Treatment of Chronic HBV Infection by Pegylated Interferon
Treatment of Chronic HBV Infection by Pegylated Interferon
Background: Pegylated interferon-α has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003.
Aim: To systematically summarize and compare the results of these studies.
Methods: Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug-resistant mutants were recorded.
Results: Three of the four trials contained predominantly Asian patients. Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one-thirds of patients after 12 months of therapy. Coadministration of lamivudine did not result in improvement in viral suppression. Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups. It was well tolerated with serious adverse events reported in <10% of patients in most trials.
Conclusions: Peginterferon-α treatment of at least 6 months should be considered as one of the first-line therapeutic options for hepatitis B virus infection.
Chronic hepatitis B virus (HBV) infection is a serious global public health problem. Of the 2 billion people who have been infected, more than 350 million have chronic hepatitis. HBV-infected patients with active disease are characterized by positive hepatitis B surface antigen (HBsAg) for at least 6 months and elevated serum transaminase and HBV-DNA levels. The aims of treatment of chronic hepatitis B are to sustain viral suppression and disease remission. Conventional interferon and nucleoside/nucleotide analogues are currently approved first-line treatments of chronic HBV infection. The end points used to assess treatment effects include biochemical, virological and histological responses. These end points are surrogate markers of the clinically important outcome measures, i.e. the development of liver-related complications and death. Previous studies on natural history revealed that HBV-infected patients with normal alanine transaminase (ALT), low viral load and mild histological disease have lower risk of cirrhosis and hepatocellular carcinoma. Hepatitis B e antigen (HBeAg)-positive patients who have achieved seroconversion with development of anti-HBe antibody also have improved prognosis.
Interferon-α acts mainly as an immunomodulator and enhances the host cell-mediated immune response in clearing the virus. A meta-analysis of 15 randomized-controlled studies found that with 3-6 months of interferon-α treatment, HBeAg loss, undetectable HBV-DNA using hybridization assays and loss of HBsAg can be achieved in 33%, 37% and 8% of patients respectively. This was highly significant compared with the corresponding figures in untreated patients of 12%, 17% and 2%. In the long-term, interferon-α-treated patients who responded with HBeAg seroconversion had a lower risk of cirrhotic complications and longer survival rate.
Anti-viral agents such as nucleoside and nucleotide analogues are more widely used in Asia because of a milder side-effect profile. At the end of 1-year therapy with lamivudine, up to 18% of patients developed HBeAg seroconversion. Although longer treatment resulted in increased HBeAg seroconversion rate, there was also increased incidence of drug-resistant YMDD mutation and viral breakthrough. Adefovir, a nucleotide analogue, is effective against the YMDD mutants but causes drug resistance of its own, albeit at a much slower rate. Another major unresolved issue with these anti-viral agents is the timing of cessation of therapy, which in a significant proportion of patients is followed by disease relapse or even severe acute reactivation.
Pegylation is a process whereby polyethylene glycol (PEG) is attached to protein molecules. This results in prolongation of in vivo half-life of the protein. Two types of pegylated interferon-α are currently available. Peginterferon-α2b contains covalently linked recombinant interferon-α2b and a straight chain molecule of 12 kDa PEG whereas peginterferon-α2a is made up of interferon-α2a and a 40 kDa branched PEG. Both peginterferons have been shown to be more efficacious than conventional interferon in treating chronic hepatitis C with similar adverse effect profiles and the added advantage of needing only once weekly dosing.
Treatment of chronic hepatitis B with peginterferons have been reported in five independent studies over past 2 years, four of them on HBeAg-positive patients. These studies suggest a more promising result using pegylated interferon than conventional interferon or lamivudine. However, there are important differences among these trials in study design, patient populations and treatment regimen. This review summarized their findings and assessed the impact on our management of the disease.
Background: Pegylated interferon-α has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003.
Aim: To systematically summarize and compare the results of these studies.
Methods: Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug-resistant mutants were recorded.
Results: Three of the four trials contained predominantly Asian patients. Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one-thirds of patients after 12 months of therapy. Coadministration of lamivudine did not result in improvement in viral suppression. Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups. It was well tolerated with serious adverse events reported in <10% of patients in most trials.
Conclusions: Peginterferon-α treatment of at least 6 months should be considered as one of the first-line therapeutic options for hepatitis B virus infection.
Chronic hepatitis B virus (HBV) infection is a serious global public health problem. Of the 2 billion people who have been infected, more than 350 million have chronic hepatitis. HBV-infected patients with active disease are characterized by positive hepatitis B surface antigen (HBsAg) for at least 6 months and elevated serum transaminase and HBV-DNA levels. The aims of treatment of chronic hepatitis B are to sustain viral suppression and disease remission. Conventional interferon and nucleoside/nucleotide analogues are currently approved first-line treatments of chronic HBV infection. The end points used to assess treatment effects include biochemical, virological and histological responses. These end points are surrogate markers of the clinically important outcome measures, i.e. the development of liver-related complications and death. Previous studies on natural history revealed that HBV-infected patients with normal alanine transaminase (ALT), low viral load and mild histological disease have lower risk of cirrhosis and hepatocellular carcinoma. Hepatitis B e antigen (HBeAg)-positive patients who have achieved seroconversion with development of anti-HBe antibody also have improved prognosis.
Interferon-α acts mainly as an immunomodulator and enhances the host cell-mediated immune response in clearing the virus. A meta-analysis of 15 randomized-controlled studies found that with 3-6 months of interferon-α treatment, HBeAg loss, undetectable HBV-DNA using hybridization assays and loss of HBsAg can be achieved in 33%, 37% and 8% of patients respectively. This was highly significant compared with the corresponding figures in untreated patients of 12%, 17% and 2%. In the long-term, interferon-α-treated patients who responded with HBeAg seroconversion had a lower risk of cirrhotic complications and longer survival rate.
Anti-viral agents such as nucleoside and nucleotide analogues are more widely used in Asia because of a milder side-effect profile. At the end of 1-year therapy with lamivudine, up to 18% of patients developed HBeAg seroconversion. Although longer treatment resulted in increased HBeAg seroconversion rate, there was also increased incidence of drug-resistant YMDD mutation and viral breakthrough. Adefovir, a nucleotide analogue, is effective against the YMDD mutants but causes drug resistance of its own, albeit at a much slower rate. Another major unresolved issue with these anti-viral agents is the timing of cessation of therapy, which in a significant proportion of patients is followed by disease relapse or even severe acute reactivation.
Pegylation is a process whereby polyethylene glycol (PEG) is attached to protein molecules. This results in prolongation of in vivo half-life of the protein. Two types of pegylated interferon-α are currently available. Peginterferon-α2b contains covalently linked recombinant interferon-α2b and a straight chain molecule of 12 kDa PEG whereas peginterferon-α2a is made up of interferon-α2a and a 40 kDa branched PEG. Both peginterferons have been shown to be more efficacious than conventional interferon in treating chronic hepatitis C with similar adverse effect profiles and the added advantage of needing only once weekly dosing.
Treatment of chronic hepatitis B with peginterferons have been reported in five independent studies over past 2 years, four of them on HBeAg-positive patients. These studies suggest a more promising result using pegylated interferon than conventional interferon or lamivudine. However, there are important differences among these trials in study design, patient populations and treatment regimen. This review summarized their findings and assessed the impact on our management of the disease.
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