deLIVER: Direct Acting Antiviral Effects on the Liver

Primary Objective: The primary objective is to estimate the 1-week change in the proportion
of HCV-infected hepatocytes in participants with HCV monoinfection and HIV/HCV coinfection on
therapy with two or three DAAs with different mechanisms of action using single cell laser
microdissection (scLCM).

Secondary Objectives:

Estimate the change over the first week in plasma HCV RNA in subjects with HCV monoinfected
and HIV/HCV coinfected participants on therapy with two or three DAAs

Estimate the 1 week change in the amount of HCV RNA per infected hepatocyte using scLCM on
liver biopsy specimens, obtained just prior to treatment initiation (pre-treatment), and
after the first week of DAA therapy.

Estimate the change in the proportion of HCV-infected hepatocytes that express
interferon-stimulated genes (ISGs) within the first week of DAA therapy using scLCM.

Measure the change in expression of ISGs in non-parenchymal intrahepatic immune cells
(Kupffer cells, plasmacytoid dendritic cells) within the first week of DAA therapy using
scLCM.

Exploratory Objectives:

Estimate the 1 week change in expression of ISGs from peripheral blood mononucleated cells
(PBMCs) within the first week of DAA+ribavirin (RBV) therapy using scLCM.

Compare sequence(s) of HCV protease, nonstructural protein 5A (NS5A), and nonstructural
protein 5B (NS5B) depending on the peripheral sequence) of intrahepatic HCV RNA in single
cells and bulk tissue, before and during week 1 of DAA+RBV therapy.

Estimate the week 1 change in the sizes and numbers of HCV-infected clusters on DAA therapy
to test whether clearance of HCV-infected hepatocytes occurs in spatially random patterns or
within specific clusters.

Inclusion Criteria:

- Ability and willingness of participant to provide written informed consent. 2. Men and
women age ≥18 to ≤70 years at study entry 3. Body mass index (BMI) ≥ 18 kg/m2 4. HCV RNA ≥
10,000 IU/mL at Screening 5. HCV genotype 1a at Screening 6. Chronic HCV infection (≥ 6
months) documented by prior medical history 7. HCV treatment-naïve with no prior treatment
with any interferon (IFN), RBV, or approved or experimental HCV-specific DAA

8. Absence of cirrhosis as defined as transient elastography (FibroScan®) liver stiffness
measurement < 12.5 kilopascal (kPa) within 6 months of screening 9. The following
laboratory values obtained within 42 days prior to study entry.

- Hemoglobin > 10 g/dL for men and > 9 g/dL for women

- Platelet count ≥90,000/mm3

- International normalized ratio (INR) ≤1.5

- Calculated creatinine clearance (CrCl) ≥ 30 mL/min

- Alanine aminotransferase (ALT) and aspartate aminotransferase level ≤ 10 x upper limit
of the normal range (ULN)

- Total bilirubin <3 mg/dL and Direct bilirubin ≤1.5 x ULN

- Albumin ≥3.5 g/dL

- CD4+ cell count ≥200 cells/microliter (uL) and CD4+ cell percentage ≥14% within 42
days of study entry at any US laboratory that has a Clinical Laboratory Improvement
Amendments (CLIA) certification [HIV seropositive participants only]

- HIV RNA < 400 copies/mL prior to study entry by any US laboratory that has a CLIA
certification or its equivalent [HIV seropositive participants only] 10. On a
qualifying antiretroviral therapy (ART) regimen for at least 14 weeks prior to
entry/day0 [HIV seropositive participants only]

- HIV antiretroviral (ARV) agents allowed in this study include combinations of
nucleos(t)ide reverse transcriptase inhibitors emtricitabine, lamivudine, tenofovir
alafenamide or disoproxil fumarate, abacavir PLUS

- Raltegravir, OR

- Dolutegravir OR

- Rilpivirine

Fixed dose combinations are permitted including emtricitabine/tenofovir alafenamide
(Descovy®), emtricitabine/ tenofovir disoproxil fumarate (Truvada®),
emtricitabine/tenofovir alafenamide/rilpivirine (Odefsey®), emtricitabine/ tenofovir
disoproxil fumarate/rilpivirine (Complera®) lamivudine/abacavir (Epzicom®),
lamivudine/abacavir/dolutegravir (Triumeq®).

11. Women of childbearing potential must have a negative serum pregnancy test at Screening
and a negative urine pregnancy test on Day 0 prior to liver biopsy 12. All participants
must agree not to participate in a conception process (e.g., active attempt to become
pregnant or to impregnate, sperm donation, in vitro fertilization).

13. If participating in sexual activity that could lead to pregnancy, the participant (men
and women) must also agree to use two reliable methods of contraception simultaneously
while receiving study treatment and for 30 days after stopping study treatment.

A combination of TWO of the following contraceptives MUST be used appropriately:

- Condoms (male or female) with or without a spermicidal agent

- Diaphragm or cervical cap with spermicide

- intrauterine device (IUD) 14. Participants who are not of reproductive potential
(women who have been post-menopausal for at least 24 consecutive months or have
undergone hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy or men
who have documented azoospermia) are eligible without requiring the use of
contraceptives. Acceptable documentation of sterilization and menopause is specified
below.

Written or oral documentation communicated by clinician or clinician's staff of one of the
following:

• Physician report/letter

- Laboratory report of azoospermia

- Follicle stimulating hormone-release factor (FSH) measurement elevated into the
menopausal range as established by the reporting laboratory.

15. Participants must be able to adhere to dosing instructions for study drug
administration and able to complete the study schedule of assessments, in the opinion
of the investigator.

Exclusion Criteria:

- Breastfeeding. 2. Known allergy/sensitivity or any hypersensitivity to components of
study drugs or their formulation.

3. Acute or serious illness requiring systemic treatment and/or hospitalization within
42 days prior to study entry.

4. Active hepatitis B infection (positive HBsAg) within 42 days prior to study entry.

5. History of decompensated liver disease (including but not limited to
encephalopathy, variceal bleeding, or ascites) prior to study entry.

6. Any cause of liver disease other than chronic HCV infection, including but not
limited to the following:

- Hemochromatosis

- Alpha-1 antitrypsin deficiency

- Wilson's disease

- Autoimmune hepatitis

- Alcoholic liver disease

- Drug-related liver disease 7. Uncontrolled or active depression or other
psychiatric disorder within 24 weeks prior to study entry that in the opinion of
the investigator might preclude adherence to study requirements.

8. Active drug or alcohol use or dependence that, in the opinion of the
investigator, would interfere with adherence to study requirements.

9. Serious illness including uncontrolled seizure disorders, active coronary
artery disease within 24 weeks prior to study entry, or other chronic medical
conditions that in the opinion of the investigator might preclude completion of
the protocol.

10. Presence of active or acute AIDS-defining opportunistic infections within 12
weeks prior to study entry.

11. Active or history of malignancy within 2 years prior to study entry other
than basal cell carcinoma of the skin and/or cutaneous Kaposi's sarcoma (KS)
and/or cervical or anal dysplasia or carcinoma in situ.

12. Clinically significant abnormal EKG, or EKG with QT interval corrected for
heart rate (QTc) using Fridericia's correction formula (QTcF) >450 msec within 42
days of study entry.

13. Infection with any HCV genotype other than genotype 1a, or mixed genotype
infection any time prior to study entry.

14. History of major organ transplantation with an existing functional graft any
time prior to study entry.

15. History of acquired or hereditary bleeding disorder (e.g., hemophilia,
warfarin use) or any other cause of or tendency toward excessive bleeding time
prior to study entry.

16. Gastrointestinal disorder or post-operative condition that could interfere
with the absorption of the study drug 17. Difficulty with blood collection and/or
poor venous access for the purposes of phlebotomy