Antiviral & Antifibrotic Liver Therapy in HCV + Drinkers and Non-Drinkers
Condition: Hepatitis C
MeSH terms: Hepatitis C
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary aim of this investigation is to evaluate the effect of a combined antiviral,
      antifibrotic and antioxidant treatment on the progression of liver disease in patients with
      hepatitis C who either abstain from alcohol or continue to drink. All subjects are given
      state-of-the-art antiviral treatment (pegylated interferon + ribavirin), supplemented with
      either placebo or polyenylphosphatidylcholine (PPC), a purified soybean extract consisting of
      95-96% polyunsaturated phosphatidylcholines (PC) and which has both antifibrotic and
      antioxidant properties. Secondary aims are to verify whether moderate alcohol consumption
      interferes with the antiviral effect of pegylated interferon + ribavirin on HCV and to
      validate the reliability of various circulating markers as substitute for liver biopsies to
      indicate the stage of liver pathology and its propensity for progression.
    

Detailed description: 
      Current therapy for HCV disease focuses on anti-viral treatment. The combination of pegylated
      interferon and ribavirin is approved by the FDA for treating HCV disease. Subjects in this
      study will be given ribavirin and pegylated interferon. One innovative aspect of this
      proposal is that the state-of-the-art antiviral treatment will be supplemented by an
      anti-fibrotic agent, namely polyenylphosphatidylcholine (PPC), or placebo, administered in a
      double blind randomized fashion. Current therapy focuses on anti-viral treatment, neglecting
      the fact that what causes the medical symptoms and eventually the demise of the HCV patient
      is the liver fibrosis, the resulting cirrhosis and the associated complications, including
      hepatocellular carcinoma. If the fibrotic process could be stopped or even prevented, the
      hepatitis C virus would lose much of its impact on health. Available anti-fibrotic agents are
      too toxic to be used in patients, except for one, namely PPC, which has been shown in various
      experimental models to have striking anti-fibrotic actions, and was found recently, in a
      European study, to be beneficial in patients with hepatitis C in terms of their circulating
      levels of transaminases. Various studies have indicated that HCV is associated with an
      oxidative stress and thus it is noteworthy that PPC was discovered to have also significant
      anti-oxidant effects.

      The study has been approved by the Institutional Review Board at each Center, and all the
      patients are provided written informed consent. After screening, patients are randomly
      assigned to one of 2 treatment groups (PPC or placebo). The two treatment groups are given
      the combination of pegylated interferon (180 μg injected once weekly) (Shiffman et al, 1999;
      Sulkowski et al, 1999), and ribavirin for 48 weeks (genotype I) or 24 weeks (other
      genotypes). If the latter do not respond in terms of HCV RNA, they are also treated for 48
      weeks. Ribavirin is administered orally twice a day at a total daily dose of 1000 mg for
      patients who weigh 75 kg or less and 1200 mg for those who weigh more than 75 kg. These drugs
      are started and stopped at the same time, the PPC (5 chewable tablets of 0.9 gm each per day)
      or corresponding placebo (obtained from PHOSPHOLIPID GmbH, a successor of Rhone-Poulenc
      Rorer, Cologne, Germany) are given to each patient for the 3 years.

      The patients in whom the hemoglobin falls by more than 2 g per deciliter are followed every 2
      weeks until stabilization. The dose of ribavirin is reduced to 600 mg per day in patients
      whose hemoglobin concentrations fall below 10 g per deciliter, and it is discontinued if the
      concentration falls below 8.5 g per deciliter. For severe adverse events other than anemia,
      the dose of interferon is reduced in half and the dose of ribavirin to 600 mg per day. The
      full dose can be resumed after the event, or discontinued if the effect persists.

      The patients are evaluated as outpatients at weeks 1, 2, 4 and then every 4 weeks during the
      24-48 weeks of interferon-ribavirin-PPC (or placebo) treatment as well as during the
      subsequent PPC (placebo) therapy. Upon cessation of antiviral treatment, study patients may
      be seen on a quarterly basis if, in the Investigator's judgment, this flexible schedule will
      not impact negatively on patient care but will impact positively on patient retention.
      Biochemical testing is performed by a central laboratory. Plasma HCV RNA levels are
      determined before treatment, during interferon-ribavirin treatment at 24 and 48 weeks, after
      interferon-ribavirin therapy at months 18, 24 and 30 and at the end of the 3 years. Plasma
      HCV RNA is measured by a quantitative reverse-transcription-polymerase-chain-reaction assay
      (Cobas Amplicor for HCV Monitor v.2, Roche Diagnostic Systems, Inc.) that has a sensitivity
      of 3000 IU/ml with a linearity up to 2.5 X 106 IU/ml. Samples negative with the quantitative
      HCV-RNA are retested with the qualitative HCV-PCR assay (Cobas Amplicor for HCV 2.0, Roche
      Diagnostic Systems, Inc.) that has a sensitivity of 60 IU/ml. HCV genotyping is carried out
      according to Stuyver et al, (1993; Inno-LIPA HCVII, Immunogenetics).

      Compliance in terms of PPC (or placebo) will be monitored by 4 methods: patient diary, pill
      count of the medication and monthly urine analysis for the presence of a riboflavin marker.
      Patients will consume 60 mg riboflavin per day. Riboflavin is rapidly excreted in the urine
      and is fluorescent when passed under an ultraviolet lamp. In addition, spot checks of blood
      levels of dilinoleoylphosphatidylcholine (DLPC, the main phosphatidylcholine species of PPC)
      will validate compliance.

      Alcohol intake will be monitored by 3 methods: patient diary, collateral history and monthly
      blood tests for markers of alcohol consumption (carbohydrate deficient transferrin)(CDT).

      Liver biopsies are performed at the end of 3 years and the specimens analyzed by two
      pathologists who are unaware of the patients' identification and treatment regimen. Fibrosis
      is the major criterion, with some assessment in additional areas, such as virologic response
      examined in both drinkers and non-drinkers.

        1. Fibrosis: The primary statistical analysis will compare the PPC and placebo groups with
           regard to changes in fibrosis score from baseline to the value after 36 months of
           treatment. The primary fibrosis end point is histological with degrees of fibrosis
           graded on liver biopsy according to Ishak et al (1995). Furthermore, we count the number
           of α-smooth muscle actin (SMA) expressing stellate cells (Reeves et al, 1996), the
           principal collagen producing cells. Activation of stellate cells and their
           transformation to myofibroblast-like cells has been demonstrated in experimental
           fibrosis (Mak et al, 1984, 1994). Smooth muscle actin α is an actin isoform typical of
           smooth muscle cells (Skalli et al, 1986), that may be localized in stellate cells of the
           human liver. Its expression in the stellate cells has been considered an indication of
           phenotypic modulation of stellate cells to myofibroblasts. In the human liver the
           appearance of smooth muscle actin α was closely related to the process of hepatic
           fibrosis (Reeves et al, 1996) and the formation of cirrhotic nodules (Nouchi et al,
           1991). In addition, circulating break-down products of collagen or other components of
           the extracellular matrix (ECM) are being used as markers of liver pathology. These
           include laminin, the major noncollagenous glycoprotein of basement membranes. Indeed,
           extracellular basement membranes undergo a continuous turnover and elevation of laminin
           has been described in the sera of patients with alcoholic liver disease (Niemelä et al.
           1988; Sato et al. 1986). Tenascin, a molecule expressed in proliferating ECM, TIMP-1 an
           inhibitor of the matrix degrading metalloproteinases (MMPs), collagen IV, collagen VI, a
           molecule that forms filaments between large collagen fibrils, the N-terminal propeptide
           of procollagen type III (PIIINP), considered a marker of fibrogenesis, hyaluronic acid
           (HA), an ubiquitous glycosaminoglycan with high extraction by the liver sinusoidal
           endothelium, and MMP-2. All these have been assessed before as markers of fibrosis, some
           specifically in patients with chronic hepatitis C (Kasahara et al, 1997; McHutchison et
           al, 2000; Kojima et la, 2001; Murawaki et al, 2001) but not in subjects who were also
           drinkers.

        2. Sustained virologic response, defined as the absence of plasma HCV RNA a minimum of 24
           weeks after antiviral treatment is completed.
    

Intervention name(s): Polyenylphosphatidylcholine (PPC); Pegylated Interferon; Ribavirin
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Interferons; Ribavirin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Chemical Compounds-drugs; Human Subjects- adults; Gastrointestinal System-liver; Pathology