A Study to Evaluate the Safety, Tolerability, and Effectiveness of a 12-Week Combination Therapy of TMC647055 and TMC435 With and Without GSK23336805 With a Pharmacokinetic Enhancer With and Without Ribavirin in Patients Infected With Chronic Genotype 1 Hepatitis C Virus
A Study to Evaluate the Safety, Tolerability, and Effectiveness of a 12-Week Combination Therapy of TMC647055 and TMC435 With and Without GSK23336805 With a Pharmacokinetic Enhancer With and Without Ribavirin in Patients Infected With Chronic Genotype 1 Hepatitis C Virus
The purpose of this study is to explore the efficacy and safety of TMC647055, TMC435, and
 low-dose ritonavir, administered together with and without ribavirin and of TMC647055,
 TMC435, low-dose ritonavir administered together with GSK233680k without ribavirin in a
 limited number of patients with chronic hepatitis C virus (HCV) infection.
This study is an open-label study (all people know the identity of the intervention) in
 patients who are chronically infected with hepatitis C virus (HCV) genotype-1a (GT1a) or
 genotype-1b (GT1b) to assess the safety, tolerability and efficacy of the coadministration of
 TMC647055, TMC435 and low-dose ritonavir (RTV), with and without ribavirin (RBV) and of
 TMC647055, TMC435, RTV administered together with GSK233680k without RBV for 12 weeks.
 Approximately 86 patients will be enrolled in this study. Patients enrolled in the study will
 be chronically infected with HCV of GT1a (n=10) or GT1b (n=20), either treatment-naive
 patients (ie, patients never having received PegIFN [Pegylated interferon alpha-2a at 180 mcg
 subcutaneous once a week], RBV, or any other approved or investigational treatment for
 chronic HCV infection) or patients who are relapsers to prior treatment with PegIFN /RBV (ie,
 "relapsers" are patients with HCV ribonucleic acid [RNA] undetectable at the last on
 treatment measurement of a prior PegIFN based regimen of at least 24 weeks, but HCV RNA
 detectable within 1 year after the last medication intake). Patients in this first part of
 the study will be divided over 4 panels: Panel 1 will consist of 10 chronic HCV GT1a infected
 treatment-naive patients/prior relapsers who will receive 12 weeks of treatment with TMC435 +
 TMC647055 + low-dose ritonavir and ribavirin. Panel 2 will consist of 20 chronic HCV GT1b
 infected treatment-naive patients/ prior relapsers who will be randomly allocated to 2 arms
 in a 1:1 ratio. Arm 1 (N=10) will receive TMC435 + TMC647055 + low-dose ritonavir and
 ribavirin. Arm 2 (N=10) will receive TMC435 + TMC647055 + low-dose ritonavir. Panel 3 will
 consist of 16 chronic HCV GT1a or GT1b infected treatment-naïve patients/prior relapsers who
 will be allocated to 2 arms: 8 HCV GT1a patients in arm 1 and 8 HCV GT1b patients in arm 2.
 Patients in Arm 1 will receive 12 weeks of treatment with TMC435 + TMC647055 + low-dose RTV
 and RBV and patients in Arm 2 will receive 12 weeks of treatment with TMC435 + TMC647055 +
 low-dose RTV. Panel 4 will consist of 40 chronic HCV GT1a or GT1b infected treatment-naïve
 patients/prior relapsers who will be allocated to 2 arms: each arm will consist of 20
 patients of which at most 8 patients will be infected with HCV GT1b. Patients will be
 randomized in 1:1 ratio between the 2 arms whereby randomization will be stratified by
 genotype. Patients in Arm 1 will receive 12 weeks of treatment with TMC435 + TMC647055 +
 low-dose RTV + GSK2336805. Patients in Arm 2 will receive 12 weeks of treatment with TMC435 +
 TMC647055 + low-dose RTV + GSK2336805. The planned duration of the investigational treatment
 is 12 weeks. Patients in Panels 1, 2, and 3 may receive follow-up treatment with 12 weeks or
 36 weeks of PegIFNα + RBV; follow-up treatment principles will not apply to Panel 4 as based
 on available proof of concept data for such combinations, the need for an additional 12 or
 36-week PegIFN/RBV follow-up therapy is expected to be very low when evaluating a 12-week
 regimen of 3 direct acting antiviral agents for treatment of HCV genotype 1 infections.
 Safety will be monitored throughout the study
Inclusion Criteria:

 -  Documented chronic genotype 1a or genotype 1b hepatitis C virus (HCV) infection with
 HCV ribonucleic acid (RNA) level >100,000 IU/mL at screening

 -  Treatment-naive or documented prior relapser to previous treatment regimens and has
 stopped treatment at least 3 months before screening

 -  Liver biopsy within 3 years before the screening visit or elastography results
 available prior to first study drug dosing

 -  Medically stable based on physical examination, medical history, vital signs, and
 electrocardiogram performed at screening

 -  Body mass index of 18.0 to 32.0 kg/m2 and body weight more than 50 kg

 Exclusion Criteria:

 -  Evidence of liver cirrhosis by liver biopsy or the presence of esophageal varices or a
 transient elastography result of >14.6 kPa within 2 years prior to first dosing

 -  Evidence of decompensated liver disease defined as prior history or current evidence
 of ascites, hepatic encephalopathy, bleeding oesophageal or gastric varices

 -  Evidence of any significant liver disease in addition to hepatitis C (including but
 not limited to hepatitis B, drug- or alcohol-related cirrhosis, autoimmune hepatitis,
 hemochromatosis, Wilson's disease, non-alcoholic steatohepatitis, or primary biliary
 cirrhosis)

 -  Receiving or has received any HCV-specific direct antiviral agent (HCV protease
 inhibitors, HCV nucleoside polymerase inhibitors, HCV non-nucleoside polymerase
 inhibitors, HCV NS5a inhibitors or any other HCV inhibitor targeting an HCV protein or
 a target involved in the HCV replication cycle

 -  Co-infected with human immunovirus (HIV)-1 or HIV-2, with non-genotype 1a/1b HCV, or
 hepatitis A or B virus infection