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Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution

  • Jean-Charles Nault
    Correspondence
    Corresponding author. Address: AP-HP, Hôpitaux universitaires Paris – Seine Saint-Denis, Site Jean Verdier, Pôle d’Activité Cancérologique spécialisée, Service d’Hépatologie, F-93143 Bondy, France. Tel.: +33 1 53 72 51 94; fax: +33 1 53 72 51 92.
    Affiliations
    Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris–Seine Saint-Denis, Site Jean Verdier, Pôle d’Activité Cancérologique Spécialisée, Service d’Hépatologie, Bondy, France

    INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France

    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France

    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR), Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France

    Université Paris Diderot, Institut Universitaire d’Hématologie, Paris, France
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  • Massimo Colombo
    Affiliations
    Division of Gastroenterology and Hepatology, Fondazione IRCCS C. a Granda Ospedale Maggiore Policlinico di Milano, Universita degli Studi di Milano, Milan, Italy
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      Linked Article

      Interferon (IFN)-free regimen using new direct acting antiviral (DAA) is a revolution for the treatment of patients with chronic hepatitis C. More than 95% of patients have a sustained viral response (SVR) using DAA except for genotype 3 virus in cirrhotic patients where SVR is still insufficient [
      • Pawlotsky J.M.
      New hepatitis C therapies: the toolbox, strategies, and challenges.
      ]. If the high rate of SVR seems constant among several clinical trials testing DAA, the impact on complications of cirrhosis is still unknown. We can only speculate from the results of observational studies among compensated cirrhotic patients treated by IFN regimens. In these patients, SVR were obtained mostly by the combination IFN and ribavirin treatments and decreased the occurrence of liver decompensation, of hepatocellular carcinoma and of death [
      • D’Ambrosio R.
      • Colombo M.
      Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression?.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ]. The rate of hepatocellular carcinoma (HCC) occurrence is strongly decreased after SVR but not abolished with an incidence of HCC ranging from 0.4 to 2% per year after viral eradication [
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ]. In contrast, the evidence of decreased liver related complications after viral clearance using DAA is still scarce. Some studies report an improvement of liver function after DAA treatments in patients with decompensated cirrhosis without decreased of mortality and rates of liver transplantation maybe due to the short follow-up after viral clearance [
      • Manns M.
      • Samuel D.
      • Gane E.J.
      • Mutimer D.
      • McCaughan G.
      • Buti M.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
      ]. However, until recently, no studies have reported the impact of DAA treatments on the rate of HCC occurrence in patients without HCC at baseline or on the rate of tumor recurrence after curative treatment of HCC.
      Two studies published in this issue of the Journal reporting increased aggressiveness and rates of HCC recurrence in patients who cleared hepatitis C virus (HCV) with DAAs after achieving a complete response to resection or local ablation, fuel the debate around such a highly unmet clinical need as adjuvant therapy of HCC [
      • Reig M.
      • Marino Z.
      • Perello C.
      • Inarrairaegui M.
      • Ribeiro A.
      • Lens S.
      • et al.
      Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution.
      ,
      • 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.
      ]. Owing to the absence of robust evidence of effectiveness, adjuvant therapy is not recommended by the international societies. Indeed, despite many efforts at bench level to disentangle recurrence caused by pretreatment tumor cells dissemination (metastasis) from a second primary tumor nodule originating from an inflamed liver environment, classification of recurrence still relies on rather disputed chronological criteria [
      • Imamura H.
      • Matsuyama Y.
      • Tanaka E.
      • Ohkubo T.
      • Hasegawa K.
      • Miyagawa S.
      • et al.
      Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.
      ,
      • Wu J.C.
      • Huang Y.H.
      • Chau G.Y.
      • Su C.W.
      • Lai C.R.
      • Lee P.C.
      • et al.
      Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.
      ]. Conventionally, tumors recurring within two years from a curative treatment are classified as a tumor metastasis, a risk that is fueled by high tumor burden and cell dedifferentiation, microscopic vascular invasion, high alpha-fetoprotein level and non-anatomical resection [
      • Zucman-Rossi J.
      • Villanueva A.
      • Nault J.C.
      • Llovet J.M.
      Genetic landscape and biomarkers of hepatocellular carcinoma.
      ]. Conversely, later occurring recurrences fall in the domain of second primary tumors, an event that is driven by degree of liver cell inflammation and proliferation, i.e., severity of the underlying liver disease, and therefore is potentially amenable to prevention by antiviral therapy [
      • Zucman-Rossi J.
      • Villanueva A.
      • Nault J.C.
      • Llovet J.M.
      Genetic landscape and biomarkers of hepatocellular carcinoma.
      ]. With all the caveats of such a fragile classification, evidence has not been gathered to support pharmacological prevention of early tumor recurrence, including the use of molecularly targeted antitumor regimens [
      • Bruix J.
      • Takayama T.
      • Mazzaferro V.
      • Chau G.Y.
      • Yang J.
      • Kudo M.
      • et al.
      Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.
      ]. By the same token, prevention of second primary tumors in patients who achieve a pharmacological control of viral hepatitis, has been reported, yet it remains highly disputed in consideration of many methodological weaknesses of studies [
      • Bruix J.
      • Gores G.J.
      • Mazzaferro V.
      Hepatocellular carcinoma: clinical frontiers and perspectives.
      ]. In the HCV scenario, in fact, a cumulative 74% reduction of tumor recurrence was calculated in a pooled analysis of 10 cohorts of patients treated with IFN-based regimens, however in the face of numerous methodological weaknesses [
      • Singal A.K.
      • Freeman Jr., D.H.
      • Anand B.S.
      Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma.
      ]. In the present issue of the Journal three studies that retrospectively evaluated HCC recurrence in patients who had a small HCC eradicated by resection or ablation while HCV was cleared with DAAs, provided conflicting results with respect to prevention of HCC recurrence. In a multicenter study in Spain of 58 patients and a single center study in Italy of 59 patients, recurrences after curative therapies in DAA treated patients appeared unusually high (28% and 29%, respectively) [
      • Reig M.
      • Marino Z.
      • Perello C.
      • Inarrairaegui M.
      • Ribeiro A.
      • Lens S.
      • et al.
      Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution.
      ,
      • 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.
      ]. In the multicenter study in Spain, recurrence rates were calculated to be higher than those annotated in the placebo arm of the multinational STORM study, which evaluated sorafenib as adjuvant therapy in patients subjected to curative ablation or resection for a HCC of various etiologies [
      • Bruix J.
      • Takayama T.
      • Mazzaferro V.
      • Chau G.Y.
      • Yang J.
      • Kudo M.
      • et al.
      Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.
      ]. Confronted with a recent meta-analysis of 11 studies of adjuvant therapy with IFN (Cabibbo et al. Submitted), the two reports in this issue of the Journal suggest accelerated HCC recurrence after DAA therapy. In fact, the 6-month recurrence rate in 701 untreated patients scrutinized by the meta-analysis ranged between 0 and 12.5% compared to more than 28% of the DAA studies. In contrast, the retrospective scrutiny of the France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) study in France presented in this same issue of the Journal, did not confirm any aggressive and accelerated pattern of recurrence seen in the multicenter study in Spain and in the single center study in Italy. In the ANRS study, in fact, the 6-month recurrence rate was 10.6% in a cohort of 189 patients receiving adjuvant DAA therapy compared to 18.7% in 267 untreated patients [
      • Pol S.
      Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma: The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CIRVIR and CO23 CUPILT cohorts).
      ]. Before attempting any interpretation of the discrepancies between the above mentioned reports, we should acknowledge that an increased aggressiveness and rate of recurrence in the 6-month period following a curative resection or ablation of a HCC is likely to reflect a biological process of cancer cell dissemination rather than metachronous tumorigenesis, the former being unlikely to be prevented by antiviral therapy. One possible explanation for the accelerated rates of HCC recurrence observed in some DAA treated patients could reflect a bias of selection owing to the fact that DAA allowed to treat patients with far impaired liver function with invisible HCCs at imaging, i.e., patients who in the past would never qualify for IFN therapy.
      The mechanism that could explain the high rate of tumor relapse after DAA treatment is one of the main issues rising from these studies. Microenvironment and viral induced inflammation play a key role in chronic liver injury and tumor initiation [
      • Makarova-Rusher O.V.
      • Medina-Echeverz J.
      • Duffy A.G.
      • Greten T.F.
      The yin and yang of evasion and immune activation in HCC.
      ]. In contrast, the immune system has also an anti-tumor function [
      • Grivennikov S.I.
      • Greten F.R.
      • Karin M.
      Immunity, inflammation, and cancer.
      ]. Overall, there is a complex and fragile equilibrium between a pro tumor and anti-tumor function of the immune system. Some studies have proposed that DAA treatment could modify natural killer function and expression of IFN response gene [
      • Meissner E.G.
      • Kohli A.
      • Virtaneva K.
      • Sturdevant D.
      • Martens C.
      • Porcella S.F.
      • et al.
      Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.
      ,
      • Serti E.
      • Park H.
      • Keane M.
      • O’Keefe A.C.
      • Rivera E.
      • Liang T.J.
      • et al.
      Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNalpha.
      ]. One of the hypothesis is a dysregulation of the anti-tumor response after the brutal decrease of HCV viral load induced by DAA that promotes tumor recurrence. Recurrence could be accelerated by DAA boosting the growth of invisible HCC as a consequence of a perturbation of immune surveillance caused by a swift clearance of HCV, a phenomenon that was unlikely in patients exposed to IFN owing the slowly developing antiviral effects of this cytokine coupled with its discrete immune modulatory and anti-proliferative properties. However, this mechanism is purely speculative and no robust preclinical studies support this hypothesis as well as an elusive direct pro oncogenic role of DAA. Overall, the high rate of HCC recurrence after DAA treatments in patients with prior HCC suggests that a close follow-up of these patients remains mandatory as well as a reassessment of these observations in prospective dedicated studies.
      On the other side, in patients with untreated HCV related cirrhosis and without any previous history of HCC, the rate of HCC occurrence varies from 2 to 5% per year [
      • Fattovich G.
      • Stroffolini T.
      • Zagni I.
      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ]. The risk of HCC development is modulated by host features such as gender (male), age, metabolic syndrome and by the severity of the underlying liver disease with a higher rate of HCC occurrence in Child Pugh B and C patients and in patients with portal hypertension [
      • Ganne-Carrie N.
      • Chastang C.
      • Chapel F.
      • Munz C.
      • Pateron D.
      • Sibony M.
      • et al.
      Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis.
      ]. In contrast to observational studies that reported a reduced incidence of HCC after SVR using IFN regimens [
      • D’Ambrosio R.
      • Colombo M.
      Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression?.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ], the study of Conti et al. recently published in the Journal, reports a high incidence (3.17% after 24 weeks of follow-up) of HCC after viral clearance [
      • 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.
      ]. However, IFN treatments were mostly successfully performed in patients with compensated cirrhosis often without clinically significant portal hypertension that have a lower incidence of HCC [
      • D’Ambrosio R.
      • Colombo M.
      Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression?.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ] whereas DAA treatments are currently used in unselected Child Pugh B patients or with significant portal hypertension, a population at high risk of HCC development. Interestingly, Cheung et al. report a decreased HCC incidence in decompensated cirrhotic patients with SVR obtained by DAA compared to patients without SVR despite DAA treatments and compared to a cohort of untreated patients [
      • 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.
      ].
      These different studies bring no strong evidence for an increased risk of HCC occurrence in “HCC naïve” patients treated by DAA. However, the persistent risk of HCC development strongly justifies HCC screening after viral clearance in patients with HCV related cirrhosis.

      Conflict of interest

      Jean-Charles Nault declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      Massimo Colombo: Grant and research support (BMS, Gilead Sciences), advisory committees (Merck, Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, Alfa Wasserman, Intercept), speaking and teaching (Tibotec, Roche, Novartis, Bayer, BMS, Gilead, Sciences, Vertex, Merck, Janssen, AbbVie).

      Authors’ contributions

      Jean-Charles Nault: drafting and revision of the manuscript, approval of the final version of the manuscript.
      Massimo Colombo: drafting and revision of the manuscript, approval of the final version of the manuscript.

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