Meaningful endpoints of therapy are often difficult to demonstrate in clinical studies due to the length of followup that may be needed.  For patients infected with hepatitis B virus (HBV), most clinical studies use surrogate biologic, virologic and histologic markers rather than endpoints like hepatocellular carcinoma (HCC) and death.  In addition, long-term randomized trials with untreated controls are difficult to justify given the success of current treatments in improving these surrogate markers.

A recent Japanese study (Hepatology 2013; 58: 98-107 and editorial pg 18) reports data on a large entecavir-treated cohort (n=472) which was matched with a historical control (retrospective control group, n=1143).  The authors used propensity score matching to eliminate any baseline differences.

Findings:

• Cumulative incidence of HCC rate at 5 years was 3.7% (for entecavir group) and 13.7% (for controls)
• Using regression analysis and adjusting for known HCC risk factors, patients treated with entecavir had a hazard ratio of 0.37 for developing HCC.
• Patients with more risk factors for HCC (eg. older, more active disease, cirrhosis) obtained greater benefit from entecavir treatment (shown in Figure 4 in manuscript)
• The authors also showed that entecavir-treated patients also had less risk of developing HCC than lamivudine-treated patients
• Entecavir-treated patients had low rates of resistance (0.8%) at 3.2 years of treatment

Take-home message: suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC.  In noncirrhotic patients, the magnitude of risk reduction is less.  Thus, patients with active disease should be treated.