Study of the Impact of Nitazoxanide on Chronic Hepatitis Patients
Condition: Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The main objective of antiviral therapy of patients with chronic hepatitis C (CHC) is the
      sustained elimination of the hepatitis C virus (HCV). The standard of care (SOC) is
      peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks according to HCV genotype.

      However, this approach is not sufficient to substantially improve the sustained virologic
      response (SVR) rates. Therefore, new therapies are needed to treat patients with hepatitis C
      virus (HCV) infection. Nitazoxanide (NTZ), originally used to treat cryptosporidium parvum
      infection, recently was shown to have an unexpected antiviral activity in the HCV replicon
      system and in chronically infected patients.

      The aim of this work is to study impact of nitazoxanide therapy in addition to
      peginterferon/ribavirin combination on virologic responses in patients with chronic hepatitis
      C genotype 4.

      Patients will be enrolled in this study and will be randomly assigned in a 1:1 ratio into 2
      groups:

      Group A: comprises 100 CHC patients who will receive the standard of care treatment,
      peginterferon-alf 2a plus weight-based ribavirin for 48 weeks.

      Group B: comprises 100 CHC patients who will receive nitazoxanide monotherapy at a dose of
      500 mg twice daily for 12 weeks as a lead-in phase followed by triple therapy, nitazoxanide
      500 mg twice daily plus peginterferon alfa-2a, and weight-based ribavirin for 48 weeks.

      Data will be collected and statistical analysis will be done comparing the groups regarding
      response to antiviral therapy. Final results will be discussed and compared to similar
      studies published in peer reviewed journals and international conferences.
    

Detailed description: 
      Chronic hepatitis C virus (CHC) infects approximately 170 million individuals worldwide.
      Egypt has the highest hepatitis C virus prevalence in the world (overall prevalence is 12%
      among the general population, and up to 40% in persons above 40 years of age and is more in
      rural areas.

      Approximately, 90% of hepatitis C patients in Egypt are infected with HCV genotype 4.

      The main objective of antiviral therapy of patients with chronic hepatitis C is the sustained
      elimination of the hepatitis C virus (HCV).

      The standard of care for the treatment of chronic hepatitis C is a 24- to 48- week course of
      peginterferon plus ribavirin, depending on genotype.

      Overall, approximately, half of the patients can be cured by SOC. For patients with genotype
      4, the sustained virologic response (SVR) rate with 48 weeks of therapy ranges from 50 to 60
      %. Based on baseline viral load and the speed of virologic response during treatment,
      individualization of treatment duration is possible. However, this approach is not sufficient
      to substantially improve the sustained virologic response (SVR) rates. A significant
      proportion of treated patients thus either fail to respond or relapse following an initial
      response and a substantial number of patients are unable to tolerate treatment. There is at
      present no alternative therapy for these patients and thus a need for new drugs for the
      treatment of chronic hepatitis C.

      Nitazoxanide, the first member of the thiazolidide anti-infective class of compounds, is an
      oral anti-parasitic agent with no major side effects that was developed and licensed in the
      US (Alinia; Romark Laboratories, L.C., Tampa FL, USA) for the treatment of cryptosporidium
      parvum and Giardia lamblia, recently was shown to have an unexpected antiviral activity in
      the HCV replicon system and in chronically infected patients. A serendipitous observation
      during drug development revealed that some patients with cryptosporidiosis and acquired
      immunodeficiency syndrome who are co-infected with hepatitis C or B viruses, had a reduction
      in serum alanine aminotransferase (ALT) levels during therapy. This observation led to
      studies of the anti-viral activity of nitazoxanide and its active metabolite tizoxanide in
      HCV genotype 1a and 1b replicons and a genotype 2 infectious clone, which showed a potent
      inhibition of HCV replication by both compounds at submicromolar concentrations.

      In addition, pretreatment of HCV replicon-containing cells with nitazoxanide was shown to
      enhance the antiviral effect of subsequent treatment with nitazoxanide plus interferon.

      The mechanism of action of nitazoxanide in protozoa and anaerobic bacteria has been shown to
      result from direct inhibition of pyruvate ferredoxin oxidoreductase enzyme-dependent electron
      transfer reaction which is essential to anaerobic energy metabolism. However, the antiviral
      mechanism of action of nitazoxanide appears to be different.

      Recent studies of the mechanism of action of nitazoxanide against HCV have shown that it
      induces double-stranded RNA-activated protein kinase (PKR) phosphorylation, which results in
      an increased intracellular concentration of phosphorylated eukaryotic initiation factor 2α, a
      naturally occurring antiviral intracellular protein and a key mediator of host cell defenses
      against viral infection, this mechanism of action is triggered only when a cell is infected
      with HCV, whereas nitazoxanide has no effect on in uninfected cells, which provides a
      potential explanation for its very low rate of toxicity.

      It worth mentioning that resistance to nitazoxanide is unlikely as it exerts its antiviral
      activity by modulating cell signaling, an interferon-like mechanism, rather than by targeting
      the virus directly and that nitazoxanide does not induce mutations that confer viral
      resistance, suggesting that the genetic barrier to the development of resistance to
      nitazoxanide is high.

      These clinical and laboratory observations prompted study of the potential effect of
      nitazoxanide in patients with chronic hepatitis C.

      Rossingol JF et al,demonstrated that treatment with nitazoxanide monotherapy at a dose of 500
      mg twice daily orally, was associated with an ETR in 7 of 23 (30.4%) patients with chronic
      hepatitis C genotype 4, the virologic responses occurred between 4 and 20 weeks of therapy
      (three at week 4, three at week 8 and one at week 20) and continued through the end of
      treatment with no virological breakthroughs. A low serum HCV RNA ≤ 400,000 IU/ml, was the
      most significant predictor of virological response (p=0.009). In addition, none of the
      patients with cirrhosis, poorly controlled diabetes, or the one patient with HBV coinfection
      responded to treatment. Four of the 7 patients with an ETR (17.4% of 23 treated patients) had
      an SVR, 24 weeks after the end of treatment.

      This preliminary data prompted the study of the efficacy and safety of Nitazoxanide as a
      triple therapy in combination with peginterferon and ribavirin in patients with chronic
      hepatitis C genotype 4 aiming at improving the rate of sustained virological response (SVR).

      A recent study by Rossignol JF et al, conducted on a total 97 treatment -naïve patients
      conducted in 2 centers in Egypt demonstrated that, significantly more patients receiving
      triple therapy with peginterferon alfa-2a, ribavirin and nitazoxanide experienced SVR
      compared with the standard of care (79% vs 50%; p=0-023). The SVR rates for the peginterferon
      plus nitazoxanide group was higher than the standard of care (61% vs 50%) although this
      difference was not statistically significant.

      The percentages of rapid virologic response (RVR), defined as undetectable HCV RNA at week 4
      of combination therapy, and SVR were significantly higher in patients given the triple
      (Nitazoxanide/ peginterferon/ ribavirin) therapy compared with the standard of care (64% vs
      38%, P = .048; and 79% vs 50%, P = .023; respectively). Patients given nitazoxanide plus
      peginterferon alfa-2a had intermediate rates of RVR (54%). There were no added side effects
      associated with the use of nitazoxanide.

      Mean reductions in serum HCV RNA from baseline to the RVR visit were -2.86, -3.74, and -4.5
      log10 IU/ml for the peginterferon plus ribavirin, dual therapy with peginterferon plus
      nitazoxanide, and triple therapy with peginterferon, ribavirin and nitazoxanide groups,
      respectively (p=0.008).

      Changes in ALT levels from baseline to week 72 in patients who achieved an SVR were
      evaluated, nearly all patients had normalization of ALT levels (15/16 patients in groups 1
      and 3, and all patients in group 2), in parallel with loss of detectable serum HCV RNA.
      Interestingly, the use of nitazoxanide in the dual- and triple-treatment arms was associated
      with reduced relapse rates (3/20 patients and 1/23 patients, respectively) compared with the
      standard of care arm (10/30 patients).

      The rationale for a nitazoxanide lead-in phase before combined therapy with peginterferon,
      with or without ribavirin, was based on an initial pilot experience that showed greater
      antiviral efficacy if nitazoxanide was administered before peginterferon rather than
      simultaneously.

      The required duration of nitazoxanide lead-in phase is unknown, and 12 weeks was selected as
      an initial conservative estimate to optimize the potential benefit of nitazoxanide
      pretreatment. A subsequent study has shown that a 4-week lead-in phase may be satisfactory,
      and this study also provides further confirmation of the antiviral efficacy of nitazoxanide
      combined with peginterferon.

      In this open-labeled study, 44 treatment-naïve patients with chronic hepatitis C were treated
      with 4 weeks on nitazoxanide 500 mg twice daily followed by combination dual therapy of
      peginterferon alfa-2a 180 µg weekly plus nitazoxanide 500 mg twice daily for an additional 36
      weeks. Interestingly, the SVR rate with dual therapy (80%), was similar to the SVR rate with
      triple therapy (79%) seen in the previous study using a 12-week lead-in phase. This shorter
      lead-in period might be adequate.

      In a preliminary experience with interferon nonresponders, a small number of patients with
      chronic hepatitis C genotype 4 who had failed prior interferon-based therapy were re-treated
      using triple therapy with nitazoxanide, peginterferon and ribavirin and achieved an SVR rate
      of 25% (3/12 patients) compared with 8% (1/12 patients) retreated with the standard of care
      using peginterferon alfa-2a plus ribavirin.

      All these data show that nitazoxanide, a novel protein kinase inducer, has the potential to
      increase the SVR rate in patients with chronic hepatitis C, however, further studies to test
      these hypotheses on larger numbers of both naïve and nonresponder patients are still
      required.
    

Intervention name(s): Placebo; Nitazoxanide
Intervention type(s): Drug; Drug
Intervention description(s): Group A: comprises 100 CHC patients who will receive placebo twice daily with food for an average of 12 weeks as a part of monotherapy lead-in phase followed by triple therapy, nitazoxanide 500 mg twice daily plus peginterferon alfa-2a (once weekly), and weight-based ribavirin (1000-1200 mg daily) for 48 weeks.; • Group B: comprises 100 chronic hepatitis patients who will receive oral Nitazoxanide 500 mg twice daily with food for an average of 12 weeks followed by the standard of care treatment, peginterferon Alfa 2a once weekly and weight-based ribavirin 1000 or 1200 mg/day (based on body weight < 75 kg or ≥ 75 kg, respectively) in divided doses plus placebo twice daily for 48 weeks.
Other intervention name(s): Control group; Alinia; Xerovirinc(Minapharm Pharmaceuticals)
Intervention MeSH terms: Nitazoxanide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: chronic hepatitis C; genotype 4; treatment naive patients; Egypt