Reversal of Hepatic Impairment in Patients With Hepatitis C Virus (HCV) and Early Decompensation of Cirrhosis

The proposed study will quantify hepatic improvement and antiviral efficacy of the open-label
interferon-free combination of 12 weeks of simeprevir (SMV, Simeprevir), sofosbuvir (SOF,
Sofosbuvir), and ribavirin (RBV) in patients with HCV genotype 1 infection and early
decompensation of cirrhosis. Early decompensation is defined by clinical complications or
laboratory deterioration but with a model for end-stage liver disease (MELD) score of 10 or
less.

The primary objective of this trial is determination of hepatic functional improvement as
measured by the HepQuant (HQ) test during and after
Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV). Standard laboratory tests, clinical models
(MELD, CTP), liver biopsy, hepatic venous pressure gradient (HVPG), and other imaging tests
are insensitive, invasive, or nonspecific.

They may not adequately assess the liver's improvement after viral eradication. In contrast,
HepQuant (HQ) tests (Systemic Hepatic Filtration Rate (HFR), Portal HFR, SHUNT,single point
cholate concentration (STAT), and DSI) are noninvasive, sensitive, specific, and target an
endogenous function, the hepatic uptake of cholate. HQ tests uses serum sampling over a time
period of up to 90 minutes to quantify the systemic circulation, portal circulation, and
portal-systemic shunt and to derive a disease severity index (DSI) in intact human subjects.
The primary endpoint in this treatment trial will be improvement in hepatic function measured
by HepQuant (HQ) tests that occurs during and after successful
Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV).

Inclusion Criteria:

1. HCV genotype 1 infection (all subtypes and Q80K a type of mutation are allowed), and
have been approved by a third party payer for the FDA-approved combination of
sofosbuvir (SOF) plus ribavirin. The study drug, simeprevir (SMV)

2. Biopsy proven cirrhosis, or clinical cirrhosis with APRI (AST to Platelet Ratio Index
to determine clinical cirrhosis)> 2, Fibrotest > 0.75, or Fibroscan > 12.5 Results
Stiffness (kPa).

3. MELD 10 or less

4. Expected survival without liver transplantation of >1 year

5. Patients with Hepatocellular carcinoma (HCC) are included as long as disease MELD is
10 or less, and anticipated time to transplant is >1 year. An example, might be a
patient with a subcentimeter HCC who is undergoing serial imaging to document tumor
growth to tumor diameter >2 cm prior to listing for transplantation (in order to
secure MELD exception). In this case, there could be a time lapse of 3 months or more
while monitoring tumor growth, and a further time lapse of 9 months or more until the
time of transplantation.

6. Patients with TIPS or Portal Vein Thrombosis may be included. -

Exclusion Criteria:

1. Inability to provide informed consent

2. Known hypersensitivity or serious adverse reaction to any of the study drugs

3. Age <18 or >80 years

4. Pregnancy as determined by subject reporting and urine dipstick testing at screening.

5. Other underlying chronic liver disease - examples that would exclude a patient from
participating include but are not limited to nonalcoholic liver disease, alcoholic
liver disease, hepatitis B, hemochromatosis, and autoimmune liver disease.

6. Serious other underlying medical condition - examples include but are not limited to
unstable cardiovascular, coronary, or pulmonary disease including right and left sided
heart failure, active malignancy other than HCC, or serious infection.

7. Estimated creatinine clearance < 30 mL min-1 1.73 m2 surface area (BSA)

8. Hemoglobin <10 g/dL

9. Neutrophils <500 /μL

10. Platelets <50,000 /μL

11. Bilirubin >4 mg/dL

12. Albumin < 2.8 g/dL

13. Blood Clotting: International Normalised Ratio (INR) > 2

14. MELD >10

15. Child-Turcotte-Pugh class B or C; or, CTP score >7

16. Conditions that would affect the absorption of orally administered cholate used in the
HepQuant® test - such as, extensive intestinal resection, diabetic gastroparesis, and
ileal disease or resection.

17. Concomitant use of both beta-blocker and ACE inhibitor

18. Subjects taking any other medications with significant drug drug interactions related
to the study medications (sofosbuvir, simeprevir, or ribavirin) who cannot discontinue
or substitute that medication, will be excluded.