Pioglitazone Before Peginterferon and Ribavirin for Hepatitis C Infection in HIV/HCV-Coinfected Patients With Insulin Resistance

New and better strategies for the treatment of HCV in HIV/HCV-coinfected people are urgently
needed. Standard therapy for HCV includes treatment with peginterferon plus ribavirin.
Peginterferon is a modified form of the drug interferon and is used either alone or in
combination with ribavirin for the treatment of HCV. Ribavirin works by stopping HCV from
multiplying inside the body. Sustained virologic response rates in past large studies of
peginterferon plus ribavirin used for treating HCV types 1 or 4 ranged from 11% to 29%.
Studies have shown that insulin resistance in HCV-infected people who are HIV uninfected
leads to poorer HCV treatment response. Improving the body's response to insulin may also
improve the outcome of treatment for HCV.

Participants in this study will take pioglitazone alone for up to 28 weeks. At Entry and
Weeks 2, 4, 8, 12,18, and 24 participants will receive clinical assessments. At Week 24,
participants will undergo additional tests to ensure that they can enter Step 2 of the study.
Participants who are able to continue will then take peginterferon and ribavirin in addition
to the pioglitazone for up to 48 additional weeks. Clinical assessments will take place at
the time of entry and Weeks 2, 4, 8, 12, 16, and 24 of Step 2. Participants who do not
exhibit a response to the treatment at Weeks 12 or 24 will not continue Step 2, as it is
unlikely that further treatment will elicit a response. Participants who continue in the
study will return to the study site for clinical assessments at Weeks 32, 40, and 48 of Step
2. Follow-up visits will be held at Weeks 60 and 72. The assessments done at clinic visits
may include any or all of the following tests: thyroid function, hematology and chemistry,
fasting plasma glucose, liver function, gamma-glutamyl transferase, pregnancy, CD4/CD8, HIV-1
RNA, qualitative HCV RNA, and quantitative HCV RNA.

On November 18, 2011 the study was closed to accrual due to not meeting targeted accrual
goals.

Inclusion Criteria:

For Step 1:

- HIV infected

- Exhibited no response to previous treatment with PEG-IFN alfa-2a 180 mcg/week or
alfa-2b 1.5 mcg/kg/week and at least 1000 mg/day ribavirin given for at least 12
consecutive weeks. More information on this criterion can be found in the protocol.

- HOMA-IR valued greater than 2.5 within 42 days prior to study entry. More information
on this criterion can be found in the protocol.

- CD4 count of at least 200 cells/mm3 within 42 days prior to study entry

- HCV RNA of at least 60 IU/ml by quantitative RT-PCR assay with or without reactive
anti-HCV antibodies within 42 days prior to study entry

- Documentation of infection with HCV genotype 1, within 42 days prior to study entry

- On stable or no antiretroviral therapy for 12 weeks prior to study entry.
Interruptions in treatment lasting 14 days or less are allowed if the participant
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.

- Participants on antiretroviral therapy should plan to remain on the same therapy for
at least 24 weeks after study entry. Participants not on antiretroviral therapy should
have no plans to initiate therapy during the first 24 weeks following study entry.

- Participants with documented or suspected hepatic cirrhosis must have a modified
Child-Pugh-Turcotte (CPT) within 42 days prior to study entry.

- Participants with documented or suspected hepatic cirrhosis must have either serum
alpha-fetoprotein level of 50 ng/ml or less within 24 weeks prior to study entry; OR
serum alpha-fetoprotein greater than 50 ng/ml but no greater than 400 ng/ml with an
imaging procedure that shows no evidence of a hepatic tumor, both obtained within 24
weeks prior to study entry.

- Certain laboratory values obtained within 42 days prior to study entry. More
information on this criterion can be found in the protocol.

- Willing to use effective forms of contraception throughout the study. More information
on this criterion can be found in the protocol.

- Ability and willingness of participant to give written informed consent.

For Step 2:

- No more than 28 days have passed since the Step 1, Week 24 visit

- Participants who were treated in Step 1 who meet the following criteria:

1. Detectable HCV RNA (> 60 IU/mL) at the Step 1, Week 24 evaluation

2. CD4 cell count of at least 200 cells/mm3 at Week 24. If the CD4 count is less
than 200 cells/mm3 at Week 24, then it must not have decreased by more than 20
cells/mm3 from the Step 1 entry value.

3. Taking pioglitazone at the time of Step 2 entry

- Certain laboratory values obtained within 28 days prior to Step 2 entry. More
information on this criterion can be found in the protocol.

- Willing to use an effective form of contraception throughout the study

- Female participants of reproductive potential are required to have a negative serum or
urine β-HCG pregnancy test within 14 days prior to Step 2 entry

- Participants without a pregnant partner.

Exclusion Criteria:

- Presence of known causes of significant liver disease. More information on this
criterion can be found in the protocol.

- Evidence of decompensated liver disease manifested by presence or history of ascites,
variceal bleeding, or hepatic encephalopathy

- History of HCV treatment within 28 days prior to study entry

- Evidence that nonresponse to prior HCV treatment may have been due to nonadherence or
certain dose reductions. More information on this criterion can be found in the
protocol.

- Use of interferon gamma, TNF-alpha inhibitors, rifampin, rifabutin, pyrazinamide,
isoniazid, ganciclovir, or hydroxyurea within 14 days prior to study entry

- Current use of didanosine or zidovudine or plans to initiate use of either during the
study

- Active drug or alcohol abuse or dependence that, in the opinion of the study
investigator, could 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 may affect tolerability of study
requirements

- History of autoimmune disorders, including but not limited to Crohn's disease,
ulcerative colitis, severe psoriasis, and rheumatoid arthritis, that have been
exacerbated by previous interferon use

- Any systematic 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 condition that could
interfere with safe study completion

- Presence of AIDS-defining opportunistic infections within 12 weeks prior to study
entry

- Hemoglobinopathy (e.g., thalassemia major) or any other cause of or tendency to
hemolysis. Subjects with thalassemia minor may be enrolled at the discretion of the
investigator.

- History of major organ transplantation with an existing functional graft

- Use of antidiabetic medications for any reason within 12 weeks prior to study entry

- Fasting plasma glucose level of at least 126 mg/dl within 42 days prior to study entry
or current or previous treatment at any time for diabetes with measures other than
diet. Women with a history of gestational diabetes, patients with diabetes or
hyperglycemia occurring in the context of short term use of corticosteroids, growth
hormone, or other diabetogenic medication, and patients with diabetes or hyperglycemia
following an episode of pancreatitis who no longer require treatment for diabetes are
not excluded.

- 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

- Known allergy, sensitivity, or hypersensitivity to components of the study drugs or
their formulation

- Regular and excessive use of alcohol within the 12 weeks prior to study entry. More
information on this criterion can be found in the protocol.

- Unwilling to restrict alcohol use during the study to 120 g of alcohol per week or
less for men and 60 g of alcohol per week or less for women

- Known glucocorticoid use in supraphysiologic doses (e.g., more than 10 mg per day of
prednisone or equivalent doses of other glucocorticoids) within 12 weeks prior to
study entry

- Known glucocorticoid use in physiologic replacement doses (e.g., 10 mg or less per day
of prednisone or equivalent doses of other glucocorticoids) initiated within 28 days
prior to study entry

- History of congestive heart failure corresponding to New York Heart Association Class
II or greater

- Current use of prohibited concomitant medications. More information on this criterion
is available in the protocol.

- Current participation in experimental studies that include treatments not approved by
the FDA or any blinded treatments, with the exception of investigational
antiretrovirals available through expanded access programs

- Body mass index (BMI) greater than 35 kg/m2

- Participant or participant's partner is pregnant or breastfeeding