People With CHC Who Achieved a Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents

We intend to observe up to 350 patients with chronic HCV infection who have successfully
eradiated HCV following therapy with direct acting antiviral agents and describe the
clinical, virological, laboratory, histological and immunological outcomes following
eradication of HCV. Subjects will be recruited from two sources: 1) subjects who have already
achieved SVR with a DAA only regimen and who have undergone a liver biopsy within five years
prior to therapy and no history of hepatic decompensation or hepatocellular carcinoma and 2)
treatment na(SqrRoot) ve or experienced who have failed a prior treatment (including
DAA-experienced) who are willing to undergo a pre-treatment liver biopsy. Subjects yet to
achieve SVR with evidence of clinical cirrhosis will undergo a transjugular liver biopsy with
measurement of portal pressures in lieu of the percutaneous liver biopsy. Subjects yet to
achieve an SVR will receive 12 weeks of therapy with sofosbuvir/velapatasvir fixed dose
combination. Subjects who have attained a SVR (or upon achieving an SVR) will undergo a
thorough medical evaluation, laboratory testing, transient elastography and hepatic
ultrasound. Thereafter, subjects will be followed prospectively every 24 weeks for liver
decompensation (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal
hemorrhage), hepatocellular carcinoma, liver-related mortality and all-cause mortality.
During each study visit, subjects will be questioned on the development of these adverse
outcomes. In addition, blood will be drawn for the assessment of routine blood tests,
quantitative viral biomarker levels, serological response markers and immune cell functional
status. Blood, urine and stool will be collected and stored for exploratory biomarker
development. Transient elastography will be performed annually in all subjects. For subjects
with cirrhosis, esophagogastroduodenoscopy will be performed annually and imaging every 24
weeks. At the end of 240 weeks, all subjects will be admitted to undergo a liver biopsy to
assess the stage of liver fibrosis. In subjects with cirrhosis at study entry, the liver
biopsy will be performed by the transjugular route with hepatic venous pressure measurements.
The primary goal of the study will be to describe the natural history of viral eradication
following treatment with direct acting antiviral agents, to identify predictors of adverse
outcomes after sustained viral eradication and regression of fibrosis/cirrhosis.

- Phase I

Inclusion Criteria for Subjects Who Have Not Achieved a SVR (Phase I)

Subjects must meet all of the following inclusion criteria to be eligible for participation
in this study:

- Male or female, age greater than or equal to 18 years.

- Either treatment na(SqrRoot) ve or experienced defined as failure of a prior course of
interferon-based and ribavirin, DAA plus interferon and DAA only (except for NS5a
failures).

- Confirmation of chronic HCV infection documented by either:

1. A positive HCV RNA or positive HCV genotyping test at least 6 months prior to the
Baseline/Day 1 visit, or

2. A liver biopsy performed prior to screening visit showing evidence of chronic
hepatitis.

5) Subjects must have the following laboratory parameters at screening:

- ALT less than or equal to 10 (SqrRoot) the upper limit of normal (ULN)

- AST less than or equal 10 (SqrRoot) ULN

- Total bilirubin <2.5 mg/dL, Direct bilirubin less than or equal 1.5 ULN

- Platelets more than or equal 50,000 K/mm3

- HbA1c less than or equal 8.5%

- eGFR more than or equal 60 mL /min, as calculated by the CKD-EPI equation.

- Hemoglobin more than or equal 10g/dL.

- Albumin more than or equal 3g/dL

- INR less than or equal 1.5 unless subject has known hemophilia or is stable on an
anticoagulant regimen affecting INR.

- HCV RNA positive at screening

6) Subject must be able to comply with the dosing instructions for study drug
administration and able to complete the study schedule of assessments, including all
required post-treatment visits.

7) Subject must be of generally good health, with the exception of chronic HCV
infection, as determined by the Investigator.

Exclusion Criteria for Subjects Who Have Not Achieved a SVR

Subjects who meet any of the following exclusion criteria will not to be enrolled in this
arm of the study:

1. Pregnancy, active breast-feeding, or inability to practice adequate contraception, in
women of childbearing potential. Adequate contraception is defined as vasectomy in
men, tubal ligation in women, or use of two methods such as condoms and spermicide
combination, birth control pills, an intrauterine device, Depo-Provera, or Norplant
until 12 weeks post therapy.

2. Current or prior history of any of the following:

- Clinically-significant illness (other than HCV) or any other major medical
disorder that may interfere with subject treatment, assessment or compliance with
the protocol; subjects currently under evaluation for a potentially
clinically-significant illness (other than HCV) are also excluded.

- Gastrointestinal disorder or post-operative condition that could interfere with
the absorption of the study drug.

- Decompensated liver disease as defined by serum bilirubin more than or equal to
2.5 mg/dL (with direct bilirubin more than or equal to 1.5 mg/dL), INR >1.5 a
serum albumin of less than 3 g/dL, or a history of ascites, hepatorenal syndrome,
variceal bleeding or hepatic encephalopathy.

- Solid organ transplantation.

- Significant pulmonary disease, significant cardiac disease or porphyria.

3. History of malignancy or treatment for a malignancy within the past 3 years that is
associated with a life expectancy <5 years (except adequately treated carcinoma in
situ or basal cell carcinoma of the skin).

4. Chronic liver disease of a non-HCV etiology with the exception of steatosis (e.g.,
chronic hepatitis B, NASH, hemochromatosis, Wilson s disease, alfa-1 antitrypsin
deficiency, cholangitis).

5. Evidence of harmful or hazardous drinking as defined as a score more than or equal to
8 on the AUDIT questionnaire.

6. Co-infection with HIV defined as the presence of anti-HIV in serum.

7. Clinically-relevant drug abuse based on patient history within 12 months of screening.

8. Use of any prohibited concomitant medications as described in concomitant medications
and Table 1 within 21 days of the Baseline/Day 1 visit; this washout period does not
apply to PPIs, which can be taken up to 7 days before baseline Day 1.

9. Use of antiviral medications within the last 30 days.

10. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
equivalent more than or equal to 10 mg/day).

11. Known hypersensitivity to sofosbuvir and velpatasvir, or formulation excipients.

12. Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver
that is suggestive of hepatocellular carcinoma, or an alphafetoprotein level of
greater than 500 ng/mL.

13. Active psychiatric problems such as major depression, schizophrenia, bipolar illness,
obsessive-compulsive disorder, severe anxiety, or personality disorder that, in the
investigator s opinion, might interfere with participation in the study.

14. Presence of conditions that, in the opinion of the investigators, would not allow the
patient to be followed in the current study for at least 1 year.

15. Inability to provide consent.

Phase II

Inclusion Criteria for Phase II (follow-up after SVR24):

1. Age greater than or equal to 18 years and older, male or female

2. SVR following therapy with a direct acting antiviral agent regimen and available liver
biopsy performed prior to treatment and up to 5 years prior to enrollment (2 unstained
slides or a hematoxylin and eosin and Mason trichrome stained slides must be
available)

3. Subject must be of generally good health as determined by the Investigator.

4. Willing and able to provide written informed consent.

Exclusion Criteria for Phase II (follow-up after SVR24):

1. Current or prior history of any of the following:

- Clinically-significant illness (other than resolved HCV) or any other major
medical disorder that may interfere with subject treatment, assessment or
compliance with the protocol; subjects currently under evaluation for a
potentially clinically-significant illness (other than HCV) are also excluded.

- Decompensated liver disease as defined by serum bilirubin greater than or equal
to 2.5 mg/dL (with direct bilirubin greater than or equal to 1.5 mg/dL), INR >1.5
a serum albumin of less than 3 g/dL, or a history of ascites, hepatorenal
syndrome, variceal bleeding or hepatic encephalopathy.

- Solid organ transplantation.

- Significant pulmonary disease, significant cardiac disease or porphyria.

2. History of malignancy or treatment for a malignancy within the past 3 years that is
associated with a life expectancy <5 years (except adequately treated carcinoma in
situ or basal cell carcinoma of the skin).

3. Chronic liver disease with the exception of steatosis (e.g., chronic hepatitis B,
NASH, hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis).

4. Evidence of harmful or hazardous drinking as defined as a score greater than or equal
to 8 on the AUDIT questionnaire.

5. Co-infection with HIV defined as the presence of anti-HIV in serum.

6. Clinically-relevant drug abuse based on patient history within 12 months of screening.

7. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
equivalent greater than or equal to 10 mg/day).

8. Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver
that is suggestive of hepatocellular carcinoma, or an alphafetoprotein level of
greater than 500 ng/mL.

9. Active psychiatric problems such as major depression, schizophrenia, bipolar illness,
obsessive-compulsive disorder, severe anxiety, or personality disorder that, in the
investigator s opinion, might interfere with participation in the study.

10. Presence of conditions that, in the opinion of the investigators, would not allow the
patient to be followed in the current study for at least 1 year.