.
      ]) as most important clinical endpoint. Direct comparison between both primary prophylaxis strategies does not show differences in all-cause mortality [
      • Gluud LL
      • Krag A.
      Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults.
      ]. Therefore, the type of primary prophylaxis should be an individual consideration based on local possibilities, patient preferences, contraindications and adverse events [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. In contrast, secondary prophylaxis after a bleeding episode necessitates combined NSBB and EBL treatment [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ].
      The high mortality of variceal bleeding and effective bleeding prophylaxis justify endoscopic monitoring of the development of GEV, which is thus recommended for patients with cirrhosis [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. In recent years, research efforts have focussed on sparing redundant endoscopies. This has led to establishment of the Baveno criteria [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. These indicate that screening can be safely omitted in patients with ongoing HCV infection in case of a LSM value <20 kPa and a platelet count >150 × 109/L [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ], as these patients have a low probability of high-risk (i.e. large) GEV. Applying these criteria saves approximately 26% of endoscopies, at the cost of missing only 3% of large GEV [
      • Stafylidou M
      • Paschos P
      • Katsoula A
      • Malandris K
      • Ioakim K
      • Bekiari E
      • et al.
      Performance of Baveno VI and Expanded Baveno VI criteria for excluding high-risk varices in patients with chronic liver diseases: a systematic review and meta-analysis.
      ]. Although small GEV are missed in a larger proportion of patients, these have a low bleeding risk. Moreover, as there is no data supporting the efficacy of primary bleeding prophylaxis in small GEV, this is not recommended by current guidelines [
      • De Franchis R
      • Abraldes JG
      • Bajaj J
      • Berzigotti A
      • Bosch J
      • Burroughs AK
      • et al.
      Expanding consensus in portal hypertension report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension.
      ]. Important to consider, is that most data on portal hypertension and GEV originate from a clinical setting in which there is an ongoing etiological cause of liver disease.

      3.2 Does clinically significant portal hypertension resolve after SVR?

      Successful interferon-based treatment in patients with HCV-related cirrhosis reduces the HVPG and decreases long-term risk of GEV development [
      • Roberts S
      • Gordon A
      • McLean C
      • Pedersen J
      • Bowden S
      • Thomson K
      • et al.
      Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis.
      ,
      • Bruno S
      • Crosignani A
      • Facciotto C
      • Rossi S
      • Roffi L
      • Redaelli A
      • et al.
      Sustained virologic response prevents the development of esophageal varices in compensated, child-pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study.
      ,
      • D'Ambrosio R
      • Aghemo A
      • Rumi MG
      • Primignani M
      • Dell'Era A
      • Lampertico P
      • et al.
      The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ribavirin therapy.
      ]. Data regarding the effect of DAA-based HCV eradication were mostly limited to studies reporting short-term post-treatment HVPG measurements (Supplementary table 1) [
      • Schwabl P
      • Mandorfer M
      • Steiner S
      • Scheiner B
      • Chromy D
      • Herac M
      • et al.
      Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease.
      ,
      • Afdhal N
      • Everson GT
      • Calleja JL
      • McCaughan GW
      • Bosch J
      • Brainard DM
      • et al.
      Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.
      ,
      • Díez C
      • Berenguer J
      • Ibañez-Samaniego L
      • Llop E
      • Pérez-Latorre L
      • Catalina M V
      • et al.
      Persistence of clinically significant portal hypertension after eradication of hepatitis C virus in patients with advanced cirrhosis.
      ,
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ,
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Chromy D
      • Semmler G
      • Stättermayer AF
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      ]. However, prior long-term observations regarding the platelet count, as an alternative non-invasive marker of portal pressure with the possibility of repeated measurements, indicated an ongoing amelioration over the years after interferon-based SVR among patients with cirrhosis [
      • van der Meer AJ
      • Maan R
      • Veldt BJ
      • Feld JJ
      • Wedemeyer H
      • Dufour JF
      • et al.
      Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.
      ]. Importantly, the main HVPG study including 226 DAA-treated patients with CSPH recently reported their 2-year follow-up results. CSPH prevalence dropped to 78% at 24 weeks post-SVR and further decreased to 53–65% at 96 weeks [
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ]. Still, as many as 17% of the patients in this prospective study showed an HVPG increase at 24 weeks following cessation of successful DAA treatment [
      • Lens S
      • Alvarado-Tapias E
      • Mariño Z
      • Londoño MC
      • LLop E
      • Martinez J
      • et al.
      Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis.
      ]. Along with previous decompensation, a high baseline HVPG was independently associated with the persistence of CSPH following HCV eradication. Indeed, 2 years after successful antiviral therapy CSPH remained in 93% of patients with a baseline HVPG ≥16 mmHg versus 40% in those with a baseline HVPG <16 mmHg (p<0.01). This finding is supported by a prior paired HVPG measurement study [
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Chromy D
      • Semmler G
      • Stättermayer AF
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      ] and might explain the lack of a clear improvement in clinical outcome following SVR in patients with decompensated HCV-related cirrhosis [
      • Krassenburg LAP
      • Maan R
      • Ramji A
      • Manns MP
      • Cornberg M
      • Wedemeyer H
      • et al.
      Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.
      ]. More studies with longer follow-up in larger numbers of patients are needed to further elucidate the long-term effects of HCV eradication on the HVPG, which remains one of the best validated surrogate markers for clinical outcome in hepatology.

      3.3 Are GEV developing in patients with HCV-related cirrhosis after SVR?

      As follow-up of patients cured with DAAs extends, more data concerning their effect on the development of GEV is emerging (Supplementary table 2) [
      • Abadía M
      • Montes ML
      • Ponce D
      • Froilán C
      • Romero M
      • Poza J
      • et al.
      Management of betablocked patients after sustained virological response in hepatitis C cirrhosis.
      ,
      • Yuri Y
      • Nishikawa H
      • Enomoto H
      • Yoh K
      • Iwata Y
      • Sakai Y
      • et al.
      Impact of sustained virological response for gastroesophageal varices in hepatitis-C-virus-related liver cirrhosis.
      ,
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ,
      • Ibrahim ES
      • Abdel-Samiee M
      • Youssef MI
      • El-Shazly H
      • Abd-El AEA
      • Sakr AA
      • et al.
      Variceal recurrence 4 years post endoscopic band ligation in hepatitis C patients who achieved sustained virological response with oral direct-acting antiviral therapy.
      ,
      • Nagaoki Y
      • Imamura M
      • Teraoka Y
      • Morio K
      • Fujino H
      • Ono A
      • et al.
      Impact of viral eradication by direct-acting antivirals on the risk of hepatocellular carcinoma development, prognosis, and portal hypertension in hepatitis C virus-related compensated cirrhosis patients.
      ,
      • Giannini EG
      • De Maria C
      • Crespi M
      • Demarzo MG
      • Fazio V
      • Grasso A
      • et al.
      Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C virus clearance in compensated advanced chronic liver disease.
      ]. In a large French cohort including 246 patients with Child-Pugh A cirrhosis due to chronic viral hepatitis (70% HCV), the cumulative rates of de novo large GEV at 1, 3 and 5 years after SVR were 2%, 4% and 4%, respectively [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ]. In contrast, incidences of de novo small or large GEV following viral eradication varied between 9% and 13% after 18 to 36 months of follow-up in three smaller studies, each including approximately 60 patients with cirrhosis [
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ,
      • Nagaoki Y
      • Imamura M
      • Teraoka Y
      • Morio K
      • Fujino H
      • Ono A
      • et al.
      Impact of viral eradication by direct-acting antivirals on the risk of hepatocellular carcinoma development, prognosis, and portal hypertension in hepatitis C virus-related compensated cirrhosis patients.
      ,
      • Giannini EG
      • De Maria C
      • Crespi M
      • Demarzo MG
      • Fazio V
      • Grasso A
      • et al.
      Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C virus clearance in compensated advanced chronic liver disease.
      ]. Among 176 patients with Child-Pugh A cirrhosis who used a maximum tolerable NSBB dosage following ligation of their GEV, the reported recurrence of GEV (size not reported) following DAA-based HCV eradication was 30% after 4 years [
      • Ibrahim ES
      • Abdel-Samiee M
      • Youssef MI
      • El-Shazly H
      • Abd-El AEA
      • Sakr AA
      • et al.
      Variceal recurrence 4 years post endoscopic band ligation in hepatitis C patients who achieved sustained virological response with oral direct-acting antiviral therapy.
      ]. Estimates of post-SVR progression of pre-existing small GEV to large GEV ranged from 16% to 62% [
      • Yuri Y
      • Nishikawa H
      • Enomoto H
      • Yoh K
      • Iwata Y
      • Sakai Y
      • et al.
      Impact of sustained virological response for gastroesophageal varices in hepatitis-C-virus-related liver cirrhosis.
      ,
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ,
      • Nagaoki Y
      • Imamura M
      • Teraoka Y
      • Morio K
      • Fujino H
      • Ono A
      • et al.
      Impact of viral eradication by direct-acting antivirals on the risk of hepatocellular carcinoma development, prognosis, and portal hypertension in hepatitis C virus-related compensated cirrhosis patients.
      ]. Several factors might explain this wide range. First, there are differences in baseline liver disease severity. Factors associated with development of GEV included a platelet count <100 × 109/L, higher LSM value and increased spleen size, which all indicate higher portal pressure [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ]. Second, there might be differences in the presence of the metabolic syndrome and alcohol abuse, even though the first small and likely underpowered studies could not relate these comorbidities favouring liver disease progression to post-SVR GEV development [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ]. Lastly, results might be influenced by differences in the interval between baseline endoscopy and DAA-initiation, and random variation due to small sample sizes. More data from larger cohorts are required to identify clear risk factors and more precise incidence rates. A positive result at the other end of the spectrum is the regression of pre-existing GEV in up to 22% of patients after 2 to 3 years following HCV eradication [
      • Yuri Y
      • Nishikawa H
      • Enomoto H
      • Yoh K
      • Iwata Y
      • Sakai Y
      • et al.
      Impact of sustained virological response for gastroesophageal varices in hepatitis-C-virus-related liver cirrhosis.
      ,
      • Ibrahim ES
      • Abdel-Samiee M
      • Youssef MI
      • El-Shazly H
      • Abd-El AEA
      • Sakr AA
      • et al.
      Variceal recurrence 4 years post endoscopic band ligation in hepatitis C patients who achieved sustained virological response with oral direct-acting antiviral therapy.
      ]. Nevertheless, for now, it seems apparent that endoscopic surveillance cannot be generally omitted in patients with HCV-induced cirrhosis and SVR.

      3.4 Can non-invasive tools be used to select patients for post-SVR varices surveillance?

      In line with reports that found persistent biopsy-proven cirrhosis in patients with normalized LSM values after SVR [
      • D'Ambrosio R
      • Aghemo A
      • Fraquelli M
      • Rumi MG
      • Donato MF
      • Paradis V
      • et al.
      The diagnostic accuracy of Fibroscan® for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response.
      ,
      • Sultanik P
      • Kramer L
      • Soudan D
      • Bouam S
      • Meritet J-F
      • Vallet-Pichard A
      • et al.
      The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.
      ], correlation between post-SVR LSM and portal pressure is limited [
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ,
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Freissmuth C
      • Schwarzer R
      • Stern R
      • et al.
      Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension.
      ]. In the main study reporting HVPG results of 226 patients with baseline CSPH successfully treated for HCV, post-SVR LSM cut-offs of <13.6 kPa and ≥21 kPa had moderate diagnostic value for the persistence of post-SVR CSPH [
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ]. Hence, the correlation between LSM alone and GEV development appears to be far from excellent and insufficiently reliable in clinical practice. Another surrogate marker for portal pressure is spleen stiffness measurement [
      • Wang H
      • Wen B
      • Chang X
      • Wu Q
      • Wen W
      • Zhou F
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      ], however more data are needed in patients with HCV-induced cirrhosis to determine its value in post-SVR follow-up.
      Recently, several studies have validated the Baveno criteria in the setting of HCV eradication [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ,
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ,
      • Giannini EG
      • De Maria C
      • Crespi M
      • Demarzo MG
      • Fazio V
      • Grasso A
      • et al.
      Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C virus clearance in compensated advanced chronic liver disease.
      ]. In a cohort of 246 cases with HBV- or HCV-related cirrhosis (70% HCV), 28% of patients had a favourable Baveno status at the time of viral suppression and none of them harboured large GEV at 1, 3 and 5 years follow-up, compared with 3%, 8% and 8% of those with an unfavourable Baveno status [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ]. In case of LSM >20 kPa and platelet count <150 × 109/L, the number needed to surveil to detect one patient with high-risk GEV in 5 years would thus be 13. In this study, however, de novo small GEV were not considered, while these might be a precursor of large GEV. Furthermore, patients with Child-Pugh B/C cirrhosis or prior decompensation were excluded, while these have the highest risk of disease progression despite SVR. Among HCV patients with an unfavourable Baveno status prior to DAAs, Baveno status became favourable in 29% after SVR and none of these patients showed progression of GEV. In comparison, large GEV developed in 12% of those in whom the Baveno status remained unfavourable [
      • Thabut D
      • Bureau C
      • Layese R
      • Bourcier V
      • Hammouche M
      • Cagnot C
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      ]. Another study confirmed the negative predictive value (NPV) of 100% for high-risk GEV in case of favourable Baveno status post-SVR, although only 15% fulfilled the criteria for a favourable Baveno status [
      • Puigvehí M
      • Londoño MC
      • Torras X
      • Lorente S
      • Vergara M
      • Morillas RM
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV–cirrhotic patients.
      ]. Extending the criteria to a platelet count <110 × 109/L and LSM value ≥25 kPa (also known as the expanded Baveno criteria) increased the proportion of patients with favourable Baveno status to 38%, at the cost of a decline of the NPV to 91%. In summary, also following HCV eradication, the Baveno criteria remain a reliable tool to determine the need for GEV surveillance. Evidently, however, the clinical implication of GEV following HCV eradication is contingent on the incidence and implications of post-SVR variceal bleeding.

      3.5 What is the risk of variceal bleeding after SVR?

      Achieving SVR has been related to a reduced risk of variceal bleeding in patients with advanced liver disease [
      • van der Meer AJ
      • Veldt BJ
      • Feld JJ
      • 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.
      ,
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      ]. Indeed, although GEV progression is often reported, variceal bleeding after DAA-based HCV eradication appears to be rare within the first years, especially in patients without GEV prior to antiviral therapy (Table 2) [
      • Pons M
      • Rodríguez-Tajes S
      • Esteban JI
      • 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.
      ,
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ,
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Chromy D
      • Semmler G
      • Stättermayer AF
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      ,
      • Abadía M
      • Montes ML
      • Ponce D
      • Froilán C
      • Romero M
      • Poza J
      • et al.
      Management of betablocked patients after sustained virological response in hepatitis C cirrhosis.
      ,
      • Giannini EG
      • De Maria C
      • Crespi M
      • Demarzo MG
      • Fazio V
      • Grasso A
      • et al.
      Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C virus clearance in compensated advanced chronic liver disease.
      ,
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      ,
      • Romano J
      • Sims OT
      • Richman J
      • Guo Y
      • Matin T
      • Shoreibah M
      • et al.
      Resolution of ascites and hepatic encephalopathy and absence of variceal bleeding in decompensated hepatitis C virus cirrhosis patients.
      ,
      • Corma-Gómez A
      • Macías J
      • Morano L
      • Rivero A
      • Téllez F
      • Ríos MJ
      • et al.
      Liver stiffness–based strategies predict absence of variceal bleeding in cirrhotic hepatitis C virus–infected patients with and without human immunodeficiency virus coinfection after sustained virological response.
      ]. The average bleeding rate from four prospective studies (including a total of 1323 patients with HCV-related cirrhosis) was 1% after a follow-up of approximately 3 years following SVR [
      • Pons M
      • Rodríguez-Tajes S
      • Esteban JI
      • 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.
      ,
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      ,
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Chromy D
      • Semmler G
      • Stättermayer AF
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      ,
      • Corma-Gómez A
      • Macías J
      • Morano L
      • Rivero A
      • Téllez F
      • Ríos MJ
      • et al.
      Liver stiffness–based strategies predict absence of variceal bleeding in cirrhotic hepatitis C virus–infected patients with and without human immunodeficiency virus coinfection after sustained virological response.
      ]. One of these studies reported no bleeding in patients with favorable expanded Baveno criteria (39% of the cohort) [
      • Corma-Gómez A
      • Macías J
      • Morano L
      • Rivero A
      • Téllez F
      • Ríos MJ
      • et al.
      Liver stiffness–based strategies predict absence of variceal bleeding in cirrhotic hepatitis C virus–infected patients with and without human immunodeficiency virus coinfection after sustained virological response.
      ]. Importantly, most of these studies excluded patients with a history of hepatic decompensation or HCC, as well as individuals with HBV co-infection. In a large retrospective analysis from the Veteran Affairs hospitals in the USA, with a mean follow-up of 3 years, the incidence rate of variceal bleeding was as low as 0.2 per 100 patient-years in patients with cirrhosis without GEV prior to DAAs [
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      ]. This is remarkably low, especially considering the almost exclusively male study population with a high prevalence of comorbidities associated with progressive liver fibrosis. As expected, in patients with pre-existing varices variceal bleeding was more frequent, with incidence rates of 4 and 13 per 100 patient-years depending on whether the patient experienced a prior bleeding episode [
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      ]. Other factors associated with an increased risk of variceal bleeding following SVR in this study were previous ascites, spontaneous bacterial peritonitis and a platelet count <150 × 109/L, while obesity was not [
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      ]. To consider, however, is that the low incidence of variceal bleeding could be due to adequate primary prophylaxis, even though population-based studies indicated that the compliance with guideline recommendations on endoscopic surveillance is far from optimal [
      • Flemming JA
      • Saxena V
      • Shen H
      • Terrault NA
      • Rongey C.
      Facility- and patient-level factors associated with esophageal variceal screening in the USA.
      ,
      • McDonald SA
      • Barclay ST
      • Hutchinson SJ
      • Stanley AJ
      • Fraser A
      • Dillon JF
      • et al.
      Uptake of endoscopic screening for gastroesophageal varices and factors associated with variceal bleeding in patients with chronic hepatitis C infection and compensated cirrhosis, 2005-2016: a national database linkage study.
      ].
      Table 2Studies reporting incidence of variceal bleeding after DAA-induced SVR in patients with HCV-related advanced liver disease.
      Author, yearStudy DesignPatients with SVR and cirrhosis (n)Varices at baseline endoscopy* (no / SV / LV)Previous variceal bleedingBL CP-score (% A/B/C)Mean/median follow-up (years)Variceal bleeding post-SVRBleeding incidence stratified for pre-treatment presence of varices
      Romano 2018
      • Romano J
      • Sims OT
      • Richman J
      • Guo Y
      • Matin T
      • Shoreibah M
      • et al.
      Resolution of ascites and hepatic encephalopathy and absence of variceal bleeding in decompensated hepatitis C virus cirrhosis patients.
      Retrospective37, decompensated cirrhosisn.r.35%Median 7 (IQR 5-11)1.02 (8%)n.r.
      Abadia 2019
      • Abadía M
      • Montes ML
      • Ponce D
      • Froilán C
      • Romero M
      • Poza J
      • et al.
      Management of betablocked patients after sustained virological response in hepatitis C cirrhosis.
      Prospective330 / 7 / 264 (12%)76% / 24% / 0%1.3 (IQR 1.2 – 1.7)1 (3%)Bleeding occurred in patient without prior bleeding
      Moon 2019
      • Moon AM
      • Green PK
      • Rockey DC
      • Berry K
      • Ioannou GN.
      Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.
      Retrospective792723% with varices, size n.r.5%n.r.3.15% of patients with cirrhosis. Rate 1.6 per 100 patients yearsNo varices: 0.2 per 100 patient years Prior varices, no bleeding: 4 per 100 patient years Prior bleeding varices: 13 per 100 patient years
      Mandorfer 2020
      • Mandorfer M
      • Kozbial K
      • Schwabl P
      • Chromy D
      • Semmler G
      • Stättermayer AF
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      Prospective90, BL HVPG≥6 mmHg57 / 17 / 16n.r.72% / 28% / 0%2.9n = 1 (1%)n.r.
      Lens 2020
      • Lens S
      • Baiges A
      • Alvarado-Tapias E
      • LLop E
      • Martinez J
      • Fortea JI
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      Prospective226, BL HVPG≥10 mmHg69 / 89 / 682679% / 21% / 0%3.7 (IQR 3.0 – 3.8)n = 3 (1%)n.r.
      Pons 2020
      • Pons M
      • Rodríguez-Tajes S
      • Esteban JI
      • 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.
      Prospective572168 / 89 / 340All CP-A2.9 (range 0.3-3.8)n = 2 (0.3%)n.r.
      Giannini 2020
      • Giannini EG
      • De Maria C
      • Crespi M
      • Demarzo MG
      • Fazio V
      • Grasso A
      • et al.
      Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C virus clearance in compensated advanced chronic liver disease.
      Prospective5633 / 16 / 7n.r.n.r.n.r.0
      Corma-Gomez 2020
      • Corma-Gómez A
      • Macías J
      • Morano L
      • Rivero A
      • Téllez F
      • Ríos MJ
      • et al.
      Liver stiffness–based strategies predict absence of variceal bleeding in cirrhotic hepatitis C virus–infected patients with and without human immunodeficiency virus coinfection after sustained virological response.
      Prospective435SV or no varices: n.r. LV: 621394% CP-A3.7 (IQR 2.5 – 4.1)n=10 (2%), 0.8 per 100 patient yearsNo prior bleeding varices: 0.6 per 100 patient years Prior bleeding varices: 3/13 (23%)
      *Small varices defined as <5mm or Paquet grade F1. Large varices defined as ≥5 mm or Paquet grade F2 or F3. Abbreviations: DAA: Direct-acting Antivirals. SVR: Sustained Virological Response. HCV: Hepatitis C Virus. SV: Small Varices. LV: Large Varices. BL: Baseline. CP: Child-Pugh. N.r.: not reported. IQR: interquartile range. HVPG: Hepatic Venous Pressure Gradient.

      4. Conclusion

      While virological cure reduces the risk of HCC and variceal bleeding in patients with HCV-related cirrhosis, their risk of these complications is not entirely eradicated with SVR. As our experience following DAA-induced SVR in patients with cirrhosis increases, we will learn how to improve their management including the optimization of surveillance strategies for HCC and GEV. For now, the average risk of HCC in patients with cirrhosis post-SVR appears to remain high enough to justify continued surveillance (Fig. 1). As sufficiently validated prognostic tools to accurately identify patients with a low risk of HCC are not yet available, all patients with HCV-related cirrhosis should currently remain included in HCC surveillance programs irrespective of successful DAA therapy or improved non-invasive parameters of liver disease severity. Future research could result in a more tailored approach. A crucial precondition, however, is that patients are able to undergo HCC treatment with reasonable expectation of clinical benefit. This should thus be repetitively evaluated during the follow-up for each patient.
      Fig 1
      Fig. 1Decisional flowchart for surveillance of hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection. Legend: *Consider to omit HCC surveillance in case of patients who are not expected to be able to undergo HCC treatment with reasonable expectation of clinical benefit. **In absence of signs of further progression of liver fibrosis. HCV: hepatitis C virus. SVR: sustained virological response. HCC: hepatocellular carcinoma.
      In contrast, endoscopic surveillance can be prevented in a substantial proportion of patients with compensated cirrhosis and SVR by applying the Baveno criteria (Fig. 1). In absence of signs of progression of liver disease, relevant GEV are indeed highly unlikely among patients with normal platelets and a LSM <20 kPa. This includes patients in whom these parameters were unfavorable prior to DAAs. In fact, as variceal bleeding after SVR seems uncommon and first variceal bleeding is associated with low mortality in case of compensated cirrhosis, future studies should elaborate on the clinical efficacy and cost-effectiveness of regular endoscopic follow-up following HCV eradication. Using the expanded Baveno criteria to further reduce the number of endoscopies might be considered. Importantly, the proportion of patients with a favorable Baveno status is at least likely to increase with time after SVR, as remodelling of the liver is a gradual process with an ongoing decrease of portal pressure. Of note, this process may be challenged by additional etiological causes of liver disease, of which metabolic syndrome and alcohol use are most prevalent. Further long-term follow-up data in patients with cirrhosis and SVR, also addressing co-factors and the evolution of liver disease parameters over time, are needed to establish optimal surveillance policies after HCV eradication.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      Cas J Isfordink follows a PhD traject in the CELINE (hepatitis C elimination in the Netherlands) initiative sponsored by Gilead. Raoel Maan received financial compensation for consultancy from AbbVie. Robert A de Man has nothing to disclose. Karel J van Erpecum participated in advisory boards of Gilead, Janssen-Cilag, BMS, Abbvie, and MSD and received research grants from Gilead, Janssen-Cilag and the DutchCancer Society (KWF Kankerbestrijding). Adriaan J van der Meer received financial compensation for lecture activities from Zambon, research funding from Gilead, MSD, AbbVie and Zambon, and compensation for consultancy from AOP Orphan.

      Appendix. Supplementary materials

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