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 (α-SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen α1(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. α-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 α-SMA expression (1.06±0.23 vs. 0.58±0.11, pre vs. post, P<0.05). Placebo recipients had increased levels of α-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 α-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.