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      Time for an active antiviral therapy for hepatitis B: An update on the management of hepatitis B virus infection

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          Abstract

          Significant advances in the management of chronic hepatitis B (CHB) have been made over the past decade. During this period we have witnessed improvements in survival as well as reduction of disease progression in CHB patients due to the introduction of effective antiviral therapy. The need for effective antiviral therapy is underscored by the results of the REVEAL-HBV study in which 3653 hepatitis B virus (HBV) carriers were followed over 12 year period. This study demonstrated that a persistently elevated serum HBV DNA level was the most important risk factor for the development of hepatocellular carcinoma (HCC). The ultimate goal of antiviral therapy for CHB patients should include halting the progression to cirrhosis and its life threatening complications and in preventing/reducing the development of HCC. An earlier study of 651 CHB patients with cirrhosis or advanced fibrosis from countries in Asia also demonstrated that treatment with lamivudine (LVD) not only delayed disease progression but also reduced the development of HCC. These landmark studies reaffirm the need for active antiviral therapy for CHB. Current treatment options for patients with CHB include interferon and nucleos(t)ide analogues. As we gain experience with these agents, it has become increasingly clear that long-term therapy benefits patients with CHB.

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          Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

          Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.
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            Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.

            Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.
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              Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.

              Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications. We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy. Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                August 2007
                August 2007
                : 3
                : 4
                : 605-612
                Affiliations
                [1 ]Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Department of Medicine
                [2 ]Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University Philadelphia, PA, USA
                [3 ]Department of Internal Medicine, Chungbuk National University Hospital Cheongju, South Korea
                Author notes
                Correspondence: Hie-Won Hann Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA Tel +1 215 955 5806 Fax +1 215 955 0770 Email hie-won.hann@ 123456jefferson.edu
                Article
                2374938
                18472982
                e6253a5c-14d4-4eb4-b73c-5a17a015a18f
                © 2007 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                adefovir,lamivudine,telbivudine,pegylated interferon,entecavir,tenofovir
                Medicine
                adefovir, lamivudine, telbivudine, pegylated interferon, entecavir, tenofovir

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