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

Study Overview
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Brief Summary
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Infection with hepatitis C virus (HCV) can cause liver scarring, or cirrhosis, and this usually occurs more rapidly among people infected with both HCV and human immunodeficiency virus (HIV). People infected with both HCV and HIV have poor response to the current HCV treatments. This phase II pilot study evaluated whether adding a new HCV medication improves response to the current standard HCV treatment with pegylated interferon and ribavirin in people with both HCV and HIV.

Detailed Description
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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.

Official Title
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The Activity of Nitazoxanide in Addition to Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Treatment-Naive Genotype 1 Subjects With HIV Coinfection

Conditions
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HIV Infection, Hepatitis C Infection

Intervention / Treatment
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* Drug: Nitazoxanide (NTZ)
* Drug: Pegylated interferon alfa-2a (PEG)
* Drug: Ribavirin (RBV)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NTZ/PEG/RBV<br>Participants received nitazoxanide (NTZ) alone for 4 weeks followed by 48 weeks of NTZ with pegylated interferon (PEG) and ribavirin (RBV). Participants who did not achieve early virologic response (EVR) at Week 16 or had detectable hepatitis C virus (HCV) viral load at Week 28 discontinued treatment. | Drug: Nitazoxanide (NTZ)<br>* 500 mg twice daily, taken orally with food<br>* Other names: Alinia;Drug: Pegylated interferon alfa-2a (PEG)<br>* 180 micrograms via subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: Ribavirin (RBV)<br>* Weight-based dosing; 1,000 mg daily, taken orally, for people weighing less than 75 kg or 1,200 mg for people weighing at least 75 kg.<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Early Virologic Response (cEVR) | Complete early virologic response (cEVR) was defined as undetectable HCV viral load (<43 IU/ml) at week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). | Week 16 | 
| Percentage of Participants With Early Virologic Response (EVR) | Early virologic response (EVR) was defined as undetectable HCV viral load (<43 IU/ml) at Week 16 or at least a 2-log10 decrease in HCV viral load from study entry at Week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). | Weeks 0, 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response (SVR) | Sustained virologic response (SVR) was defined as undetectable HCV viral load (<43 IU/ml) at 24 weeks after treatment discontinuation, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). Participants who failed to achieve EVR or had detectable HCV RNA at Week 28 and per protocol discontinued study, and participants without HCV RNA from 24 weeks after treatment discontinuation, were considered non-responders. | 24 weeks after treatment discontinuation | 
| Percentage of Participants With Rapid Virologic Response (RVR) | Rapid virologic response (RVR) was defined as undetectable HCV viral load (<43 IU/ml) at Week 8 where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). | Week 8 | 
| Number of Participants With Adverse Events of Grade 2 or Higher | Number of participants who experienced an adverse event of Grade 2 or higher at any time after study entry. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004. | From study entry to up to week 76 | 
| Change in Hemoglobin Level From Study Entry | Change in hemoglobin (HGB) was calculated as HGB at later time point (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76) minus HGB at study entry. | Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76. | 
| Percent Change in Fasting Insulin Level From Study Entry | Percent Change in fasting insulin (FINS) was calculated as FINS at later time point (16, 28, 52, 76) minus FINS at study entry, divided by FINS at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin testing. | Weeks 0, 16, 28, 52, and 76 | 
| Percent Change in Fasting Glucose Level From Study Entry | Percent Change in fasting glucose (FGLUC) was calculated as FGLUC at later time point (16, 28, 52, 76) minus FGLUC at study entry, divided by FGLUC at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting glucose testing. | Weeks 0, 16, 28, 52, and 76 | 
| Percent Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) From Study Entry | HOMA-IR was calculated as [fasting glucose (mg/dL) x fasting insulin (uIU/mL)]/405. Percent Change in HOMA-IR was calculated as HOMA-IR at later time point (16, 28, 52, 76) minus HOMA-IR at study entry, divided by HOMA-IR at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin and fasting glucose testing. | Weeks 0, 16, 28, 52, and 76 | 
| Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy. | Change in log10 HCV viral load was calculated as log10-transformed HCV viral load at Week 4 minus log10-transformed HCV viral load at study entry. HCV viral load testing was done using Cobas AmpliPrep/Taqman HCV Test. | Weeks 0, 4 | 
| Number of Participants With HCV Genotype 1 | Confirmatory HCV genotyping was performed on stored plasma from entry using VERSANT HCV Genotype assay v2.0 (LiPA, RUO, Siemens Healthcare Diagnostics Inc., Tarrytown, NY). | Week 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C genotype 1, HCV treatment naive, HCV/HIV coinfection, Antiretroviral, Ribavirin, Pegylated Interferon alfa, Nitazoxanide