Safety and Efficacy of LDV/SOF Fixed-Dose Combination (FDC) ± Ribavirin in HCV Genotype 1 Subjects

• Percentage of Participants With Sustained Virologic Response (SVR) at 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: Posttreatment Week 12 ] [ Designated as safety issue: No ]
  SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 25 IU/mL) 12 weeks after stopping study treatment.
• Incidence of Adverse Events Leading to Permanent Discontinuation of Study Drug(s) [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
  The number of participants experiencing an adverse event leading to permanent discontinuation of study drug(s) was summarized.

• Sustained virologic response after discontinuation of therapy [ Time Frame: 12 weeks after discontinuation of therapy ] [ Designated as safety issue: No ]
  Sustained virologic response (SVR) 12 weeks after the end of treatment (SVR12 defined as HCV RNA < lower limit of quantification [LLOQ] 12 weeks after last dose of study drug).
• Safety and tolerability of combination treatment with sofosbuvir (SOF)/GS-5885 fixed-dose combination (FDC) +/- RBV as measured by review of the accumulated safety data. [ Time Frame: Safety and tolerability on treatment and 30 days post last dose. ] [ Designated as safety issue: Yes ]
  Frequency and severity of adverse events.

• Percentage of Participants With SVR at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) [ Time Frame: Posttreatment Weeks 2, 4, 8, and 24 ] [ Designated as safety issue: No ]
  SVR2, SVR4, SVR8, and SVR24 was defined as HCV RNA < LLOQ at 2, 4, 8, and 24 weeks following the last dose of study drug, respectively.
• Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse [ Time Frame: Baseline to Posttreatment Week 24 ] [ Designated as safety issue: No ]
  • Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while receiving treatment, confirmed with 2 consecutive values (second confirmation value could be posttreatment), or last available on-treatment measurement with no subsequent follow-up values.
  • Viral relapse was defined as HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement.

• Sustained virologic response after discontinuation of therapy. [ Time Frame: 2,4,8, and 24 weeks after discontinuation of therapy ] [ Designated as safety issue: No ]
  Sustained virologic response (SVR) at 2,4,8, and 24 weeks after discontinuation of therapy (SVR 2, SVR4, SVR 8, and SVR24 defined as HCV RNA < lower limit of quantification [LLOQ] after last dose of study drug).
• Viral resistance to sofosbuvir and GS-5885 combination therapy during and after treatment. [ Time Frame: 12 and 24 weeks ] [ Designated as safety issue: No ]
  To evaluate the emergence of viral resistance to sofosbuvir and GS-5885 during treatment and after treatment discontinuation
• Characterization of viral dynamics during treatment and after treatment discontinuation. [ Time Frame: 12 and 24 weeks ] [ Designated as safety issue: No ]
  To characterize viral dynamics during treatment and after treatment discontinuation.
• Characterization of steady state pharmacokinetics of sofosbuvir and GS-5885 during treatment and after treatment discontinuation. [ Time Frame: 12 and 24 weeks ] [ Designated as safety issue: No ]
  To characterize steady state pharmacokinetics of sofosbuvir and GS-5885 during treatment and after treatment discontinuation.

This study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) with or without ribavirin (RBV), administered for 8 or 12 weeks of treatment in participants with chronic genotype 1 hepatitis C virus (HCV) infection who are treatment-naive, and for 12 weeks in participants who had previously received a regimen containing a protease inhibitor for the treatment of HCV.

• Drug: LDV/SOF
  LDV 90 mg/SOF 400 mg FDC tablet administered orally once daily
  Other Name: Harvoni®
• Drug: RBV
  RBV tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

• Experimental: LDV/SOF 8 Weeks (TN)
  Treatment-naive (TN) participants will be randomized to receive LDV/SOF for 8 weeks.
  Intervention: Drug: LDV/SOF
• Experimental: LDV/SOF+RBV 8 Weeks (TN)
  Treatment-naive participants will be randomized to receive LDV/SOF plus RBV for 8 weeks.
  Interventions:

  • Drug: LDV/SOF
  • Drug: RBV
• Experimental: LDV/SOF 12 Weeks (TN)
  Treatment-naive participants will be randomized to receive LDV/SOF for 12 weeks.
  Intervention: Drug: LDV/SOF
• Experimental: LDV/SOF 12 Weeks (TE)
  Treatment-experienced (TE) participants (had virologic failure following prior therapy with a protease-inhibitor [PI]+pegylated interferon [PEG]+RBV regimen) will be randomized to receive LDV/SOF for 12 weeks.
  Intervention: Drug: LDV/SOF
• Experimental: LDV/SOF+RBV 12 Weeks (TE)
  Treatment-experienced participants (had virologic failure following prior therapy with a PI+PEG+RBV regimen) will be randomized to receive LDV/SOF plus RBV for 12 weeks.
  Interventions:

  • Drug: LDV/SOF
  • Drug: RBV

Inclusion Criteria:

• Age ≥ 18 years, with chronic genotype 1 HCV infection
• HCV RNA equal to or greater than 10,000 IU/mL at screening
• Cirrhosis determination; a liver biopsy may be required
• Screening laboratory values within defined thresholds
• Use of two effective contraception methods if female of childbearing potential or sexually active male

Exclusion Criteria:

• Pregnant or nursing female or male with pregnant female partner
• Current or prior history of clinical hepatic decompensation
• Hepatocellular carcinoma (HCC) or other malignancy (with exception of certain resolved skin cancers)
• Chronic use of systemic immunosuppressive agents
• History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol