New Treatment Response in People With and Without Cirrhosis From Chronic Hepatitis C

-INCLUSION CRITERIA:

INCLUSION CRITERIA FOR BOTH GENOTYPES 1a and 1b:

• Adults, ages 18 and above
• Chronic hepatitis C (HCV RNA in serum for more than 6 months)
• HCV Genotype 1
• HCV RNA in serum above 10, 000 IU/mL
• Non-response to previous therapy with peginterferon and ribavirin categorized as null-response as defined by a less than 1 log IU/mL decline in HCV RNA at treatment week 4 or a less than 2 log IU/mL decline in HCV RNA at treatment week 12; and partial response as defined by a greater than or equal to 2 log decrease in HCV RNA at treatment week 12 but continued detection of HCV RNA at treatment week 24
• No contraindications to agents being used (asunaprevir, daclatasvir, peginterferon and ribavirin).
• No evidence or history of hepatic decompensation.
• Females of childbearing potential must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours before the first dose of study drug.
• Women of childbearing potential (WOCBP) and men must use highly effective methods of birth control to minimize the risk of pregnancy. WOCBP must follow instructions for birth control for the entire duration of the study including a minimum of 24 weeks after the last dose of P/R. Birth control requirements are or WOCBP and men who are sexually active with WOCBP
• Women must not be breastfeeding
• Fully informed, written consent to the study including repeat liver biopsy.

ADDITIONAL INCLUSION CRITERIA FOR GENOTYPE 1a

• Liver biopsy showing Ishak stages 0-2 or 5-6 within 12 weeks of initiating therapy OR a prior biopsy performed within 96 weeks of screening visit WITH saved tissue. Up to 10 subjects who do not fulfill the entry histologic criteria will be allowed to participate in the trial at the discretion of the investigator.

ADDITIONAL INCLUSION CRITERIA FOR GENOTYPE 1b

• Baseline sequence analysis of the NS5A region to exclude presence of mutations known to confer resistance to daclatasvir.

INCLUSION CRITERIA FOR GT 1b SUBJECTS WHO RECEIVE RESCUE THERAPY AT THE DISCREATION OF THE INVESTIGATOR (THESE CRITERIA MUST BE ASSESSED PRIOR TO INITIATIONOF PEG INFa/RBV THERAPY):

Important: In addition to the Inclusion Criteria listed above, the following

Inclusion Criteria apply to all Rescue Subjects:

a) Subject met a definition of virologic breakthrough or treatment futility, defined

as:

i) Any confirmed > 1 log10 increase in HCV RNA from nadir, OR;

ii) Any confirmed HCV RNA greater than or equal to Lower Limit of quantification (LLOQ) after confirmed HCV RNA 100 ng/mL OR

ii) AFP greater than or equal to 50 ng/mL and less than or equal 100 ng/mL requires a liver ultrasound and subjects with findings suspicious for HCC are excluded

j) QTcF or QTcB > 500 msec

• Allergies and Adverse Drug Reaction

a) History of hypersensitivity to drugs with a similar biochemical structure to asunaprevir

or daclatasvir.

• Prohibited Treatments and /or Therapies
• Exposure to any investigational drug or placebo within 4 weeks of study drug administration;
• Prior exposure to any HCV DAA;
• Prior exposure to pegIFN or RBV within 12 weeks prior to screening;
• Subjects receiving all tricyclic anti-depressants (TCAs) including amitriptyline, clomipramine, desiprmine, dosepin, imipramine, nortriptyline, protriptyline; OR selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, fluvoxamine, paroxetine and

sertraline; OR additional agents including venlafaxine, duloxetine, aripiprazole and mirtazapine within 2 weeks prior to Day 1; (subjects may switch to non-prohibited antidepressant therapies (eg citalopram, escitalopram and bupropion) within 2 weeks prior to

Day 1). The study eligibility of subjects on any anti-depressant not listed above, may be considered after a consultation with the central medical monitor, prior to Day 1;

• Sex and Reproductive Status
• Sexually active men whose partners are pregnant at screening are excluded fr