Does hepatitis B treatment reduce the incidence of hepatocellular carcinoma?

I t has been difficult to prove that hepatitis B virus (HBV) treatment reduces the incidence of hepatocellular carcinoma (HCC). Most previous studies have been retrospective without adequate controls. In this issue of HEPATOLOGY Hosaka et al. present data on a large cohort, propensity matched for HCC risk with historical controls, demonstrating that HCC incidence is reduced with entecavir therapy. The advent of potent oral antivirals for the treatment of chronic HBV has had a major impact on our ability to treat this disease. Entecavir and tenofovir are both highly effective, very well tolerated, and there is very little to no resistance. The fall in viral load on treatment is dramatic. The effect on inflammation as measured by alanine aminotransferase (ALT) or on biopsy is equally impressive. Yet the effect of these agents on long-term outcomes such as the development of cirrhosis and HCC remains in question. Hepatologists and others have embraced the use of potent antivirals as effective methods to reduce the incidence of these outcomes, but the evidence supporting this action has been remarkably difficult to come by. In part this is because it takes many years for these outcomes, HCC in particular, to present themselves, much longer than pharmaceutical companies are prepared to wait for licensing, and longer than the duration of most investigator-initiated follow-up studies. The other reason is that it is no longer possible to undertake a randomized controlled trial with an untreated control group, so strong is the belief that these agents are effective. It is considered unethical to leave patients untreated for the duration required to assess changes in incidence of cirrhosis and HCC. There has been a single randomized controlled trial using oral agents in which patients with HBV cirrhosis were treated with lamivudine or nothing. This study showed that there was a reduction in ‘‘outcomes’’ in the treated group. However, it was not clear that there was a reduction in the incidence of HCC. Once those who developed HCC early after recruitment, and who presumably had undiagnosed HCC prior to enrollment, were excluded, the improvement in HCC incidence was no longer significant. A number of studies have attempted to address this question, the results of which were summarized in a review earlier this year. Lai and Yuen found that the results from interferon studies are inconsistent, but the vast majority of studies of oral antiviral agents demonstrated a decrease in HCC incidence. Only one study was randomized (referred to above). The agents used included only lamivudine and adefovir. The studies included more than 2,000 subjects, cirrhosis and noncirrhosis patients, and demonstrate a reduction in HCC incidence in both groups. A prior meta-analysis and a systematic review came to the same conclusion. Nonetheless, with the one exception these were all retrospective data, with all the caveats that come with such studies. Implicit in the discussion of these studies is that even in the absence of additional randomized controlled data the evidence is sufficiently strong to support that antiviral therapy does reduce HCC incidence. In addition to these analyses there is a considerable amount of indirect evidence that adequate suppression of viral replication, however achieved, leads to improved outcomes. Entecavir has been shown to reverse fibrosis and even cirrhosis. We also know that the risk of HCC is related to the viral load, so that presumably reduction of viral load with therapy will reduce the incidence of HCC. Virological response to entecavir has been shown to be associated with better outcomes than in those who did not achieve a sufficient response (and therefore, presumably better outcomes than those who have not been treated). However, this would not be considered high-level evidence, and would not convince skeptics. Despite the fact that most of those who treat HBV have accepted that suppression of viral replication is a useful surrogate marker of improved outcomes, there are those who have reservations about this. At the recent American Association for the Study of Liver Abbreviations: ALT, alanine aminotransferase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Address reprint requests to: Morris Sherman, M.B., B.Ch., Ph.D., F.R.C.P. (C), Toronto General Hospital, 585 University Ave., Toronto, ON, M5G 2N2, Canada. E-mail: morris.sherman@uhn.on.ca; fax: 416-591-2107. CopyrightVC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26317 Potential conflict of interest: Dr. Sherman consults and is on the speakers’ bureau for Bristol-Myers Squibb and Gilead.