Nitazoxanide Plus Ribavirin and Peginterferon for Therapy of Treatment Naive HCV Genotype 1 and HIV Coinfected Subjects

Chronic hepatitis C virus (HCV) is a significant cause of liver scarring, or cirrhosis, and
accounts for up to 30% of all liver transplants in the United States. People infected with
HIV are at a high risk of coinfection with HCV, and the combination of these two infections
appears to accelerate progression to cirrhosis. Current treatment for HCV infection includes
a 48-week course of two medications taken together, peginterferon alfa-2a (PEG) and ribavirin
(RBV). This combination is only effective in 14% to 29% of people infected with both HIV and
HCV genotype 1 (the genotype most common in the United States). Further complicating
treatment, antiretrovirals (which are used to treat HIV) and HCV medications can often have
high toxicity when taken together, limiting dosing.

Nitazoxanide (NTZ) is a medication currently approved to treat intestinal infections that is
being investigated for use in treating HCV. NTZ has few side effects and has been shown to
increase effectiveness of HCV treatment when combined with PEG and RBV among HCV monoinfected
people. This study will test whether adding NTZ to PEG+RBV regimen for people coinfected with
HCV and HIV improves HCV treatment outcomes.

Participation in this study will last up to 76 weeks. At study entry, participants completed
a brief physical exam, provided a urine sample for a routine safety test, provided a blood
sample, and completed a pregnancy test. Participants then initiated NTZ, which they took
twice a day with food for up to a year. After 4 weeks on NTZ, participants completed the
second study visit, at which they completed the same assessments as at study entry and were
asked about the medications they were taking. At this visit, participants initiated the other
two study drugs, PEG and RBV. PEG was delivered via injection weekly and RBV was taken orally
twice a day with dose dependent on participant's weight at entry.

Participants took NTZ, PEG and RBV together for up to 48 weeks. During this time,
participants completed study visits every 4 weeks until Week 52 and then completed follow-up
visits at Weeks 64 and 76. At these visits, participants completed the same assessments as at
previous visits, and, at certain weeks, also fasted for 8 hours before blood draw. Additional
blood samples were collected and stored at Weeks 4, 8, 16, 52 and 76 in order to do future
testing.

Participants who did not achieve an early virologic response to the study treatment (at least
a 2-log10 decrease in HCV viral load or undetectable HCV viral load at Week 16), or had
detectable HCV viral load at Week 28), stopped study treatment and discontinued study early,
at about 20 or 32 weeks, respectively.

Inclusion Criteria:

- HIV-1 infection

- Documentation of hepatitis C virus (HCV) genotype 1 infection prior to entry

- Chronic HCV infection for at least 180 days

- CD4+ cell count greater than 200 cells/mm3 obtained within 90 days prior to study
entry

- Detectable HCV viral load obtained within 90 days prior to study entry

- Any change in antiretroviral (ARV) regimen, including initiation of antiretroviral
therapy (ART), a switch in ART regimen, or a discontinuation of ART, had to have
occurred more than 60 days prior to study entry. Breaks in therapy for a maximum of 14
days total during the 60-day period were allowed. Participants not on ART should have
had no plans to initiate therapy during the first 24 weeks after study entry.
Participants who did start ART did not have to discontinue study treatment.
Participants on ART should have planned to remain on the same therapy for at least 12
weeks after study entry. Changes in formulation or dosage were permitted.

- Certain laboratory values obtained within 42 days prior to study entry

- Agreement to use contraception, if participating in sexual activity that could lead to
pregnancy, for the duration of study and for 6 months afterward

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase less than or equal to five times the upper limit of normal (ULN)

- Hemoglobin >=11 g/dl for men and >=10 g/dl for women

Exclusion Criteria:

- Use of the ARV didanosine (ddI)

- Receipt of any interferon

- Receipt of any therapy for HCV, including ribavirin (RBV) or experimental treatment

- Decompensated cirrhosis

- Currently active or other known causes of significant liver disease, including chronic
or acute hepatitis B, acute hepatitis A, hemochromatosis, or homozygous alpha-1
antitrypsin deficiency

- Pregnancy or breastfeeding

- Men with pregnant sexual partners or men planning pregnancy with any sexual partner
during treatment or for 24 weeks after treatment completion

- Uncontrolled or active depression, other psychiatric disorder, or any hospitalization
within the past 52 weeks that, in the opinion of the site investigator, would prevent
participation

- Prior suicide attempt

- Active thyroid disease (use of thyroid hormone replacement therapy permitted if
thyroid stimulating hormone [TSH] or free thyroxine [T4] in the normal range)

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

- Systemic antineoplastic or immunomodulatory treatment or radiation within 24 weeks
prior to study entry

- Serious illness, including malignancy or active coronary artery disease, within 24
weeks prior to study entry

- Chronic medical condition that, in the site investigator's opinion, might preclude
completion of the protocol

- Presence of acute or active opportunistic infections within 24 weeks prior to study
entry

- Evidence of hepatocellular carcinoma (HCC) or alpha-fetoprotein level of greater than
50 ng/ml unless an imaging procedure (e.g., computed tomography [CT] scan or magnetic
resonance imaging [MRI]) showed no evidence of a hepatic tumor. Each may have been
obtained up to 24 weeks before study entry.

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

- History of major organ transplantation with an existing functional graft

- Known allergy, sensitivity, or any hypersensitivity to components of study drugs or
their formulations

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