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

• Grade 3 or higher signs and symptoms and laboratory abnormalities and other serious adverse events (AEs) during the study [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: Yes ]
• Undetectable HCV RNA discontinuation (SVR12) [ Time Frame: Measured at Weeks 4, 8, 12, and at 12 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
• Baseline HIV-1 viral load and changes from baseline at each post-entry visit [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: No ]
• Baseline CD4+ T-cell count and changes from baseline at each post-entry visit [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: No ]
• Baseline fibrosis stage, race, gender, insulin sensitivity, and HCV viral load level [ Time Frame: Measured at baseline ] [ Designated as safety issue: No ]
• Undetectable HCV RNA [ Time Frame: Measured at Weeks 16, 20, 24, and 28 ] [ Designated as safety issue: No ]
• Grade 2 or higher signs and symptoms and laboratory abnormalities and other serious AEs [ Time Frame: Measured at Week 28 ] [ Designated as safety issue: Yes ]

• Grade 3 or higher signs and symptoms and laboratory abnormalities and other serious adverse events (SAEs) [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: Yes ]
• Undetectable HCV RNAdiscontinuation (SVR12) [ Time Frame: Measured at Weeks 4, 8, 12, and at 12 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
• Baseline HIV-1 viral load and changes from baseline at each post-entry visit [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: No ]
• Baseline CD4+ T-cell count and changes from baseline at each post-entry visit [ Time Frame: Measured through Week 72 ] [ Designated as safety issue: No ]
• Baseline fibrosis stage, race, gender, insulin sensitivity, and HCV viral load level [ Time Frame: Measured at baseline ] [ Designated as safety issue: No ]

Hepatitis C virus (HCV) infection is a leading cause of death and illness in people with HIV-1. Currently, the standard treatment for people with HIV-1 and HCV coinfection includes two drugs—pegylated-interferon alfa 2b (PEG-IFN) and ribavirin (RBV). The purpose of this study is to evaluate the effectiveness of giving boceprevir (BOC) together with standard treatment in treating HCV infection in people with HIV-1 and HCV coinfection.

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.

• HIV Infections
• Hepatitis C

• Drug: Pegylated-Interferon Alfa 2b (PEG-IFN)
  Week 1 through Week 48: 1.5 mcg/kg SC once a week (based on participant's weight at entry).
• Drug: Ribavirin (RBV)
  Week 1 through Week 48: 800-1400 mg orally per day with food (based on participant's weight at entry).
• Drug: Boceprevir (BOC)
  Participants will receive 800 mg orally every 8 hours with food at Week 5 through Week 36 or through Week 48.

• Experimental: HCV Treatment-Naive (Group A)
  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. Participants will receive PEG-IFN and RBV followed by triple therapy with PEG-IFN, RBV, and BOC until Week 36 or until the end of the study treatment duration (Week 48). Participants who stop triple therapy at Week 36 will receive an additional 12 weeks of PEG-IFN and RBV (until Week 48). Some participants will discontinue study treatment at Week 28.
  Interventions:

  • Drug: Pegylated-Interferon Alfa 2b (PEG-IFN)
  • Drug: Ribavirin (RBV)
  • Drug: Boceprevir (BOC)
• Experimental: HCV Treatment-Experienced (Group B)
  Group B will include participants who have received any treatment with standard interferon or PEG-IFN with or without RBV, provided the last dose of treatment was 90 days or more before study entry. Participants will receive PEG-IFN and RBV followed by triple therapy with PEG-IFN, RBV, and BOC until Week 36 or until the end of the study treatment duration (Week 48). Participants who stop triple therapy at Week 36 will receive an additional 12 weeks PEG-IFN and RBV (until Week 48).
  Interventions:

  • Drug: Pegylated-Interferon Alfa 2b (PEG-IFN)
  • Drug: Ribavirin (RBV)
  • Drug: Boceprevir (BOC)

• Shire NJ, Welge JA, Sherman KE. Response rates to pegylated interferon and ribavirin in HCV/HIV coinfection: a research synthesis. J Viral Hepat. 2007 Apr;14(4):239-48.
• Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, Galati JS, Gordon SC, Ravendhran N, Rossaro L, Anderson FH, Jacobson IM, Rubin R, Koury K, Pedicone LD, Brass CA, Chaudhri E, Albrecht JK. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010 Aug 28;376(9742):705-16. Epub 2010 Aug 6.
• Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, Little LD, Qiu P, Bertelsen AH, Watson M, Warner A, Muir AJ, Brass C, Albrecht J, Sulkowski M, McHutchison JG, Goldstein DB. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010 Mar 18;464(7287):405-8. Epub 2010 Feb 21.

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