Antiviral & Antifibrotic Liver Therapy in HCV + Drinkers and Non-Drinkers

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.