title: Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1.
abstract: OBJECTIVE
  To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.
  
  
  METHODS
  In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.
  
  
  RESULTS
  Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.
  
  
  CONCLUSIONS
  Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Flisiak
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Brygida
authors.initials: B
authors.lastname: Knysz
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lueth
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zarebska-Michaluk
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Ewa
authors.initials: E
authors.lastname: Janczewska
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Moises
authors.initials: M
authors.lastname: Diago
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Anna Linda
authors.initials: AL
authors.lastname: Zignego
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Baruch
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Dzhamal
authors.initials: D
authors.lastname: Abdurakhmanov
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Shafran
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bruck
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gadano
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Alexander James
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Kopit
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Michener
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hughes
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Yin
authors.affiliation: Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D055815:Young Adult; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011759:Pyrrolidines; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D014633:Valine; D017361:Viral Nonstructural Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C486464:telaprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C100416:peginterferon alfa-2a
keywords: Chronic hepatitis C; Daclatasvir; Direct-acting antiviral; Genotype 1b; Liver disease; NS5A inhibitor