title: Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.
abstract: BACKGROUND
  All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.
  
  
  METHODS
  In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.
  
  
  RESULTS
  Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.
  
  
  CONCLUSIONS
  Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).
authors.affiliation: From Johns Hopkins University (M.S.S.) and Mercy Medical Center (P.J.T.) - both in Baltimore; Bristol-Myers Squibb, Hopewell (D.F.G., T.E., D.S., C.P., D.M.G.), and Bristol-Myers Squibb, Princeton (M.W.-R., S.-P.H.) - both in New Jersey; Fundacion de Investigacion, San Juan, Puerto Rico (M.R.-T.); University of Pennsylvania, Philadelphia (K.R.R.); Southern California GI and Liver Center, Coronado (T.H.); Weill Cornell Medical College, New York (I.J.); University of Texas Health Science Center, San Antonio (E.L.); University of Michigan, Ann Arbor (A.S.L.); Orlando Immunology Center, Orlando (F.H.), Miami Research Associates, South Miami (H.S.), and University of Florida, Gainesville (D.R.N.) - all in Florida; University of Colorado Denver, Aurora (G.T.E.); Bristol-Myers Squibb, Wallingford, CT (M.G., D.H., F.M.); Skillman, NJ (R.H.); and Gilead Sciences, Foster City, CA (W.S.).
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: David F
authors.initials: DF
authors.lastname: Gardiner
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Anna S
authors.initials: AS
authors.lastname: Lok
authors.forename: Federico
authors.initials: F
authors.lastname: Hinestrosa
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thuluvath
authors.forename: Howard
authors.initials: H
authors.lastname: Schwartz
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Everson
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Diane
authors.initials: D
authors.lastname: Sherman
authors.forename: Robert
authors.initials: R
authors.lastname: Hindes
authors.forename: William
authors.initials: W
authors.lastname: Symonds
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquinelli
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use; D011759:Pyrrolidines; D012367:RNA, Viral / Q000032:analysis; D012254:Ribavirin / Q000627:therapeutic use; D000069474:Sofosbuvir; D014542:Uridine Monophosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012367:RNA, Viral; D012254:Ribavirin; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir