title: Ombitasvir, paritaprevir, and ritonavir plus ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a multicentre, phase 3, randomised open-label trial.
abstract: Hepatitis C virus (HCV) genotype 4 infection is most commonly reported in sub-Saharan Africa and the Middle East; however, prevalence is increasing worldwide through immigration. HCV genotype 4 accounts for 20% of all infections, but clinical trial data for treatment remain limited. We assessed the combination of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibitor; co-dosed with ritonavir) plus ribavirin in patients with HCV genotype 4 infection and compensated cirrhosis.
  
  
  
  In this multicentre, randomised, open-label phase 3 trial (AGATE-I), treatment-naive and interferon or pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 4 infection and compensated cirrhosis were recruited from academic, public, and private hospitals in Austria, Belgium, Canada, France, Germany, Greece, Italy, and the USA. Key eligibility criteria were age 18 years or older, with chronic HCV infection assessed by the presence of anti-HCV antibodies or HCV RNA. Patients were randomly assigned (1:1) to receive 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir once daily, with weight-based ribavirin dosed twice daily for either 12 weeks or 16 weeks. Randomisation was stratified by HCV treatment history (treatment-experienced vs treatment-naive patients) and further stratified by type of non-response to previous HCV treatment (null responders, partial responders, or relapsers) for treatment-experienced patients. Treatments were assigned by an interactive response technology system with computer-generated randomisation lists prepared by personnel from the study's funding sponsor who were not involved with the conduct of the study or with data analysis. The primary outcome was the proportion of patients with a sustained virological response (HCV RNA <25 IU/mL) at post-treatment week 12 (SVR12) in the intention-to-treat population, with the lower 97·5% CI compared with a clinically relevant threshold (67%; based on SVR reported for pegylated interferon and ribavirin) to achieve superiority. The safety population included all patients who received at least one dose of study drug, and safety analyses were done by the treatment duration received (12 weeks or 16 weeks). Data presented are from the planned primary interim analysis of part one of the study when all patients enrolled in part one had reached post-treatment week 12 or prematurely discontinued from the study. This trial is registered with ClinicalTrials.gov, number NCT02265237, and part two of the trial is ongoing but closed to new participants.
  
  
  
  Between Nov 18, 2014, and May 19, 2015, we enrolled 120 eligible patients, with 59 patients assigned to receive 12 weeks of treatment and 61 patients assigned to receive 16 weeks of treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. One patient in the 12-week group experienced virological breakthrough and one discontinued prematurely after the first day of treatment. One patient missed the post-treatment week 12 visit in the 16-week group. SVR12 was achieved in 57 (97%; 97·5% CI 86·7-99·2) of 59 patients in the 12-week group and 60 (98%; 89·6-99·8) of 61 in the 16-week group. Adverse events in more than 10% of all patients were asthenia (11 [18%] of 60 in the 12-week group; 19 [32%] of 60 in the 16-week group), fatigue (ten [17%] in the 12-week group; 20 [33%] in the 16-week group), headache (14 [23%] in the 12-week group; 14 [23%] in the 16-week group), anaemia (nine [15%] in the 12-week group; 12 [20%] in the 16-week group), pruritus (five [8%] in the 12-week group; 14 [23%] in the 16-week group), nausea (six [10%] in the 12-week group; eight [13%] in the 16-week group), and dizziness (four [7%] in the 12-week group; nine [15%] in the 16-week group).
  
  
  
  With SVR12 achieved in a high proportion of patients, no post-treatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, extending treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin beyond 12 weeks seems to have no additional benefit for patients with HCV genotype 4 infection and compensated cirrhosis and might not be necessary for this patient group.
  
  
  
  AbbVie.
authors.affiliation: Centre de Recherche sur l'Inflammation, Inserm UMR 1149, Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France. Electronic address: tarik.asselah@aphp.fr.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Roula B
authors.initials: RB
authors.lastname: Qaqish
authors.affiliation: Toronto Liver Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Magdy
authors.initials: M
authors.lastname: ElKhashab
authors.affiliation: Southern California Liver Centers and Southern California Research Center, Coronado, CA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.affiliation: Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Papatheodoridis
authors.affiliation: Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.affiliation: JW Goethe University, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Medical University Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redman
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014633:Valine; D055815:Young Adult
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D011392:Proline; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir