INCLUSION CRITERIA:
Step 1 INCLUSION CRITERIA:
HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, HIV-1 DNA or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
Nonresponder to previous treatment with PEG-IFN alfa-2a 180 mcg/wk, or alfa-2b 1.5 mcg/kg/wk, and greater than or equal to 1000 mg/d RBV given for at least 12 consecutive weeks.
Nonresponder status is defined as:
- less than 2 log(10) drop in HCV RNA from pretreatment levels AND detectable HCV RNA by RT-PCR assay after greater than or equal to 10 weeks and less than 22 weeks of therapy.
OR
- Detectable HCV RNA by RT-PCR assay after more than or equal to 22 weeks and less than 30 weeks of therapy.
HOMA-IR value greater than 2.5 within 42 days prior to study entry.
NOTE: HOMA-IR is calculated using the following formula:
-- Fasting serum insulin (micro U/mL) times fasting plasma glucose (mg/dL)/405
CD4+ count greater than or equal to 200 cells/mm(3) within 42 days prior to study entry at any laboratory that has a CLIA certification or its equivalent.
Documentation of HCV viremia within 42 days prior to study entry as defined by HCV RNA greater than 60 IU/mL by quantitative RT-PCR assay with or without reactive anti-HCV antibodies
Documentation of infection with HCV genotype 1, within 42 days prior to study entry.
Subjects must be on stable or no antiretroviral (ARV) therapy for 12 weeks prior to study entry.
NOTES:
-- Interruptions in treatment less than or equal to 14 consecutive days are allowed if the subject reinitiated the same regimen prior to study entry.
-- Dose modifications or changes in drug formulations during the 12 weeks prior to study entry are permissible.
Subjects on ARV therapy should plan to remain on the same therapy for at least 24 weeks after study entry. Subjects not on ARV therapy should have no plans to initiate therapy during the first 24 weeks after study entry.
Subjects with documented or suspected hepatic cirrhosis must have a Modified Child-Pugh-Turcotte (CPT) Score of 5 within 42 days prior to study entry.
Subjects with documented or suspected hepatic cirrhosis must have either:
- Serum alpha-fetoprotein level of less than or equal to 50 ng/mL within 24 weeks prior to study entry;
OR
- Serum alpha-fetoprotein greater than 50 ng/mL and less than or equal to 400 ng/mL with an imaging procedure (e.g., ultrasound, CT scan, or MRI) that shows no evidence of a hepatic tumor, both obtained within 24 weeks prior to study entry.
Laboratory values obtained within 42 days prior to study entry:
- Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3).
- Hemoglobin greater than or equal to 11.0 g/dL for men and greater than or equal to 10.0 g/dL for women.
- Platelet count greater than or equal to 70,000/mm(3).
- International normalized ratio (INR) less than 1.5.
- Creatinine less than or equal to 1.5 mg/dL.
- AST (SGOT), ALT (SGPT), and alkaline phosphatase less than or equal to 5 times ULN.
- Direct bilirubin less than or equal to 1.5 times ULN.
- Serum lipase less than or equal to 1.5 times ULN.
- TSH less than or equal to ULN, unless accompanied by a free T4 level that is within the normal limits.
Female subjects of reproductive potential (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 or bilateral oophorectomy or salpingectomy) must have a negative serum or urine beta-HCG pregnancy test with a sensitivity of 25-50 mIU/mL performed within 14 days prior to study entry.
Subjects who are not of reproductive potential (women who have been post menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingectomy, 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
- Operative report or other source documentation in the subject record (a laboratory report of azoospermia is required to document successful vasectomy)
- Discharge summary
- Laboratory report of azoospermia
- Follicle stimulating hormone-release factor (FSH) measurement elevated into the menopausal range as established by the reporting laboratory.
All subjects of reproductive potential must agree not to participate in a conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, or in vitro fertilization).
If participating in sexual activity that could lead to pregnancy, all subjects (both men and women) must agree that two of the following reliable methods of contraception will be used simultaneously while receiving protocol-specified medications, and for 6 months after stopping Step 2 medications:
- Condoms (male or female) with or without a spermicidal agent (condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission).
- Diaphragm or cervical cap with spermicide.
- IUD.
- Hormone-based contraceptive.
For subjects who terminate study during Step 1, only 1 of above methods is needed for 6 weeks after discontinuation of study treatment.
Men and women age greater than or equal to 18 years.
Ability and willingness of subject to give written informed consent.
EXCLUSION CRITERIA:
Step 1 EXCLUSION CRITERIA:
Presence of known causes of significant liver disease including chronic or acute hepatitis B, acute hepatitis A, autoimmune hepatitis, hemochromatosis, or homozygote alpha-1 antitrypsin deficiency.
Evidence of decompensated liver disease manifested by presence of or history of ascites, variceal bleeding, or hepatic encephalopathy.
Receipt of HCV treatment within 28 days prior to study entry.
Evidence that nonresponse to prior HCV treatment may have been due to nonadherence or dose reductions defined as follows:
- Known or suspected non-adherence with the HCV treatment regimen (e.g., missing greater than or equal to 20 percent of RBV doses).
- Having missed greater than 1 dose of PEG-IFN during the first 12 weeks of HCV treatment
- Dose reductions of RBV to less than 800 mg/day during the first 12 weeks of therapy
- Dose reductions of PEG-IFN alfa-2a to less than 90 mcg or alfa-2b to less than 0.75 mcg/kg/week for greater than 2 doses during the first 12 weeks of therapy.
NOTE: Subject self-report or clinician report of adherence and dosing of PEG
-- IFN/RBV will be deemed sufficient for source documentation.
Breast-feeding.
Use of interferon gamma, TNF-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid, ganciclovir, or hydroxyurea within 14 days prior to study entry.
Current use of ddI or zidovudine (ZDV) or plan to initiate ddI or zidovudine during the study.
Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
History of uncontrolled seizure disorder.
Uncontrolled depression or other psychiatric disorder such as untreated Grade 3 psychiatric disorder, Grade 3 disorder not amenable to medical intervention, or any hospitalization within the past 52 weeks that in the opinion of the site investigator might preclude tolerability of study requirements.
History of autoimmune processes, including but not limited to Crohn's disease, ulcerative colitis, severe psoriasis, rheumatoid arthritis, that have been exacerbated by previous interferon use.
Any systemic antineoplastic or immunomodulatory treatment or radiation within 24 weeks prior to study entry.
Serious illness including malignancy, active symptomatic coronary artery disease within 24 weeks prior to study entry, or other chronic medical conditions that may preclude completion of the protocol in the site investigator's opinion. If there is doubt that a condition may be exclusionary, such condition may be discussed with the protocol chairs.
Presence of AIDS-defining opportunistic infections within 12 weeks prior to study entry.
A list of AIDS-defining opportunistic infections as defined by the CDC, can be found in the following document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm.
Hemoglobinopathy (e.g., thalassemia) or any other cause of or tendency to hemolysis.
History of major organ transplantation with an existing functional graft.
Use of antidiabetic medications within 12 weeks prior to study entry.
NOTE: Use of any of these drugs for other indications (e.g., lipodystrophy) during this time period is also exclusionary.
Fasting plasma glucose greater than or equal to 126 mg/dL within 42 days prior to study entry or currently or previously treated at any time for diabetes with measures other than diet.
NOTE: Women with a history of gestational diabetes not requiring any treatment for diabetes before or after pregnancy are eligible for participation. Subjects with diabetes/hyperglycemia occurring in the context of short-term use of corticosteroids, growth hormone, or other diabetogenic medication, but not requiring any treatment for diabetes after discontinuation of the implicated medication, are eligible to participate. Subjects with diabetes/hyperglycemia following an episode of pancreatitis who no longer require treatment for diabetes are eligible.
Known osteoporosis or receipt of treatment of osteopenia or osteoporosis within 12 weeks prior to study entry with the following medications: risedronate (Actonel), ibandronate (Boniva), etidronate (Didronel), raloxifene (Evista), teriparatide (Forteo), aledronate (Fosamax), calcitonin (Miacalcin).
Known initiation or change in dose of any statins, fibrates, omega-3 fatty acids, bile acid sequestrants, ezetimibe, and niacin derivatives within 12 weeks prior to study entry.
NOTE: These medications are allowed if they were initiated more than 12 weeks prior to study entry, were utilized in doses stable until the time of study entry and are anticipated to be utilized in the same doses over the duration of the subject's participation in this study.
Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
Regular and excessive use of alcohol defined as self-reported alcohol intake greater than 120 g of alcohol/week in a male or greater than 60 g alcohol/week in a female within 12 weeks immediately prior to study entry.
NOTE:
- Approximately 10 g of alcohol equals one unit. One unit equals 1 ounce of distilled spirits, one 12-oz beer, or one 4-oz glass of wine.
- Subjects with past history of alcohol abuse or dependence who have taken less than these defined amounts within 12 weeks prior to study entry will not be excluded.
Unwilling to restrict alcohol use during the study (both Step 1 and Step 2) to less than or equal to 120g alcohol/week in a male or less than or equal to 60 g alcohol/week in a female.
Known glucocorticoid use in supraphysiologic doses (prednisone > 10 mg/day or equivalent doses of other glucocorticoids) within 12 weeks prior to study entry.
Known glucocorticoid use in physiologic replacement doses (prednisone less than or equal to 10 mg/day or equivalent doses of other glucocorticoids) initiated within 28 days prior to study entry.
NOTE: Individuals on physiologic replacement doses of glucocorticoids initiated more than 28 days prior to study entry will not be excluded.
History of congestive heart failure corresponding to New York Heart Association Class II or greater.
Current use of prohibited concomitant medications.
Current participation in experimental studies that include treatments not approved by the FDA or any blinded treatments, with the exception of investigational ARVs available though expanded access programs.
Body mass index (BMI) greater than 35 kg/m(2).
NOTE: A calculator utility for BMI can be found on the DMC website.
Subjects with a pregnant partner.
Step 2 INCLUSION CRITERIA:
No more than 28 days have elapsed since the Step 1, week 24 visit.
Subjects treated on Step 1 who meet the following criteria:
- Detectable HCV RNA (HCV RNA greater than 60 IU/mL) at Step 1 week 24 evaluation.
- CD4+ cell count greater than or equal to 200 cells/mm(3) at week 24 or if the CD4+ cell count is less than 200 cells/mm(3) at week 24, then it must not have decreased more than 20. cells/mm(3) from the Step 1 entry value.
- On pioglitazone treatment at time of Step 2 entry.
Laboratory values obtained within 28 days prior to Step 2 entry:
- ANC greater than or equal to 1000/mm(3).
- Hemoglobin greater than or equal to 11.0 g/dL for men and greater than or equal to 10.0 g/dL for women.
- Platelet count greater than or equal to 70,000/mm(3).
- International normalized ratio (INR) less than 1.5.
- Creatinine less than or equal to 1.5 mg/dL.
- AST (SGOT) and ALT (SGPT) less than or equal to 5 times ULN OR if greater than 5 times ULN the absolute increase from step 1 entry must be less than or equal to 100 IU/dL.
- Alkaline phosphatase less than or equal to 5 times ULN
- Direct bilirubin less than or equal to 1.5 times ULN.
- TSH less than or equal to ULN, unless accompanied by a free T4 level that is within the normal limits.
Female subjects of reproductive potential are required to have a negative serum or urine beta -HCG pregnancy test within 14 days prior to Step 2 entry and continued willingness to adhere to contraception requirements as previously described.
Subjects without a pregnant partner.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/30/2009