Viral Kinetics, Interferon Stimulated Genes (ISGs) and mirRNA Among Subjects Infected With Different Hepatitis C Virus Genotypes During Therapy With Sofosbuvir and GS-5816
Viral Kinetics, Interferon Stimulated Genes (ISGs) and mirRNA Among Subjects Infected With Different Hepatitis C Virus Genotypes During Therapy With Sofosbuvir and GS-5816
Background:

 - Chronic hepatitis C is a serious liver disease. Current treatments have side effects. New
 drugs have been developed, but they work better in some people than others. Researchers want
 to learn why.

 Objective:

 - To learn why new hepatitis C drugs sometimes do not work. Also, to learn if these drugs are
 safe and how well they work in people with different virus strains.

 Eligibility:

 - Adults age 18 and older who are infected with hepatitis C virus genotypes 1-4 and who have
 either never been treated or treated previously with an interferon regimen (with or without
 ribavirin) that failed to clear the virus.

 Design:

 -  Participants will be screened with medical history and physical exam. They will have
 blood and urine tests and complete questionnaires.

 -  Participants will have a Fibroscan, an ultrasound that measures liver stiffness and
 other liver scans. They will have an electrocardiogram.

 -  Eligible participants will have a liver biopsy.

 -  Participants will be admitted to the Clinical Center. They will have a physical exam and
 blood tests, and complete questionnaires.

 -  They will take the first study drug dose as a tablet taken once daily.

 -  Participants will take the drug at home for 12 weeks.

 -  Participants will have 6 study visits. They will have blood and vital signs taken, and
 complete questionnaires.

 -  At week 4, participants will have another liver biopsy.

 -  After their last drug dose, participants will have 5 follow-up visits. They will have
 blood and vital signs taken, and complete questionnaires. They will discuss their
 medications and side effects. They may have another Fibroscan.
Up to 140 patients with chronic hepatitis C, genotypes 1-4, who were never treated or
 previously treated but failed a course of therapy with any interferon and ribavirin
 combination regimen will be eligible to be enrolled into this pilot study to evaluate the
 combination of sofosbuvir and GS-5816 as a fixed dose tablet to improve response to antiviral
 therapy. To enrich the study population with subjects with a greater likelihood of
 virological relapse after stopping therapy, we plan to enroll a minimum of 60%
 treatment-experienced subjects and 50% with cirrhosis. These two drugs inhibit key enzymes
 that are necessary for viral replication. Sofosbuvir, an NS5B polymerase inhibitor is already
 approved for use in combination with interferon and ribavirin for the treatment of HCV
 genotype 1 infection. GS-5816 is an NS5A replication complex inhibitor with potent activity
 against most strains of hepatitis C virus. Combining these two agents into a single pill
 should improve patient compliance and improve tolerability because interferon and ribavirin
 will not be part of the regimen. After medical evaluation and liver biopsy, patients will
 receive combination therapy with sofosbuvir and GS-5816 one pill a day for 12 weeks. The
 baseline liver biopsy is necessary to assess the amount of liver damage caused by the HCV and
 to measure expression of genes associated with clearance of HCV. Blood samples will be
 collected to monitor safety and response to therapy and for research purposes. HCV RNA levels
 will be monitored frequently for the initial 4 weeks and then at monthly intervals for the
 remaining 8 weeks of antiviral therapy. All subjects will undergo a second liver biopsy, 4
 weeks after starting therapy. The second biopsy is being performed for research purposes so
 investigators can determine specifically which liver genes are associated with failure of
 therapy (and response to therapy). Subjects who refuse the second liver biopsy will continue
 to receive SOF/GS-5816 treatment for the planned 12 week duration Patients in whom serum HCV
 RNA is greater than or equal to lower limit of quantification (LLOQ) after 2 consecutive HCV
 RNA < LLOQ or who have a confirmed > 1 log10 increase from nadir will discontinue therapy
 (because continuing therapy is considered futile i.e. it is unlikely to work). The major
 endpoints will be changes in interferon stimulated gene and protein expression in the liver
 and changes in HCV RNA levels in liver and serum between baseline and 4 weeks and rates of
 sustained virologic response at post-treatment week 12. Secondary endpoints will be safety
 and sustained virologic response at post-treatment week 24 weeks.
-  INCLUSION CRITERIA:

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

 -  Willing and able to provide written informed consent.

 -  Male or female, age greater than or equal to18 years.

 -  Body mass index (BMI) greater than or equal to 18 kg/m^2.

 -  HCV RNA greater than or equal to10^4 IU/mL at Screening

 -  HCV genotypes 1a, 1b, 2, 3 or 4 at screening

 -  Confirmation of chronic HCV infection documented by either:

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

 -  A liver biopsy performed within 12 weeks prior to the Baseline/Day 1 visit with
 evidence of chronic HCV infection. A prior biopsy would be acceptable if
 performed with 12 weeks AND liver tissue stored in RNALater was available.

 -  Screening ECG without clinically significant abnormalities.

 -  Subjects must have the following laboratory parameters at screening:

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

 -  AST less than or equal to 10 times ULN

 -  Direct bilirubin less than or equal to 1.5 ULN

 -  Platelets > 70,000

 -  HbA1c less than or equal to8.5%

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

 -  Hemoglobin greater than or equal to 10g/dL.

 -  Albumin greater than or equal to 3g/dL

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

 -  A female subject is eligible to enter the study if it is confirmed that she is:

 -  Not pregnant or nursing

 -  Of non-childbearing potential (i.e., women who have had a hysterectomy, have both
 ovaries removed or medically documented ovarian failure, or are postmenopausal
 women > 50 years of age with cessation (for greater than or equal to 12 months)
 of previously occurring menses),

 OR

 -  Of childbearing potential (i.e., women who have not had a hysterectomy, have not had
 both ovaries removed, and have not had medically documented ovarian failure). Women
 less than or equal to 50 years of age with amenorrhea will be considered to be of
 childbearing potential. These women must have a negative serum pregnancy test at
 Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior to
 randomization. They must also agree to one of the following from 3 weeks prior to
 Baseline/Day 1 until 90 days after last dose of study drug:

 -  Complete abstinence from intercourse. Periodic abstinence from intercourse (e.g.,
 calendar, ovulation, symptothermal, post-ovulation methods) is not permitted.

 -  Consistent and correct use of 1 of the following methods of birth control listed
 below in addition to a male partner who correctly uses a condom from the date of
 Screening until 90 days after last dose of study drug:

 -  intrauterine device (IUD) with a failure rate of < 1% per year

 -  female barrier method: cervical cap or diaphragm with spermicidal agent

 -  tubal sterilization

 -  vasectomy in male partner

 -  hormone-containing contraceptive:

 -  implants of levonorgestrel

 -  injectable progesterone

 -  oral contraceptives (either combined or progesterone only)

 -  contraceptive vaginal ring

 -  transdermal contraceptive patch

 -  All male study participants must agree to consistently and
 correctly use a condom, while their female partner agrees to use 1
 of the methods of birth control listed above, from the date of
 Screening until 90 days after last dose of study drug.

 -  Male subjects must agree to refrain from sperm donation from 90
 days after their last dose of study drug.

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

 -  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.

 EXCLUSION CRITERIA:

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

 -  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.

 -  Difficulty with blood collection and/or poor venous access for the purposes of
 phlebotomy.

 -  Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal
 hemorrhage).

 -  Solid organ transplantation.

 -  Significant pulmonary disease, significant cardiac disease or porphyria.

 -  Psychiatric hospitalization, suicide attempt, and/or a period of disability as a
 result of their psychiatric illness within the last 5 years. Subjects with
 psychiatric illness (without the prior mentioned conditions) that is
 well-controlled on a stable treatment regimen for at least 12 months prior to
 randomization or has not required medication in the last 12 months may be
 included.

 -  Malignancy within 5 years prior to screening, with the exception of specific
 cancers that are entirely cured by surgical resection (basal cell skin cancer,
 etc). Subjects under evaluation for possible malignancy are not eligible.

 -  Significant drug allergy (such as anaphylaxis or hepatotoxicity).

 -  Any prior treatment with a direct acting antiviral agent (protease inhibitors, NS5A
 inhibitors and NS5B polymerase inhibitors/non-nucleoside polymerase inhibitors.)

 -  Pregnant or nursing female or male with pregnant female partner.

 -  Chronic liver disease of a non HCV etiology (e.g., hemochromatosis, Wilson s disease,
 alfa 1 antitrypsin deficiency, cholangitis).

 -  Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).

 -  Clinically-relevant drug abuse within 12 months of screening. A positive drug screen
 will exclude subjects unless it can be explained by a prescribed medication; the
 diagnosis and prescription must be approved by the investigator.

 -  Use of any prohibited concomitant medications as described 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.

 -  Use of antiviral medications within the last 30 days.

 -  Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
 equivalent > 10 mg/day).

 -  Known hypersensitivity to GS-5816, SOF, or formulation excipients.