title: Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.
abstract: Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, Hannover, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.affiliation: Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
authors.affiliation: Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, INSERM U955, Université Paris-Est, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: Liver Unit, University of Calgary, Calgary, Canada.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Global Product Development Immunology, Respiratory, Roche Products Ltd, Welwyn, United Kingdom.
authors.forename: Astrid
authors.initials: A
authors.lastname: Scalori
authors.affiliation: Global Product Development Clinical Science, Roche Products Ltd, Welwyn, United Kingdom.
authors.forename: Athina
authors.initials: A
authors.lastname: Voulgari
authors.affiliation: Clinical Development-Infectious Diseases, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.affiliation: Roche Pharma and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.affiliation: Product Development Immunology, Genentech Inc., South San Francisco, California, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Thommes
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood; D000963:Antimetabolites / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D000914:Antibodies, Viral; D000963:Antimetabolites; D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012367:RNA, Viral; D011994:Recombinant Proteins; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C100416:peginterferon alfa-2a