COMBIVIR IN PBC

There is circumstantial evidence to suggest an infectious etiology of PBC with clustering of cases in non-related family members. Recurrence of disease occurs in up to 40% of liver transplant recipients who develop characteristic granulomatous destruction of bile ducts and diagnostic anti-mitochondrial antibodies (AMA). We have explored the hypothesis that an infectious agent causes PBC and used a variety of techniques to clone a potentially infectious agent from these patients. We have identified an exogenous retrovirus from a PBC biliary epithelium cDNA library and found evidence for infection in the majority of PBC patients using standard Western blot, immunohistochemistry and hybridization techniques. We have also established an in vitro co-culture model to demonstrate that this virus induces changes consistent with a PBC phenotype in normal biliary epithelial cells.

Lamivudine has proven to be a safe and effective treatment for patients with chronic hepatitis B; therefore, we embarked on preliminary pilot studies using anti-retroviral treatment. Resolution of ductopenia and decreased AMA were seen in some patients on lamivudine but little change in hepatic biochemistry studies was found. In a subsequent pilot study, we found that therapy with Combivir (lamivudine and Zidovudine) resulted in significant improvement in all hepatic biochemistry studies after 6 months and normalization of liver function tests in a proportion of patients. Accordingly, this pilot study is being done to assess the short-term efficacy and safety of Combivir treatment in a multicenter, randomized trial of 55 PBC patients on maintenance therapy with ursodeoxycholic acid. After treatment, patients will be followed for 6 months to study the biochemical and virologic responses to therapy and the potential reservoirs of viral infection. These data will be used to determine whether a long term, randomized, controlled trial with Combivir can be justified for patients with PBC.