Study of A Combination Pill With GS-7977 and GS-5885 for Hepatitis C in People With HIV

Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated
180 million people infected worldwide. In the US an estimated 4.1 million people are
infected with HCV which is the principal cause of death from liver disease and leading
indication for liver transplantation. Significant advances have been made with the approval
of directly acting antivirals (DAA) namely the protease inhibitors, telaprevir (TVR) and
boceprevir (BOC) which have been shown to significantly improve rates of sustained virologic
response (SVR). Response rates to these new combinations in HIV/HCV are also very promising,
however treatment has been characterized with high rates of toxicities.

Recently several trials have confirmed the efficacy of potent DAA therapy without
concomitant IFN in the treatment of HCV monoinfected individuals. Given the improved
response rates achieved with a combination of DAAs with fast HCV suppression and improved
side-effect profiles; and the need for better therapy for HIV/HCV co-infected subjects, we
propose a study to determine the safety, tolerability and efficacy of 12 weeks of treatment
with a fixed dose combination of GS-7977 and GS-5885 in HIV/HCV Genotype 1 (GT-1) subjects.
We hypothesize that anti-HCV therapy that does not rely on the host immune system will
provide an enhanced rate of SVR among HIV/HCV GT-1 coinfected subjects. The findings from
this study will aid in our understanding of determinants of response to an IFN-free regimen
in HIV/HCV coinfected individuals.

- INCLUSION CRITERIA:

1. Eighteen years of age or older at screening.

2. HCV treatment-na(SqrRoot) ve, as defined as no prior exposure to any IFN, RBV,
or other approved or experimental HCV-specific direct-acting antiviral agent.

3. Participants must be willing to practice either:

1. Abstinence from sexual intercourse or

2. At least 2 forms of contraception including one barrier method from 2 weeks
prior to Day 0 through 30 days after the last dose is received.

i. Female partners of male study subjects may rely upon hormonal contraception
as one of the 2 methods; however female study subjects may not.

4. Chronic hepatitis C infection defined as one of the following:

1. Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6
months before screening, and positive for HCV RNA and anti-HCV antibody at
the time of screening or

2. Positive for anti-HCV antibody and HCV RNA at the time of screening with a
liver biopsy consistent with chronic HCV infection (or a liver biopsy
performed before enrollment with evidence of chronic hepatitis C disease,
such as the presence of fibrosis).

5. HIV treatment status:

1. Documented HIV infection, ARV untreated for > 8 weeks preceding dosing and
having either:

1. a CD4 T-cell count greater than or equal to 500 cells/mm3 within 8
weeks of Day 0 or

2. an HIV viral load less than 500 copies/mL with a stable CD4 count for
at least 3 months.

2. Documented HIV infection on a stable, protocol-approved, ARV regimen for
greater than or equal to 8 weeks prior to dosing and is expected to
continue the current ARV regimen through the end of study with all of the
following:

1. a CD4 T-cell count > 100 cells/mm3

2. a documented plasma HIV-1 RNA level less than the level of detection
for at least 8 weeks preceding dosing.

If the lower limit of detection of the local HIV-1 RNA assay is < 50
copies/mL (e.g.,< 20 copies/mL), the Screening plasma HIV-1 RNA level
cannot exceed 50 copies/mL.

3. HIV ARV agents including only combination regimens consisting of
medications from the following list: tenofovir (TDF), emtricitabine
(FTC), efavirenz, raltegravir, and rilpivirine administered according
to their manufacturer s prescribing information. (reference Section
10.3 for additional information)

6. Documentation of hepatitis C genotype 1a, 1b or mixed 1a/1b

7. Absence of cirrhosis, defined as one of the following:

1. A liver biopsy performed within 36 calendar months of screening showing
absence of cirrhosis.

2. FibroTest score of < 0.48 AND APRI of < 1 performed during the 8 weeks
preceding dosing (In the absence of a definitive diagnosis of presence or
absence of cirrhosis by the above criteria, a liver biopsy is required).

8. Able to effectively communicate with the Investigator and other center
personnel.

9. Willing to give written informed consent and comply with the study restrictions
and requirements.

10. If opioid-dependent, subjects must be participating in a supervised treatment.

11. Participants must have a primary medical provider outside of OP8 and the NIH for
medical management.

EXCLUSION CRITERIA:

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

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

1. 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.

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

3. Poor venous access interfering with required study blood collection.

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

5. Solid organ transplantation.

6. Significant pulmonary disease, significant cardiac disease or porphyria.

7. Unstable psychiatric disease (Subjects with psychiatric illness that is
well-controlled on a stable treatment regimen or currently not requiring
medication may be included).

8. Any malignancy or its treatment that in the opinion of the PI may cause ongoing
interference with host immunity; subjects under evaluation for malignancy are
not eligible.

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

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

11. Patients with renal impairment or uncontrolled medical problems that could place
them at high risk for developing renal impairment.

2. Positive test at screening for either HBsAg or quantifiable HBV DNA (completed only
if necessary to rule out chronic HBV)

3. Current use of non-protocol approved ARVs.

4. A new AIDS-defining condition diagnosed within 30 days prior to screening or active,
serious infection (other than HIV or HCV) requiring parenteral antibiotics,
antivirals or antifungals within 30 days prior to Day 0.

5. Cirrhosis of the liver

6. Screening or baseline ECG with clinically significant ECG findings.

7. Abnormal hematological and biochemical parameters, including:

1. Neutrophil count < 750 cells/mm(3)

2. Hemoglobin < 9 g/dL. If Hgb is < 11g/dL in women or < 12 g/dL in men. Other
causes of anemia should be excluded as medically indicated.

3. Platelet count less than or equal to 50,000 cells/mm(3)

4. Estimated GFR (calculated by the CKD-EP(I) equation) < 50 mL/min/per 1.73 m(2)
if not on ARV or < 60 mL/min if on ARVs

5. ALT or AST greater than or equal to 10 times ULN

6. Serum lipase greater than or equal to 1.5 times ULN (at screening or during the
screening period)

7. Direct bilirubin greater than or equal to 1.50 times ULN

8. Albumin less than or equal to 3.0 g/dL

9. INR greater than or equal to 1.5 times ULN unless subject has known hemophilia
or is stable on an anticoagulant regimen affecting INR.

8. Donation or loss of more than 400 mL blood within 8 weeks prior to first dose
administration.

9. Poorly controlled diabetes mellitus indicated by hemoglobin A1C > 10% at screening
for known diabetics.

10. Known hypersensitivity to, GS-5885, GS-7977, or formulation excipients.

11. Pregnant/Breastfeeding women.

12. Co-enrollment in other clinical trials is restricted, and requires approval of the
Investigator.

Study staff should be notified of co-enrollment status.

13. Need for use of the following medications from 21 days prior to the start of study
drugs through the end of treatment:

1. Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs);
granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

2. Chronic systemic immunosuppressants including, but not limited to,
corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks),
azathioprine, or monoclonal antibodies (e.g., infliximab)

3. Investigational agents or devices for any indication

4. Medications for disease conditions excluded from the protocol (e.g., active
cancer, transplantation) are not listed under this Concomitant Medication
section and are disallowed in the study.

5. Concomitant use of certain medications or herbal/natural supplements per PI
discretion expected to result in pharmacokinetic interactions resulting in
increases or decreases in exposure of study drug(s) as listed in Table of this
protocol.