Fabrice Carrat1, Hélène Fontaine2, Céline Dorival3, Mélanie Simony4, Alpha Diallo5, Christophe Hezode6, Victor De Ledinghen7, Dominique Larrey8, Georges Haour3, Jean-Pierre Bronowicki9, Fabien Zoulim10, Tarik Asselah11, Patrick Marcellin11, Dominique Thabut12, Vincent Leroy13, Albert Tran14, François Habersetzer15, Didier Samuel16, Dominique Guyader17, Olivier Chazouilleres18, Philippe Mathurin19, Sophie Metivier20, Laurent Alric21, Ghassan Riachi22, Jérôme Gournay23, Armand Abergel24, Paul Cales25, Nathalie Ganne26, Véronique Loustaud-Ratti27, Louis D'Alteroche28, Xavier Causse29, Claire Geist30, Anne Minello31, Isabelle Rosa32, Moana Gelu-Simeon33, Isabelle Portal34, François Raffi35, Marc Bourliere36, Stanislas Pol37. 1. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Unité de Santé Publique, Paris, France. Electronic address: fabrice.carrat@iplesp.upmc.fr. 2. AP-HP, Hôpital Cochin, Unité d'Hépatologie, Paris, France. 3. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France. 4. ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), Unit for Basic and Clinical Research on Viral Hepatitis, Paris, France. 5. Clinical Trial Safety and Public Health, Paris, France. 6. Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France. 7. Hepatology Unit Hôpital Haut-Lévêque, Pessac, and INSERM U1053, Université Bordeaux Segalen, Bordeaux, France. 8. Liver Unit, Institute for Regenerative Medicine and Biotherapy-INSERM 1183, Hôpital Saint Eloi, Montpellier, France. 9. INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France. 10. Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France. 11. INSERM, Hepatology, Hospital Beaujon, Centre de Recherche sur l'Inflammation (CRI), University Paris Diderot, Clichy, France. 12. Sorbonne Université, Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpétrière, AP-HP, INSERM Unité Mixte de Recherche (UMR)-S938, Paris, France. 13. Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire (CHU), INSERM U1209, Université Grenoble Alpes, Grenoble, France. 14. Digestive Centre, CHU de Nice, INSERM U1065-8, Nice, France. 15. Centre d'Investigation Clinique (CIC), INSERM 1110, and Pôle Hépato-digestif des Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France. 16. AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Université Paris-Sud, UMR-S1193, Université Paris-Saclay, and Hepatinov, Villejuif, France. 17. CHU de Rennes, Service d'Hépatologie, University Rennes 1, L'Institut National de la Recherche Agronomique (INRA), INSERM, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR-A1341, and UMR-S1241, Rennes, France. 18. Department of Hepatology, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France. 19. Service des Maladies de l'Appareil Digestif, Université Lille 2, and INSERM U795, Lille, France. 20. Department of Hepatology and Gastroenterology, CHU Purpan, Toulouse, France. 21. Department of Internal Medicine and Digestive Diseases, CHU Purpan, Toulouse, France; UMR 152 PHARMA-DEV (Pharmacochimie et Biologie pour le Développement), Institut de Recherche pour le Développement (IRD)-Université Toulouse 3, Toulouse, France. 22. Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France. 23. Gastroenterology and Hepatology Department, Institut des Maladies de l'Appareil Digestif, University Hospital Nantes, Nantes, France. 24. Department of Digestive and Hepatobiliary Diseases, Estaing University Hospital, and UMR Auvergne University, Centre National de la Recherche Scientifique (CNRS) 6284 ISIT (Image Sciences for Innovations Techniques), Clermont-Ferrand, France. 25. Hepatology Department, University Hospital, Angers, France; Hémodynamique, Interaction Fibrose et Invasivité Tumorales Hépatiques (HIFIH) Laboratory, Bretagne Loire University, Angers, France. 26. Department of Hepatology, Hôpitaux Universitaires Paris Seine-Saint-Denis, site Jean Verdier, AP-HP, Bondy, France; Université Paris 13, Sorbonne Paris Cité et INSERM UMR 1162, Paris, France. 27. Department of Hepatology and Gastroenterology, CHU Limoges, INSERM U1248, Université de Limoges, Limoges, France. 28. Unit of Hepatology, Hépatogastroentérologie, CHU Trousseau, Tours, France. 29. Department of Hepatology and Gastroenterology, Centre Hospitalier Régional (CHR), Orléans, France. 30. Department of Hepatology and Gastroenterology, CHR, Metz, France. 31. Department of Hepatology and Gastroenterology, University Hospital Dijon, INSERM UMR 1231, Dijon, France. 32. Department of Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Créteil, France. 33. Service d'Hépato-Gastroentérologie, CHU de Pointe-à-Pitre, and Faculté de Médecine, Université des Antilles, Pointe-à-Pitre, Guadeloupe, France; INSERM, UMR-S1085, Institut de Recherche en Santé, Environnement et Travail (IRSET), Rennes, France. 34. Service d'Hépato-Gastroentérologie, Hôpital de la Timone, Aix-Marseille Université, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France. 35. Department of Infectious Diseases, Hotel-Dieu Hospital, INSERM CIC 1413, Nantes University Hospital, Nantes, France. 36. Department of Hepatology and Gastroenterology, Hôpital Saint Joseph, Marseille, France. 37. AP-HP, Hôpital Cochin, Unité d'Hépatologie, Paris, France; Université Paris Descartes, INSERM U1223 and USM-20, Institut Pasteur, Paris, France.
Abstract
BACKGROUND: Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS: We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS: Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION: Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING: INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
BACKGROUND: Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS: We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS: Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION: Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING: INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
Authors: Dong Hyun Sinn; Seung Up Kim; Hye Kyung Hyun; Eun Ju Cho; Soo Young Park; Young Mi Hong; Soon Sun Kim; Hwi Young Kim; Nae-Yun Heo; Jung Gil Park; Wonseok Kang; Song Won Jeong; Myeong Jun Song; Hana Park; Danbi Lee; Yong Sun Lee; Sung Bum Cho; Chan Sik An; Hyung Jin Rhee; Hyun Woong Lee; Beom Kyung Kim; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Kwang-Hyub Han; Jeong-Hoon Lee; Su Jong Yu; Yoon Jun Kim; Jung-Hwan Yoon; Won Young Tak; Young Oh Kweon; Ki Tae Yoon; Mong Cho; Jae Youn Cheong; Seung Ha Park Journal: Dig Dis Sci Date: 2020-08-28 Impact factor: 3.199
Authors: Matthew J Akiyama; Daniel Lipsey; Moonseong Heo; Linda Agyemang; Brianna L Norton; Jennifer Hidalgo; Kiara Lora; Alain H Litwin Journal: Clin Infect Dis Date: 2020-06-10 Impact factor: 9.079