Evaluating the Effectiveness of Boceprevir, Pegylated-Interferon Alfa 2b and Ribavirin in Treating Hepatitis C Virus (HCV) Infection in Adults With HIV and HCV Infection

For HIV-1-infected individuals, HCV infection is a leading cause of morbidity and mortality,
and the prevalence of HCV infection is higher among those infected with HIV-1. The current
standard-of-care (SOC) therapy for HCV infection is treatment with both PEG-IFN and RBV.
This therapy is 40%-45% effective in patients with HCV infection but is significantly less
effective in patients with both HCV and HIV-1. This study will evaluate the effectiveness of
adding BOC, a novel HCV protease inhibitor, to SOC therapy in treating HCV infection
(genotype 1) in HCV/HIV-1-coinfected adults.

Participants will be assigned to one of two groups based on previous HCV treatment. Group A
will include HCV treatment-naive participants who have never received treatment with PEG-IFN
or experimental agents used to treat HCV, with or without RBV. Group B will include HCV
treatment-experienced participants who have received any treatment with standard interferon
or with PEG-IFN with or without RBV, provided the last dose of treatment was 90 days or more
before study entry. All participants should be on stable antiretroviral therapy (ART) for at
least 8 weeks prior to study entry using a dual nucleos(t)ide reverse transcriptase
inhibitor (NRTI) backbone plus one of the following: efavirenz (EFV), raltegravir (RAL),
lopinavir (LPV)/ritonavir (RTV) 400/100 mg twice daily, atazanavir (ATV)/RTV, darunavir
(DRV)/RTV 600/100 mg twice daily OR not have received any ART for at least 4 weeks
immediately prior to entry. Participation in this study will last approximately 72 weeks.

GROUP A (HCV Treatment-Naive)

STEP 1:

Lead In

Participants will receive PEG-IFN subcutaneously (SC) once weekly and oral RBV daily for the
first 4 weeks.

Triple Therapy

Participants will receive PEG-IFN SC once weekly, oral RBV daily, and oral BOC every 8 hours
for an additional 24 weeks.

At Week 28, after completion of Step 1, Group A participants with undetectable HCV RNA at
Week 8 and without cirrhosis at study screening will discontinue study treatment;
participants with detectable or missing viral HCV viral load at Week 8 will continue to Step
2.

All study drugs must be stopped if HCV RNA is 100 international units (IU)/mL or greater at
Week 12 or detectable at Week 24 or there is a confirmed increase to more than 1000 IU/mL at
any time after Week 12.

STEP 2:

Participants without cirrhosis at study screening:

Participants will receive PEG-IFN SC once weekly, oral RBV daily, and oral BOC every 8 hours
for an additional 8 weeks (to Week 36) followed by PEG-IFN SC once weekly plus oral RBV
daily for 12 weeks (to Week 48).

Participants with cirrhosis at study screening:

Participants will receive PEG-IFN SC once weekly, oral RBV daily, and oral BOC every 8 hours
for an additional 20 weeks (to Week 48).

GROUP B (HCV Treatment-Experienced)

All participants will receive PEG-IFN SC once weekly and oral RBV daily for the first 4
weeks.

Participants without cirrhosis at study screening will then receive PEG-IFN SC once weekly,
oral RBV daily, and oral BOC every 8 hours for 32 weeks (to Week 36); followed by PEG-IFN SC
once weekly and oral RBV daily for 12 weeks (to Week 48).

Participants with cirrhosis at study screening will receive triple therapy for 44 weeks
(Week 5 to Week 48).

All participants will have study visits at screening and at Weeks 2, 4, 6, 8, 10, 12, 16,
20, and 24. Select participants may also have study visits on Weeks 28, 40, 52, 60, and 72
or at Weeks 28, 32, 36, 40, 44, 48, 60, and 72. At each visit, participants will undergo a
physical examination and blood collection. Participants will also complete an HCV treatment
adherence questionnaire. At select visits, participants will undergo urine collection and
pregnancy testing (for women of reproductive potential). Plasma, serum, and peripheral blood
mononuclear cells (PBMCs) will be stored for use in future studies.

Inclusion Criteria (Groups A and B):

- Men and women 18 years of age or older

- Presence of chronic HCV infection, defined by presence of plasma or serum HCV RNA in
a participant with HCV antibody for at least 180 days, two documented HCV RNA
positive results greater than 180 days apart, or positive HCV RNA with biopsy
demonstrating chronic hepatitis. More information on this criterion can be found in
the protocol.

- Serum or plasma HCV RNA level 10,000 IU/mL or greater obtained within 42 days prior
to study entry by any laboratory that has a Clinical Laboratory Improvement
Amendments (CLIA) certification or its equivalent. NOTE: This must be a quantitative
HCV RNA test, not a qualitative HCV RNA test.

- Screening HCV genotype 1 performed within 6 months prior to study entry from a
College of American Pathologists (CAP)/CLIA-approved laboratory. Screening genotype
test MUST BE performed locally; ONLY IF IT IS NOT AVAILABLE LOCALLY can it be done at
the designated virology specialty laboratory (VSL) (see A5294 Laboratory Processing
Chart [LPC] in protocol).

- Liver biopsy or HCV FibroSURE™ test within 104 weeks prior to study entry with
interpretation consistent with chronic HCV infection. If a liver biopsy HCV
FibroSURE™ test has not been performed within 104 weeks prior to study entry, then
either a biopsy or HCV FibroSURE™ test must be obtained prior to enrollment. The
cut-off value for the FibroSURE™ test is 0.74, where greater than 0.74 is interpreted
as cirrhosis. More information on this criterion can be found in the protocol.

- Participants should have alpha feto protein (AFP) levels less than 50. If 50 or
greater, they should have a liver imaging study (e.g., ultrasound, computed
tomography [CT] scan, magnetic resonance imaging [MRI] showing no evidence of
hepatocellular carcinoma.

- HIV-1 infection, documented by any licensed rapid HIV test or HIV 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 and/or E/CIA, by HIV-1 p24 antigen, or by plasma HIV-1 RNA
viral load. More information on this criterion can be found in the protocol.

- Currently not on any antiretroviral therapy (ART) for at least 4 weeks immediately
prior to entry or on stable ART for at least 8 weeks prior to study entry using a
dual NRTI backbone PLUS one of the following: EFV, RAL, LPV/RTV 400/100 mg twice
daily, ATV/RTV, DRV/RTV 600/100 mg twice daily. Breaks in therapy for a maximum of 14
days will be allowed. Dose modifications or changes in drugs during the 8 weeks prior
to study entry are permitted unless the change in drug was due to treatment failure.
Participants not on ART should have no plans to initiate therapy during the first 24
weeks after study entry. Participants on ART should plan to remain on the same
therapy for at least 12 weeks after study entry. More information on this criterion
can be found in the protocol.

- CD4+ T-cell count greater than 200 cells/mm^3 obtained within 42 days prior to study
entry at any laboratory that has a CLIA certification or its equivalent

- For participants on ART, screening plasma HIV-1 RNA less than 50 copies/mL obtained
within 42 days prior to study entry by any Food and Drug Administration
(FDA)-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA
certification or its equivalent. For participants who are not on ART, plasma HIV-1
RNA less than 50,000 copies/mL obtained within 42 days prior to study entry by any
FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA
certification or its equivalent.

- The following laboratory values must be obtained within 42 days prior to entry:

- Absolute neutrophil count (ANC) 1000/mm^3 or greater

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

- Platelet count greater than 80,000 per mm3

- Creatinine less than 1.5 mg/dL

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT),
alkaline phosphatase (ALT)/serum glutamic pyruvic transaminaseless (SGPT) less
than or equal to 10 x the upper limit of normal (ULN)

- Direct bilirubin less than 1.5 mg/dL

- International normalized ratio (INR) less than 1.5

- Serum lipase less than or equal to 1.5 x ULN

- Thyroid stimulating hormone (TSH) within normal range, unless accompanied by
thyroid profile consistent with normal thyroid function

- Female participants 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
the preceding 24 months, or women who have not undergone surgical sterilization,
specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy)
must have a negative serum or urine pregnancy test with a sensitivity of at least 50
mIU/mL performed within 42 days prior to study entry

- 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)

- When participating in sexual activity that could lead to pregnancy, participants must
agree to use at least two reliable methods of contraception simultaneously while
receiving protocol-specified medications, and for 6 months after stopping the
medications. Such methods include:

- Condoms (male or female) with a spermicidal agent

- Diaphragm or cervical cap with spermicide

- Intrauterine device (IUD)

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

- Participants who are not of reproductive potential (women who have been
post-menopausal for at least 24 consecutive months or have undergone hysterectomy
and/or bilateral oophorectomy or salpingectomy or men who have documented azoospermia
or have undergone vasectomy) are eligible without requiring the use of
contraceptives. Acceptable documentation of sterilization and menopause is detailed
in protocol.

- Ability and willingness of participant to provide written informed consent

Step 2 Inclusion Criterion (Group A):

Completion of Step 1.

Exclusion Criteria (Groups A and B):

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

- Evidence of decompensated liver disease manifested by the presence of or history of
ascites, variceal bleeding, or hepatic encephalopathy. If hepatic cirrhosis is
determined by liver biopsy (Stage 4 Metavir or Stage 5, 6 Ishak) or by imaging, then
participants must be no more than Child-Pugh Class A and have a Child-Pugh-Turcotte
(CPT) score of 6 or less. More information on this criterion can be found in the
protocol.

- Other known causes of significant liver disease including chronic or acute hepatitis
B, acute hepatitis A, hemochromatosis, or homozygote alpha-1 antitrypsin deficiency

- Infection with any HCV genotype other than genotype 1, or mixed genotype infection

- Uncontrolled or active depression or other psychiatric disorder such as untreated
Grade 3 psychiatric disorder or Grade 3 disorder not amenable to medical intervention
that in the opinion of the site investigator might preclude tolerability or safety of
study requirements. Individuals with suicidal ideation or history of a suicidal
attempt in the last 5 years prior to enrollment will be excluded.

- History of uncontrolled seizure disorders

- Serious illness including malignancy, active coronary artery disease within 24 weeks
prior to study entry, or other chronic medical conditions that in the opinion of the
site investigator may preclude completion of the protocol. Such conditions may be
discussed with the study chairs.

- Presence of active or acute AIDS-defining opportunistic infections within 12 weeks
prior to study entry. More information on this criterion can be found in the
protocol.

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

- History of major organ transplantation with an existing functional graft

- History of autoimmune processes including Crohn's disease, ulcerative colitis, severe
psoriasis, or rheumatoid arthritis that may be exacerbated by IFN use.

- Breastfeeding

- Male participants with pregnant sexual partner

- Use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage
colony-stimulating factor (GM-CSF) within 14 days prior to study entry

- Use of systemic corticosteroids, lovastatin, simvastatin, interferon gamma, tumor
necrosis factor(TNF)-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid,
ganciclovir or hydroxyurea within 14 days prior to study entry

- Previous use of any HCV protease or polymerase inhibitor

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

- Serious illness requiring systemic treatment and/or hospitalization within 42 days
prior to entry

Step 2 Exclusion Criterion (Group A):

- Virologic failure as defined in protocol