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1. Hepatitis B Treatment Improves Clinical Outcomes

   • Anna SF Lok, MD
   • Marc G. Ghany, Norah A. Terrault, W. Ray Kim, Marion Peters, Jules L. Dienstag

   Division of Gastroenterology, University of Michigan

   In a recent issue of the Journal, a review panel concluded that there was insufficient evidence to assess the effect of treatment of chronic hepatitis B virus (HBV) infection on meaningful clinical outcomes, liver failure, hepatocellular carcinoma (HCC), and death (1). We submit, however, that the single randomized placebo-controlled trial (RCT) of lamivudine treatment in patients with chronic HBV infection and advanced fibrosis or cirrhosis demonstrated convincingly that antiviral treatment has a clinical benefit (2). This trial had to be terminated prematurely after 32 months, when a significant difference in the incidence of the primary endpoint was observed between treated patients and controls (7.8% vs. 17.7%, hazard ratio [HR] 0.45, p=0.001). Because liver failure, HCC, and death generally follow decades of HBV infection, evaluation of the benefit of treatment should not rely solely on RCTs, which are usually limited to 1-2 years. Therefore, we would like to draw attention to substantial and compelling data from retrospective and prospective cohort studies demonstrating that antiviral treatment is associated with improvement in liver histology and clinical outcomes.

   Studies in patients with decompensated cirrhosis showed that antiviral treatment improved biochemical and clinical endpoints as well as survival (3). In RCTs of nucleoside analogs for chronic hepatitis B, a significantly higher proportion of treated patients had a reduction in fibrosis than placebo recipients, and, in follow-up studies of treated patients, regression of cirrhosis was documented (4, 5). Antiviral treatment has also been shown to lead to hepatitis B surface antigen (HBsAg) loss, i.e., resolution of HBV infection, increasing from 3%-4% after 1 year of pegylated interferon treatment to 11% 3-4 years posttreatment (6). The panel indicated that intermediate endpoints such as hepatitis B e antigen (HBeAg) seroconversion or HBV DNA suppression used in RCTs of hepatitis B treatment have not been shown in RCTs to be valid surrogates for clinical outcomes. We submit that evidence supporting the validity of such surrogate intermediate endpoints can be deduced from natural history studies and long-term follow-up studies of patients who received antiviral therapy. In one cohort study of HBeAg-positive patients, 25-year survival was 40% for those who remained HBeAg-positive, 50% for those progressing to HBeAg- negative chronic hepatitis or reverting to HBeAg-positive, and 95% for those with maintained HBeAg seroconversion (7). Similarly, in long-term follow-up studies after interferon treatment, patients who cleared HBeAg had significantly better survival and fewer liver-related complications than those who remained HBeAg-positive (8, 9). Several large population-based studies have shown that high serum HBV DNA levels are associated with an increased risk of cirrhosis, HCC, and liver- related deaths (10, 11). In a prospective study of 3,653 HBsAg-positive persons followed for a median of 11.4 years, those with HBV DNA levels persistently >100,000 copies/mL had a 4.3 to 5.3 fold higher risk of HCC than those with baseline HBV DNA <10,000 copies/mL, whereas those with baseline HBV DNA >100,000 copies/mL but follow-up HBV DNA <10,000 copies/mL had a 1.9-fold risk indicating that the risk of HCC declined with declining viremia (10). Similarly, retrospective studies of lamivudine-treated patients confirmed that those with maintained viral suppression, achieved in 70-95% of patients receiving long-term antiviral therapy (4), had lower rates of HCC or death compared to those with virological breakthrough (12). In conclusion, a direct benefit of antiviral treatment on clinical outcomes was demonstrated in a landmark RCT (2). Antiviral treatment has also been shown to suppress HBV replication and to increase HBeAg seroconversion, and these intermediate endpoints, in turn, have been shown to be associated with improved clinical outcomes. We do not support indiscriminate treatment of all patients with chronic HBV infection; however, patients who meet treatment guidelines (those with advanced liver disease or active liver disease and high levels of serum HBV DNA) have been shown to derive clinical benefit and should be considered for treatment.

   References

   1. Shamliyan TA, MacDonald R, Shaukat A, et al. Antiviral Therapy for Adults with Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference. Annals of Internal Medicine. 2009;150(2):111-124.

   2. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521-31.

   3. Yao FY, Terrault NA, Freise C, et al. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology. 2001;34(2):411-6.

   4. Hadziyannis S, Tassopoulos N, Heathcote E, et al. Long-term Therapy With Adefovir Dipivoxil for HBeAg-Negative Chronic Hepatitis B for up to 5 Years. Gastroenterology. 2006;131(6):1743-51.

   5. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124(1):105-17.

   6. Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg Loss after Long-Term Follow-up of HBeAg-Positive Patients Treated with Peginterferon a-2b. Gastroenterology. 2008;135:459-467.

   7. Fattovich G, Olivari N, Pasino M, et al. Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut. 2008;57(1):84-90.

   8. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. New England Journal of Medicine. 1996;334(22):1422-7.

   9. Lau DT, Everhart J, Kleiner DE, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology. 1997;113(5):1660-7.

   10. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65-73.

   11. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97(4):265-72.

   12. Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004;40(4):883-91.

   Conflict of Interest:

   Anna Lok receives research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Schering and serves on advisory boards of Gilead Sciences, Roche Pharmaceuticals, Schering Plough and Pharmasset. Norah Terrault receives research support from Gilead Sciences and Roche Pharmaceuticals and serves on advisory boards for Schering Plough, Roche Pharmaceuticals, and Bristol-Myers Squibb. Ray Kim receives consulting fees from Bristol-Myers Squibb, Gilead Sciences and Hoffman La Roche. Marion Peters receives consulting fees from Hoffman La Roche, Merck, Pharmasset, Genentech and Clinical Care Options. Jules Dienstag Serves on Scientific/Clinical/Antiviral Advisory Boards of Bristol-Myers Squibb, Gilead Sciences, Metabasis, and Nucleonics and on a Data Monitoring Committee for Schering-Plough Research Institute.

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   Published June 16, 2009