Pierre Nahon1, Richard Layese2, Valérie Bourcier3, Carole Cagnot4, Patrick Marcellin5, Dominique Guyader6, Stanislas Pol7, Dominique Larrey8, Victor De Lédinghen9, Denis Ouzan10, Fabien Zoulim11, Dominique Roulot12, Albert Tran13, Jean-Pierre Bronowicki14, Jean-Pierre Zarski15, Ghassan Riachi16, Paul Calès17, Jean-Marie Péron18, Laurent Alric19, Marc Bourlière20, Philippe Mathurin21, Jean-Frédéric Blanc22, Armand Abergel23, Lawrence Serfaty24, Ariane Mallat25, Jean-Didier Grangé26, Pierre Attali27, Yannick Bacq28, Claire Wartelle29, Thông Dao30, Dominique Thabut31, Christophe Pilette32, Christine Silvain33, Christos Christidis34, Eric Nguyen-Khac35, Brigitte Bernard-Chabert36, David Zucman37, Vincent Di Martino38, Angela Sutton39, Françoise Roudot-Thoraval2, Etienne Audureau2. 1. AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France; Université Paris 13, Sorbonne Paris Cité, "Equipe labellisée Ligue Contre le Cancer," F-93206 Saint-Denis, France; Inserm, UMR-1162, "Génomique fonctionnelle des tumeur solides," F-75000, Paris, France. Electronic address: pierre.nahon@jvr.aphp.fr. 2. AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, A-TVB DHU, CEpiA (Clinical Epidemiology and Aging) Unit EA4393, UPEC, F-94000, Créteil, France. 3. AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France. 4. Unit for Basic and Clinical research on Viral Hepatitis, ANRS (France REcherche Nord and sud Sida-HIV Hépatites-FRENSH), France. 5. AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France. 6. CHU Pontchaillou, Service d'Hépatologie, Rennes, France. 7. AP-HP, Hôpital Cochin, Département d'Hépatologie, France; Inserm UMS20 et U1223, Institut Pasteur, Université Paris Descartes, Paris, France. 8. Hôpital Saint Eloi, Service d'Hépatologie, Montpellier, France. 9. Hôpital Haut-Lévêque, Service d'Hépatologie, Bordeaux, France. 10. Institut Arnaud Tzanck, Service d'Hépatologie, St Laurent du Var, France. 11. Hospices Civils de Lyon, Service d'Hépatologie et Université de Lyon, Lyon, France. 12. AP-HP, Hôpital Avicenne, Service d'Hépatologie, Bobigny, France. 13. CHU de Nice, Service d'Hépatologie, F-06202, Cedex 3, Nice, France; Inserm U1065, C3M, Team 8, "Hepatic Complications in Obesity", F-06204, Cedex 3, Nice, France. 14. Inserm 954, CHU de Nancy, Université de Lorraine, Vandoeuvre-les-Nancy, France. 15. Hôpital Michallon, Service d'Hépatologie, Grenoble, France. 16. Hôpital Charles-Nicolle, Service d'Hépatologie, Rouen, France. 17. CHU d'Angers, Service d'Hépato-Gastroentérologie, Angers, France. 18. Hôpital Purpan, Service d'Hépatologie, Toulouse, France. 19. CHU Toulouse, Service de Médecine Interne-Pôle Digestif UMR 152, Toulouse, France. 20. Hôpital Saint Joseph, Service d'Hépatologie, Marseille, France. 21. Hôpital Claude Huriez, Service d'Hépatologie, Lille, France. 22. Hôpital St André, Service d'Hépatologie, Bordeaux, France. 23. Hôpital Hôtel Dieu, Service d'Hépatologie, Clermont-Ferrand, France. 24. AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, Paris, France. 25. AP-HP, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France. 26. AP-HP, Hôpital Tenon, Service d'Hépatologie, Paris, France. 27. AP-HP, Hôpital Paul Brousse, Service d'Hépatologie, Villejuif, France. 28. Hôpital Trousseau, Unité d'Hépatologie, CHRU de Tours, France. 29. Hôpital d'Aix-En-Provence, Service d'Hépatologie, Aix-En-Provence, France. 30. Hôpital de la Côte de Nacre, Service d'Hépatologie, Caen, France. 31. AP-HP, Groupe Hospitalier de La Pitié-Salpêtrière, Service d'Hépatologie, Paris, France. 32. CHU Le Mans, Service d'Hépatologie, Le Mans, France. 33. CHU de Poitiers, Service d'Hépatologie, Poitiers, France. 34. Institut Mutualiste Montsouris, Service d'Hépatologie, Paris, France. 35. Hôpital Amiens Nord, Service d'Hépatologie, Amiens, France. 36. Hôpital Robert Debré, Service d'Hépatologie, Reims, France. 37. Hôpital Foch, Service de Médecine Interne, Suresnes, France. 38. Hôpital Jean Minjoz, Service d'Hépatologie, Besançon, France. 39. CRB (liver disease biobank) Groupe Hospitalier Paris Seine-Saint-Denis BB-0033-00027, Paris, France; AP-HP, Hôpital Jean Verdier, Service de Biochimie, Bondy, France; Inserm U1148, Université Paris 13, Bobigny, France.
Abstract
BACKGROUND & AIMS: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). METHODS: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. RESULTS: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73). CONCLUSIONS: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.
BACKGROUND & AIMS: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). METHODS: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. RESULTS: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73). CONCLUSIONS: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.