title: The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C.
abstract: Tegobuvir (GS-9190), a non-nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg-IFN) alpha-2a and RBV, was assessed in a phase II, randomized, open-label trial. Treatment-naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice-daily (BID) and GS-9256 75 mg BID (n = 16), tegobuvir and GS-9256 plus RBV 1,000-1,200 mg daily (n = 15), or tegobuvir and GS-9256 plus Peg-IFN alpha-2a (180 μg once-weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg-IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5-log(10) increase in HCV RNA from nadir or <2-log decrease at day 5, initiated Peg-IFN/RBV immediately. Median maximal reductions in HCV RNA were -4.1 log(10) IU/mL for tegobuvir/GS-9256, -5.1 log(10) IU/mL for tegobuvir/GS-9256/RBV, and -5.7 log(10) IU/mL for tegobuvir/9256/Peg-IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS-9256, 38% (5 of 13) receiving tegobuvir/GS-9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of Peg-IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups.
  
  
  CONCLUSIONS
  In genotype 1 HCV, adding RBV or RBV with Peg-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256.
authors: University Hospital, JW Goethe University, Frankfurt, Germany. zeuzem@em.uni-frankfurt.de
authors: Stefan
authors: S
authors: Zeuzem
authors: Peter
authors: P
authors: Buggisch
authors: Kosh
authors: K
authors: Agarwal
authors: Patrick
authors: P
authors: Marcellin
authors: Daniel
authors: D
authors: Sereni
authors: Hartwig
authors: H
authors: Klinker
authors: Christophe
authors: C
authors: Moreno
authors: Jean-Pierre
authors: JP
authors: Zarski
authors: Yves
authors: Y
authors: Horsmans
authors: Hongmei
authors: H
authors: Mo
authors: Sarah
authors: S
authors: Arterburn
authors: Steven
authors: S
authors: Knox
authors: David
authors: D
authors: Oldach
authors: John G
authors: JG
authors: McHutchison
authors: Michael P
authors: MP
authors: Manns
authors: Graham R
authors: GR
authors: Foster
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000627:therapeutic use; D010721:Phosphinic Acids / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D011724:Pyridazines / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C571665:GS-9256; D016898:Interferon-alpha; D010456:Peptides, Cyclic; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D011687:Purines; D011724:Pyridazines; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C571890:tegobuvir; C100416:peginterferon alfa-2a