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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00991289
• Collaborator: (none)
• Enrollment: 68
• Locations: 18
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infection; Hepatitis C Infection	Drug: Nitazoxanide (NTZ); Drug: Pegylated interferon alfa-2a (PEG); Drug: Ribavirin (RBV)	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Activity of Nitazoxanide in Addition to Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Treatment-Naive Genotype 1 Subjects With HIV Coinfection
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NTZ/PEG/RBV 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); 500 mg twice daily, taken orally with food; Other Names: Alinia ; Drug: Pegylated interferon alfa-2a (PEG); 180 micrograms via subcutaneous injection once weekly; Other Names: Pegasys ; Drug: Ribavirin (RBV); 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.; Other Names: Copegus

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete Early Virologic Response (cEVR) [Week 16]

   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).

2. Percentage of Participants With Early Virologic Response (EVR) [Weeks 0, 16]

   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).

Secondary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response (SVR) [24 weeks after treatment discontinuation]

   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.

2. Percentage of Participants With Rapid Virologic Response (RVR) [Week 8]

   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).

3. Number of Participants With Adverse Events of Grade 2 or Higher [From study entry to up to week 76]

   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.

4. Change in Hemoglobin Level From Study Entry [Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76.]

   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.

5. Percent Change in Fasting Insulin Level From Study Entry [Weeks 0, 16, 28, 52, and 76]

   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.

6. Percent Change in Fasting Glucose Level From Study Entry [Weeks 0, 16, 28, 52, and 76]

   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.

7. Percent Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) From Study Entry [Weeks 0, 16, 28, 52, and 76]

   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.

8. Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy. [Weeks 0, 4]

   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.

9. Number of Participants With HCV Genotype 1 [Week 0]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Therapeutics CRS	Birmingham	Alabama	United States	35294-2050
2	UCLA CARE Center CRS	Los Angeles	California	United States	90035
3	Stanford AIDS Clinical Trials Unit CRS	Palo Alto	California	United States	94304-5350
4	UCSD Antiviral Research Center CRS	San Diego	California	United States	92103
5	Ucsf Hiv/Aids Crs	San Francisco	California	United States	94110
6	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts	United States	02114
7	New Jersey Medical School- Adult Clinical Research Ctr. CRS	Newark	New Jersey	United States	07103
8	Weill Cornell Chelsea CRS	New York	New York	United States	10011
9	Columbia P&S CRS	New York	New York	United States	10032
10	Trillium Health ACTG CRS	Rochester	New York	United States	14607
11	Univ. of Rochester ACTG CRS	Rochester	New York	United States	14642
12	Chapel Hill CRS	Chapel Hill	North Carolina	United States	27514
13	Cincinnati Clinical Research Site	Cincinnati	Ohio	United States	45267-0405
14	MetroHealth CRS	Cleveland	Ohio	United States	44109
15	Penn Therapeutics, CRS	Philadelphia	Pennsylvania	United States	19104
16	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island	United States	02906
17	Virginia Commonwealth Univ. Medical Ctr. CRS	Richmond	Virginia	United States	23298
18	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan		Puerto Rico	00935

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Marion Peters, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• Korba BE, Montero AB, Farrar K, Gaye K, Mukerjee S, Ayers MS, Rossignol JF. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res. 2008 Jan;77(1):56-63. Epub 2007 Sep 4.
• Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009 Mar;136(3):856-62. doi: 10.1053/j.gastro.2008.11.037. Epub 2008 Nov 19.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00991289
• Other Study ID Numbers: A5269; 10764; ACTG A5269
• First Posted: Oct 8, 2009
• Last Update Posted: Nov 4, 2021
• Last Verified: Jan 1, 2019

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Hepatitis C genotype 1; HCV treatment naive; HCV/HIV coinfection; Antiretroviral; Ribavirin; Pegylated Interferon alfa; Nitazoxanide
• Additional relevant MeSH terms: Infections; Communicable Diseases; Hepatitis A; Hepatitis C; Hepatitis; Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Nitazoxanide

Study Results

Participant Flow

Recruitment Details	Men and women at least 18 years of age with genotype 1 hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection and naive to previous HCV treatment were recruited for participation in this study.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Period Title: Overall Study
STARTED	67
COMPLETED Week 16	61
COMPLETED	55
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Overall Participants	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.1 (8.5)
Age, Customized (participants) [Number]
<25 years	1 1.5%
25 to <30 years	1 1.5%
30 to <35 years	4 6%
35 to <40 years	3 4.5%
40 to <45 years	11 16.4%
45 to <50 years	13 19.4%
50 to <55 years	18 26.9%
55 to 60 years	13 19.4%
>=60 years	3 4.5%
Sex: Female, Male (Count of Participants)
Female	15 22.4%
Male	52 77.6%
Race/Ethnicity, Customized (Number) [Number]
White, Non-Hispanic	21 31.3%
Black, Non-Hispanic	32 47.8%
Hispanic, Regardless of Race	12 17.9%
Other/Unknown	2 3%
Region of Enrollment (participants) [Number]
United States	67 100%
HCV viral load level (log10 IU/ml) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 IU/ml]	6.4
CD4+ T cell count (cells/mm3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm3]	452
Number of participants with indicated HIV viral load (participants) [Number]
Undetectable HIV viral load	49 73.1%
Detectable HIV viral load	16 23.9%
Unknown	2 3%
HIV Antiretroviral therapy (ART) status (participant) [Number]
On ART	61
Not on ART	6

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete Early Virologic Response (cEVR)
Description	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).
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry. The analysis was intention to treat wherein participants who dropped out early without Week 16 HCV viral load result were considered non-responders.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number (90% Confidence Interval) [percentage of participants]	38.8 57.9%

2. Primary Outcome

Title	Percentage of Participants With Early Virologic Response (EVR)
Description	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).
Time Frame	Weeks 0, 16

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry. The analysis was intention to treat wherein participants who dropped out early without Week 16 HCV viral load result were considered non-responders.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number (90% Confidence Interval) [percentage of participants]	65.7 98.1%

3. Secondary Outcome

Title	Percentage of Participants With Sustained Virologic Response (SVR)
Description	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.
Time Frame	24 weeks after treatment discontinuation

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one who was found to have been ineligible after entry. The analysis was intention to treat wherein participants who dropped out early without HCV RNA from 24 weeks after treatment discontinuation, non-EVRs and those with detectable HCV RNA at Week 28, were considered non-responders.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number (90% Confidence Interval) [percentage of participants]	32.8 49%

4. Secondary Outcome

Title	Percentage of Participants With Rapid Virologic Response (RVR)
Description	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).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry. The analysis was intention to treat wherein participants who dropped out early without Week 8 HCV viral load result were considered non-responders.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number (90% Confidence Interval) [percentage of participants]	10.4 15.5%

5. Secondary Outcome

Title	Number of Participants With Adverse Events of Grade 2 or Higher
Description	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.
Time Frame	From study entry to up to week 76

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number [participants]	65 97%

6. Secondary Outcome

Title	Change in Hemoglobin Level From Study Entry
Description	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.
Time Frame	Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76.

Outcome Measure Data

Analysis Population Description

All participants who enrolled (except one participant who was found to have been ineligible after entry) and had HGB measurements available at entry and at the respective post-entry time point.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Change in HGB at Week 4	-0.1
Change in HGB at Week 8	-2.1
Change in HGB at Week 12	-2.5
Change in HGB at Week 16	-2.5
Change in HGB at Week 20	-2.5
Change in HGB at Week 24	-2.4
Change in HGB at Week 28	-2.5
Change in HGB at Week 32	-2.7
Change in HGB at Week 36	-2.5
Change in HGB at Week 40	-2.6
Change in HGB at Week 44	-2.6
Change in HGB at Week 48	-2.7
Change in HGB at Week 52	-2.9
Change in HGB at Week 76	-0.9

7. Secondary Outcome

Title	Percent Change in Fasting Insulin Level From Study Entry
Description	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.
Time Frame	Weeks 0, 16, 28, 52, and 76

Outcome Measure Data

Analysis Population Description

All participants who enrolled (except one participant who was found to have been ineligible after entry) and had FINS measurements available at entry and the respective post-entry time point.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Percent change in FINS at Week 16	0
Percent change in FINS at Week 28	8.8
Percent change in FINS at Week 52	28.2
Percent change in FINS at Week 76	8.3

8. Secondary Outcome

Title	Percent Change in Fasting Glucose Level From Study Entry
Description	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.
Time Frame	Weeks 0, 16, 28, 52, and 76

Outcome Measure Data

Analysis Population Description

All participants who enrolled (except one participant who was found to have been ineligible after entry) and had FGLUC measurements available at entry and the respective post-entry time point.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Percent change in FGLUC at Week 16	-3.2
Percent change in FGLUC at Week 28	-5.3
Percent change in FGLUC at Week 52	1.1
Percent change in FGLUC at Week 76	0

9. Secondary Outcome

Title	Percent Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) From Study Entry
Description	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.
Time Frame	Weeks 0, 16, 28, 52, and 76

Outcome Measure Data

Analysis Population Description

All participants who enrolled (except one participant who was found to have been ineligible after entry) and had fasting insulin and fasting glucose measurements available at entry and the respective post-entry time point.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Percent change in HOMA-IR at Week 16 (n=56)	-13.0
Percent change in HOMA-IR at Week 28 (n=39)	-6.3
Percent change in HOMA-IR at Week 52 (n=27)	23.2
Percent change in HOMA-IR at Week 76 (n=22)	9.5

10. Secondary Outcome

Title	Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy.
Description	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.
Time Frame	Weeks 0, 4

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry, and had HCV viral load measurements available at entry and at Week 4 were analyzed.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	64
Median (Inter-Quartile Range) [log10 IU/mL]	-0.12

11. Secondary Outcome

Title	Number of Participants With HCV Genotype 1
Description	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).
Time Frame	Week 0

Outcome Measure Data

Analysis Population Description

All participants who enrolled, except one participant who was found to have been ineligible after entry.

Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
Measure Participants	67
Number [participants]	67 100%

Adverse Events

Time Frame	From study entry to Week 76.
Arm/Group Title	NTZ/PEG/RBV
Arm/Group Description	Participants received nitazoxanide (NTZ) alone for 4 weeks followed by up to 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.
All Cause Mortality
	NTZ/PEG/RBV
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	NTZ/PEG/RBV
	Affected / at Risk (%)	# Events
Total	13/67 (19.4%)
Blood and lymphatic system disorders
Anaemia	2/67 (3%)
Neutropenia	3/67 (4.5%)
Gastrointestinal disorders
Abdominal pain	2/67 (3%)
Diarrhoea	1/67 (1.5%)
Haematemesis	1/67 (1.5%)
Vomiting	1/67 (1.5%)
General disorders
Pyrexia	1/67 (1.5%)
Infections and infestations
Cellulitis	1/67 (1.5%)
Pneumonia	3/67 (4.5%)
Urosepsis	1/67 (1.5%)
Injury, poisoning and procedural complications
Joint injury	1/67 (1.5%)
Investigations
Blood creatine phosphokinase increased	1/67 (1.5%)
Nervous system disorders
Syncope	1/67 (1.5%)
Renal and urinary disorders
Haematuria	1/67 (1.5%)
Renal failure acute	1/67 (1.5%)
Other (Not Including Serious) Adverse Events
	NTZ/PEG/RBV
	Affected / at Risk (%)	# Events
Total	67/67 (100%)
Blood and lymphatic system disorders
Anaemia	12/67 (17.9%)
Neutropenia	16/67 (23.9%)
Gastrointestinal disorders
Abdominal pain	7/67 (10.4%)
Constipation	4/67 (6%)
Diarrhoea	18/67 (26.9%)
Dysphagia	4/67 (6%)
Nausea	13/67 (19.4%)
Vomiting	6/67 (9%)
General disorders
Fatigue	23/67 (34.3%)
Irritability	4/67 (6%)
Pain	5/67 (7.5%)
Pyrexia	5/67 (7.5%)
Infections and infestations
Pneumonia bacterial	4/67 (6%)
Investigations
Alanine aminotransferase increased	36/67 (53.7%)
Aspartate aminotransferase increased	29/67 (43.3%)
Blood albumin abnormal	7/67 (10.4%)
Blood alkaline phosphatase increased	6/67 (9%)
Blood bicarbonate abnormal	5/67 (7.5%)
Blood bilirubin increased	14/67 (20.9%)
Blood glucose abnormal	11/67 (16.4%)
Blood glucose increased	6/67 (9%)
Blood phosphorus decreased	14/67 (20.9%)
Blood potassium decreased	6/67 (9%)
Blood sodium decreased	9/67 (13.4%)
Blood triglycerides abnormal	4/67 (6%)
Blood uric acid increased	11/67 (16.4%)
Haemoglobin decreased	24/67 (35.8%)
Lipase increased	11/67 (16.4%)
Neutrophil count decreased	54/67 (80.6%)
Platelet count decreased	35/67 (52.2%)
Weight decreased	21/67 (31.3%)
White blood cell count decreased	23/67 (34.3%)
Metabolism and nutrition disorders
Decreased appetite	14/67 (20.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/67 (7.5%)
Back pain	5/67 (7.5%)
Pain in extremity	5/67 (7.5%)
Nervous system disorders
Dizziness	9/67 (13.4%)
Headache	7/67 (10.4%)
Psychiatric disorders
Anxiety	5/67 (7.5%)
Depression	9/67 (13.4%)
Insomnia	5/67 (7.5%)
Respiratory, thoracic and mediastinal disorders
Cough	5/67 (7.5%)
Dyspnoea	7/67 (10.4%)
Oropharyngeal pain	4/67 (6%)
Respiratory tract congestion	4/67 (6%)
Skin and subcutaneous tissue disorders
Alopecia	4/67 (6%)
Pruritus	4/67 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In accordance with the Clinical Trial Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights