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MULTI-CENTER, DOUBLE BLIND, RANDOMIZED CONTROLLED TRIAL OF COMBIVIR THERAPY FOR PATIENTS WITH PRIMARY BILIARY CIRRHOSIS (PBC)
A Mason1, K Lindor2, B Bacon3, C Vincent4, J Neuberger5, S Wasilenko1
1University of Alberta; 2Mayo Clinic, Rochester; 3St. Louis University; 4University of Montreal; 5University of Birmingham, UK
A human betaretrovirus has been linked with PBC and uncontrolled pilot studies of PBC patients receiving Combivir have shown biochemical and histological improvement. Our aim was to conduct a proof of concept trial linking viral infection with PBC.
METHODS: 59 PBC patients on 13-15 mg/kg ursodeoxycholic acid for 6 or more months with an alk phos level > 1.5 upper limit of normal were entered into the study. A stratified randomization process using a double blind was employed to match biochemical abnormalities in both study arms. Patients received either 300mg Zidovudine and 150mg Lamivudine (Combivir) BID or placebo BID for 6 months. Serial hepatic biochemistry levels were evaluated from baseline, 1, 3, and 6 months with a 6 month wash out period. The established endpoints were normalization of alk phos, ALT or AST; normalization of AST and ALT; as well as 50% reduction from baseline to normal range for alk phos, ALT and AST.
RESULTS: No differences in baseline hepatic biochemistry were observed in the Combivir (n=29) or placebo (n=30) arms; 7 patients were withdrawn from the study (4 Combivir and 3 placebo). A serial reduction in mean alk phos levels was only observed in patients taking Combivir (p<0.0001), where the levels decreased incrementally over the 6 months treatment by > 100 IU/ml from baseline value. Likewise, significant reductions in mean ALT and mean AST were only observed in the Combivir patients (p<0.03). Endpoints were observed in 86% on Combivir and 46% of placebo patients; none achieved normalization of alk phos, 39% Combivir vs. 29% placebo normalized ALT, 32% Combivir vs. 19% placebo normalized AST and 23% Combivir vs. 19% placebo normalized both ALT and AST. Half normalization towards baseline was found in 32% Combivir vs. 19% placebo for alk phos, 69% Combivir vs. 42% placebo for ALT and 68% Combivir vs. 35% placebo for AST (p < 0.05). Combivir was well tolerated and the 2 serious adverse events occurred in patients randomized to placebo.
CONCLUSIONS: In this proof of principal study, combination antiviral therapy provided significant changes in hepatic biochemistry. This study supports the hypothesis that a human betaretrovirus plays a role in the pathogenesis of PBC. Combivir lacks potency and highly active anti-viral therapy may be required to halt disease in PBC patients with demonstrable retroviral infection.
This study was funded by GSK and Axcan.