Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B

Background: Activation of hepatic stellate cells is the earliest step in fibrogenesis. Alpha-smooth muscle actin (alpha -SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen alpha1(III) propeptide (PIIICP) are early markers of fibrogenesis and should precede fibrosis. Aim: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. Methods: Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine (n = 47) or placebo (n = 33) were studied. alpha -SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. Results: Liver biopsies from patients treated with lamivudine showed a significant decrease in ei-SMA expression (1.06 +/- 0.23 vs. 0.58 +/- 0.11, pre vs. post, P < 0.05). Placebo recipients had increased levels of a-SMA (0.82 +/- 0.14 vs. 1.32 +/- 0.21, P < 0.05). PIIICP was similarly decreased after lamivudine. Among subjects whose Histologic Activity Index fibrosis score was unchanged or worsened, the mean change in cz-SMA expression was significantly decreased in the lamivudine group compared with placebo. Conclusions: Lamivudine decreased markers of hepatic stellate cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibrogenesis and will be useful in trials of antiviral and antifibrotic agents. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.