Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy

This study will evaluate the safety, tolerability, and effectiveness of a combination of
drugs to treat HCV in adults who are coinfected with HIV and HCV. The three drugs are
paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV). RBV will
be given to participants with HCV genotype 1a only; participants with HCV genotype 1b will
not receive RBV.

This study will enroll HCV genotype 1a or 1b and HIV-1 coinfected participants (HCV
treatment-naïve or HCV treatment-experienced) who are on a concurrent integrase inhibitor
(INI)-based (raltegravir [RAL] or dolutegravir [DTG]) or protease inhibitor (PI)-based
(darunavir [DRV] or atazanavir [ATV]) ART regimen. (The ART regimens will not be provided by
the study.) The participants will be assigned to one of four cohorts (Cohorts A, B, C, and
D). Participants in Cohorts A and B will be on INI-based ART; participants in Cohorts C and
D, on PI-based ART. For each group, the study will proceed in two steps: Step 1: on-HCV
treatment and Step 2: post-HCV treatment follow-up. Participants in Cohorts A and C will
receive the HCV drugs for 24 weeks; participants in Cohorts B and D, for 12 weeks.

Total study duration will be up to 48 weeks. During Step 1 (on-HCV treatment), all
participants will have study visits at Weeks 2, 4, 6, 8, 10, and 12. Participants in Cohorts
A and C will have additional Step 1 study visits at Weeks 16, 20, and 24.

All participants will have Step 2 (post-treatment follow-up) study visits 4, 12, and 24 weeks
after registration to Step 2. Participants in Cohorts B and D will have an additional Step 2
visit 36 weeks after registration to Step 2.

All study visits will include a brief physical exam and blood collection. Select study visits
will include pregnancy testing for participants able to become pregnant, an electrocardiogram
(EKG), an IFN gamma-induced protein 10 (IP-10) test, and collection of plasma samples.

Some participants may take part in two optional substudies. In one substudy, participants
will attend two study visits at entry/Day 0 and Week 4 for 12-hour intensive pharmacokinetic
(PK) sampling. In another substudy, participants will undergo liver biopsies at two time
points and PK sampling.

Step 1 Inclusion Criteria:

- Men and women age greater than or equal to 18 to less than or equal to 70 years at
study entry.

- Body mass index (BMI) from greater than or equal to 18 to less than 38 kg/m^2 within
42 days of study entry. BMI is calculated as weight measured in kilograms (kg) divided
by the square of height measured in meters (m).

- HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 enzyme or
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
confirmed by a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV-1 and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral
load. More information on this criterion can be found in the protocol.

- CD4+ cell count greater than or equal to 200 cells/uL and CD4+ cell percentage greater
than or equal to 14% within 42 days of study entry at any U.S. laboratory that has a
Clinical Laboratory Improvement Amendments (CLIA) certification

- On a stable, qualifying ART regimen for at least 8 weeks prior to entry. More
information on this criterion can be found in the protocol.

- HIV-1 RNA less than 50 copies/mL for at least 6 months prior to study entry by any
U.S. laboratory that has a CLIA certification or its equivalent. HIV-1 RNA testing
must have been performed at least once during the 6 months prior to study entry. More
information on this criterion can be found in the protocol.

- Presence of chronic HCV infection defined as positive for anti-HCV antibody or HCV RNA
at least 6 months before screening, and positive for HCV RNA at the time of screening;
OR positive for HCV RNA at the time of screening with a liver biopsy consistent with
chronic HCV infection any time prior to study entry

- HCV treatment-naïve or unsuccessful treatment with pegylated or standard IFN alfa with
or without RBV. NOTE: No prior exposure to HCV NS3/4A PI (including but not limited to
TVR, BOC, simeprevir), NS5A inhibitors (including but not limited to daclatasvir or
ledipasvir), NS5B NNI or NI inhibitors (including but not limited to sofosbuvir) is
allowed.

- HCV genotype 1a or 1b infection confirmed by testing at the A5329 VSL Quest
Diagnostics. More information on this criterion can be found in the protocol.

- Serum HCV RNA greater than 10,000 IU/mL obtained within 42 days prior to study entry
by any assay performed by the designated A5329 VSL Quest Diagnostics

- The following laboratory values obtained within 42 days prior to study entry.

- Absolute neutrophil count (ANC) greater than or equal to 750/mm^3

- Hemoglobin greater than or equal to 12 g/dL for men and greater than or equal to
11 g/dL for women

- Platelet count greater than or equal to 90,000/mm^3

- International normalized ratio (INR) less than or equal to 1.5.

- Participants with known inherited bleeding disorder and INR greater than or equal
to 1.5 may be enrolled.

- Calculated creatinine clearance (CrCl) using Cockcroft-Gault method greater than
or equal to 60 mL/min

- Alanine aminotransferase (ALT) less than or equal to 7 times the upper limit of
the normal range (ULN)

- Aspartate aminotransferase (AST) less than or equal to 7 times the ULN range

- Total bilirubin less than 3 mg/dL for participants not on ATV and less than 6
mg/dL for participants on ATV

- Direct bilirubin less than or equal to 1.5 times the ULN

- Albumin greater than or equal to 3.5 g/dL

- Serum alfa-fetoprotein (AFP) less than or equal to 100 ng/mL

- Classification of liver disease as non-cirrhotic prior to study entry according to
specified criteria. See the protocol for more information.

- Females of reproductive potential (defined as women who have not been post-menopausal
for at least 24 consecutive months [i.e., who have had menses within 24 months prior
to study entry, or women who have not undergone surgical sterilization, specifically
hysterectomy, tubal ligation, and/or bilateral oophorectomy]) must have a negative
serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL
within 42 days prior to study entry by any U.S. laboratory that has a CLIA
certification or its equivalent.

- 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).

- If participating in sexual activity that could lead to pregnancy, the participant (men
and women) with HCV genotype 1a infection who will receive RBV must agree to use two
reliable methods of contraception simultaneously while receiving study treatment and
for 6 months after stopping study treatment and participants (men and women) with HCV
genotype 1b infection who will not receive RBV must 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)

- Hormone-based contraceptives (only female partners of male study participants)
NOTE: Hormone-based contraceptives are NOT considered an acceptable form of
contraception for female study participants.

- 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. More
information on the criterion can be found in the protocol.

- Ability and willingness of the participant to provide written informed consent

Step 1 Exclusion Criteria:

- Breastfeeding

- Pregnant sexual partner for male participants with HCV genotype 1a infection who will
receive RBV. This criterion does not apply to male participants with HCV genotype 1b
infection who will not receive RBV.

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

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

- Active hepatitis B infection (positive hepatitis B surface antigen [HBsAg]) within 42
days prior to study entry

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

- 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, or drug-related liver disease. More
information on this criterion can be found in the protocol.

- Uncontrolled or active depression or other psychiatric disorder within 24 weeks prior
to study entry that in the opinion of the site investigator might preclude adherence
to study requirements

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

- 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 site investigator might preclude completion of the protocol

- Presence of active or acute AIDS-defining opportunistic infections within 12 weeks
prior to study entry. See the protocol for more information.

- Active or history of malignancy within 5 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

- Clinically significant abnormal EKG, or EKG with QT interval corrected for heart rate
(QTc) using Fridericia's correction formula (QTcF) greater than 450 msec within 42
days of study entry. For Fridericia's correction refer to the calculator located on
the Frontier Science & Technology Research Foundation, Inc. (FSTRF) website at
www.fstrf.org.

- Use of colony stimulating factors, such as granulocyte colony stimulating factor
(GCSF) or erythropoietin within 42 days of study entry

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

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

- History of hemoglobinopathy (e.g., thalassemia) or any other cause of or tendency to
hemolysis any time prior to study entry

- Anticoagulants such as Coumadin (Warfarin), Dicumarol, Plavix (Clopidrogel),
low-molecular weight Heparin, Lovenox (Enoxaparin), or Dabigatran (Pradaxa), aspirin,
and Non-steroidal Anti-Inflammatory Drugs (NSAIDs) within 2 weeks prior to entry.

Step 2 Inclusion Criteria:

- Completion or premature discontinuation (including HCV VF) of Step 1 study treatment
(i.e., HCV) regimen. See the protocol for more information.

Step 2 Exclusion Criteria:

- Premature study discontinuation. See the protocol for more information.