Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis

Georges-Philippe Pageaux, Clovis Lusivika Nzinga, Nathalie Ganne, Didier Samuel, Céline Dorival, Fabien Zoulim, Carole Cagnot, Thomas Decaens, Dominique Thabut, Tarik Asselah, Philippe Mathurin, François Habersetzer, Jean-Pierre Bronowicki, Dominique Guyader, Isabelle Rosa, Vincent Leroy, Olivier Chazouilleres, Victor de Ledinghen, Marc Bourliere, Xavier Causse, Paul Cales, Sophie Metivier, Véronique Loustaud-Ratti, Ghassan Riachi, Laurent Alric, Moana Gelu-Simeon, Anne Minello, Jérôme Gournay, Claire Geist, Albert Tran, Armand Abergel, Isabelle Portal, Louis d'Alteroche, François Raffi, Hélène Fontaine, Fabrice Carrat, Stanislas Pol, French ANRS CO22 Hepather Cohort, Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Caroline Chevalier, Isabelle Hubert, Pierre Goepfert, Adrien Lannes, Françoise Lunel, Jérôme Boursier, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amandine Legendre, Faiza Chermak, Marie Irlès-Depé, Si Nafa Si Ahmed, Christelle Ansaldi, Nisserine Ben Amara, Valérie Oules, Jacqueline Dunette, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Héloïse Goin, Damien Labarrière, Pascal Potier, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Pierre Nahon, Séverine Brulé, Rym Monard, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Sarah Launay, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Nisserine Ben Amara, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Carole Cagnot, Alpha Diallo, Lena Wadouachi, Ventzi Petrov-Sanchez, Douae Ammour, Loubna Ayour, Jaouad Benhida, Fabrice Carrat, Frederic Chau, Céline Dorival, Audrey Gilibert, Isabelle Goderel, Warda Hadi, Clovis Luzivika Nzinga, Grégory Pannetier, François Pinot, Odile Stahl, François Téloulé, Georges-Philippe Pageaux, Clovis Lusivika Nzinga, Nathalie Ganne, Didier Samuel, Céline Dorival, Fabien Zoulim, Carole Cagnot, Thomas Decaens, Dominique Thabut, Tarik Asselah, Philippe Mathurin, François Habersetzer, Jean-Pierre Bronowicki, Dominique Guyader, Isabelle Rosa, Vincent Leroy, Olivier Chazouilleres, Victor de Ledinghen, Marc Bourliere, Xavier Causse, Paul Cales, Sophie Metivier, Véronique Loustaud-Ratti, Ghassan Riachi, Laurent Alric, Moana Gelu-Simeon, Anne Minello, Jérôme Gournay, Claire Geist, Albert Tran, Armand Abergel, Isabelle Portal, Louis d'Alteroche, François Raffi, Hélène Fontaine, Fabrice Carrat, Stanislas Pol, French ANRS CO22 Hepather Cohort, Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Caroline Chevalier, Isabelle Hubert, Pierre Goepfert, Adrien Lannes, Françoise Lunel, Jérôme Boursier, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amandine Legendre, Faiza Chermak, Marie Irlès-Depé, Si Nafa Si Ahmed, Christelle Ansaldi, Nisserine Ben Amara, Valérie Oules, Jacqueline Dunette, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Héloïse Goin, Damien Labarrière, Pascal Potier, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Pierre Nahon, Séverine Brulé, Rym Monard, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Sarah Launay, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Nisserine Ben Amara, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Carole Cagnot, Alpha Diallo, Lena Wadouachi, Ventzi Petrov-Sanchez, Douae Ammour, Loubna Ayour, Jaouad Benhida, Fabrice Carrat, Frederic Chau, Céline Dorival, Audrey Gilibert, Isabelle Goderel, Warda Hadi, Clovis Luzivika Nzinga, Grégory Pannetier, François Pinot, Odile Stahl, François Téloulé

Abstract

Background: In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort.

Methods: We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits.

Results: 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7-51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24-0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08-0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15-0.54, p < 0.0001), liver-related mortality (HR 0.40, 95% CI 0.17-0.96, p = 0.04), non-liver-related mortality (HR 0.17, 95% CI 0.06-0.49, p = 0.001), liver transplantation (HR 0.17, 95% CI 0.05-0.54, p = 0.003), and hepatocellular carcinoma (HR 0.52, 95% CI 0.29-0.93, p = 0.03).

Conclusion: Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis.

Trial registration: ClinicalTrials.gov registry number: NCT01953458.

Keywords: Decompensated cirrhosis; Direst-acting antiviral agents; Hepatitis C virus; Hepatocellular carcinoma; Survival; Sustained virological response.

Conflict of interest statement

Prof. Pageaux received lecturing fees from Gilead, Abbvie, outside the submitted work. Dr Lusivika Nzinga has nothing to disclose. Prof. Ganne reports grants from Echosens, personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from Abbvie, non-financial support from MSD, personal fees and non-financial support from Bayer, outside the submitted work. Prof. Samuel reports other from Astellas, BMS, Gilead, LFB, MSD, Novartis, Roche, Biotest, Abbvie, Intercept, outside the submitted work. Dr Dorival has nothing to disclose. Prof. Zoulim reports personal fees from Abbvie, Gilead, during the conduct of the study. C. Cagnot has nothing to disclose. Prof. Decaens reports personal fees from Bayer, MSD, Abbvie, Gilead Sciences, outside the submitted work. Prof. Thabut reports personal fees from MSD, Abbvie, Gilead Sciences, outside the submitted work. Prof. Asselah reports grants from ANRS-INSERM, personal fees from ABBVIE, GILEAD, JANSSEN, MSD, outside the submitted work. Prof. Mathurin reports personal fees from MSD, Abbvie, Gilead Sciences, outside the submitted work. Prof. Habersetzer reports personal and travel fees from Abbvie and Gilead, during the conduct of the study. Prof. Bronowicki reports personal fees from Abbvie, Gilead, MSD, BMS, JANSSEN outside the submitted work. Prof. Guyader reports personal fees and non-financial support from Gilead sciences, MSD, and Abbbvie, grants, personal fees and non-financial support from Janssen, during the conduct of the study. Dr Rosa has nothing to disclose. Prof. Leroy reports grants, personal fees and non-financial support from Abbvie, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Gilead, personal fees and non-financial support from MSD, personal fees from echosens, outside the submitted work. Prof. Chazouillères reports personal fees from Abbvie, Gilead Sciences, Intercept, Pliant Therapeutics, outside the submitted work. Prof. De Lédinghen has received consulting and/or lecturing fees from Gilead, AbbVie, Echosens, Intercept Pharma, SuperSonic Imagine, Indivior, Spimaco, Pfizer, Bristol Myers Squibb, Myr-Pharma. Dr Bourlière reports grants and personal fees from AbbVie, grants and personal fees from Gilead, personal fees from MSD, personal fees from Janssen, personal fees from Boehringher Ingelheim, personal fees from intercept, personal fees from BMS, outside the submitted work. Dr Causse reports personal fees from AbbVie, Gilead, Intercept, Janssen, MSD, during the conduct of the study, outside the submitted work. Prof. Cales has nothing to disclose. Dr Metivier has nothing to disclose. Prof. Loustaud-Ratti is a Clinical Investigator/Speaker for AbbVie, Gilead Sciences, Merck Sharp & Dohme. Dr Riachi reports personal fees from MSD, Abbvie, Gilead Sciences, outside the submitted work. Dr Alric reports personal fees from MSD, Abbvie, Gilead Sciences, outside the submitted work. Dr Gelu-Simeon reports invitations for medical meeting from Gilead, Abbvie. Pr. Minello reports personal fees from for Gilead, Abbvie, Intercept, during the conduct of the study, outside the submitted work. Dr Gournay reports personal fees from Gilead, MSD, Abbvie, during the conduct of the study; personal fees from Intercept, outside the submitted work. Dr Geist has nothing to disclose. Prof. Tran has nothing to disclose. Dr Abergel reports personal fees from AbbVie, Gilead Sciences, Merck Sharp & Dohme, Intercept, during the conduct of the study, outside the submitted work. Dr Portal reports personal fees from MSD, Abbvie, Gilead Sciences, outside the submitted work. Dr D’Alteroche reports invitations for medical meeting from Gilead, Abbvie, BMS, MSD and Janssen outside this work. Prof. Raffi reports personal fees from for Gilead, ViiV, Abbvie, MSD, Janssen during the conduct of the study, outside the submitted work. G. Haour has nothing to disclose. Dr. Fontaine reports personal fees and invitations for medical meeting from Gilead, Abbvie, BMS, MSD, Janssen, MSD outside this work. Prof. Carrat reports grants from INSERM-ANRS, during the conduct of the study; personal fees from Imaxio, outside the submitted work. Prof. Pol received consulting and lecturing fees from Bristol-Myers Squibb, Janssen, Gilead, Roche, Biotest, Shinogi, ViiV, MSD and Abbvie, and grants from Bristol-Myers Squibb, Gilead and MSD.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
a Survival using inverse probability of treatment weighting (IPTW)-based analysis of hepatocellular carcinoma for all patients under study. b Survival using inverse probability of treatment weighting (IPTW)-based analysis of all-cause mortality for all patients under study. c Survival using inverse probability of treatment weighting (IPTW)-based analysis of liver transplantation for all patients under study
Fig. 2
Fig. 2
Inverse probability of treatment weighting (IPTW)-adjusted cumulative incidence functions of hepatocellular carcinoma, all-cause mortality, and liver transplantation in all patients under study. HCC hepatocellular carcinoma, DAA direct-acting antiviral, IPW inverse probability of treatment weighting

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