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Hepatic benefits of HCV cure

  • Vincenza Calvaruso
    Correspondence
    Corresponding author. Address: Gastroenterologia & Epatologia, PROMISE, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy. Tel.: 0039 09123890679, fax: 0039 0916552156.
    Affiliations
    GI & Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
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  • Antonio Craxì
    Affiliations
    GI & Liver Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
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Published:August 06, 2020DOI:https://doi.org/10.1016/j.jhep.2020.08.006

      Summary

      Direct-acting antiviral (DAA)-induced HCV clearance conceivably leads to improved outcomes at all stages of liver disease. However, available data suggest that the maximum measurable benefit is obtained by treating patients before they reach the stage of compensated advanced chronic liver disease (cACLD). Ideally, all patients with chronic hepatitis C should be treated before they develop advanced fibrosis or cirrhosis, since even if sustained virologic response (SVR) reduces the risk of hepatic events (e.g. decompensation and hepatocellular carcinoma [HCC]) and improves survival, further progression of liver disease and adverse outcomes, including hepatic deaths, cannot be entirely avoided. The hepatic venous pressure gradient (HVPG) correlates closely with the stage of liver disease. Measurements of HVPG in patients with severe fibrosis or cirrhosis treated with DAAs show that those with the highest degree of portal hypertension have the lowest probability of a meaningful reduction of portal pressure after SVR, and remain at significant risk of decompensation. Reduced liver stiffness is commonly observed in patients with cACLD but its role in predicting prognosis is yet to be demonstrated. In patients with decompensated cirrhosis, prevention of further decompensation and of HCC is only weakly associated with SVR. Overall, the main clinical predictors of a high risk of HCC in patients who obtain SVR on DAAs are all indexes strongly reflecting advanced fibrosis and impaired hepatic function. Long-term follow-up of large real-life cohorts of patients treated at all stages of liver disease, but mainly those with mild to moderate fibrosis, will be needed to confirm the impact of SVR among diverse HCV-infected populations and, more importantly, to better stratify patients at higher risk of complications in order to define their correct surveillance.

      Keywords

      Linked Article

      Introduction

      Given their almost universal effectiveness and tolerability, as well as their rapidly reducing costs, direct-acting antivirals (DAAs) are considered standard of care for all individuals with chronic HCV infection, regardless of the stage of liver disease.
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      While containment and ultimately control of HCV at a global level over the next decade has become a realistic goal, justifying expansion of treatment,
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      What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?.
      further evaluation of the clinical benefits of DAAs, especially in the long term, is still needed at the individual patient level. In fact, while the projected number of adverse liver disease outcomes over a relatively short period is high enough to make treatment benefits measurable in patients with fibrotic liver disease (Metavir F3/F4), patients with mild to moderate fibrosis (Metavir F1/F2), if left untreated, would only have a significant number of disease outcomes after years or even decades, and only after progressing to F3/F4 fibrosis. Herein, we re-evaluate the evidence of short and long-term benefit of DAAs for patients with HCV infection according to the stage of disease at the time of treatment.

      Hepatic benefit in patients with mild to moderate fibrosis

      The main objective of obtaining HCV clearance in patients without advanced liver disease, excluding non-hepatic manifestations of HCV,
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      is to avoid progression into fibrotic stages and ultimately prevent disease outcomes such as cirrhosis and hepatocellular carcinoma (HCC). Indeed, antiviral therapy in patients with HCV and mild to moderate fibrosis is usually easier since regimens can be shorter and ribavirin is never needed. Reducing the progression of fibrosis is not the only objective, since HCV clearance eliminates the risk of transmitting HCV, an issue of major relevance for people who inject drugs, men who have sex with men with high-risk sexual behaviour, incarcerated individuals, patients on long-term haemodialysis, or healthcare workers who perform invasive procedures.
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      performed a cost-effectiveness analysis to compare a staging-guided vs. treat all strategy with interferon-based vs. interferon-free regimens in patients with HCV genotype 1 and concluded that staging fibrosis in these patients is not cost effective for DAAs; thus, the indication to treat or not treat should not be based on the stage of liver disease. These data were later confirmed by Chhatwal et al.
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      who evaluated the cost effectiveness of sofosbuvir and ledipasvir, concluding that treatment not only reduces HCV-related outcomes but is cost-effective in the majority of patients.
      Avoidance of liver biopsy before and after treatment for HCV has nowadays become almost universal, hence we are left without direct proof that F1/F2 hepatic fibrosis actually regresses to an F0 stage with a complete restitutio ad integrum of liver architecture. Also, evidence on the non-invasive evaluation of fibrosis using Fibroscan is scarce in this group of patients. Knop et al.
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      prospectively evaluated the dynamics of liver stiffness (LS) by transient elastography (TE) in patients with chronic HCV infection receiving DAA-based treatment. Stratified by fibrosis stage, like patients classified with F0–F1, patients with F2–F3 had only a marginal LS reduction between baseline and 24 weeks after end of treatment (5.3 vs. 5.2 kPa; p = 0.064) and (8.9 vs. 8.8 kPa; p = 0.060), respectively.
      Finally, data on the real-world effectiveness of new antivirals have been reported by Backus et al.
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      Direct-acting antiviral sustained virologic response: impact on mortality in patients without advanced liver disease.
      who evaluated 103,346 HCV-monoinfected patients without advanced liver disease identified from the Veterans Affairs Hepatitis C Clinical Case Registry. In patients who achieved SVR, with fibrosis-4 (FIB-4) <1.45 or 1.45–3.25, mortality rates were reduced by 46.0% and 63.2%, respectively, compared to patients who did not achieve SVR, and by 66.7% and 70.6%, respectively, compared to untreated patients. These data demonstrate that successfully treating HCV with DAAs in patients without clinically apparent advanced liver disease translates into a significant mortality benefit.
      HCV clearance is a major goal that can be achieved with DAAs regardless of the stage of liver disease. Patients achieving virological cure have better outcomes than non-responders at all disease stages.

      Hepatic benefit in patients with compensated cirrhosis

      Establishing the actual role of HCV clearance in terms of hepatic benefit for patients with advanced fibrosis or cirrhosis is a multifaceted task. While on one hand halting the progression of fibrosis even at a late stage of disease may prove beneficial in terms of prevention of liver decompensation and death, there is no clear evidence that F4 fibrosis may entirely revert. Moreover, when dealing with patients with compensated advanced chronic liver disease (cACLD), the risk of cirrhosis-related outcomes remains significant after HCV clearance. The disconnection between an easily obtainable virologic cure and a disease unmodified in its course is often disappointing for physicians and patients.
      Data on post-clearance disease course from studies carried out in the era of interferon-based therapies are scarcely significant nowadays, owing to the huge selection biases of these populations. Evidence on the medium- and long-term course of individuals with F3/F4 fibrosis is accumulating, but further follow-up is definitely still needed to assess the ultimate impact on different liver outcomes.

      Regression of liver fibrosis

      Studies on interferon-based therapies have shown that liver fibrosis and even cirrhosis may regress in a large percentage of patients with HCV once SVR is achieved.
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      • Bacon B.R.
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      ,
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      A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.
      In 2012, D'Ambrosio et al.
      • D'Ambrosio R.
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      • Donato M.F.
      • Paradis V.
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      A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.
      demonstrated regression of F4 to lesser stages of fibrosis in more than 60% of 38 patients treated with IFN plus ribavirin, a median of 5 years after SVR.
      With the arrival of DAAs and the validation of non-invasive tests (NITs) of liver fibrosis, the use of biopsy in patients with chronic HCV hepatitis has rapidly vanished. Thus, many studies have focused on the improvement of NITs after SVR. Bachofner et al.
      • Bachofner J.A.
      • Valli P.V.
      • Kröger A.
      • Bergamin I.
      • Künzler P.
      • Baserga A.
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      Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index.
      have shown a rapid decrease in LS as measured by TE after treatment with DAAs. At the same time, fibrosis scores (aspartate aminotransferase to platelet ratio index [APRI] and FIB-4) improved significantly. More recently a Spanish study
      • 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.
      evaluated the evolution of LS in more than 500 patients with HCV-associated cACLD who obtained SVR after oral antivirals. The authors observed that after 1 year of follow-up, mean LS after SVR decreased by nearly 30% from baseline. More than 70% of patients had an improvement of LS ≥20% and remarkably almost 40% of the patients achieved an LS <10 kPa at follow-up. This change in LS cannot be explained only by a decrease in actual fibrosis since the time course is too short for significant remodelling. Further long-term longitudinal evaluations of the dynamics of LS changes should be performed to consolidate results and to assess if they are associated with a better disease outcome.

      Effect on portal hypertension

      The first study showing an impact of SVR on hepatic venous pressure gradient (HVPG) was performed by Mandorfer et al. in 2016
      • 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.
      ; the authors analysed 60 patients with an HVPG measurement before and after DAAs and stratified them according to baseline HVPG (6–9 mmHg; 10–15 mmHg, ≥16 mmHg). They showed that SVR ameliorates portal hypertension across all HVPG strata at baseline. However, an HVPG decrease was less likely in patients with HVPG ≥16 mmHg (more advanced liver dysfunction).
      Further evidence on this issue comes from a Spanish multicentre prospective study,
      • Lens S.
      • Alvarado-Tapias E.
      • Mariño Z.
      • Londoño M.C.
      • 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.
      assessing 226 patients with HCV-related cirrhosis and clinically significant portal hypertension (CSPH). The portal pressure gradient was determined based on HVPG at baseline and 24 weeks after IFN-free therapy. Even if HVPG decreased by 10% or more from baseline in more than 60% of patients, CSPH persisted in 78% of patients, indicating a persistent risk of decompensation despite SVR.
      Both the Austrian and the Spanish study recorded LS by TE. In the first case, LS reduction was a predictor of an HVPG decrease of ≥10%, and follow-up LS had an AUROC of 0.931 for the diagnosis of CSPH.
      • 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.
      Conversely, in the second study, changes in LS did not correlate with HVPG and no reliable cut-off values were found to rule out CSPH after SVR.
      • Lens S.
      • Alvarado-Tapias E.
      • Mariño Z.
      • Londoño M.C.
      • 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.
      More recently, Mandorfer et al.
      • Mandorfer M.
      • Kozbial K.
      • Schwabl P.
      • Chromy D.
      • Semmler G.
      • Stättermayer A.F.
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      evaluated the change in HVPG after SVR as a tool to assess the prognosis of patients with pre-treatment CSPH. An HVPG decrease ≥10% was associated with a significant reduction in the likelihood of hepatic decompensation. Importantly, in the same study, NITs such as TE were inadequate for diagnosing an HVPG reduction ≥10%.
      NITs seem, at least up to now, relatively inconsistent and insensitive for predicting changes of HVPG after DAAs. That said, HVPG measurement, albeit accurate and reproducible, is an invasive technique with limited availability outside specialised centres; hence it cannot be broadly used to assess the ability of SVR to reduce portal hypertension (PHT). In this setting, the role of the best proxy for HVPG, i.e. assessment of gastroesophageal varices (GEVs) by endoscopy (which bears an intrinsic bias owing to intra- and interobserver variability), has only been explored in 2 studies.
      Thabut et al.
      • 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.
      evaluated the rate of PHT progression (development of medium/large EVs in patients with no or small EVs at baseline, or PHT-related bleeding) in a cohort of patients with HCV (most represented) or HBV infection. They found that viral suppression and an absence of EV at inclusion were associated with a reduced risk of PHT progression. The cumulative rates of PHT progression at 1, 3, and 5 years were 1.8%, 4.1%, and 4.1%, respectively, in patients with no EV at inclusion in whom viral suppression was achieved; 0%, 15.7%, and 15.7%, respectively, in patients with grade 1 EV at inclusion who obtained viral suppression; 2.2%, 7.7%, and 14.2%, respectively, in patients with no EV at inclusion in whom viral suppression was not achieved; and 2.7%, 31.7%, and 52.6%, respectively, in patients with grade 1 EV at inclusion without viral suppression (p <0.001). They also evaluated the role of Baveno VI criteria in predicting PHT progression which reached 0%, 0.8%, and 2.5% at 1, 3, and 5 years respectively, in the 136 patients with an initially favourable Baveno VI status vs. 3.9%, 15.9%, and 24.3%, respectively, among the 412 patients with an initially unfavourable Baveno VI status (p <0.001). Furthermore, the authors found that 17 out of 58 patients (28.3%) with HCV who achieved SVR, and had an unfavourable Baveno VI status at inclusion, subsequently developed a favourable Baveno VI status; none of these patients displayed any progression of PHT, while 5 (8.6%) patients whose Baveno VI status remained unfavourable during follow-up experienced progression.
      Puigvehi et al.
      • Puigvehí M.
      • Londoño M.C.
      • Torras X.
      • Lorente S.
      • Vergara M.
      • Morillas R.M.
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV-cirrhotic patients.
      analysed 151 patients with HCV-related cirrhosis who had upper endoscopy before and after HCV clearance, showing that 12.5% of patients without GEVs at baseline developed them after SVR. This rate reached 24% for patients with baseline low-risk GEVs who developed high-risk GEVs. As for studies evaluating HVPG, GEV changes were also studied in relation to LS.
      • Puigvehí M.
      • Londoño M.C.
      • Torras X.
      • Lorente S.
      • Vergara M.
      • Morillas R.M.
      • et al.
      Impact of sustained virological response with DAAs on gastroesophageal varices and Baveno criteria in HCV-cirrhotic patients.
      The rate of patients with baseline LS ≥25 kPa was significantly higher in those with GEV progression (64.7%) than in those without (39.4%) (p = 0.043). After SVR, the rate of patients with an LS ≥20 kPa was higher in those with GEV progression (66.7%) than in those without (41.9%) (p = 0.043).
      The ultimate hepatic benefit of viral clearance is proportional to the functional class of liver disease reached by the patient at the time of treatment.

      Prevention of decompensation

      In patients with cirrhosis, the likelihood of decompensation is closely related to the degree of portal hypertension. A significant reduction in decompensation rates has been demonstrated in prospective studies of patients with HCV infection and compensated cirrhosis who achieved SVR on IFN-based therapy and were followed-up for at least 5 years.
      • Di Marco V.
      • Calvaruso V.
      • Ferraro D.
      • Bavetta M.G.
      • Cabibbo G.
      • Conte E.
      • et al.
      Effects of eradicating hepatitis C virus infection in patients with cirrhosis differ with stage of portal hypertension.
      ,
      • Nahon P.
      • Bourcier V.
      • Layese R.
      • Audureau E.
      • Cagnot C.
      • Marcellin P.
      • et al.
      Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
      These patients almost all had Child-Pugh A cirrhosis because of the intrinsic limits posed by interferon and thus had a lower probability of decompensation in the short/medium term, regardless of HCV clearance. The possibility of using DAAs to treat patients with the entire spectrum of liver disease regardless of residual liver function and of cytopenia sets a new stage for evaluating the ultimate relevance of HCV clearance in patients with cirrhosis. Due to the relatively short-term follow-up available since the inception of DAAs, only a few studies have assessed the rate of de novo liver decompensation in patients with cACLD after DAA-induced SVR.
      In the French Hepather cohort, Carrat et al.
      • 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.
      failed to demonstrate lower rates of decompensation in patients exposed to DAAs and followed for a median time of 33.4 months, after adjustment for numerous variables including comorbidities such as alcohol consumption, diabetes, and arterial hypertension. However in a cohort of 1,760 patients in South America, Mendizabal et al.
      • Mendizabal M.
      • Piñero F.
      • Ridruejo E.
      • Wolff F.H.
      • Anders M.
      • Reggiardo V.
      • et al.
      Disease progression in patients with hepatitis C virus infection treated with direct-acting antiviral agents.
      found that SVR was significantly associated with a lower incidence of decompensation (hazard ratio [HR] 0.3; 95% CI 0.1–0.8; p = 0.016) in a cohort of 1,760 patients with HCV infection followed for a median follow-up period of 26.2 months. Other data come from our experience with the RESIST-HCV cohort, currently encompassing more than 15,000 patients with HCV treated with DAAs in Sicily. In an analysis of the outcomes of the first 5,000 treated patients, followed for a median of 18 months, decompensation only occurred after SVR in patients with a diagnosis of cirrhosis at baseline, which accounted for 75% of the cohort. In patients with Child-Pugh A cirrhosis achieving SVR made a significant difference to outcome (p = 0.001), while in those with Child-Pugh B cirrhosis the rate of liver decompensation was not associated with SVR (p = 0.44), suggesting that HCV clearance may be of less benefit in these patients.
      • Calvaruso V.
      • Petta S.
      • Cacciola I.
      • Cabibbo G.
      • Cartabellotta F.
      • Di Rosolini M.A.
      • et al.
      Disease outcomes after DAA-induced SVR: data from the resist-HCV cohort.

      Prevention of HCC

      More data are available on the role of SVR on HCC, as most major international HCV cohorts have been analysed with this objective. After an initial warning about the possible relation between treatment with DAAs and a higher risk of HCC occurrence,
      • Conti F.
      • Buonfiglioli F.
      • Scuteri A.
      • Crespi C.
      • Bolondi L.
      • Caraceni P.
      • et al.
      Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.
      most cohort studies did not support this relationship. A meta-analysis of the earlier studies available up to 2017 by Waziry et al.
      • Waziry R.
      • Hajarizadeh B.
      • Grebely J.
      • Amin J.
      • Law M.
      • Danta M.
      • et al.
      Hepatocellularcarcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.
      excluded a higher rate of HCC in patients treated with DAAs vs. those receiving IFN-based therapies and confirmed the positive role of SVR on this outcome, indicating that HCV clearance significantly reduces the risk of HCC even if the oncogenic risk linked to fibrosis and cirrhosis persists in the long term, proportionally to the stage of liver disease.
      Some further large cohort studies confirm this statement. A retrospective analysis of registries from the Veterans Affairs system, evaluating the short/medium term occurrence of HCC in more than 62,000 patients with HCV receiving antivirals, of whom 21,948 were only treated with DAAs, demonstrated that SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted HR 0.29; 95% CI 0.23–0.37), DAA + IFN (adjusted HR 0.48; 95% CI 0.32–0.73) or IFN-only (adjusted HR 0.32; 95% CI 0.28–0.37). The VA study concluded that eradication of HCV infection with DAAs reduces the risk of liver cancer by 71%.
      • Ioannou G.N.
      • Green P.K.
      • Berry K.
      HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.
      This result was later confirmed by Kanwal et al.
      • Kanwal F.
      • Kramer J.
      • Asch S.M.
      • Chayanupatkul M.
      • Cao Y.
      • El-Serag H.B.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
      who focused only on patients treated with DAAs. The prospective study by Carrat et al.,
      • 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.
      in 7,344 French patients (ANRS CO22 Hepather cohort) treated with DAAs and followed for 33.4 months, also confirmed that antiviral treatment was associated with a reduced HCC risk (adjusted HR 0.66; 95% CI 0.46–0.93) after adjustment for several variables correlated to stage of liver disease and comorbidities.
      None of the examined cohorts reported a reduction of HCC cases to near zero, and a recent long-term evaluation of HCC occurrence in the Veterans cohort found that the incidence rate of HCC remained stable between 1.5 to 2.3/100 person-years (PY) in patients with cirrhosis, confirming that the risk of HCC had not regressed 3.6 years after DAA-induced 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.
      Once it was ascertained that the risk of HCC is reduced but not altogether eliminated by DAA-induced HCV clearance, research has been devoted to identifying the potential predictors of HCC in order to tailor surveillance to risk classes. Our group
      • 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.
      analysed 2,249 DAA-treated patients with cirrhosis prospectively included in the RESIST-HCV cohort. We observed a cumulative incidence of HCC at 12 and 24 months of follow-up of 2.6% and 6.1%, respectively, in SVR patients vs. 8% and 23% in patients who did not achieve SVR. We stratified the residual risk of HCC as a function of liver function impairment and stratified patients with HCV-related cirrhosis into different risk profiles according to baseline albumin value and platelet count together with SVR. The predicted cumulative incidence of HCC in the 6 classes of risk identified is reported in Fig. 1, showing that risk profiling is possible using these easily available parameters. Along this line, in their most recent study, Kanwal et al.
      • 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.
      show that patients with cirrhosis and persistently high FIB-4/APRI scores during follow-up had the highest HCC incidence (between 3.3 and 6.5 per 100 PY), while the risk of HCC decreased in patients with a decline of FIB-4/APRI over time, but remained mostly above 1.5 per 100 PY as mentioned. Finally, the most recent report published by Iannou et al.,
      • Ioannou G.N.
      • Beste L.A.
      • Green P.K.
      • Singal A.G.
      • Tapper E.B.
      • Waljee A.K.
      Increased risk for hepatocellular carcinoma persists up to 10 Years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores.
      who retrospectively analysed patients who achieved SVR between 2000 and 2015 in the Veterans Health Administration, over a mean follow-up of 5.4 years, shows that in DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, the annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year. In IFN-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. In conclusion, a decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year.
      Individuals with Child B and C cirrhosis retain a significant risk of worsening, HCC and death after SVR.
      Figure thumbnail gr1
      Fig. 1Predicted cumulative incidence of HCC in risk classes defined by SVR, albumin and platelets. Reproduced from
      • 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.
      with permission.
      HCC, hepatocellular carcinoma; SVR, sustained virological response.
      Table 1Impact of SVR on further decompensation, liver function and mortality in patients with decompensated cirrhosis.
      Patients (%)SVR (%)Further decompensationImprovement of liver functionMortality/LT
      Curry et al.
      • Curry M.P.
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      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      26783%47%3.4%
      Follow-up interrupted at 12 weeks after end of treatment.
      Foster et al.
      • Foster G.R.
      • Irving W.L.
      • Cheung M.C.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • et al.
      Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.
      40980.4%3.7%
      Cheung
      • Cheung M.C.M.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • McLauchlan J.
      • Mutimer D.J.
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      317100%16%15%
      McCaughan et al.
      • McCaughan G.W.
      • Thwaites P.A.
      • Roberts S.K.
      • Strasser S.I.
      • Mitchell J.
      • Morales B.
      • et al.
      Sofosbuvir and daclatasvir therapy in patients with hepatitis C-related advanced decompensated liver disease (MELD ≥ 15).
      10876%61%25%
      Calvaruso et al.
      • Calvaruso V.
      • Mazzarelli C.
      • Milazzo L.
      • Badia L.
      • Pasulo L.
      • Guaraldi G.
      • et al.
      Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program.
      27587.3%48.7%2.5%
      Follow-up interrupted at 12 weeks after end of treatment.
      Gentile et al.
      • Gentile I.
      • Scotto R.
      • Coppola C.
      • Staiano L.
      • Amoruso D.C.
      • De Simone T.
      • et al.
      Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).
      8995.5%3.4%62%
      Verna et al.
      • Verna E.C.
      • Morelli G.
      • Terrault N.A.
      • Lok A.S.
      • Lim J.K.
      • Di Bisceglie A.M.
      • et al.
      DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: realworld experience from HCV-TARGET cohort.
      64290.5%12.9%29%
       Baseline MELD
      • D'Ambrosio R.
      • Aghemo A.
      • Rumi M.G.
      • Ronchi G.
      • Donato M.F.
      • Paradis V.
      • et al.
      A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.
      • Bachofner J.A.
      • Valli P.V.
      • Kröger A.
      • Bergamin I.
      • Künzler P.
      • Baserga A.
      • et al.
      Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index.
      • 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.
      • 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.
      • Lens S.
      • Alvarado-Tapias E.
      • Mariño Z.
      • Londoño M.C.
      • 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.
      • Mandorfer M.
      • Kozbial K.
      • Schwabl P.
      • Chromy D.
      • Semmler G.
      • Stättermayer A.F.
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      4%;6.4%;10.3%
      Rate of mortality at 1, 2 and 3 years of follow-up.
       Baseline MELD (≥16)14.1%;17.6%;28.3%
      Rate of mortality at 1, 2 and 3 years of follow-up.
      Belli et al.
      • 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.
      10333%n.a.
      Pascasio et al.
      • Pascasio J.M.
      • Vinaixa C.
      • Ferrer M.T.
      • Colmenero J.
      • Rubin A.
      • Castells L.
      • et al.
      Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.
      23886%60%
      Rate evaluated only among 122 candidates for delisting with decompensated cirrhosis without HCC.
      n.a.
      HCC, hepatocellular carcinoma; LT, liver transplantation; MELD, model for end-stage liver disease; SVR, sustained virological response.
      Follow-up interrupted at 12 weeks after end of treatment.
      ∗∗ Rate of mortality at 1, 2 and 3 years of follow-up.
      ∗∗∗ Rate evaluated only among 122 candidates for delisting with decompensated cirrhosis without HCC.
      Another relevant issue is the potential cancerous evolution of pre-existing nodules present before DAAs. Marino et al.
      • 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.
      focused on this point and concluded that the presence of indeterminate nodules before starting DAAs is associated with a 3-fold greater risk of HCC. Indeed, the incidence of HCC in Child-Pugh A patients with non-characterised nodules before DAA treatment was 7.24 HCC/100 PY (95% CI 3.62–14.48), compared with 2.77 HCC/100 PY (95% CI 1.29–5.93; p = 0.0087) in Child-Pugh A patients without non-characterised or benign nodules before DAAs. Nahon et al.
      • Nahon P.
      • Layese R.
      • Boursier 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.
      hypothesised this association, highlighting that physicians should perform rigorous recall procedures in the event of unspecified focal lesions before the initiation of DAA therapy.
      Table 2Hazard risk values for overall, liver-related and non-liver-related mortality in SVR vs. non SVR patients according to stage of liver disease before treatment.
      Overall mortality

      HR (95% CI)
      Liver related mortality

      HR (95% CI)
      Non liver related mortality

      HR (95% CI)
      Chronic hepatitis (Backus et al. 2018
      • Backus L.I.
      • Belperio P.S.
      • Shahoumian T.A.
      • Mole L.A.
      Direct-acting antiviral sustained virologic response: impact on mortality in patients without advanced liver disease.
      )
      0.32 (0.29–0.36)NRNR
      Compensated cirrhosis
       (Carrat et al. 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.
      )
      0.34 (0.22–0.55)0·28 (0.15–0.54)0.40 (0.19–0.83)
       (Backus et al. 2019
      • Backus L.I.
      • Belperio P.S.
      • Shahoumian T.A.
      • Mole L.A.
      Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease.
      )
      0.26 (0.22–0.31)NRNR
      Decompensated cirrhosisNRNRNR
      Previous HCC (Cabibbo et al. 2019
      • Cabibbo G.
      • Celsa C.
      • Calvaruso V.
      • Petta S.
      • Cacciola I.
      • Cannavò M.R.
      • et al.
      Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients.
      )
      0.02 (0.00–0.19)NRNR
      NR, not reported; SVR, sustained virological response.
      The authors also observed that patients screened within 6 months before DAA initiation and without detectable nodules had a lower HCC incidence than other DAA-treated patients. This evidence further supports the fact that patients with cirrhosis before SVR must undergo regular ultrasound surveillance because they remain at high risk of developing HCC.

      Reduction of mortality

      The ultimate goal of antiviral therapy is to improve survival. There are now several studies assessing the survival benefit associated with HCV clearance in patients with compensated cirrhosis. In 3,045 patients with cirrhosis from the French ANRS C022 Hepather cohort,
      • 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.
      exposure to DAAs was strongly associated with a decrease in all-cause mortality (HR 0.34; 95% CI 0.22–0.55; p <0.001), liver-related mortality (HR 0.28; 0.15–0.54; p = 0.001) and non-liver-related mortality (HR 0.40; 0.19–0.83; p = 0.015) on adjusted multivariable analyses. Another important result comes from the Veterans cohort, Backus et al.
      • Backus L.I.
      • Belperio P.S.
      • Shahoumian T.A.
      • Mole L.A.
      Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease.
      evaluated the impact of DAA–induced SVR on all-cause mortality in 15,059 HCV-infected patients with advanced liver disease defined by a FIB-4 >3.25. Mortality rates were 12.3 deaths/100 PY for non-SVR patients and 2.6 deaths/100 PY for SVR patients, a reduction of 79% in the latter. In multivariable Cox proportional hazard models controlling for baseline demographics, clinical characteristics, and comorbidities, SVR was independently associated with a reduced risk of death compared to no SVR (HR 0.26; 95% CI 0.22–0.31; p <0.001).
      A more recent evaluation of the Italian cohort of RESIST-HCV aimed to assess the role of SVR on liver and cardiovascular mortality in patients with HCV-related cACLD. By multivariate competing risk analysis, DAA-induced SVR was independently associated with a reduced risk of both liver and cardiovascular mortality.
      • Calvaruso V.
      • Petta S.
      • Cacciola I.
      • Cabibbo G.
      • Cartabellotta F.
      • Di Rosolini M.A.
      • et al.
      Disease outcomes after DAA-induced SVR: data from the resist-HCV cohort.
      The impact of comorbidities remains to be determined. Indeed, Ampuero et al.
      • Ampuero J.
      • Jimeno C.
      • Quiles R.
      • Rosales J.M.
      • Llerena S.
      • Palomo N.
      • et al.
      Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C.
      evaluated the combination of Charlson comorbidity Index, age, and liver function in patients who received DAAs in order to detect a group at high risk of 1- and 2-year mortality. They concluded that, taken as a group, patients with severe comorbidities did not have significant benefits in terms of survival from HCV clearance.

      Benefit in patients with decompensated cirrhosis

      The ability to obtain HCV clearance in patients with decompensated cirrhosis, previously unachievable with IFN, is one of the most impressive results of DAAs. Following demonstrations of improvement in these patients, various studies reporting on outcomes in patients with decompensated cirrhosis on sofosbuvir-based DAA regimens have been published. In 2015, the results of the randomised controlled trial ASTRAL-4, showed that about 50% of patients treated with sofosbuvir-velpatasvir experienced an improvement in Child-Pugh score and model for end-stage liver disease (MELD) score at post-treatment week 12 compared to baseline.
      • Curry M.P.
      • O'Leary J.G.
      • Bzowej N.
      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      One year later, Foster et al.
      • Foster G.R.
      • Irving W.L.
      • Cheung M.C.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • et al.
      Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.
      performed a retrospective analysis in 409 patients included in the NHS England early access program (EAP) and showed that, compared to no treatment, DAAs led to a significant decrease in MELD scores (mean change −0.85) within 6 months. They also established that baseline serum albumin level <35 g/L, low serum sodium level (<135 mmol/L) and age >65 years were associated with a low probability of MELD decrease and therefore less benefit from HCV clearance. In the same cohort Cheung et al.
      • Cheung M.C.M.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • McLauchlan J.
      • Mutimer D.J.
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      later evaluated the occurrence of liver events in the 317 patients who achieved SVR. Over a follow up of 15 months, 15% of patients died or were transplanted and 16% had a major decompensation episode. When compared to the first 6 months from treatment start and to untreated patients, there was a reduction in incidence of decompensation (7% in months 6–15 and 18% in months 0–6 for treated patients vs. 28% in untreated patients).
      Other experiences comes from the compassionate use programmes of daclatasvir in Australia and Italy.
      • McCaughan G.W.
      • Thwaites P.A.
      • Roberts S.K.
      • Strasser S.I.
      • Mitchell J.
      • Morales B.
      • et al.
      Sofosbuvir and daclatasvir therapy in patients with hepatitis C-related advanced decompensated liver disease (MELD ≥ 15).
      ,
      • Calvaruso V.
      • Mazzarelli C.
      • Milazzo L.
      • Badia L.
      • Pasulo L.
      • Guaraldi G.
      • et al.
      Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program.
      In the TOSCAR study, 108 patients with MELD ≥15 were treated with sofosbuvir-daclatasvir for 24 weeks.
      • McCaughan G.W.
      • Thwaites P.A.
      • Roberts S.K.
      • Strasser S.I.
      • Mitchell J.
      • Morales B.
      • et al.
      Sofosbuvir and daclatasvir therapy in patients with hepatitis C-related advanced decompensated liver disease (MELD ≥ 15).
      In the 76% of patients who achieved SVR at 12 weeks after the end of treatment (SVR12), median MELD and Child-Pugh decreased from 16 (IQR 15–17) to 14 (12–17) and 10 (9–11) to 8 (7–9), respectively. However, 27 patients (25%) died or required liver transplantation and a baseline MELD cut-off of 20 has been identified as a predictor of rapid deterioration and need for liver transplant (odds ratio [OR] 13.8; 95% CI 2.78–69.04). By contrast, in the Italian EAP of daclatasvir, the reduction in MELD values between baseline and follow-up week 12 was not significant.
      • Calvaruso V.
      • Mazzarelli C.
      • Milazzo L.
      • Badia L.
      • Pasulo L.
      • Guaraldi G.
      • et al.
      Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program.
      In a more recent prospective Italian multicentre study, Gentile et al.
      • Gentile I.
      • Scotto R.
      • Coppola C.
      • Staiano L.
      • Amoruso D.C.
      • De Simone T.
      • et al.
      Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).
      analysed 89 patients with HCV-related decompensated cirrhosis who received DAA treatment (SVR12: 95.5%) and observed a significant increase in the rate of switch (62%) to Child-Pugh A, at 24 weeks post-SVR.
      A long-term analysis of patients with MELD ≥10 included in the TARGET cohort has just been published by Verna et al.
      • Verna E.C.
      • Morelli G.
      • Terrault N.A.
      • Lok A.S.
      • Lim J.K.
      • Di Bisceglie A.M.
      • et al.
      DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: realworld experience from HCV-TARGET cohort.
      Over a median follow-up of 4 years, a decline of at least 3 MELD points occurred in less than one-third of patients, with a final MELD score <10 only achieved in 25% of cases. The presence of ascites at baseline (OR 0.49; 95% CI 0.24–1.01; p = 0,057) was negatively associated with MELD improvement and baseline MELD <16 was predictive of overall survival (log-rank, p <0.0001).
      One-, 2-, and 3- year survival rates in participants with baseline MELD 10–15 and baseline MELD ≥16 were 96.0%, 93.6%, 89.7% and 85.9%, 82.4%, 71.7%, respectively.
      Other relevant information in this setting can be obtained from studies analysing patients on the waiting list for liver transplant. Belli et al.
      • 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.
      evaluated if the clinical improvements in liver function obtained with DAAs may lead to the delisting of some patients in a real life setting. Among 103 consecutive listed patients without HCC, the cumulative incidence of inactivation 24, 48 and 60 weeks after the start of DAA therapy was 15.5%, 27.6% and 33.3%, respectively, while the cumulative incidence of delisted patients at the same time points was 0%,10.3% and 19.2%, respectively. The 34 patients who were inactivated showed a median improvement of 3.4 points for MELD (delta MELD, p <0.0001) and 2 points for Child-Pugh (delta-Child-Pugh, p <0.0001).
      Further data on this setting have been provided by the Spanish multicentre study of Pascasio et al.
      • Pascasio J.M.
      • Vinaixa C.
      • Ferrer M.T.
      • Colmenero J.
      • Rubin A.
      • Castells L.
      • et al.
      Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.
      in which 29 (24%) out of the 122 patients with decompensated cirrhosis (without HCC) were delisted during the study period after a median time from DAA start of 50 weeks. It must be noted that no patient with a baseline MELD score >20 was excluded from the waiting list, while an MELD higher than 20 at baseline was inversely associated with the probability of inactivation from the list in the study of Belli et al. (HR 0.042; 95% CI 0.013–0.138; p <0.0001). Data on the impact of SVR in patients with decompensated cirrhosis are summarized in Table 1.
      Finally, patients with decompensated cirrhosis after SVR are still at high risk of developing HCC due to the advanced stage of cirrhosis. The analysis of Cheung et al.
      • Cheung M.C.M.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • McLauchlan J.
      • Mutimer D.J.
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      shows no significant difference in incidence of HCC (2.5% in months 6–15 and 4% in months 0–6 for treated patients vs. 4% in untreated patients). A further analysis of HCV Research UK database
      • Mecci A.J.
      • Kemos P.
      • Leen C.
      • Lawson A.
      • Richardson P.
      • Khakoo S.I.
      • et al.
      The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis.
      recorded HCC occurrence in 80 patients over a mean follow-up from start of DAA therapy of 32.4 months. Baseline non-malignant lesions (HR 1.99), thrombocytopenia (HR 1.59) and diabetes (HR 1.68) increased the likelihood of HCC. A higher annual incidence of HCC following SVR in patients with Child-Pugh B (7.8%) than A cirrhosis (2.1%) was estimated based on results from the Italian RESIST-HCV cohort.
      • 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.
      This evidence clearly indicates that in patients with advanced/decompensated cirrhosis the risk of further decompensation and hepatic mortality remain high over the long term regardless of SVR. We still need to define a reliable “point-of-no-return” for recovery of liver function in these patients.
      DAAs improve survival in patients with successfully treated HCC but do not impact on HCC recurrence.

      Benefit in patients with previous or active HCC

      In patients with a previous, supposedly cured, HCC, the impact of SVR on 2 main outcomes should be assessed: HCC recurrence and survival. Concerning the first outcome, we should bear in mind that the estimated likelihood of HCC recurrence after its presumed cure (excluding orthotopic liver transplant) in patients with HCV-related cirrhosis not treated with antivirals is estimated to be 20% and 50% at 1 and 2 years following treatment.
      • Calvaruso V.
      • Craxì A.
      Hepatocellular carcinoma and direct-acting antivirals: a never ending story?.
      Several prospective studies
      • Pol S.
      Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts.
      • Virlogeux V.
      • Pradat P.
      • Hartig-Lavie K.
      • Bailly F.
      • Maynard M.
      • Ouziel G.
      Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.
      • Cabibbo G.
      • Petta S.
      • Calvaruso V.
      • Cacciola I.
      • Cannavò M.R.
      • Madonia S.
      • et al.
      Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study.
      • 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.
      and 2 meta-analyses
      • Waziry R.
      • Hajarizadeh B.
      • Grebely J.
      • Amin J.
      • Law M.
      • Danta M.
      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.
      prove that the risk of HCC recurrence after treatment with DAAs in patients with a history of successful treatment of early HCC is similar, if not lower, than that observed in IFN-treated or DAA-unexposed controls.
      In this setting, the identification of predictors of recurrence has been attempted. Cabibbo et al.
      • Cabibbo G.
      • Petta S.
      • Calvaruso V.
      • Cacciola I.
      • Cannavò M.R.
      • Madonia S.
      • et al.
      Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study.
      observed that previous HCC recurrence and tumour size can be used to stratify the risk of early HCC recurrence in a cohort of 143 consecutive patients with complete response after curative treatment of HCC, subsequently treated with DAAs and monitored by the web-based RESIST-HCV database. Lleo et al.
      • 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.
      analysed 161 patients who received DAAs after a successfully treated HCC; the recurrence rate was 24.8/100 PY during follow-up. Lack of SVR and high alpha-fetoprotein (AFP) were independent predictors of HCC recurrence. A large group of patients (459 patients whose HCC was cured by surgery or ablation before DAAs) was analysed by Nakano et al.
      • Nakano M.1
      • Koga H.1
      • Ide T.1
      • Kuromatsu R.1
      • Hashimoto S.2
      • 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.
      Akin to previous studies, they found that high AFP level and multiple recurrences of HCC before DAA therapy were associated with a high risk of HCC recurrence after curative treatment.
      The latest evaluation of patients with HCV and previous HCC included in the RESIST-HCV cohort gives further information regarding the impact of SVR on survival.
      • Cabibbo G.
      • Celsa C.
      • Calvaruso V.
      • Petta S.
      • Cacciola I.
      • Cannavò M.R.
      • et al.
      Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients.
      By propensity score matching, we compared outcomes of 102 patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs, to those of 102 patients with the same features who did not receive DAAs (ITALICA cohort). Albeit the HCC recurrence rate was not different between treated and untreated patients (HR 0.70; 95% CI 0.44–1.13; p = 0.15), we observed a significant reduction in the rate of hepatic decompensation in the DAA group compared with the No DAA group (HR 0.32; 95% CI 0.13–0.84; p = 0.02). Therefore, overall survival was significantly higher in the treated vs. untreated patients (HR 0.39; 95% CI 0.17–0.91; p = 0.03). SVR was once again a strong predictor of overall survival (HR 0.02; 95% CI 0.00–0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11–0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02–0.38; p = 0.02; Table 2).
      This evidence lends support to the use of DAA therapy in patients with advanced liver disease and successfully treated HCC. These results also have implications regarding whether to treat patients with uncured HCC with DAAs, an issue which is still debated.

      Conclusions

      The hepatic benefits obtained by DAA-induced HCV clearance are inversely proportional in terms of effect size to the stage of liver disease (Fig. 2). Viral elimination will ultimately have a greater overall impact both in terms of survival and overall quality of life if obtained at the earlier stages of liver disease before significant fibrosis develops. Virologic cure will reduce, but not eliminate the risk of disease events in patients with fibrotic liver disease, especially at the stage of cACLD and even more so after decompensation. Although there are now many studies evaluating the role of HCV clearance in patients with advanced liver disease, we still do not have robust data to define the ‘point-of-no-return’ in these patients. The analysis of the clinical variables has in fact been focused on the use of MELD with different cut-offs as a major predictor, but further studies designed with the aim of correctly defining the subset of patients who do not have a chance of reversing their hepatic condition are warranted and therefore strongly encouraged. While a plea must be made at a global level for universal DAA treatment at all stages of liver disease, refining the risk stratification after SVR in order to properly inform patients and assign them to appropriate surveillance when needed remains a major challenge.
      Figure thumbnail gr2
      Fig. 2Hepatic benefit of SVR according to stage of liver disease.
      HCC, hepatocellular carcinoma; SVR, sustained virological response.

      Abbreviations

      APRI, aspartate aminotransferase to platelet ratio index; cACLD, compensated advanced chronic liver disease; CHC, chronic hepatitis C; CSPH, clinical significant portal hypertension; DAA, direct-acting antiviral; EAP, early access programme; FIB-4, fibrosis-4; GEVs, gastroesophageal varices; HCC, hepatocellular carcinoma; HR, hazard ratio; HVPG, hepatic venous pressure gradient; LS, liver stiffness; MELD, model for end-stage liver disease; NIT, non-invasive test; OR, odds ratio; PHT, portal hypertension; PY, person-years; SVR, sustained virological response; SVR12, SVR 12 weeks after end of treatment; TE, transient elastography.

      Financial support

      The author received no financial support to produce this manuscript.

      Authors' contributions

      VC: Study concept, writing the draft and approving the final version. AC: Study concept, writing the draft and approving the final version.

      Conflicts of interest

      Vincenza Calvaruso: Travel Grant, Speaking, and Participation to Advisory Boards for: AbbVie, Gilead Sciences and Intercept. Grant and research support: MSD.
      Antonio Craxì: Research grants, lecturing fees, advisory boards, scientific consultancy for Abbvie, Gilead Sciences, BMS, MSD, Intercept.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      References

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