title: All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study.
abstract: BACKGROUND
  An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both.
  
  
  METHODS
  We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203.
  
  
  RESULTS
  This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each).
  
  
  CONCLUSIONS
  Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors: Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de.
authors: Michael
authors: M
authors: Manns
authors: Hôpital Cochin, Paris, France.
authors: Stanislas
authors: S
authors: Pol
authors: Weill Cornell Medical College, New York, NY, USA.
authors: Ira M
authors: IM
authors: Jacobson
authors: Hôpital Beaujon, Clichy, France.
authors: Patrick
authors: P
authors: Marcellin
authors: Henry Ford Health Systems, Detroit, MI, USA.
authors: Stuart C
authors: SC
authors: Gordon
authors: School of Medicine, China Medical University, Taichung, Taiwan.
authors: Cheng-Yuan
authors: CY
authors: Peng
authors: National Cheng Kung University Hospital, Tainan, Taiwan.
authors: Ting-Tsung
authors: TT
authors: Chang
authors: University of Colorado Denver, Aurora, CO, USA.
authors: Gregory T
authors: GT
authors: Everson
authors: Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea.
authors: Jeong
authors: J
authors: Heo
authors: University of Duisburg-Essen, Essen, Germany.
authors: Guido
authors: G
authors: Gerken
authors: VAMC, Baylor College of Medicine, Houston, TX, USA.
authors: Boris
authors: B
authors: Yoffe
authors: Kaiser Permanente, Los Angeles, CA, USA.
authors: William J
authors: WJ
authors: Towner
authors: Hôpital Saint Joseph, Marseille, France.
authors: Marc
authors: M
authors: Bourliere
authors: CHU Purpan, Toulouse, France.
authors: Sophie
authors: S
authors: Metivier
authors: Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.
authors: Chi-Jen
authors: CJ
authors: Chu
authors: Monash Health and Monash University, Melbourne, VIC, Australia.
authors: William
authors: W
authors: Sievert
authors: INSERM Unité 954, Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France.
authors: Jean-Pierre
authors: JP
authors: Bronowicki
authors: Hôpital Pitié-Salpêtrière, Paris, France.
authors: Dominique
authors: D
authors: Thabut
authors: Inje University Busan Paik Hospital, Busan, South Korea.
authors: Youn-Jae
authors: YJ
authors: Lee
authors: National Taiwan University Hospital, Taipei, Taiwan.
authors: Jia-Horng
authors: JH
authors: Kao
authors: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors: Fiona
authors: F
authors: McPhee
authors: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors: Justin
authors: J
authors: Kopit
authors: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors: Patricia
authors: P
authors: Mendez
authors: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors: Misti
authors: M
authors: Linaberry
authors: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors: Eric
authors: E
authors: Hughes
authors: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors: Stephanie
authors: S
authors: Noviello
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007546:Isoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D012367:RNA, Viral; D013449:Sulfonamides; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir