Hepatitis B: Hepatic Events After Interferon-alfa Therapy
Hepatitis B: Hepatic Events After Interferon-alfa Therapy
Background The long-term benefit of interferon-alfa (IFN-α) treatment in preventing various hepatic complications is not certain.
Aim To study the effects of IFN-α on reducing the risk of developing overall hepatic events (hepatocellular carcinoma, cirrhotic complications and liver-related mortality) in chronic hepatitis B patients.
Methods Randomized controlled trials, case–control studies and cohort studies were retrieved from electronic databases and conference abstracts. Relative risks (RRs) of different hepatic complications among patients treated by IFN-α vs. no treatment or placebo were studied.
Results Eleven studies were identified totalling 975 patients treated by IFN-α vs. 1147 untreated controls for analysis. Patients were treated by IFN-α for 1–24 months with a post-treatment follow-up of 1–13 years. Treatment by IFN-α reduced the risk of overall hepatic events (RR 0.55, 95% confident interval or CI 0.43–0.70, P < 0.001) and cirrhotic complications (RR 0.46, 95% CI 0.32–0.67, P < 0.001) by 45% and 54% respectively. Patients who responded to IFN-α had more profound reduction in overall hepatic events (RR 0.20, 95% CI 0.05–0.87, P = 0.03) and cirrhotic complications (RR 0.19, 95% CI 0.09–0.38, P < 0.001) vs. the untreated controls.
Conclusion Interferon-alfa treatment reduces the risk of hepatic events particularly among responders to treatment.
Chronic hepatitis B virus (HBV) infection is one of the major global healthcare problems affecting around 350 million people worldwide. It can cause various complications including liver failure, hepatic decompensation and hepatocellular carcinoma (HCC), which lead to significant morbidity and mortality with more than 1 million deaths annually. Liver cirrhosis is the major risk factor for the development of HCC, as more than 80% of HCC developed in the presence of cirrhosis. Approximately 75% of HCC patients die within 2 years after diagnosis of the tumour.
One of the short-term goals of anti-viral treatment is persistent viral suppression, which can retard the progression of liver disease, reduce hepatic complications and ultimately prolong patient survival. Interferon-alfa (IFN-α) was the first agent approved by the Food and Drug Administration for CHB in 1980s. Unlike oral anti-viral agents, IFN-α is given for finite treatment duration and administrated subcutaneously. Around 33% of CHB patients respond to IFN-α treatment with beneficial effects including normalization of alanine aminotransferase (ALT), clearance of hepatitis B virus e antigen (HBeAg) and suppression of HBV DNA. A small proportion of patients can even lose hepatitis B surface antigen after a course of IFN-α therapy. Peginterferon is produced by the addition of a polyethylene glycol moiety to interferon, thus prolonging the half-life of the drug and the average drug concentration in the body. It is currently widely used due to the convenient weekly dosing. This therapy gives good short-term effect, as 30–40% of the recipients develop HBeAg seroconversion after a course of treatment. Some data suggested that the virological response of peginterferon was sustained up to 5 years after cessation of therapy.
Whether virological response can be extrapolated to improvement in long-term clinical outcome remains uncertain. In a study in Hong Kong, surrogate endpoints such as biochemical and histological responses at the end of anti-viral therapy were found associated with decreased hepatic complications in a follow-up of 7 years. With the limited efficacy of IFN-α therapy, its long-term benefit in preventing hepatic complications has been controversial. These conflicting findings might be partly related to the relatively small sample sizes, lack of adequate controls, differences in treatment regimes, as well as different study designs and patient populations in these clinical trials. A few meta-analyses have suggested a reduced risk of HCC after IFN-α treatment. However, the analysis of other cirrhotic complications, which may cause 30–40% of death in cirrhotic patients, and patient mortality was lacking. Therefore, we conducted a meta-analysis to compare the effect of IFN-α vs. no treatment or placebo on the incidence of various hepatic complications and patient mortality. The different outcomes of the responders and the nonresponders to IFN-α in the risk of hepatic complications were also investigated.
Abstract and Introduction
Abstract
Background The long-term benefit of interferon-alfa (IFN-α) treatment in preventing various hepatic complications is not certain.
Aim To study the effects of IFN-α on reducing the risk of developing overall hepatic events (hepatocellular carcinoma, cirrhotic complications and liver-related mortality) in chronic hepatitis B patients.
Methods Randomized controlled trials, case–control studies and cohort studies were retrieved from electronic databases and conference abstracts. Relative risks (RRs) of different hepatic complications among patients treated by IFN-α vs. no treatment or placebo were studied.
Results Eleven studies were identified totalling 975 patients treated by IFN-α vs. 1147 untreated controls for analysis. Patients were treated by IFN-α for 1–24 months with a post-treatment follow-up of 1–13 years. Treatment by IFN-α reduced the risk of overall hepatic events (RR 0.55, 95% confident interval or CI 0.43–0.70, P < 0.001) and cirrhotic complications (RR 0.46, 95% CI 0.32–0.67, P < 0.001) by 45% and 54% respectively. Patients who responded to IFN-α had more profound reduction in overall hepatic events (RR 0.20, 95% CI 0.05–0.87, P = 0.03) and cirrhotic complications (RR 0.19, 95% CI 0.09–0.38, P < 0.001) vs. the untreated controls.
Conclusion Interferon-alfa treatment reduces the risk of hepatic events particularly among responders to treatment.
Introduction
Chronic hepatitis B virus (HBV) infection is one of the major global healthcare problems affecting around 350 million people worldwide. It can cause various complications including liver failure, hepatic decompensation and hepatocellular carcinoma (HCC), which lead to significant morbidity and mortality with more than 1 million deaths annually. Liver cirrhosis is the major risk factor for the development of HCC, as more than 80% of HCC developed in the presence of cirrhosis. Approximately 75% of HCC patients die within 2 years after diagnosis of the tumour.
One of the short-term goals of anti-viral treatment is persistent viral suppression, which can retard the progression of liver disease, reduce hepatic complications and ultimately prolong patient survival. Interferon-alfa (IFN-α) was the first agent approved by the Food and Drug Administration for CHB in 1980s. Unlike oral anti-viral agents, IFN-α is given for finite treatment duration and administrated subcutaneously. Around 33% of CHB patients respond to IFN-α treatment with beneficial effects including normalization of alanine aminotransferase (ALT), clearance of hepatitis B virus e antigen (HBeAg) and suppression of HBV DNA. A small proportion of patients can even lose hepatitis B surface antigen after a course of IFN-α therapy. Peginterferon is produced by the addition of a polyethylene glycol moiety to interferon, thus prolonging the half-life of the drug and the average drug concentration in the body. It is currently widely used due to the convenient weekly dosing. This therapy gives good short-term effect, as 30–40% of the recipients develop HBeAg seroconversion after a course of treatment. Some data suggested that the virological response of peginterferon was sustained up to 5 years after cessation of therapy.
Whether virological response can be extrapolated to improvement in long-term clinical outcome remains uncertain. In a study in Hong Kong, surrogate endpoints such as biochemical and histological responses at the end of anti-viral therapy were found associated with decreased hepatic complications in a follow-up of 7 years. With the limited efficacy of IFN-α therapy, its long-term benefit in preventing hepatic complications has been controversial. These conflicting findings might be partly related to the relatively small sample sizes, lack of adequate controls, differences in treatment regimes, as well as different study designs and patient populations in these clinical trials. A few meta-analyses have suggested a reduced risk of HCC after IFN-α treatment. However, the analysis of other cirrhotic complications, which may cause 30–40% of death in cirrhotic patients, and patient mortality was lacking. Therefore, we conducted a meta-analysis to compare the effect of IFN-α vs. no treatment or placebo on the incidence of various hepatic complications and patient mortality. The different outcomes of the responders and the nonresponders to IFN-α in the risk of hepatic complications were also investigated.
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