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

 Chronic hepatitis C infects the liver. It may scar the liver. This is called cirrhosis and
 may lead to liver cancer or death. Current chronic hepatitis C treatments cure most people.
 But some keep getting complications even after it is cured. Researchers want to study why.

 Objective:

 To study the course and complications of liver disease after cure of hepatitis C infection.

 Eligibility:

 Adults 18 years and older infected with chronic hepatitis C virus who were never treated or
 were treated and not cured and those who were cured

 Design:

 Participants will be screened with:

 Blood and urine tests

 Questionnaires

 Liver ultrasound

 Fibroscan. A probe vibrates the liver, testing stiffness.

 In Phase 1, people with chronic hepatitis C will:

 Have a 3-day clinic stay to repeat some screening tests and have a liver biopsy. A small
 piece of liver is removed by needle passed through the skin.

 Take 1 tablet containing 2 hepatitis C drugs once a day for 12 weeks.

 Repeat some screening tests at 3 visits in those 12 weeks, then 4 visits in the next 24
 weeks.

 Phase 1 participants who test negative for hepatitis C and all other participants will enter
 Phase 2.

 Phase 2 participants will have a visit every 24 weeks for 10 years. These may include:

 Repeats of screening tests

 Scans

 Stool tests

 Chest x-ray

 Heart function test

 Endoscopy. A tube guides a camera into the upper digestive system.

 At about 5 years, participants will have another liver biopsy.

 Some participants will give separate consent for genetic testing and a special blood
 procedure.
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:

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

 2. 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).

 3. 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.

 4. 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

 5. 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.

 6. 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 one method 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

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

 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.

 11. Inability to provide consent.