Marc Bourlière1, Pascaline Rabiega2, Nathalie Ganne-Carrie3, Lawrence Serfaty4, Patrick Marcellin5, Yoann Barthe2, Dominique Thabut6, Dominique Guyader7, Christophe Hezode8, Magali Picon9, Xavier Causse10, Vincent Leroy11, Jean Pierre Bronowicki12, Patrizia Carrieri13, Ghassan Riachi14, Isabelle Rosa15, Pierre Attali16, Jean Michel Molina17, Yannick Bacq18, Albert Tran19, Jean Didier Grangé20, Fabien Zoulim21, Hélène Fontaine22, Laurent Alric23, Inga Bertucci24, Magali Bouvier-Alias25, Fabrice Carrat26. 1. Hôpital Saint Joseph, Marseille, France. Electronic address: mbourliere@hopital-saint-joseph.fr. 2. Sorbonne Universités, University Pierre and Marie Curie Univ Paris 06, Institut National de la santé et de la Recherche Médicale, Institut Pierre Louis d'épidémiologie et de Santé Publique, Paris, France. 3. Hôpital Jean Verdier, Bondy, France. 4. Hôpital Saint Antoine, Paris, France. 5. Hôpital Beaujon, Clichy, France. 6. Hôpital La Pitié Salpêtrière, Paris, France. 7. Hôpital Pontchaillou, Rennes, France. 8. Hôpital Henri Mondor, Créteil, France. 9. Centre Hospitalier du Pays d'Aix, Aix en Provence, France. 10. Hôpital de la Source, Orléans, France. 11. Centre Hospitalier Universitaire de Grenoble, La Tronche, France. 12. Hôpital de Brabois, Nancy, France. 13. Institut national de la santé et de la recherche médicale, unité mixte de recherche 912 (Sciences Economiques and Sociales de la Santé and Traitement de l'Information Médicale), Marseille, France; Aix Marseille Université, Unité Mixte de Recherche S912, Institut de Recherche Pour le développement, Marseille, France; Observatoire Régional de la Santé Provence-Alpes-Côte-d'Azur, Marseille, France. 14. Hôpital Charles Nicolle, Rouen, France. 15. Centre Hospitalier Intercommunal de Créteil, Créteil, France. 16. Hôpital Bicêtre, Le Kremlin Bicêtre, France. 17. Hôpital Saint Louis, Paris, France. 18. Hôpital Trousseau, Tours, France. 19. Hôpital de L'Archet, Nice, France. 20. Hôpital Tenon, Paris, France. 21. Hôpital Hotel Dieu, Lyon, France. 22. Hôpital Cochin, Paris, France. 23. Internal Medicine Digestive Department Centre Hospitalier Universitaire Purpan Unité Mixte de Recherche 125 Institut de Recherche Pour le Développement Toulouse-3 University, Toulouse, France. 24. Institut National de la Santé et de la Recherche Médicale-Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Paris, France. 25. Institut National de la Santé et de la Recherche Médicale U635, Creteil, France. 26. Sorbonne Universités, University Pierre and Marie Curie Univ Paris 06, Institut National de la santé et de la Recherche Médicale, Institut Pierre Louis d'épidémiologie et de Santé Publique, Paris, France; Hôpital Saint Antoine, Paris, France.
Abstract
BACKGROUND: Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy. METHODS: In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log10 IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392. FINDINGS:Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] topegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analoguesgroup from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4). INTERPRETATION: Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance. FUNDING: Institut national de la santé et de la recherche médicale-Agence nationale de recherches sur le sida et les hépatites virales (France Recherche Nord&sud Sida-vih Hepatites).
RCT Entities:
BACKGROUND: Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy. METHODS: In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log10 IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392. FINDINGS: Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4). INTERPRETATION: Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance. FUNDING: Institut national de la santé et de la recherche médicale-Agence nationale de recherches sur le sida et les hépatites virales (France Recherche Nord&sud Sida-vih Hepatites).
Authors: Norah A Terrault; Abdus S Wahed; Jordan J Feld; Stewart L Cooper; Mark G Ghany; Mauricio Lisker-Melman; Robert Perrillo; Richard K Sterling; Mandana Khalili; Raymond T Chung; Philip Rosenthal; Robert J Fontana; Arif Sarowar; Daryl T Y Lau; Junyao Wang; Anna S Lok; Harry L A Janssen Journal: Hepatology Date: 2022-01-26 Impact factor: 17.425
Authors: Robin Erken; Vladimir V Loukachov; Annikki de Niet; Louis Jansen; Femke Stelma; Jeltje T Helder; Martine W Peters; Hans L Zaaijer; Neeltje A Kootstra; Sophie B Willemse; Hendrik W Reesink Journal: J Clin Exp Hepatol Date: 2022-01-04