Clinical trial NCT00991289: Nitazoxanide Plus Ribavirin and Peginterferon for Therapy of Treatment Naive HCV Genotype 1 and HIV Coinfected Subjects
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infection
Hepatitis C Infection
Keywords: Hepatitis C genotype 1
HCV treatment naive
HCV/HIV coinfection
Antiretroviral
Ribavirin
Pegylated Interferon alfa
Nitazoxanide
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2009-10-08
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Complete Early Virologic Response (cEVR)
timeFrame: Week 16
measure: Percentage of Participants With Early Virologic Response (EVR)
timeFrame: Weeks 0, 16
Secondary outcomes:
measure: Percentage of Participants With Sustained Virologic Response (SVR)
timeFrame: 24 weeks after treatment discontinuation
measure: Percentage of Participants With Rapid Virologic Response (RVR)
timeFrame: Week 8
measure: Number of Participants With Adverse Events of Grade 2 or Higher
timeFrame: From study entry to up to week 76
measure: Change in Hemoglobin Level From Study Entry
timeFrame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76.
measure: Percent Change in Fasting Insulin Level From Study Entry
timeFrame: Weeks 0, 16, 28, 52, and 76
measure: Percent Change in Fasting Glucose Level From Study Entry
timeFrame: Weeks 0, 16, 28, 52, and 76
measure: Percent Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) From Study Entry
timeFrame: Weeks 0, 16, 28, 52, and 76
measure: Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy.
timeFrame: Weeks 0, 4
measure: Number of Participants With HCV Genotype 1
timeFrame: Week 0
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford AIDS Clinical Trials Unit CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Newark
country: United States
facility: New Jersey Medical School- Adult Clinical Research Ctr. CRS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS
state: Virginia
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: University of California, San Francisco
name: Marion Peters, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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. doi: 10.1016/j.antiviral.2007.08.005. Epub 2007 Sep 4.