A Safety and Tolerability Study of Nitazoxanide in HIV-HCV Treatment Failures

Chronic hepatitis C (CHC) viral infection is a major health problem affecting 130-170 million
worldwide, and 2.7-3.9 million in the US, more than 3 times those with HIV infection.
One-third of persons with HIV have CHC, a more rapid progression to cirrhosis and liver
failure, with liver disease as one of the leading causes of mortality.

Standard treatment, pegylated-interferon (IFN) alfa and ribavirin (RBV), has an efficacy,
sustained virologic response (SVR), of less than 50% in those with HCV genotype 1 (GT 1); and
only about 25% of those with HIV-HCV GT1 co-infection. SVR is even lower in those retreated,
who were prior treatment relapsers or non-responders; few published studies exist, especially
in those with HIV. Improved therapy is imperative given increasing morbidity and mortality
and the proportion of persons who are relapsers or non-responders. Newer and promising
anti-HCV therapies, directly acting antivirals (DAA), are in development. However, only 2 are
in Phase 3 clinical trials and most remain far from FDA approval.

An oral agent, nitazoxanide (NTZ), with broad in vitro anti-microbial activity and a good
safety profile, has higher efficacy rates in treatment na ve participants mono-infected with
HCV GT 1 or 4. There have not been studies in HIV co-infected persons, nor pharmacokinetic
(PK) studies in liver or renal disease. In vitro studies suggest that NTZ has both a direct
suppressive effect on HCV replication, as well as a sensitizing effect on IFN-mediated
suppression of HCV replication, yet the exact mechanism of action giving rise to higher SVR
rates is not well understood.

This is an open-label study in 35 HIV-HCV GT 1 co infected persons, prior relapsers (n=25) or
non-responders (n=10) after a full course of IFN and RBV therapy. Participants will receive 4
weeks of NTZ lead-in therapy, followed by NTZ/peg-IFN/RBV triple combination therapy for an
additional 48 weeks. Slow responders will receive 72 weeks of triple therapy after the 4-week
NTZ lead-in.

The primary endpoint is safety and tolerability of NTZ. Secondary endpoints are exploratory:
(1) efficacy rate estimation, (2) viral dynamics assessment, and determination of predictive
response, (3) pharmacologic level assessment, (4) indirect mechanistic action evaluation of
NTZ through virologic response, and, (5) IFN-stimulated genetic expression evaluation and
determination of predictive response. There will be a sub-study evaluating the PK of NTZ in a
group of 10 participants who are on a ritonavir-based HIV antiretroviral regimen.

- ELIGIBILITY CRITERIA:

To be eligible for participation on this protocol, a participant must satisfy all of the
following conditions:

Be greater than or equal to 18 years old and have an identifiable Primary Care Provider.

Have either documentation of HIV-1 infection by licensed enzyme-linked immunosorbent assay
(ELISA) and confirmed by a Western Blot or HIV RNA of 1,000 copies/mLor greater.

Have documentation of chronic HCV (CHC) infection by demonstration of a positive test for
hepatitis C antibocy and HCV RNA of 2,000 IU/mL or greater

Have histopathologic features consisten with CHC at the time of enrollment. A liver biopsy
done for a participant with 36 months prior to his or her participant may be used as the
baseline biopsy. Participants can opt out of a biopsy if they had one or more than 36
months prior and have a contraindication, sucha as receiving chronic anticoagulation
therapy. Participants with decompensated liver disease are excluded from study.

Are co-infected infected with HCV genotype 1 and HIV viruses.

1. Relapsers: Participants who had an undetectable HCV RNA (< 10 IU/mL) at the end of
prior treatment (ETR) but have detectable HCV RNA by Week 72 or thereafter.

2. Non-responders: Participants who have received at least 12 weeks of treatment with any
IFN alfa 2a or 2b with ribavirin and have not achieved either a 2 log (10) drop in HCV
viral levels at week 12 (null responder) nor has not achieved a HCV RNA below the
level of detection by Week 24 (< 10 IU/mL).

3. Washout period from prior treatment of at least 3 months.

Participants with CD(4) cell counts greater than or equal to 100 cells/mm(3)

Capacity to understand and sign or thumbprint the Informed Consent document, as well
as willingness to comply with the study requirements and clinic policies.

Absolute neutrophil count > 1,000 cells/mm3.

Platelets > 50,000/mm3.

Hemoglobin > 10.5 mg/dL.

Not pregnant or breast-feeding. Serum pregnancy test must be negative 2 weeks prior to
Day -28 and to Day 0 prior to dosing with study medications for female participants.

If the participant is able to become pregnant, then she must use 2 effective methods
of contraception during the study. Effective contraceptive methods include abstinence,
surgical sterilization of either partner, barrier methods such as diaphragm, condom,
cap, or sponge, or use of hormonal contraception with an anti-HIV regimen that will
not alter metabolism of hormonal contraception. This is advised on the basis of using
ribavirin, which may have a potential teratogenic effect on the fetus in pregnant
women. NTZ had not been studied during lactation.

Be willing to not become pregnant until 6 months after completion of ribavirin
therapy.

Male participants who are not documented to be sterile agree to either abstain from
intercourse or consistently and correctly use a condom while their female partner (if
applicable) agrees to use one of the appropriate medically accepted methods of birth
control listed above from the date of screening until 6 months after their last dose
of ribavirin.

Participants with documented illicit drug use must demonstrate ability to adhere to
HIV medication (with an undetectable or stable HIV viral load) and their prior primary
care provider appointments (more than 80% as scheduled).

Be willing to abstain from alcohol use during the trial and enter treatment program if
necessary.

Be able to learn to safely inject medication, be able to find another person or a
clinic to inject the medication for him/her, or is willing to come to the clinic for
weekly injections.

Be willing to allow stored blood or tissue samples to be used in the future.

EXCLUSION CRITERIA

A participant will be ineligible to participate on this study if any of the following
criteria are met:

A participant cannot be on other experimental therapies (including expanded
access/compassionate use of antiretrovirals) for 28 days prior to Day -28 and during
his/her participation in this protocol.

Mixed genotypes (e.g., 1 & 2, 1 & 3,1 & 4). Mixed genotype 1a/1b will be enrolled.

Has any other known, or clinically suspected, cause of liver disease, including active
hepatitis B.

For participants with cirrhosis, a Child Turcotte Pugh score > 7, or Child's B or C
cirrhosis.

Has a prothrombin time International Normalized Ratio (PT-INR) > 2 and is not on
chronic anti-coagulation medications, or has a history of hemophilia.

Has had an organ transplantation other than cornea or hair.

Has an estimated creatinine clearance (estimated glomerular flow rate) < 50 mL/min.

For a participant with higher than 20 ng/mL of alpha-fetoprotein, a negative
ultrasound or computerized tomography scan to rule out hepatoma is required for
enrollment.

Has any neoplastic disease EXCEPT for (1) Kaposi's sarcoma not requiring systemic
chemotherapy, (2) any non-metastatic skin cancer that has been resected or (3)
non-metastatic cervical or anal cancer that has been resected.

Has evidence of severe cardiac disease (greater than or equal to Grade 3 congestive
cardiac failure, symptomatic coronary artery disease, significant arrhythmias, or
uncontrolled hypertension) despite intervention or medical therapy.

Has evidence of severe chronic pulmonary disease with functional impairment or a DLCO
(diffusing capacity of the lung for carbon monoxide) less than or equal to 70% at
baseline.

Has a severe psychiatric disorder that would interfere with the adherence to protocol
requirements, and that is not stably treated with risk of decompensation.

Has evidence of autoimmune disorders including inflammatory bowel diseases, psoriasis,
and optic neuritis.

Has evidence of an uncontrolled seizure disorder defined as more than 1 episode of
generalized seizure within the past year.

Has chronic pancreatitis.

Has severe retinopathy, as determined by the ophthalmologist.

Has any hemoglobinopathy (e.g., Thalassemia, sickle cell disease).

Is currently taking didanosine or d4T as part of antiretroviral regimen.

If total bilirubin is greater than 1.5 mg/dL then direct bilirubin can be no more than
70% of the total, up to a direct bilirubin of 2.0 mg/dL.

Concurrent use of any immunosuppressive therapy, including systemic steroids
(prednisone equivalent of > 10 mg/day) for a duration of 6 weeks or more within 6
months prior to enrollment. Inhaled steroids will be allowed, even with ritonavir.

Has active systemic infections other than HCV and HIV.

Has a hepatic mass suggestive of hepatocellular carcinoma as detected by ultrasound
scan, dual-phase computerized tomography, or magnetic resonance imaging.

Has evidence of moderate or heavy alcohol use (> 50 grams/day), or substance abuse,
within the past 6 months that potentially could interfere with participant compliance.
(Urine toxicology will be completed at screening.)

Currently uses warfarin, ganciclovir, isoniazid, pyrazinamide, rifabutin,
rifampin/rifampicin, thalidomide, or theophylline.

Has a history of esophageal or gastric varices.

Has any systemic illness that will make it unlikely that the participant will be able
to return for the required study visits.

Has evidence of gastrointestinal malabsorption, chronic nausea, or vomiting.

The participant is the male partner of a pregnant woman and does not always use a
condom during intercourse.

Women who are pregnant.

Women who are breast-feeding.

Has a hypersensitivity to NTZ, interferon products, or ribavirin.

Has ingested silymarin (milk thistle), s-adenosylmethionine (SAM-e), glycyrrhizin,
Sho-saiko-to (SST), or other herbal supplements that may be either liver beneficial or
toxic, within 28 days prior to Day -28.