- Email: [email protected]
Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution
Accepted Manuscript Editorial Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution Jean-Charles Nault, Massimo Colombo PII: DOI: Reference:
S0168-8278(16)30327-0 http://dx.doi.org/10.1016/j.jhep.2016.07.004 JHEPAT 6179
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
30 June 2016 3 July 2016
Please cite this article as: Nault, J-C., Colombo, M., Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.07.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution Jean-Charles Nault1,2,3, Massimo Colombo4
1 Assistance
Publique–Hô pitaux de Paris (AP-HP), Hô pitaux Universitaires Paris–Seine
Saint-Denis, Site Jean Verdier, Pô le d’Activité Cancé rologique Spé cialisé e, Service d’Hé patologie, Bondy, France. 2 INSERM,
Unité Mixte de Recherche (UMR) 1162, Gé nomique Fonctionnelle des
Tumeurs Solides, Equipe Labellisé e Ligue contre le Cancer, Paris, France. 3
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 , Mé decine, Biologie Humaine (SMBH), Bobigny, France. Université Paris Diderot, Institut Universitaire d’Hé matologie, Paris, France. 4
Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca Granda Ospedale
Maggiore Policlinico di Milano, Universita degli Studi di Milano, Milan, Italy
Corresponding author: Jean-Charles Nault, APHP, Hôpitaux universitaires Paris – Seine Saint-Denis, Site Jean Verdier, Pôle d’Activité Cancérologique spécialisée, Service d’Hépatologie, F-93143 Bondy, France. Email: [email protected]. Phone number: 33 1 53 72 51 94. Fax number: 33 1 53 72 51 92.
Conflicts of interest Jean-Charles Nault: no conflicts of interest 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).
Financial supports : no financial supports for this work Author’s contribution 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.
Interferon-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 [1]. 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 interferon regimens. In these patients, SVR were obtained mostly by the combination interferon and ribavirin treatments and decreased the occurrence of liver decompensation, of hepatocellular carcinoma and of death [2, 3]. The rate of 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 [3]. 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 [4]. 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 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 [5, 6]. 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 a rather disputed chronological criteria [7, 8]. 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 alphafetoprotein level and non-anatomical resection [9]. 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, ie severity of the underlying liver disease, and therefore is potentially amenable to prevention by antiviral therapy [9]. 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 [10]. 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 [11]. 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 interferon-based regimens, however in the face of numerous methodological weaknesses [12]. 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) [5, 6]. 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 [10]. Confronted with a recent meta-analysis of 11 studies of adjuvant therapy with interferon (Cabibbo G, 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 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[13]. 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 interferon 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 [14]. In contrast, the immune system has also an anti tumor function [15]. 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 interferon response gene [16, 17]. 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 interferon 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 [18]. 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 [19]. In contrast to observational studies that reported a reduced incidence of HCC after SVR using interferon regimens[2, 3], the study of Conti F et al recently published in the Journal, reports a high incidence (3.17% after 24 weeks of
follow up) of HCC after viral clearance[6]. However, interferon treatments were mostly successfully performed in patients with compensated cirrhosis often without clinically significant portal hypertension that have a lower incidence of HCC [2, 3] 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 M 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[20]. 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.
[1] Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 2014;146:1176-1192. [2] D'Ambrosio R, Colombo M. Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression? Liver international : official journal of the International Association for the Study of the Liver 2016;36:783790. [3] van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA : the journal of the American Medical Association 2012;308:2584-2593. [4] Manns M, Samuel D, Gane EJ, 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. The Lancet Infectious diseases 2016;16:685-697. [5] 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. Journal of hepatology 2016. [6] Conti F BF, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early Occurrence and Recurrence of Hepatocellular Carcinoma in HCV-related Cirrhosis Treated with Direct Acting Antivirals. Journal of hepatology 2016;In press. [7] 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. Journal of hepatology 2003;38:200-207. [8] Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. Journal of hepatology 2009;51:890-897. [9] Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology 2015;149:1226-1239 e1224. [10] Bruix J, Takayama T, Mazzaferro V, Chau GY, 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. The lancet oncology 2015;16:13441354.
[11] Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 2014;63:844-855. [12] Singal AK, Freeman DH, Jr., Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Alimentary pharmacology & therapeutics 2010;32:851-858. [13] 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). Journal of hepatology 2016. [14] Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. Journal of hepatology 2015;62:1420-1429. [15] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-899. [16] Meissner EG, Kohli A, Virtaneva K, Sturdevant D, Martens C, Porcella SF, et al. Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis. Journal of viral hepatitis 2016;23:496-505. [17] Serti E, Park H, Keane M, O'Keefe AC, Rivera E, Liang TJ, et al. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNalpha. Gut 2016. [18] Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50. [19] 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. Hepatology 1996;23:1112-1118. [20] Foster GR, Irving WL, Cheung MC, Walker AJ, Hudson BE, Verma S, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Journal of hepatology 2016;64:1224-1231.
S0168-8278(16)30327-0 http://dx.doi.org/10.1016/j.jhep.2016.07.004 JHEPAT 6179
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
30 June 2016 3 July 2016
Please cite this article as: Nault, J-C., Colombo, M., Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.07.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution Jean-Charles Nault1,2,3, Massimo Colombo4
1 Assistance
Publique–Hô pitaux de Paris (AP-HP), Hô pitaux Universitaires Paris–Seine
Saint-Denis, Site Jean Verdier, Pô le d’Activité Cancé rologique Spé cialisé e, Service d’Hé patologie, Bondy, France. 2 INSERM,
Unité Mixte de Recherche (UMR) 1162, Gé nomique Fonctionnelle des
Tumeurs Solides, Equipe Labellisé e Ligue contre le Cancer, Paris, France. 3
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 , Mé decine, Biologie Humaine (SMBH), Bobigny, France. Université Paris Diderot, Institut Universitaire d’Hé matologie, Paris, France. 4
Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca Granda Ospedale
Maggiore Policlinico di Milano, Universita degli Studi di Milano, Milan, Italy
Corresponding author: Jean-Charles Nault, APHP, Hôpitaux universitaires Paris – Seine Saint-Denis, Site Jean Verdier, Pôle d’Activité Cancérologique spécialisée, Service d’Hépatologie, F-93143 Bondy, France. Email: [email protected]. Phone number: 33 1 53 72 51 94. Fax number: 33 1 53 72 51 92.
Conflicts of interest Jean-Charles Nault: no conflicts of interest 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).
Financial supports : no financial supports for this work Author’s contribution 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.
Interferon-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 [1]. 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 interferon regimens. In these patients, SVR were obtained mostly by the combination interferon and ribavirin treatments and decreased the occurrence of liver decompensation, of hepatocellular carcinoma and of death [2, 3]. The rate of 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 [3]. 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 [4]. 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 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 [5, 6]. 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 a rather disputed chronological criteria [7, 8]. 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 alphafetoprotein level and non-anatomical resection [9]. 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, ie severity of the underlying liver disease, and therefore is potentially amenable to prevention by antiviral therapy [9]. 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 [10]. 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 [11]. 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 interferon-based regimens, however in the face of numerous methodological weaknesses [12]. 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) [5, 6]. 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 [10]. Confronted with a recent meta-analysis of 11 studies of adjuvant therapy with interferon (Cabibbo G, 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 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[13]. 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 interferon 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 [14]. In contrast, the immune system has also an anti tumor function [15]. 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 interferon response gene [16, 17]. 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 interferon 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 [18]. 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 [19]. In contrast to observational studies that reported a reduced incidence of HCC after SVR using interferon regimens[2, 3], the study of Conti F et al recently published in the Journal, reports a high incidence (3.17% after 24 weeks of
follow up) of HCC after viral clearance[6]. However, interferon treatments were mostly successfully performed in patients with compensated cirrhosis often without clinically significant portal hypertension that have a lower incidence of HCC [2, 3] 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 M 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[20]. 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.
[1] Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 2014;146:1176-1192. [2] D'Ambrosio R, Colombo M. Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression? Liver international : official journal of the International Association for the Study of the Liver 2016;36:783790. [3] van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA : the journal of the American Medical Association 2012;308:2584-2593. [4] Manns M, Samuel D, Gane EJ, 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. The Lancet Infectious diseases 2016;16:685-697. [5] 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. Journal of hepatology 2016. [6] Conti F BF, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early Occurrence and Recurrence of Hepatocellular Carcinoma in HCV-related Cirrhosis Treated with Direct Acting Antivirals. Journal of hepatology 2016;In press. [7] 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. Journal of hepatology 2003;38:200-207. [8] Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. Journal of hepatology 2009;51:890-897. [9] Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology 2015;149:1226-1239 e1224. [10] Bruix J, Takayama T, Mazzaferro V, Chau GY, 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. The lancet oncology 2015;16:13441354.
[11] Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 2014;63:844-855. [12] Singal AK, Freeman DH, Jr., Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Alimentary pharmacology & therapeutics 2010;32:851-858. [13] 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). Journal of hepatology 2016. [14] Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. Journal of hepatology 2015;62:1420-1429. [15] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-899. [16] Meissner EG, Kohli A, Virtaneva K, Sturdevant D, Martens C, Porcella SF, et al. Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis. Journal of viral hepatitis 2016;23:496-505. [17] Serti E, Park H, Keane M, O'Keefe AC, Rivera E, Liang TJ, et al. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNalpha. Gut 2016. [18] Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50. [19] 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. Hepatology 1996;23:1112-1118. [20] Foster GR, Irving WL, Cheung MC, Walker AJ, Hudson BE, Verma S, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Journal of hepatology 2016;64:1224-1231.