title: Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial.
abstract: 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.
  
  
  
  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 log10IU/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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.affiliation: Hôpital Saint Joseph, Marseille, France. Electronic address: mbourliere@hopital-saint-joseph.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.affiliation: 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.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Rabiega
authors.affiliation: Hôpital Jean Verdier, Bondy, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne-Carrie
authors.affiliation: Hôpital Saint Antoine, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Hôpital Beaujon, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: 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.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Barthe
authors.affiliation: Hôpital La Pitié Salpêtrière, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.affiliation: Hôpital Pontchaillou, Rennes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.affiliation: Hôpital Henri Mondor, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hezode
authors.affiliation: Centre Hospitalier du Pays d'Aix, Aix en Provence, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Picon
authors.affiliation: Hôpital de la Source, Orléans, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Causse
authors.affiliation: Centre Hospitalier Universitaire de Grenoble, La Tronche, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.affiliation: Hôpital de Brabois, Nancy, France.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: 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.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carrieri
authors.affiliation: Hôpital Charles Nicolle, Rouen, France.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Riachi
authors.affiliation: Centre Hospitalier Intercommunal de Créteil, Créteil, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rosa
authors.affiliation: Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Attali
authors.affiliation: Hôpital Saint Louis, Paris, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Molina
authors.affiliation: Hôpital Trousseau, Tours, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bacq
authors.affiliation: Hôpital de L'Archet, Nice, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: Hôpital Tenon, Paris, France.
authors.forename: Jean Didier
authors.initials: JD
authors.lastname: Grangé
authors.affiliation: Hôpital Hotel Dieu, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Hôpital Cochin, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Fontaine
authors.affiliation: Internal Medicine Digestive Department Centre Hospitalier Universitaire Purpan Unité Mixte de Recherche 125 Institut de Recherche Pour le Développement Toulouse-3 University, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Institut National de la Santé et de la Recherche Médicale-Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Paris, France.
authors.forename: Inga
authors.initials: I
authors.lastname: Bertucci
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U635, Creteil, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Bouvier-Alias
authors.affiliation: 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.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Carrat
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood*; D004334:Drug Administration Schedule; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000009:adverse effects / Q000627:therapeutic use; D009711:Nucleotides / Q000009:adverse effects / Q000627:therapeutic use; D000071066:Patient Reported Outcome Measures; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D009705:Nucleosides; D009711:Nucleotides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a